Cleanrooms

Art & Technology

2011-01-24T07:43:00.001-08:00

Barbara Kanegsberg

Ed Kanegsberg

Chris Stavroudis

On the surface, critical cleaning/contamination control and art conservation seem worlds apart. Scratch the surface (or, better still, avoid scratching the surface) and you find parallels between critical cleaning and art conservation. As a point of clarification, conservation encompasses actions taken toward the long-term preservation of cultural property. In contrast, restoration is a type of conservation treatment. It specifically refers to an attempt to bring cultural property closer to its original appearance. A primary task in the conservation of paintings is to remove accumulated contamination (surface dirt, discolored varnish, or non-original paint) without undesirable change in the aesthetics. Manufacturers would say that the goal is to clean without negatively affecting the original surface. Those concerned with contamination on or embedded in coated surfaces and manufacturers of components containing plastics or composites, can benefit from the approaches of the art conservator.
CUSTOMIZED CLEANING
In contrast with critical cleaning or industrial cleaning, where commercial cleaning agents are used, the conservator acts as a formulator, preparing cleaning agents customized to the task at hand. One of the tools that conservators use to manage the chemistry of their cleaning solutions is the Modular Cleaning Program (MCP), developed by Chris Stavroudis, our co-author for this month’s column. The MCP is an interactive database computer program that incorporates chemical and physical properties of constituent materials. The MCP can be used to “fashion” a solution that is optimally suited for soil removal. It can be used for cleaning with solvent, solvent gels, or water-based systems. The system is complex. For example, parameters of the current MCP for aqueous cleaners include pH, ionic strength, gelling agents, surfactants, and chelators (and the next version will include osmotic modifiers and organic co-solvents).
One of Chris’ latest projects is to modify the MCP to assist the conservator in the cleaning of acrylic paint surfaces. Acrylic paints, emulsions of pigmented acrylic plastic particles in a water-based carrier, are the basis of most water-based paints for architectural coatings and have been used in the art world for about 50 years. After half a century, some works of art are candidates for conservation. Since many industrial products also have acrylic coatings, or coatings with similar properties or are constructed from plastics, the techniques of the art conservator are of global value.
THE YIN AND YANG OF ACRYLIC PAINTS
Acrylic paints are chemically and physically complex. Simple paints consist of a pigment to provide color and a binder to provide both cohesion and adhesion. In contrast, most acrylic paints are complex mixtures containing a number of chemical modifiers. The modifiers impart some of the visual and physical properties such as viscosity, improved film formation, pigment wetting, and extenders to reduce the amount of pigment necessary. One reason that acrylic coatings are valued is because, once the water carrier evaporates, the coating is stable and is relatively impervious to water. The key word here is “relatively” because water can affect the acrylic.

WATCHING PAINT DRY
Watching acrylic paint dry is actually fascinating. In terms of surface area, the polymerized emulsion spheres in 1.5 ml of acrylic emulsion have a surface area of 37 square meters. There needs to be sufficient surfactant, one of the modifiers, in the emulsion to stabilize the 37 square meters to form and maintain the emulsion. In actual practice, additional surfactant is added to the base emulsion to make the paint. As the paint dries and coalesces, the surfactants have less and less surface area to stabilize and must go somewhere. Therefore the surfactants are forced into the interstitial spaces. After the paint dries, the surfactants and other modifiers remain in the interstitial spaces between the coalesced spheres of acrylic medium. This reservoir of surfactant can be mobile and exude to the surface, sometimes causing visible changes to the acrylic surface. The surfactant can also reduce the glass transition temperature (Tg) of the surface of the acrylic film causing the film to become soft enough at room temperature to increase the possibility of dirt particles irreversibly migrating into the paint layer.
Some of the soluble modifiers in acrylics (salts, semi-soluble pigments or extenders, anionic surfactants, or ionic thickeners) cause the paint film to have an ionic quality. The ionic environment within the paint can cause the paint to interact with an aqueous cleaning system. If the paint is considered a porous surface, the movement of the ionic species is driven by entropy. If the acrylic paint is considered to be a semipermiable membrane, osmotic pressure will need to be accounted for.
Due to ionic or osmotic pressure, water can be drawn from a hypotonic solution (lower solute concentration) to a hypertonic one (higher solute concentration) and be retained, causing swelling.
The cutting edge of cleaning practice has the conservator paying attention to solution conductivity to minimize ionic pressure. Chris is currently exploring non-ionic osmotic effects on the grounds that while consideration of ionic strength is useful, consideration of osmotic effects may allow more subtle control of the conservation process. Ionic and osmotic pressures are related, both referring to the effect of differing concentrations of solutes on different sides of a surface or membrane. Osmotic pressure is a term used to characterize transport across a semi-permeable membrane. An example is reverse osmosis, a process to remove solute from water that requires input of energy (pressure) to overwhelm the osmotic pressure, reverse the flow, and cause water to flow from the hypertonic side to the hypotonic side. Ionic pressure describes the stored energy in a hypertonic solution of ionic solute, such as the energy that could theoretically be harnessed when fresh water flows into salt water at the mouth of a river.
To counter these effects, the conservator adjusts the cleaning agents. The MCP provides a tool to facilitate such adjustments. Chris finds that by controlling the pH and the ionic strength of the water used in cleaning acrylic paintings, it is possible to achieve cleaning while controlling the degree of surface modification. An isotonic cleaning agent (one with balanced solute concentrations that is therefore neither hypotonic nor hypertonic) combined with a low pH minimizes surface swelling. Combining isotonicity with a relatively low pH, approximately five to six, provides effective removal of surface soils. Most cleaning agents used in manufacturing are high pH. However, a low pH is needed to prevent deprotonation of the polyacrylic acid thickeners in the paint.
LOVE/HATE RELATIONSHIPS
Even more adjustments to the cleaning agent may be needed. Remember that surfactants are effective because they have a love/hate relationship with water and with soils. One end of a surfactant likes water; it is hydrophilic or lipophobic. The other end likes oils and hates water; it is hydrophobic or lipophilic. The property allows surfactants to trap soils, most of which are oily, and to hold soils in suspension, eventually in a micelle.
One of the parameters that characterize surfactants is the hydrophilic/lipophilic balance (HLB) number. The higher the HLB, the higher the solubility in water. Most detergents have an HLB in the range of 13-15. A solution with a high HLB can help to suspend lightly bound pigment particles in the acrylic paint. A conservator wants to remove accumulated grime from a surface but not the artist applied pigment. Therefore the conservator might add 1% ethanol, with an HLB of 8, to lower the effective HLB, and therefore the detergency, of the cleaning solution.
THE FUTURE OF ART AND MANUFACTURING
The MCP is a work in progress. It is an active area of research. As theories are put into practice, and as feedback is obtained from users, new approaches to conservation will evolve. The cleaning of acrylics in the 21st century will begin on a very strong footing. Fine art has many parallels to manufacturing. Both may have stringent demands on performance and durability. Both may involve complex materials of construction. While custom formulations for each manufacturing process may not be realistic, it is reasonable to expect approaches to cleaning developed by conservators of fine art to be of value to manufacturers who are concerned with the quality and preservation of their product.
Chris Stavroudis is a paintings conservator in private practice. He has over two decades of experience. The Modular Cleaning Program was developed by Chris Stavroudis, with the cooperation and support of Professor Richard C. Wolbers, Winterthur/University of Delaware Art Conservation Program. He has presented a number of workshops on the theory of cleaning art surfaces and the MCP. Stavroudis and Wolbers have co-authored a chapter for the Handbook for Critical Cleaning, 2nd Edition, due from CRC Press early in 2011. Chris has a M.S. in Conservation from the University of Delaware/Winterthur Program in Art Conservation, a B.S. in Chemistry, and a B.A. in Art History, both from the University of Arizona. Contact: 1272 N. Flores Street, Los Angeles, CA 90069; Phone: (323) 654-8748; e-mail: cstavrou@ix.netcom.com.
Barbara Kanegsberg and Ed Kanegsberg, Ph.D. “The Cleaning Lady” and “The Rocket Scientist,” are independent consultants in surface quality including critical/precision cleaning, contamination control, and validation. They are editors of The Handbook for Critical Cleaning, CRC Press; an expanded second edition is scheduled for publication in the 4th quarter of 2010. Contact BFK Solutions LLC, 310-459-3614; info@bfksolutions.com.

Protection or Hype? Making Sense of Anti-Microbial Fabric Coatings

2011-01-24T07:42:00.000-08:00

Robert Nightingale

In a climate of pandemics, acquired immune diseases, and common viruses, the demand for products claiming to have anti-microbial properties has risen substantially. The textile industry has not been immune to the phenomena.
Whether it is for consumer, commercial, or institutional applications, textile manufacturers, converters, and chemical vendors have risen to provide an array of anti-microbial product offerings with an assortment of product claims. The challenge is to discern fact from hype. This article documents the findings of a study that explored the efficacy of three different anti-microbial coatings and additives as tested.

ANTI-MICROBIAL TREATMENTS DO NOT ALL PERFORM IN THE SAME MANNER
The vast majority of anti-microbials work by leaching or moving from the surface on which they are applied. Leaching anti-microbials will poison a microorganism. Such chemicals have been used for decades in agricultural applications with mixed results. In addition to affecting durability and useful life, leaching technologies have the potential to cause a variety of other problems when used in textiles or garments, including skin irritation and the potential to affect normal skin bacteria. There are several types of anti-microbials that apply to this discussion including both topical and permanent finishes.
Topical anti-microbial finishes usually include quaternary ammonium cations, also known as quaternary ammonium salts, quaternary ammonium compounds, or “Quats.” The majority of applications for quaternary ammonium compounds are related to their very strong affinity for surfaces, which can make them powerful surfactants. The quaternary ammonium compounds adsorb on almost any surface and can be introduced into a laundry rinse cycle for most fabrics, as a temporary anti-microbial agent. Chlorine and oxygenated bleach charged anti-microbial finishes are also found in the realm of topical finishes. There are essentially two schools of thought for this part of the discussion. The first includes textile manufacturers and converters that are now presenting fabrics that claim to retain high levels of chlorine to kill microbes. The second school utilizes oxygenated bleach including hydrogen peroxide and peracidic acid to sanitize products, whereby chemistry is added to a laundry wash step to sanitize a laundered product.
Permanent anti-microbial finishes include Bound Unconventional Anti-microbial Technology, or an organofunctional silane, that has a mode of action that relies on the technology remaining affixed to the substrate, killing microorganisms as they contact the surface to which it is applied. Excluding substances like silver, there are essentially two technologies that have evolved for permanent finishes. The more exploited technology consists of silicon, organic alcohol, hydrocarbons (methanol), and nitrogen. This technology must be added at the fabric manufacturing stage. The second permanent finish consists of propyldimethyloctadecyl ammonium, which is considered to be food safe. These products can be added to a rinse like a “Quat” agent for semi-permanent results, or at the fabric manufacturing stage for a permanent finish. Bound Unconventional Anti-microbial Technology, or an organofunctional silane, has a mode of action that relies on the technology remaining affixed to the substrate, killing microorganisms as they contact the surface to which it is applied.
THE STUDY
In order to evaluate the efficacy of two permanent and one topical anti-microbial technology on industrially laundered garments, AmeriPride and Canadian Linen and Uniform Services undertook three studies at their Toronto, Ontario, branch whereby a set of treated and non-treated garments were intentionally soiled with Staphylococcus aureus and then washed in a non-bleach wash formula to assess the ability of the fabric coating or treatment to reduce pathogen based bioburden as measured in colony for ming units (CFUs). The trial subjected the garments to 25 soil and wash replicates to assess the garments’ ability to reduce bioburden. Each study was conducted over an approximate four week period, with sampling done for each gar ment after drying.
Each trial tested a total of 20 garments made from 100% polyester. A control sample of ten garments had no pre-treatment applied to them, whereas ten gar ments were received with either a permanent finish or subjected to an anti-microbial treatment in the laundry process. The garments were then washed and dried in separate lots to eliminate cross contamination. Garments were washed in a 125 pound industrial-type washer, and dried in a 125 pound industrial-type gas dryer using a bleach free standard commercial wash formula. The wash formula included an alkali, non-ionic detergent and sour to reduce pH during the final wash step.
Prior to each wash cycle, each garment from each “Set” was contaminated with Staphylococcus aureus at the collar area. After the wash cycle, each garment from each “Set” was sampled using a Tryptic Soy Agar (TSA) with Lecithin and Polysorbate 80 (Tween 80), Rodac™ plate. The front and back surfaces of each collar were tested by placing the Rodac™ plate firmly on the fabric surface. The plates were then incubated for aerobic bacteria for three days at 32°C +/-2°C and then an additional two days for molds and yeasts at room temperature. Incubated Rodac™ plates were then sent to a third party laboratory for testing and evaluation. Target values were set at less than 47 CFU per garment. Any garments with a value higher than 47 CFU would be deemed unacceptable for use.
The first trial utilized a permanent finish consisting of Bound Unconventional Antimicrobial Technology which included propyldimethyloctadecyl ammonium.
The second trial utilized organofunctional silanes that included silicon, organic alcohol, hydrocarbons (methanol), and nitrogen.
The third trial utilized a topical treatment of oxygenated bleach. During this trial, the control Set of garments was not subjected to the topical treatment.
At the end of each trial, after the 25 wash cycles per garment, the two Sets of garments were then contaminated once again with Staphylococcus aureus for 144 hours. The two Sets were then tested for bioburden and then tested again after a wash cycle as described.
FINDINGS
For the first trial which utilized a permanent finish of propyldimethyloctadecyl ammonium the data yielded little difference in CFU counts from the treated garments to un-treated control group, with the exception of one sample within the control group that had <200 CFU as tested. Otherwise, the data had little variance and performed in a similar fashion.
However, when the garments were subjected to the 144 hour soiling period, the observations differed substantially, though only after being subjected to the final wash cycle. The treated and non-treated garments yielded similar CFU counts at the soil stage, but the treated garments had significantly lower CFU counts after the final wash cycle. Of the non-treated garments, one garment failed to have less than 47 CFU. For the treated garments, all garments had very low CFU counts, and showed significant log reductions in bioburden.
For the second trial which utilized organofunctional silanes, the data yielded little difference in CFU counts from the treated garments to un-treated control group, with the exception of five samples within the treated group and three samples in control group that had <2800 CFU after the fifth wash cycle as tested, and four samples within the treated group and three samples in control group that had <2800 CFU after the seventh wash cycle. The wash trials produced eight more failures for the treated garments than for the controlled group, which was unexpected.
When the garments were subjected to the 144 hour soiling period, the observations did not differ substantially. The treated and non-treated garments yielded similar CFU counts at the soil stage and after the final wash cycle, which was also unexpected.
For the third trial which utilized oxygenated bleach products, the data gathered yielded little difference in CFU counts from the treated garments to un-treated control group. The treated garments however, showed a very consistent and low, single digit CFU reading, which was very encouraging.
When the garments were subjected to the 144 hour soiling period, the observations did not differ substantially after being subjected to the final wash cycle. The treated and non-treated garments yielded similar CFU counts at the soil stage, and the treated garments had consistently low CFU counts after the final wash cycle. The nontreated garments also exhibited low CFU counts, though less consistently than the treated group. For the treated garments, all garments had very low CFU counts, and showed significant log reductions in bioburden.
SUMMARY
The three trials generated some interesting and surprising results. Most notably the poor results demonstrated by the garments treated with organofunctional silanes. This treatment can be found on a number of textiles that include continuous polyester filament cleanroom products and a wide array of consumer sportswear products. The relatively strong performance of the control groups for each of the three trials was also unexpected. The theories that support most anti-microbial treatments are based upon disruption of bacteria or biofilms. The demonstration of an untreated fabric performing even reasonably well, with low or moderate CFU levels, challenged some of these assumptions and may lend credence to European assertions regarding minimum temperature, pH, and surfactant levels for the reprocessing of these textiles.
The trial utilizing propyldimethyloctadecyl ammonium as a permanent treatment showed promising, though inconsistent results, with the exception of the 144 hour contamination challenge, where it appeared to assist the wash efficacy and removal of the Staphylococcus aureus contamination. Similarly, the treatment utilizing oxygenated bleach appeared to assist the wash efficacy during the 144 hour contamination challenge and yielded consistent CFU counts for the treated garments.
The most intriguing result from all three trials was the performance of the control sets of garments. With a few exceptions during the second trial, they performed well, with counts well within an acceptable range, lending credence to the value of a stringent wash and handling process.
It is important to note that it is not the intent of this article to recommend or support any of the presented technologies.
Robert Nightingale is Director of Quality, Research, and Development for Ameripride Services Inc., Canadian Linen and Uniform Services, and their CleanStyle Cleanroom Division. He has over 20 years of experience in human source contamination and cleanroom apparel processing, as founder and President of Cleanroom Garments ™, with multiple cleanrooms supporting a vast array of cleanroom applications from aseptic fill operations, aerospace, and MEMS fabrication, to automotive paint spray operations. Robert is also a co-owner of several international patents for cleanroom soil removal processes.

Finding The Optimal Analytical Test Part 1

2011-01-24T07:41:00.001-08:00

Barbara Kanegsberg

Ed Kanegsberg

What analytical test should you use? A recent teachable and successful case study does not provide a miracle all-purpose analytical technique (there is no such thing) but rather illustrates the process of how a decision might be reached, and the considerations involved. It illustrates the importance of exploring beyond the methods that are in one’s immediate comfort zone, of understanding the features and limitations of any analytical method, and of adopting a scientific, rational, and defensible approach.
Testing involves “somehow perturbing the area to be analyzed and observing the results.”¹ The key to successful analytical testing involves perturbing and observing the material to be analyzed in a meaningful, reproducible manner and in such a manner that meets the requirements at hand. This is easier said than done; and the process of selecting, developing, and validating a rational analytical method can involve interminable testing and discussion.
The case study involved collaboration between regulators at the South Coast Air Quality Management District (SCAQMD) in southern California and the Independent Lubricant and Manufacturers Association (ILMA). The approach to selecting the method involved determining and emulating likely manufacturing situations, testing and evaluation, assessment of method practicality, refinement of a standardized method, and consensus building.
In this instance, the goal was to determine evaporative loss of relatively volatile materials from metal working fluids so that a method could be included in an SCAQMD regulation with the goal of reducing VOC air emissions.
THE COLLABORATION
John M. Burke is Director of Engineering Services at Houghton International, Inc. in Valley Forge, PA. In 2008, as Chair of the Safety, Health, Environmental, and Regulatory Affairs (SHERA) Committee at ILMA, “I received a call from an ILMA member in southern California who described discussions with SCAQMD regarding all sorts of metalworking fluids, including vanishing oil, rust preventatives, and other protective fluids. As we learned more about the efforts to determine the VOC content, we knew we needed to be involved.”
The ILMA involvement developed into a major scientific effort, one that benefited the environment and considered requirements of industry. Naveen Berry, Planning and Rules Manager at SCAQMD, Diamond Bar, CA, described the association with ILMA as “a truly collaborative effort.”
WHICH METHOD?
Berry explains that “we considered EPA Method 24,³ it has many strengths. However, it is recognized as not being an optimal method to use for coatings but not for use with metalworking fluids and lubricants.” Burke adds that “Method 24 requires application of heat. While the temperature conditions are appropriate for aqueous solutions, there is a point when you heat a lubricant, which you go past the point of evaporating it, you are cooking it. The breakdown products are artifactual and do not truly emulate VOCs that would be released with normal, lower temperature, evaporation. In addition, Method 24 uses a laboratory oven. Placing a given sample at four different positions within the oven might yield four different results.”
Readers might want to note these limitations, because EPA Method 24 has been known to be used in manufacturing applications. In addition, loss and/or modification of a mixture of analytes during sample preparation are important considerations for everyone involved in manufacturing. Many complex mixtures can be readily modified during evaporation, especially with heating. For example, years ago, one of us (BK) participated in aerospace studies of Non-Volatile Residue (NVR) to qualify higher-boiling point solvents as replacements for lower-boiling point chlorinated and fluorinated solvents. We found that the evaporation temperature had to be lowered; and that the position of the sample in the laboratory oven had to be specified.
“In 2008 there was no standardized method for measuring VOCs in metalworking fluids,” continues Burke. “SCAQMD proposed a test method that they termed Method 313L.⁴ It called for determining VOCs by separation using gas chromatography (GC) with a flame ionization detector (FID).” Burke recounts that “after a year of testing with 313L, we could not get consistent test results among laboratories. In fact, we saw run to run variability even using the same GC system and using the same technician.”
Berry explains that SCAQMD decided not to pursue Method 313L, GC/FID for the current version of Rule 1144 because it did not meet the requirements of ASTM E-691 in terms of reproducibility. He adds that the project “raises the issue of how to treat semi-volatiles. When you test a mixture of multiple solvents in a gas chromatogram, generally you see distinct peaks. Some of the semi-volatiles did not form distinct peaks. They formed a smear.”⁵
THERMOGRAVIMETRIC ANALYSIS (TGA)
Burke recounts that “we were in a quandary. How could we agree to regulatory limits? How could we find a consistent test method? What constitutes volatility? Then, one of our company scientists suggested using TGA. TGA use is called out in military standards to determine the volatility in hydraulic oil. The thought was that perhaps TGA could be adapted to the problem at hand.”
On the surface, TGA might seem like EPA Method 24; and Burke notes that if TGA was used at the temperature called out for EPA Method 24, the results were indeed similar. ILMA contended that 110°C +/- 5°C was too hot, and that modification of the fluid was occurring. Burke recounts that “we finally said that we really need to define what constitutes volatility.”
CHARACTERIZING VOLATILITY
The SCAQMD/ILMA committee designed a test to characterize the evaporative properties of oils, using a time/temperature combination that might emulate realworld conditions. Burke notes that “it was important that we agreed to methods and to pass/fail criteria in advance. We tested three common naphthenic oils, with three different viscosities,* obtained from a single refinery. We selected a 26 week time span using the rationale that “two turns” of oil per year would replicate actual production conditions. The temperature was 40°C, emulating warm but realistic factory conditions. We agreed that we would observe the volatility curves (rate of change of fluid weight). If the curves flattened out before 26 weeks, we would stop earlier. We were surprised, not very pleasantly, by the results.”
The samples were still evaporating at 26 weeks. Burke explains that while the most viscous oil was beginning to asymptotically approach a leveling-off point, the other oils were still evaporating steadily. We thought that the medium viscosity oil would not be very evaporative; but it was almost 100% evaporative.”
“Since a 26 week testing protocol would be a bit cumbersome, the next step was to determine time and temperature conditions that emulated behavior of the oils used in the 26 week protocol. We tested five temperatures (71, 81, 91, 101, and 111°C) over shorter time periods. For each temperature, 120 minute by minute data points were collected.” Burke explains that they were able to set analytical conditions that matched results of the six month study to within 1%.
In summary, the group characterized the evaporative properties of oils used in lubricants, evaluated analytical approaches, and selected a promising method, TGA. In the next column, we continue with how the TGA method was tested and optimized, the current status, and a look to the future.
* The oils were characterized as 40 second, 60 second, and 100 second oils. The units refer to Universal Saybolt Seconds, a viscosity unit. It is the time for a given volume of oil to flow through a certain orifice. The longer the time, the more viscous the fluid.

Metalworking Fluid Restrictions May Affect You

We suggest that you, the reader, peruse Rule 1144.² Metalworking fluids are being restricted to less evaporative materials in the SCAQMD area. SCAQMD rules sometimes are precedents for regulations in other areas and states. Features of the rule may impact your manufacturing facility either by current or future regulatory mandate or by corporate edict. If metalworking fluids that you or your suppliers use are reformulated or restricted, critical cleaning processes and approaches to determining surface residue on high-value product may also need to be revisited.

References

B. Schiefelbein in Kanegsberg and Kanegsberg, “Find the Contaminant by Perturbing the Surface: XPS and Auger (Part 1),” Controlled Environments Magazine, November, 2007.
SCAQMD Rule 1144, “Metalworking Fluids and Direct Contact Lubricants,” Amended July 9, 2010 http://aqmd.gov/rules/reg/reg11_tofc.html
EPA Method 24, Method 24 – “Determination Of Volatile Matter Content, Water Content, Density, Volume Solids, and Weight Solids Of Surface Coatings” www.epa.gov/ttn/emc/promgate/m-24.pdf
Appendix I SCAQMD Method 313: Determination of Volatile Organic Compounds (VOC) by Gas Chromatography/Mass Spectrometry (GC/MS) http://www.aqmd.gov/rules/cas/app1.html
Clean Air Solvent Certification Protocol http://www.aqmd.gov/rules/cacc/index.html and www.aqmd.gov/rules/cacc/CACCprotocol.pdf

Barbara Kanegsberg and Ed Kanegsberg, Ph.D.“The Cleaning Lady” and “The Rocket Scientist,” are independent consultants in surface quality including critical/precision cleaning, contamination control, and validation. They are editors of The Handbook for Critical Cleaning, CRC Press; an expanded second edition is scheduled for publication in the 4th quarter of 2010. Contact BFK Solutions LLC, 310-459-3614; info@bfksolutions.com.

Finding The Optimal Analytical Test Part 2

2011-01-24T07:40:00.003-08:00

Barbara Kanegsberg

Ed Kanegsberg

Previously we discussed how regulators at the South Coast Air Quality Management District (SCAQMD) and the Independent Lubricant and Manufacturers Association (ILMA) evaluated and selected a test method to be used in SCAQMD Rule 1144¹ to determine the VOC level of metalworking fluids. Thermographic Analysis (TGA) was selected rather than Gas Chromatography with a flame ionization detector (GC/FID), SCAQMD Method 313L, or EPA Method 24 because TGA shows greater reproducibility and is more readily adapted to the fluids under consideration.
In the fall of 2009, as John Burke, Director of Engineering Services at Houghton International Inc., Valley Forge, PA, explains, ASTM was engaged as a neutral, consensus- driven agency to modify an existing ASTM TGA test, E1868-09.² The ASTM activity was both rigorous and turbo-charged, because SCAQMD had to come up with a method in support of improving air quality that could be rationally communicated to the Federal regulators. Modified ASTM E1868-10³ is now in place.
Burke points out that, compared with GC/FID, TGA is a relatively simple method. A fixed amount of material is added to a wing pan; the temperature is ramped up; and losses are determined gravimetrically. However, the devil is in the details and E1868-10 is no exception. Details include whether or not to begin data collection during the warm-up period, the three-dimensional configuration and material of construction of the wing pan, and the amount of liquid to be tested. Materials handling prior to test must also be specified; for example, Burke notes that fluids with a high solvent content can show evaporative losses prior to testing. “We used ASTM 691,⁴ including replicate samples and multiple labs to determine that we had a robust method. The tests were successful; they will be published.”
GC METHOD DEVELOPMENT
Naveen Berry, Planning and Rules Manager at SCAQMD, Diamond Bar, CA, notes that “if we had a standardized, reproducible method, we would have adopted Rule 1144 for all categories of metalworking fluids and lubricants in March 2009. “We held back on regulating metalworking fluids, especially oils and low viscosity oils with semivolatiles because the GC/FID test method was not ready for prime time. Together, industry and SCAQMD developed a TGA method that provides repeatable and reproducible results. SCAQMD is in the process of doing a second phase round robin with 313L. This will include academic, government, and private laboratories. According to our Board, for Rule 1144, we have yet to meet the robustness specified in ASTM E619. There are many variables that must be defined; GC analysis is a very fine art, as well as a science.”
MEETING TECHNICAL CHALLENGES
Burke adds that the next step is to reformulate metalworking fluids based on the new limits. He notes that vegetable-based lubricants tend to be naturally lower in VOCs than are naphthenic lubricants and therefore could be good candidates; he notes that relative reactivity may eventually provide a more meaningful estimate of the impact of volatiles on air quality. A conference at SCAQMD is planned to discuss lubricant options and real-world findings for ultra low-VOC technology, as well as test methods.
TAKE-HOME LESSONS
Testing is an evolving and collaborative effort. Within your own organization, consider assembling what regulators term the “stakeholders” and obtain their input. There is no one optimal analytical test, so we suggest evaluating the options on a scientific and practical level.
Rule 1144 has improved air quality. Berry estimates that “we eliminated a little more than 3.5 tons per day from this category alone, which is almost the equivalent of shutting down three of the Southland’s major oil refineries. These were very cost-effective reductions. It is fortunate that the rule has been developed rationally, because there are encompassing implications. California is a trendsetter,” concludes Burke. “We believe the rule will morph away from California and will be adopted throughout the United States.”
References

SCAQMD Rule 1144, “Metalworking Fluids and Direct Contact Lubricants,” Amended July 9, 2010 http://aqmd.gov/rules/reg/reg11_tofc.html
ASTM E1868-09, Standard Test Method for Loss-On-Drying by Thermogravimetry, http://www.astm.org/DATABASE.CART/HISTORICAL/E1868-09.htm
ASTM E1868-10 was developed as ASTM WK26130 - Revision of E1868 - 09. http://www.astm.org/Standards/E1868.htm
ASTM E691 Standard Practice for Conducting an Interlaboratory Study to Determine the Precision of a Test Method

Barbara Kanegsberg and Ed Kanegsberg, Ph.D. “The Cleaning Lady” and “The Rocket Scientist,” are independent consultants in surface quality including critical/precision cleaning, contamination control, and validation. They are editors of The Handbook for Critical Cleaning, CRC Press; an expanded second edition is scheduled for publication in the 4th quarter of 2010. Contact BFK Solutions LLC, 310-459-3614; info@bfksolutions.com.

Point of View: Why Clean the Cleanroom?

2011-01-24T07:40:00.001-08:00

Barbara Kanegsberg

Ed Kanegsberg

There may be fear of regulatory agencies or of customers. Cleaning most often relates to particles; increasingly, it is also concerned with Airborne Molecular Contamination (AMC) or with minimizing biofilms.
DESIGN
Effective cleaning begins with thoughtful design. For the product, this means avoiding or at least being aware of areas where contamination is likely to occur. For the cleanroom, it means consideration of materials and configuration that minimize contamination. As part of the design, we also include determining what processes will be conducted within the cleanroom and how process flow will occur. Cleanroom real estate is valuable; conducting as much cleaning as possible outside of the cleanroom is not only economical, but can also minimize cleanroom contamination.
PROVENANCE
Extrapolation is necessary, but it may not be sufficient. We may say that a new product is substantially like an existing one and use cleanliness standards and cleaning practices for the existing product as benchmarks for the new one. However, after a few generations of extrapolation, modified cleaning processes and other, more pertinent, tests for cleanliness may be required.
In cleanrooms, a design to be used for one application may not be readily adaptable to another. Cleanrooms are often reutilized for applications other than those for which they were originally designed. In such instances, it is important to take a dispassionate look at the previous use or perhaps misuse of the cleanroom and to take corrective action. It is also important to assess how the cleanroom is to be used and to make needed changes.
REQUIREMENTS
This means not just specifications and standards, but also actual performance requirements. Meeting a specification is not a substitute for logical analysis. Such analysis must involve the expected end-use of the product as well as an assessment of likely contaminants and of the consequences of contamination.
EDUCATION
Teaching employees to adhere to rules of behavior or to a specific cleaning protocol is necessary. However, for both product and cleanrooms, there is no substitute for understanding the “why” of the cleaning process. Education is important whether your product and cleanrooms are cleaned inhouse or are outsourced. In fact, when you outsource, educating the employees of the contractor may be even more important.
VIGILANCE
Monitoring and auditing are part of vigilance. However, monitoring and auditing are not sufficient, particularly with complex products. One reason for the importance of an educated workforce is that you have to expect the unexpected; and this is true for both the cleanroom and the product itself.
CLEAN CRITICALLY—IN AND OUT OF THE CLEANROOM
Too often, cleaning the cleanroom to a particular standard becomes an end in itself; reaching the goal or staying within limits of contamination may not be adequate. The ultimate goals—assuring cleanliness and quality performance of the product—are lost. We have to meet or exceed the requirements. In cleaning the cleanroom and the product, our goal should be to clean critically, to adopt valueadded cleaning. By the way, our view of critical cleaning is that it is a lynch-pin process, one that is essential to product quality. Therefore, critical cleaning may occur not only in the cleanroom but also very early in the fabrication and assembly process. But, more about critical cleaning next year.
Barbara Kanegsberg and Ed Kanegsberg, Ph.D. “The Cleaning Lady” and “The Rocket Scientist,” are independent consultants in surface quality including critical/precision cleaning, contamination control, and validation. They are editors of The Handbook for Critical Cleaning, CRC Press; an expanded second edition is scheduled for publication in the 4th quarter of 2010. Contact BFK Solutions LLC, 310-459-3614; info@bfksolutions.com.

The Microbial ID Breakthrough

2011-01-24T07:39:00.002-08:00

Dennis Champagne

How DNA Sequencing Services Help Prevent Catastrophic Cleanroom Shutdowns
Every minute of every day, modern cleanrooms used for the manufacture of medical devices, pharmaceuticals, or combination products face widespread, persistent threats of contamination. Much of this contamination comes from the people working in these environments. They carry invasive organisms on their hands, feet, and clothes. They also bring contaminated equipment and materials into the environment. Risks of contamination also may increase with the seasons. For example, molds are prevalent during spring blooms or summer flowerings.
Other threats may exist in the cleanroom environments themselves. Water sources and drains are ready sources of foreign organisms, often due to broken, improperly installed, or clogged filtration devices. Heating, ventilation, and air conditioning systems may suffer similar problems with airborne contaminants. A HEPA filter charged with protecting against contaminants, when malfunctioning or filled to capacity may instead do the opposite. Any cleanroom surface may contain a sporeforming organism allowed to grow due to improper disinfectant selection or procedures.
As the U.S. Food and Drug Administration (FDA) states, “Characterization of recovered microorganisms provides vital information for the environmental monitoring program. Environmental isolates often correlate with the contaminants found in a media fill or product sterility testing failure and the overall environmental picture provides valuable information for an investigation. Monitoring critical and immediately surrounding clean areas as well as personnel should include routine identification of microorganisms to the species (or, where appropriate, genus) level.”1
However, identifying the culprits is a challenging task indeed. Cumulatively, thousands of organisms pose plausible threats, including the following:

Gram-positive bacteria—numerous different species, including many that produce hard to kill spores
Gram-negative bacteria—including numerous pseudomonases
Molds—often during seasonal peaks
Yeast

Discovery of contaminants from any of these sources poses serious problems for quality managers, lab managers, and other executives responsible for cleanroom facilities. In almost all cases, serious contamination means the cleanroom must temporarily shut down. This brings production of pharmaceuticals or medical devices to a halt—for days, weeks, or even months. Deadlines are missed. Schedules are thrown into chaos. Projects, contracts, and other relationships with the facility’s customers can be imperiled, or terminated outright. Profits plummet. In some cases, personnel responsible for quality and productivity may lose their jobs.
Fast action is vital. To get the cleanroom up and running as quickly as possible, the extent and location of areas affected must be determined, and the responsible organism identified.
TRADITIONAL ANSWERS
Conventional procedures for the identification of unknown microorganisms are well established. Samples are gathered and submitted to a series of biochemical or phenotypic testing techniques. These traditional methods may still have some utility as part of a regular series of preventive measures. When coupled with minimal-contamination cleanroom design, properly designed operating procedures, and regular testing of surfaces and equipment, routine screening and identification with biochemical or phenolic-based techniques may provide some level of prophylaxis.
Unfortunately, numerous problems are associated with these systems and methods. They must be based on the observed qualities of the target organism. Identification relies on observing a suspect organism’s morphology, development, and behavior over time, as well as analyzing the structure and function of its cellular components.
These tests are unsuitable for identifying such commonly encountered contaminants as mycoplasmas or molds. They demand the use of multiple isolated colonies of living organisms. Testers must make subjective decisions to attempt growth of the organism in media of a specific nature (aerobic or anaerobic) and Gram reaction (bacteria, mycobacteria, or yeast). If they suspect the organism is a bacterium, they must decide whether its source is environmental or clinical. Finally, testers must typically match the isolate against one of five libraries in the testing equipment’s software: aerobic, environmental/clinical, anaerobic, yeast, or mycobacteria.
Reproducibility is also a common problem. A suspect organism may be identified one way in one test, but another way in the next. Accuracy also suffers. A number of laboratories have discovered that, in this example, both identifications may subsequently prove incorrect. In addition, due to their frequent origination in medical settings, these tests may produce more accurate identifications of organisms common to clinical contexts, as opposed to isolates often encountered in the challenging environment of a large-scale manufacturing process.

Perhaps most important, these tests take time. Attempting to regrow the organism for identification is far from an overnight process. In fact, with traditional methods, routine identification of a single sample may take as much as one month. Again, from a manufacturing viewpoint, this magnitude of delay can be catastrophic.
When significant contamination has already occurred, traditional microbial identification techniques have proved increasingly unsatisfactory. Their results are too uncertain and arrive much too slowly. These methods simply can’t meet the urgent scheduling and production needs of a modern medical device or pharmaceutical manufacturing operation.

NEW BREAKTHROUGHS
When environmental microbial contamination poses problems—up to and including catastrophic facility shutdowns—quality control and production managers need their samples tested by a fast, accurate, highly reliable identification system. To provide that level of confidence, leading testers increasingly rely on DNA sequencing, a high-precision, gene-based method that represents a breakthrough in microbial identification.
According to the FDA, “Genotypic methods have been shown to be more accurate and precise than traditional biochemical and phenotypic techniques. These methods are especially valuable for investigations into failures (e.g., sterility test; media fill contamination).”¹
Experts agree that DNA sequencing is faster, more accurate, and more reproducible than phenotypic or biochemical identification methods. It provides the definitive information needed to control contamination and reduce risks associated with production downtime. That’s why DNA sequencing has become the new gold standard in microbial identification, outpacing traditional methods.
The new microbial identification systems, such as the MicroSEQ® instrument from Applied Biosystems, employ ribosomal DNA (rDNA) sequencing to replace phenotypic microbial ID methods, fatty acid ID methods, traditional plate identification, ELISA, or antibody-based methods. Using a phylogenetic approach, the systems sequence the stable 16S ribosomal RNA (rRNA) gene present in all bacteria. For fungi, they sequence the D2 region of the large fungi sub-unit. (Note that a single isolated colony—alive or dead—is sufficient for identification purposes.) After sequencing the rRNA gene, the systems automatically compare the results to validated sequences in their customizable microbial libraries. They then deliver a list of the closest matches, ranked according to genetic distance from the sample.
In contrast to traditional methods, DNA sequencing for microbial identification has proven highly accurate. Experienced users report positive identification rates over 99% for all suspect categories, including bacteria, mycoplasmas, yeast, and molds. Testers also observe that sequencing avoids the traditional bias toward clinical settings, showing strong results in identifying organisms widely encountered in environmental testing.
Nor is accuracy impeded by subjective judgments. Unlike traditional methods, wherein testers must observe an organism’s morphology and behavior or make best-guess estimates in choosing growth media or software libraries, testers can rely on straightforward procedures and objective criteria. They can easily decide between only two necessary libraries: bacterial or fungal. Reproducibility is also much improved. The systems identify the same microbe the same way from run to run, sample to sample. Identification can be tied to the unique DNA sequence of a target organism with extremely high confidence.
Finally and most importantly, DNA sequence identification saves time. Where traditional methods may take weeks, a month, or longer to return results, DNA sequencing works in hours or at most days for results. Virtually all identifications can be completed within a week. On this count alone, DNA ID methodology is highly attractive for all manufacturing managers. DNA sequencing is ideal for testing applications including pharmaceutical quality assurance/quality control labs, finished product and in-process testing, media fill failure investigations, sterile medical products, opthalmics, medical devices, cosmetics, and nutritional supplements.

Once the organism is positively identified, managers can much more easily deduce the source or sources of contamination and take swift corrective action to enable the resumption of manufacturing production.
Microbial identification is a demanding specialty requiring advanced equipment and expertise. Many testing laboratories send out their identification work to subcontractors narrowly focused on this field. But this can only delay the production of timely answers.
Pharmaceutical and medical device manufacturers should seek laboratory partners that have fully committed to the new microbial identification technologies. Look for labs that have recently expanded their resources by adding state-of-the-art thermocyclers, centrifuges, water baths, and DNA sequencing ID units. The genotypic-based identification technology enables identification of contaminating environmental organisms

More quickly
More accurately
Reproducibly

DNA sequencing allows these labs to identify both viable and nonviable organisms. This ability becomes important, for example, in cases where clients need comparison of samples of dead organisms collected four weeks previously to living samples collected the day before. (If the organisms are identical, it may indicate a recurring problem.) It also enables clients to build libraries of common contaminants in their areas over time, developing systematic trending data.
Make sure your testing laboratory has at least two genotypic-based identification systems. This allows the lab to run about 60 organisms in a 24-hour period, normally utilizing two shifts. This capability can be vital when a client’s operation is down and every hour counts. For example, testers can run a yeast and mold plate on one instrument, and bacteria on the other; or put through two large batches of only mold, yeast, or bacteria (including mycoplasmas).

Speed is the most obvious result of the new testing technologies. A lab can often produce preliminary microbial identification in 24 hours. Comprehensive final reports on a variety of samples from a given manufacturing area or an entire facility are typically available in one week or less. This contrasts strongly with traditional methodologies that can take one month or longer.
A reputable lab can perform both remote and onsite services for clients anywhere in the U.S. At the client’s location, their specialists can perform microbial sampling of water, surfaces, air, and compressed air/gases. For remote monitoring, the lab supplies sampling plates and sterile water collecting vials— everything needed for clients to collect samples in their own cleanrooms or manufacturing spaces. The lab also furnishes full instructions for receipt, sampling, storage, and return.
A high-quality lab with new microbial identification technology will produce quick, reliable results in failure investigations involving sterility testing, media fills, and more. It will help clients control contamination, both by taking immediate corrective action and by initiating long-term programs of prevention. And it will reduce the loss and risk associated with manufacturing production downtime—including delayed product releases, back orders, and recalls.
Besides cutting-edge technology, a laboratory with these capabilities will have a highly technically qualified, experienced staff. Their microbiologists are intensively trained on advanced testing equipment and will have performed literally thousands of successful identifications based on DNA sequencing in recent years. The lab will assign an experienced team leader to each project to facilitate effective communications and ensure that client objectives are clearly understood and quickly achieved. In addition, clients should feel free at any time to talk with the analysts performing their individual testing. Clients must be confident that the correct tests are carried out on the most accelerated possible schedule, with the most accurate results.
Some testing laboratories also have their own contract manufacturing suites. These labs can verify new methods in their own facilities before recommending them to clients. Improvement in cleanroom equipment and procedures are implemented constantly for optimum results.
REFERENCES

Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing— Current Good Manufacturing Practice; U.S. Department of Health and Human Services, Food and Drug Administration (FDA); September 2004; section X.B., “Microbiological Media and Identification.”

Dennis Champagne is Director, Laboratory Services, at Microtest Laboratories, Inc., Agawam, Mass., http://www.microtestlabs.com. With more than 13 years’ experience in regulatory microbiology and contract laboratory operations, Dennis Champagne leads Microtest’s microbiology, contract analytical chemistry, laboratory support, and virology departments. Mr. Champagne holds a B.S. degree in microbiology from Iowa State University, and is a nationally registered microbiologist. Contact Dennis at DChampagne@microtestlabs.com.

Estimating Hydrochloric Acid and Ammonium Hydroxide Loss

2011-01-24T07:39:00.000-08:00

Mark Caulfield

C. W. Extrand

Sung In Moon

Calculations suggest break-through from semiconductor bulk chemical distribution systems occurs in a matter of days and steady state permeation accounts for several milliliters of chemical loss each day.
Permeability (P) and diffusion (D) coefficients were measured for hydrogen chloride and ammonia gas transport through a polytetrafluoroethylene copolymer, perfluoroalkoxy (PFA), using standard manometric techniques. These data were subsequently used to estimate the performance characteristics, such as break-through times and permeation rates, of a representative chemical distribution system that might be found inside a semiconductor wafer fabrication facility. Our findings suggest that break-through occurs in a matter of days and that steady state permeation can account for the loss of several grams of hydrochloric acid or ammonium hydroxide each day. This loss rate for hydrogen chloride would be equivalent to dumping five milliliters of concentrated hydrochloric acid on to the floor of a fabrication facility each day, or more likely into the secondary containment sub-system, and allowing the acid to dissipate over the course of a day. This equates to two liters per year. Everything else being equal, the loss rate of ammonium hydroxide is expected to be more than two times that of hydrochloric acid. To prevent accumulation of hydrogen chloride or ammonia, the secondary containment sub-system must be purged. The necessary purge rate can be estimated using the mass transport data making this study useful to facility planners and operators.
Among melt-processable thermoplastics, tetrafluoroethylene (TFE) - perfluoroalkoxy copolymers, often abbreviated simply as PFA, have a unique combination of purity, toughness, and nearly universal chemical inertness. Therefore, PFA has been used broadly for the transport and storage of high purity chemicals in semiconductor wafer fabrication facilities or “fabs.”^1,2 Although much is known about the purity, mechanical, and thermal properties of PFA,^3-5 less information is available regarding its permeation characteristics.
Some permeation testing has been performed on PFA,^6-13 but most studies have not addressed two of the most widely used semiconductor process chemicals, hydrochloric acid and ammonium hydroxide. The active ingredient in both of these aqueous chemicals is dissolved gas, hydrogen chloride or ammonia, respectively. Thus, they are quite mobile and have caused concerns about unwanted permeation, cross-contamination, and corrosion.¹³ In this article, we explore breakthrough times and steady-state permeation rates of hydrogen chloride and ammonia for a PFA chemical distribution system.
A REPRESENTATIVE BULK CHEMICAL SYSTEM
In the following examples, we use a representative bulk chemical system that could be used for distributing hydrochloric acid or ammonium hydroxide. It is shown schematically in Figure 1. The distribution system consists of a bulk chemical container, a pump, tubing, pipe, and valves. The various PFA components are tabulated in Table 1. The valves are mounted inside containment boxes. The chemical, hydrochloric acid or ammonium hydroxide, is pumped from a chemical container through a one inch (25 mm) PFA supply line to three tee boxes that each contain two PFA drop valves. The drop valves feed six valve boxes that in turn distribute the chemical to 30 points of use via ¾ inch (19 mm) PFA tubing. Unused chemical is sent back to the storage container through a one inch PFA return line. For simplicity, we assume that all components are constructed from PFA.
Tee and valve boxes would typically be fabricated from polypropylene (PP). The tee boxes shown here have dimensions of 48 cm x 42 cm x 24 cm. The valve boxes are larger, approximately 90 cm x 80 cm x 30 cm. Although not shown, a typical system would also have secondary containment around the runs of pipe and tubing, often two inch (50 mm) poly vinyl chloride (PVC) pipe.
Table 1 also includes quantities and dimensions of the chemical distribution components: length (L), thickness (B), surface area (A), and fractional surface area (fA) relative to the entire system. The total surface area is 660,529 cm², which can inconspicuously allow chemical to escape the PFA via permeation. This system has a large surface area that is approximately equivalent to one side of a volleyball court (66 m² or 710 ft²). The total length of the system is one kilometer, so it is not surprising that most of the surface area is from the tubing and pipe, which accounts for >98% of the total surface area. Almost all of that area (97%) lies outside the tee and valve boxes. The remainder of the wetted surface area listed in Table 1 is from the valve diaphragms. We also estimated the area of the valve bodies, a total sum of 12,600 cm². This is much larger than the area associated with the diaphragms (1,660 cm²).

MASS TRANSPORT PROPERTIES OF PFA
Permeability (P) and diffusion (D) coefficients of PFA for both hydrogen chloride and ammonia gas were measured at 25°C by standard manometric techniques. ¹⁴ Gas pressures for hydrogen chloride ranged between 15 and 25 cmHg or for ammonia, from 42 to 47 cmHg. Values of P and D did not depend on gas pressure in these ranges. Their averages are summarized in Table 2. The diffusion coefficient describes the mobility of a molecule in a material, while the permeability coefficient is an inherent material property that describes the normalized “flow” rate through a material. Greater solubility of ammonia in PFA led to a permeability coefficient (P) that was nearly two times larger than for hydrogen chloride. The measured values agreed with the few published values found in open literature.^9,13

PERFORMANCE OF THE BULK CHEMICAL SYSTEM
Break-through times. If hydrochloric acid or ammonium hydroxide were introduced into our representative distribution system, how much time would pass before hydrogen chloride or ammonia gas would begin to appear at the outer surface of our PFA components? The break-through time (tb) depends on the sample thickness (B) and the diffusion coefficient (D) of the material,¹⁵

Assuming we have a perfectly sealed system, breakthrough of hydrogen chloride or ammonia would occur first in the thinnest wall sections of the valve diaphragms (7-8 hours). These gases would begin to emerge from the tubing in tb = four to five days.
Steady state permeation rates. Once break-through occurs, steady state is generally reached after 3tb.¹⁵ For the tubing in this system, that would happen approximately three weeks after introduction of hydrochloric acid or ammonium hydroxide into the dry system. If we assume the concentration in the surrounding atmosphere (tee boxes, valve boxes, and containment sub-systems, etc.) is effectively zero and is kept there, then volumetric loss rates (Q) due to permeation can be estimated from each component using the following equation,^15,16

where q is the volume of gas at standard temperature and pressure (To = 0°C = 273 K and Po = 1 atm = 76 cmHg) that permeates, t is time, P is the permeability coefficient, B is the component thickness, A is the area (A), and (ph) is the internal partial pressure of the gas. In turn, the volumetric loss rates can be converted into mass loss rates (m˙ ) using the ideal gas law,

where M is the molar mass of the gas in question (36.46 g/mol for HCl and 17.03 g/mol for ammonia) and R is the ideal gas constant (6236.6 cm3cmHg/K•mol). Steady state permeation rates depend on the vapor pressure of hydrogen chloride and ammonia, which are determined by the concentrations of hydrochloric acid and ammonium hydroxide. In the calculations, we used 22.5 cmHg for hydrogen chloride and 47.0 cmHg for ammonia as vapor pressures. These numbers represent 37% hydrochloric acid and 25% ammonium hydroxide, respectively.
Considering one of the components as a scenario— the chemical supply line is comprised of 152 m of one inch PFA tubing. Under steady state conditions, it would be expected to lose 225 standard cm³ of hydrogen chloride gas per day to permeation or 832 standard cm3 per day of ammonia. On a mass basis, this equates to 0.37 g or 0.63 g per day, respectively. Steady state mass loss rates are listed in Table 3 for all components. Since most of the area available for transport is found in the tubing, it accounts for most of the steady state gas loss. The daily totals are 2.1 g/day for hydrogen chloride and 3.6 g/day for ammonia. These loss rates of hydrogen chloride and ammonia can be converted into the amount of hydrochloric acid and ammonium hydroxide using concentration and density. The loss rate for hydrogen chloride would be equivalent to dumping five milliliters of concentrated hydrochloric acid on to the floor of a fab each day, or more likely into the secondary containment sub-system, allowing the acid to dissipate over the course of a day. This equates to two liters per year. Everything else being equal, the loss rate of ammonium hydroxide is expected to be more than two times that of hydrochloric acid.
Removal of permeants from the secondary containment sub-system. If we assume the secondary containment sub-system for a hydrochloric acid or ammonium hydroxide line is sealed and isolated from the ambient fab environment, it should be purged periodically to prevent accumulation of errant hydrogen chloride or ammonia. At the other extreme, if it were required to maintain levels of either gas in the secondary containment below the Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL), then constant purging of the sub-system would be necessary.
Again, let us use hydrogen chloride to make a few estimates. Without purging, the rate of accumulation will vary throughout the system. Hydrogen chloride levels will rise more slowly in the large valve boxes and more quickly in the confines of the tubing secondary containment. Therefore, to minimize hydrogen chloride concentration rise in the secondary containment sub-system, it is sufficient to address the smallest annular volume surrounding the tubing outside the boxes.
The daily hydrogen chloride loss at 25°C from a unit length of one inch tubing is 0.016 cm³ per day, while the annular volume of a unit length of secondary containment is 15 cm³. The OSHA PEL for hydrogen chloride is 5 ppm.¹⁷ In order to dilute the hydrogen chloride gas to this level, the air volume inside the containment sub-system should be turned over roughly 200 times per day. This corresponds to a residence time of seven minutes. Thus, the purge gas flow rate through the containment sub-system (0.8 m3) should be 0.1 m3/min (3.5 ft³/min). The highest purge gas velocities would occur in the PVC conduit containing the one inch PFA tubing. With an annular cross-sectional area of 15 cm², the average velocity in the conduit would be 75 m/min (4.5 km/hour = 3 mi/hour).

CONCLUSIONS
Permeability and diffusion coefficients of hydrogen chloride and ammonia gas were measured for PFA and then used to estimate the performance of a representative bulk chemical distribution system in a semiconductor wafer fab constructed from PFA. Our calculations suggest that for real systems, break-through occurs in a matter of days and steady state permeation accounts for several milliliters of chemical loss each day. Most of that loss comes from the long runs of tubing that transport chemical throughout fabrication facilities. To prevent accumulation and maintain very low levels of hydrogen chloride or ammonia, the secondary containment sub-system must be purged. The purge rate can be estimated using mass transport data.
Acknowledgements
We thank Entegris management, especially D. Brettingen, R. Lindblom, and B. Reichow for supporting this work and allowing publication. Also, thanks to E. Adkins, A. Anderson, B. Arriola, S. Cantor, C. Duston, L. Goedecke, J. Goodman, J. Hennen, T. King, S. Moroney, S. Sirignano, and V. Szpara for their suggestions on the technical content and text.
References

Khaladkar, P.R., “Fluoropolymers for Chemical Handling Applications,” Scheirs, J. (Ed.), Modern Fluoropolymers, Wiley, New York, 1997, Chapter 16.
Extrand, C.W., “The Use of Fluoropolymers to Protect Semiconductor Materials,” Journal of Fluorine Chemistry, 2003, 122, 121.
Goodman, J., Andrews, S., Solid State Technol. 1990, 33, 65–68.
Goodman, J., Van Sickle, P.M., Microcontamination. 1991, 9 ,21–25.
Kerbow, D.L., Sperati, C.A., “Physical constants of fluoropolymers,” Polymer Handbook, 4th ed.; Brandrup, J., Immergut,E. H., Grulke, E. A., Eds., Wiley: New York, 1999, pp. V31–V58.
Giacobbe, F. W. J Appl Polym Sci 1990, 39, 1121–1132.
Giacobbe, F. W. J Appl Polym Sci 1991, 42, 2361–2364.
Giacobbe, F. W. J Appl Polym Sci 1992, 466, 1113.
Pauly, S. Polymer Handbook, 4th ed.; Brandrup, J., Immergut, E. H., Grulke, E. A., Eds., Wiley: New York, 1999.
Monson, L., Moon, S.I., Extrand, C.W., “Gas Permeation Resistance of Various Grades of Perfluoroalkoxy-polytetrafluoroethylene Copolymers,” Journal of Applied Polymer Science, 2009, 111, 141- 147.
De Angelis, M. G.; Sarti, G. C.; Sanguineti, A.; Maccone, P. J Polym Sci Part B: Polym Phys 2004, 42, 1987–2006.
Aminabhavi, T. M.; Naidu, B. V. K. J Appl Polym Sci 2004, 92, 991–996.
Grant, D. & Carrieri, D. “The effect of HCl permeaton through PFA on expected component life,” Fabtech, Vol 37, 01 March 2008, 101-105.
Standard Test Method for Determining Gas Permeability Characteristics of Plastic Film and Sheeting; American Society for the Testing of Materials: West Conshohocken, PA, 1998; ASTM D1434-82. Test Method for Gas Transmission Rate through Plastic Film and Sheeting; Japanese Industrial Standard: Tokyo, Japan, 1987, JIS K7126.
Crank, J. The Mathematics of Diffusion; Oxford University Press: London, 1970.
Daynes, H. A., The Process of Diffusion through a Rubber Membrane, Proceedings of the Royal Society of London. Series A, Containing Papers of a Mathematical and Physical Character, 1920, 97, 286.
“Occupational Safety and Health Guidelines for Hydrogen Chloride.” United States Department of labor. 22 Oct. 2010. http://www.osha.gov/SLTC/healthguidelines/hydrogenchloride/ recognition.html.

Mark Caulfield, BS is Applications Engineering Manager for Entegris, Inc. He has sixteen years of experience in technical support and customer interface with fluid handling components and systems. mark_caulfied@entegris.com
Chuck Extrand, Ph.D. is a Principal Scientist and Manager of the Surface Science Research and Development Group for Entegris, Inc. His responsibilities include materials research, new product concepts, new processing technologies, and the design of new test methods. chuck_extrand@entegris.com
Sung In Moon, Ph.D. is a scientist of the Surface Science Research and Development Group for Entegris, Inc. His research area includes surface engineering, surface analysis, and permeation resistance of polymers. sungin_moon@entegris.com Entegris, Inc., 3500 Lyman Boulevard, Chaska, MN 55318, USA Tel: 952-556-8619; www.entegris.com

Basics of Ultrasonics

2011-01-24T07:38:00.000-08:00

Barbara Kanegsberg

Ed Kanegsberg

You don’t clean without energy. It takes energy to overcome the forces binding contaminants to the substrate. In most cleaning systems, a liquid cleaning agent is used; and energy, beyond the innate solvency properties of the cleaning agent, is required. This energy can come from the motion of atoms and molecules, such as from the kinetic energy associated with high temperatures. The motion associated with liquid spray is another source of kinetic energy widely used in critical cleaning. Another method for providing this motion is from sound waves in the ultrasonic frequency range.
Ultrasonics have proven to be an effective tool for many critical cleaning applications, ranging from initial cleaning after machining to final assembly in controlled environments. The forces associated with ultrasonics are very powerful; the local atoms have kinetic motions equivalent to temperatures as hot as the surface of the sun. The phenomenon is instantaneous and transient, so that successful cleaning with ultrasonics can be achieved without damage to fragile surfaces. Ultrasonics include omni-directional action. In contrast with line-of-sight processes, this allows the cleaning energy to reach complex surfaces, in some cases including blind holes. Both particulates and thin films can be removed from surfaces by ultrasonic action.
HOW ULTRASONICS WORKS
Generation of sound waves in a liquid in an ultrasonic tank is analogous to generation of sound waves in air by an audio system. A transducer converts electrical signals to mechanical vibrations that generate sinusoidal sound waves in the liquid. The sine wave has a positive or compressive phase during which liquid molecules move toward one another, and a negative or rarefaction phase during which the molecules move away from each other. The instantaneous pressure, P, in the fluid at time, t, can be expressed as

When Ps > Po, the pressure during the rarefaction phase is reduced to less than the vapor pressure of the liquid. During this time of “negative” pressure, a tear or vacuum “bubble” will form and grow. During the subsequent compression, the bubbles suddenly collapse, creating shock waves and microjets of fluid (Figure 1).¹ It is these shock waves or microjets, not the transducer generated sound, that provides the energy to dislodge unwanted soils. The creation and collapse of vapor bubbles is called “cavitation.”

MORE IS NOT NECESSARILY BETTER
The frequency and amplitude of the ultrasonic sound waves determine the energy created by the collapsing cavitation bubbles. The energy increases with increasing amplitude but decreases with increasing frequency. As the frequency increases, the positive and negative phases of the sine wave become shorter. As a result, smaller, “gentler” bubbles are produced.
Any force, including ultrasonic forces used in cleaning, has the potential for both positive and negative effects. The shock waves and jets that dislodge soil can also dislodge (erode) the underlying surface, the substrate that is being cleaned. On a macro level, cavitation also occurs with ship propellers creating vacuum tears in the liquid. This causes erosion that is a major cause of ship and boat propeller failure. Therefore a balancing act, a compromise, must be reached—sufficient energy to dislodge the soils but not so much as to damage the substrate. Substrates from softer metals, like aluminum and copper, are more easily damaged. This does not mean that one can not use ultrasonics to clean them, but rather that the process must be appropriately controlled. In fact, it is important to consider potential damage issues when considering any cleaning force. For example, many critical cleaning processes use high-pressure spray in air. When miniature components are cleaned using inline systems, longer exposure to high-pressure spray may be recommended. Excessively high impingement spray can damage delicate components; just as, on a macro level, wind-driven rain can damage property.
Commercially available ultrasonic systems have frequencies that range from 20kHz to over 400kHz. The lower end (20kHz-40kHz) are effective for hard metals, such as steel or titanium, and for removal of larger particles. Higher frequency units, because the duration of negative pressure is shorter, create cavitation with smaller bubbles and “gentler” implosions and are less likely to damage the surface. The higher frequencies can also be more effective at reaching small particles. This is because, as cavitation energy decreases at high frequency, a fluid flow effect called “acoustic streaming” dominates and can penetrate a fluid surface boundary layer to reach the smaller particles. At even higher frequencies, above about 500kHz, the cleaning process, essentially entirely from acoustic streaming, is referred to as megasonics. Acoustic streaming is unidirectional as are classic megasonic systems; and megasonics is traditionally used in microelectronics where surfaces are flat.
Some ultrasonics systems feature multiple frequencies in the same tank to address both large and small particles.² There are many other parameters that affect the efficacy of an ultrasonic system.³ One of those parameters is the liquid medium in the tank. Bubble collapse is a function of viscosity, surface tension, and temperature. For instance, adding a surfactant to water lowers its surface tension, and makes the creation of cavitation bubbles easier. At low temperatures, viscosity impedes cavitation; at temperatures close to the boiling point, a high vapor pressure causes vapor filled or “squishy” bubbles, reducing the impact of the collapse. For water, there is an optimal temperature at about 55°C.⁴
References

J. Fuchs, “The Fundamental Theory and Application of Ultrasonics for Cleaning,” Handbook for Critical Cleaning, B. Kanegsberg and E. Kanegsberg, editors; CRC Press (2001).
K. Gopi & S. Awad, “Ultrasonic Cleaning with Two Frequencies,” Handbook for Critical Cleaning, Second Edition, B. Kanegsberg and E. Kanegsberg, editors; CRC Press (expected 2011).
B. Kanegsberg & E. Kanegsberg, “Parameters in Ultrasonic Cleaning for Implants and other Critical Devices,” Journal of ASTM International, April 2006, Vol. 3, No.
4. L.D. Rosenberg, “On the Physics of Ultrasonic Cleaning,” Ultrasonic News, 4, p. 16 (1960).

Barbara Kanegsberg and Ed Kanegsberg, Ph.D. “The Cleaning Lady” and “The Rocket Scientist,” are independent consultants in surface quality including critical/precision cleaning, contamination control, and validation. They are editors of “The Handbook for Critical Cleaning,” CRC Press; an updated two-volume second edition is scheduled for publication in the first quarter of 2011. Contact BFK Solutions LLC, 310-459-3614; info@bfksolutions.com.

Standing Operating Procedure: Logbooks/Sheets for Contamination Control Cleaning

2011-01-24T07:36:00.003-08:00

Geoffrey Robinson

Let me preface this article with an explanation of my approach to the simplification of contamination control cleaning SOPs (standard operating procedures) and their associated log books/sheets.
Developing and implementing Standing (yes, itís ìStanding,î not ìStandard;î most SOPs differ, making them non-standard) Operating Procedures, and forms to record the completion of a scheduled contamination control procedure, chemicals used, and completion time, etc. should be as ìhuman being proofî as possible.
We are in a very serious business. Potentially, the lives, health, and safety of thousands of people rely on our detailed, timely, and accurate application of contamination control procedures. Having said that, it is my hypothesis that rather than limiting or eliminating human error, intricate and cumbersome SOPs and logs serve as amplifiers of human error.
SOPs
SOP development needs to be as thorough as possible, but it should also be logical, straight forward, and easily amended. Although SOPs are frequently drafted and reviewed for changes and updates by the professional staff, they are seldom initially given for review by those actually tasked with carrying out the procedures. The old axiom ìNo plan survives contact with the enemy,î often applies to SOP development. The enemy here is the actual, sequential implementation of the procedure.
Having the freedom to develop and implement your own SOPs can be a double edged sword of which ìadherenceî is the sharper sideóyou wrote it, you better adhere to it. Remember, your SOP is the blueprint for appropriate, applicable, and accurate procedural performance, and should not be a straight jacket. Unless you are fond of writing, being overly detailed in procedural construction can be a pitfall. Detailed descriptions such as 9î x 9î wipes, 14î sponge mops, 36î x 36î tacky mats, and similar items can put you in a pickle if your supplies run out and your vendorís delivery truck is snowed in. More flexible terms should be employed such as, ìindustry or organizationally approvedî clean room wipes, mops, and tacky mats. Wording it in this manner provides your SOP with some operational breathing room. However, this simplification should not be applied to cleaning chemicals or their concentration or areas for use. Chemical information should be detailed.
Specifying exact times for contamination control cleaning can also have serious drawbacks. If the production, manufacturing, and research team works overtime or late, blocking the scheduled cleaning time, you have violated your own SOP by not having the cleaning done at the appointed time. The options here are: 1) stop production/manufacturing/ research so you can clean, resulting in losing time and money; 2) hope someone in authority is on site to write a deviation to avoid violating your SOP. These problems can be avoided by changing the verbiage to allow flexibility. Rather than a specific time, use words like: daily; weekly; monthly; changeover; and special cleaning, etc.
However, this approach does not eliminate the possibility of errors when the contamination control crew starts their work, as many do, at 11:00pm (2300hrs). The problem starts when a scheduled cleaning is for the calendar date the crew starts, but doesnít get performed, for whatever reason, until after midnight, the next calendar date; back to drafting deviations. Back-dating the cleaning to correct this problem is a data error entry and a serious violation of your SOP.
To remedy this, consider this scenario. On arrival at the site, the contamination control crew has to check their assignments, prepare fresh chemicals, gather equipment, and gown up before any cleaning gets started. Under the best of circumstances, that adds up to twenty or thirty minutes of prep time. If you have scheduled a large room needing a monthly cleaning for the calendar date the crew signs-in on, youíve created your own problem. Eleven to seven schedules work well in hospitals, but can present problems in clean room environments. Calculate the prep time and then schedule the staff earlier or later as needed.
Frequently additions, deletions, or changes are made to product lines and processes necessitating SOP changes. Just how difficult you want the change process to be is up to you. Developing a change/update approval list for each SOP and publishing that list will help facilitate the change process. The importance of knowing exactly who is impacted by the change, and needs to be involved in the process cannot be overstated. But also knowing who does not need to be involved is important to simplifying the change process. Example: you are not changing the type, concentration, or usage quantity of your chemical so why elongate your change approval process by routing the change through purchasing? Also, there should be considerable staff review and input when developing these change lists. Donít forget to involve a representative of the contamination control cleaning team.

Developing Log Book/Sheets
Keep in mind that every manual entry (for example 01/02/04 = 8 possible entry errors) could become a write-over because of a faulty pen, illegibility, or around January, for example, entering an incorrect year. Remember the human factor when developing your logs. Log book/sheet development should be based on accuracy, applicability, and simplicity.
Here are some tips in designing log books:
1. Restrict entries to that data your procedures dictate you MUST capture.
2. Make data entry blocks large enough for ìIn Boxî corrections. This eliminates most of that annoying group of footnote error explanations at the bottom of the sheet. Beware: these error explanations can also generate errors.
3. Eliminate ìcommentî lines on your sheets. A frequent error here is staffers writing ìNone,î which is an entry error. If there are no comments then the line is not used, necessitating a line through, initials, and date. Your in-box error corrections should be comment enough.
4. Institute an ìauthorized signature & initialsî page as the front page of your logs. This will match people to their initials and also aids in identifying unauthorized sign-offs on procedures and corrections.
5. Supervisor/Inspector initials on logs sheet can be highly misunderstood. Do the initials mean the super visor/inspector was physically present during the procedure or chemical preparation and is verifying its correct completion or preparation, or does it mean they were not present and are only verifying the data line log entry was done correctly? Unless your company is small enough, or have enough supervisors/inspectors to view every procedure or chemical preparation, stipulate that all supervisor initial entries are for verifying data entry correctness.
6. Simplify as many entries as possible. Example: If you rotate Chemical A, Chemical B, and Chemical C, pre-populate the data block with a CA, CB and CC so staffers only have to circle the correct chemical applied that day. Likewise, daily, weekly, monthly, changeover or special cleanings can be reduced to a D, W, M, C, S circle entries. Also drains, sinks, wall, ceiling and floors and equipment can be abbreviated. If youíve completed a triple wash down of an area, or a special cleaning, you can circle as many items as applicable.

See Tables 1 and 2 for ìLimitless Errorî and ìReduced Errorî samples.
Having passed this article through technical, and process oriented staff in my own organization for comment, concurrence, and criticism, I am acutely aware of the ìwhat ifs,î ìsuppose it,î and the ìbut thenî arguments this article will invoke. Those arguments are the reason we are authorized the deviation alternative. It is not my intent to violate any industry guidance on the development of SOPs, or log books/sheets. It is my intent to convince you that there is no industry guidance that mandates you make your processes and logs so intricate and difficult to complete, that you become your own worst enemy.

Cleanroom Fire Prevention

2011-01-24T07:36:00.001-08:00

Vincent Degiorgio

A Material Difference

As computer chips get smaller and faster, the manufacturing process required to create them gets more complex. Even the slightest delay in production can mean millions of dollars in lost revenue. To offset the potential for contamination, chips are manufactured in the highly filtered environment of a cleanroom.
However, because computer chips are so susceptible even to the tiniest speck of dust, cleanrooms, historically, have been difficult areas to protect from fires. Contamination from a fire, no matter how small, could potentially puta chip maker out of business for weeks—if not permanently.
In 1997, FM Approvals, a Nationally Recognized Testing Laboratory, introducedthe Cleanroom Materials Flammability Test Protocol (Class 4910) [1].
In the past, cleanrooms and wet benches (plastic or stainless steel workstations upon which computer chips are manufactured) often needed to be protected by sprinklers or more expensive special fire-protection systems like carbon dioxide, fine-waterspray, or halon. By the time a cleanroom fire propagated and triggered a sprinkler or special fire protection system, millions of dollars in property damage could already have occurred in the rest of the cleanroom. With FM4910, wet-bench manufacturers and users can now develop plastic materials and equipment capable of resisting fire and emitting little, if any,smoke.
Due to such factors as potential lost earnings, chip makers are requiring suppliers to use materials in wet-bench fabrication that are less flammable. This should reduce the need for additional—and costly—fire protection systems because the materials will be inherently safe when they arrive in the cleanroom. Consequently, interest in cleanroom plastics with low fire risk has soared among semiconductor manufacturers and tool providers since the turn of the millennium. During that time, an increasing amount of tools constructed of FM4910 fire-safe materials have been installed in semiconductor cleanrooms and the frequency of devastating cleanroom fires has plummeted by approximately75 percent.
FM4910 measures two crucial fire-related elements of a product or material:

The Fire Propagation Index (FPI), an indicator of the tendency of a material to ignite and propagate fire, and
The Smoke Development Index (SDI), an indicator of the amount of smoke generated.

For material to be considered fire-safe under FM4910, its FPI must be equal to or less than 6 and its SDI equal to or less than 0.4. Today, scores of FM4910-listed materials and products made with such materials are available from nearly two dozen manufacturers. This ever-expanding list has led semiconductor tool vendors to build the majority of products (e.g., wet benches) out of FM4910 materials. In fact, for some tool vendors, FM4910-material-constructed tools have become their standard. Tools made with less expensive (but highly combustible) polypropylene or polyvinyl chloride are, in many cases, now available only by special order. While FM4910 materials are prevalent in semiconductor cleanrooms, they can easily be applied in other industries that utilize cleanrooms (pharmaceutical, biotech, food processing, etc.). FM4910 fire-safe materials are helping preventcleanroom fires. But they can’t do it alone.
Codes and Standards
The following codes and standards have significantly improved cleanroom fireprevention:

National Fire Protection Association (NFPA) 318 “Standard for the Protection of Semiconductor Fabrication Facilities”
Semiconductor Equipment Materials International (SEMI) S2 “Environmental, Health, and Safety Guideline for Semiconductor Manufacturing Equipment”
SEMI S14 “Safety Guidelines for Fire Risk Assessment and Mitigation for Semiconductor Manufacturing Equipment”
FM Global Property Loss Prevention Data Sheet 7-7 “Semiconductor Fabrication Facilities”
Each of these documents recommends the use of fire-safe construction materials for cleanroom applications. In cases where such materials are not used, fixed fire detection and suppression units are the recommended alternative. If neither measure is taken, the results can be catastrophic.

Proper Con-Duct
During the past ten years, a handful of semiconductor companies have suffered crippling fires in a frighteningly similar manner. A fire would start in a process tool, such as a wet bench, and then be drawn into the fume exhaust system. The fume exhaust system was typically made of combustible material and devoid of internal automatic sprinkler protection. As a result, the fire would spread rapidly throughout the ductwork system all the way to the scrubbers. In new fume exhaust ductwork installations, the preferred material is one which meets FM Approval Standard for Fume Exhaust Ducts or Fume and Smoke Exhaust Ducts (Class 4922) [1]. Even when subjected to a severe fire, FM4922-Approved ductwork will not collapse, will not propagate fire, and will release only minimal amounts of smoke. Increasingly, new and retrofitted cleanrooms are installing FM4922-Approved ductwork. However, a considerable amount of combustible ductwork with no automatic sprinkler protection remains in many facilities. Installing either FM4922 products or proper sprinkler protection in these cleanrooms is highly recommended. Replacing combustible ductwork with FM4922-Approved ductwork in existing operating semiconductor cleanrooms is not as daunting a challenge as it may appear. In fact, a major semiconductor manufacturer is successfully conducting such a replacement right now. To that company, the benefits substantially outweigh the potentially astronomical costs ofnot having the proper protection. And more help is on the horizon.
Where We’re Headed
At least one significant cleanroom fire hazard still needs to be addressed:containers used to store in-process wafers.
Wafer carriers or pods (200mm wafers) and front opening unified pods, or FOUPs (300mm wafers), are currently made of highly combustible materials like polycarbonate and polypropylene. These pods or FOUPs are typically placed inside vertical storage systems known as stockers. Fire loves few things more than highly combustible materials placed in a vertical array.
In December 2002, FM Approvals issued the Approval Standard for Wafer Carriers for use in Cleanrooms (Class 4911) [1]. This standard provides testing criteria similar to FM4910 in order for a fire-safe wafer carrier to earn FM Approval. An FM4911-Approved wafer carrier is expected to be brought to market sometime this year.
In 2005, FM Approvals expects to issue an evaluation standard for Tools Used in the Semiconductor Industry (Class 7701). This new product test standard will address design and construction features of semiconductor production equipment including:

Fire
Chemical
Materials
Electrical
Ventilation
Control and/or safety interlocks

Currently, before new tools are installed, they often require on-site evaluation (either at the manufacturer or client’s facility) by a semiconductor manufacturing specialist on a case-by-case basis. Due to the complexity and diversity of semiconductor manufacturing equipment, this can be a time-consuming,potentially costly endeavor.
When a tool is evaluated under FM7701, it will only require a spot check after installation, saving tool vendors and semiconductor manufacturing companies significant amounts of time and money. Having fire-safe semiconductor equipment is critical in the event of a fire. Consider the fire damage consequences citedat the outset of this article.
While great progress has been made recently in cleanroom fire prevention, there’s still work to be done. We may not be there yet, but our destination is clearlyin sight.
[1] Note: for more on FM4910 (including an up-to-date listing of manufacturersand materials), FM4922, and FM4911, visit www.fmglobal.com/approvals.
Vincent DeGiorgio is Industry Leader for Semiconductor & High Technology at FM Global, Inc., 1301 Atwood Avenue, P.O. Box 7500, Johnston, RI 02919.He can be reached at 401-275-3000 x 1994, or vincent.degiorgio@fmglobal.com.

Toxicological Risk Assessment for Medical Devices - What Is It?

2011-01-16T01:57:00.001-08:00

Barbara Kanegsberg

Dr. David Albert

Ed Kanegsberg

WHAT IS THE SIGNIFICANCE of a residue or a mixture of residues on an implantable biomedical device? If I perform chemical characterization of materials, do I need risk assessment? With similar processes, historical performance data of the device can provide a level of assurance. However, with new products and new processes, there is the need for a better understanding not only of the identity of the residue but of the significance of the residue. One of the greatest challenges in chemical characterization is performing adequate assessment of biological or toxicological risks from extractables or chemical residuals that can compromise patient safety. ISO-10993-17 has clearly articulated to the medical device community why and how risk assessments are a part of material biocompatibility [1]. But what is not clear is when and if they are absolutely required.
A Decision-Making Tool
Risk assessment is not new, but has only recently been promulgated by international standards and government agencies as a necessary part of chemical characterization and biocompatibility studies. It is really a tool for decision making that has evolved with time. Toxicological risk assessments have a long history with strong ties to the U.S. FDA, EPA, and OSHA. Risk Assessment is important and absolutely necessary to understand the ultimate biological or toxicological human response to materials and chemical processes. It becomes clear that to understand or predict human response to chemicals or materials, there must be close collaboration between the analytical chemist and the toxicological risk assessor.
Risk assessment is a scientific attempt to identify and estimate the true risks, and is the result of considerations of four primary steps. (1) Hazard Identification: identification of adverse health effects associated with exposure to a specific chemical; (2) Hazard Characterization: determination of the quantitative potency of any adverse effect of a chemical; (3) Exposure Assessment: measurement or prediction of the intake a chemical in terms of magnitude, duration, and frequency of exposure; (4) Risk Characterization: the integration of hazard identification, hazard characterization, and exposure assessment to determine the probability of occurrence and severity of risk to human health from the chemical(s).
Protocols for Complex Data
Those who are accustomed to a standard calling out of a specific procedure to identify or quantify a specific analyte may find themselves in unfamiliar territory with ISO 10993-17. Because toxicological data inherently consists of a wealth of complex variables and because the data and supporting studies for a given substance may vary in quantity and quality, a one-size-fits-all standard is impossible.
Instead, ISO 10993-17 is an ambitious, much needed step to define and document consistent protocols for evaluation of the risk factors for specific leachable substances.
This standard provides a systematic method for assessing complex studies. For example, the modifying factor is derived as the product of various component uncertainty factors. One example of a commonly used uncertainty factor is the factor used in extrapolating the effects of animal studies to humans. If only limited long-term exposure studies were available, a higher uncertainty factor leading to a lower acceptable exposure in the human population would be employed. It is noted in the standard that when this factor is combined with other uncertainty factors, modifying factors may be expected to differ by two orders of magnitude. Uncertainty factors and ultimately, the modifying factors, are derived on a case-by-case basis and are highly dependant on the quality of the toxicological database.
A dose or concentration of a chemical substance that does not produce any adverse effect [(i.e., “No-Observed-Adverse-Effect-Level” (NOAEL)] is identified, usually from toxicological studies involving animals, but sometimes from epidemiological studies of human populations. A modifying factor is applied to the NOAEL to derive a Tolerable Daily Intake (TDI), the intake or concentration which is believed that a person can be exposed to daily over a lifetime without deleterious effect.
Higher levels of cleaning, contamination control, and contaminant identification are inherent to the standard. Where only limited toxicological and long-term usage data are available, the modifying factor may be increased by an additional order of magnitude or more. Worker safety and regulatory constraints on cleaning agents and processing agents with known environmental risks as well as outsourcing of manufacturing processes tend to result in a multiplicity of process chemicals. Many of these are complex mixtures, often with poorly-defined toxicological profiles. Cleaning and contamination control processes will become increasingly important because moving from a chemical with well-established risks to a chemical we know less about can make it difficult to define the risk; so a higher risk will be assigned.
Mixtures
Risk assessment of mixtures remains a thorny problem. It is now recognized that significant data gaps exist in the area of mixtures toxicology, and these can preclude accurate risk assessments [2]. Most analytical chemists are acutely aware that leachable residue is likely to be a blend. The assumption is made that compounds with similar metabolic pathways or even with similar structures will have an additive effective. Sometimes, a small change in chemical structure produces sharply different toxicological effects. In addition, there is the possibility that mixtures will have a synergistic effect (i.e. far greater than additive, so that the risk to humans is magnified). Or the effect could be antagonistic, where the various residues cancel each other out.
Conclusions
To be effective, the risk assessment must be well organized, documented, and evidence based for use in support of decision making with respect to product or material safety. The goal is a process that ultimately protects public health and safety of medical devices. If following risk assessment, the conclusion is that there is still an important inherent risk which cannot be reduced, then risk communication and risk management techniques can be used to inform and protect. Decisions on whether to proceed using the material(s) involve a mixture of economic, societal and political factors. Risk assessment is absolutely necessary and must become an integral part of any chemical or material characterization process.
References:
1 ISO 10993-17, Biological evaluation of medical devices – Part 17: Establishment of allowable limits for leachable substances.
2 J.V. Bruckner, D.A. Warren. “Toxic Effects of Solvents and Vapors,” in Casarett & Doull’s, Toxicology, the Basic Science of Poisons, 6th Edition, C.D. Klaassen, editor, (2001) p.871.
Barbara Kanegsberg and Ed Kanegsberg are independent consultants in critical and precision cleaning, surface preparation, and contamination control. They are the editors of “Handbook for Critical Cleaning,” CRC Press.Contact them at BFK Solutions LLC., 310-459-3614; info@bfksolutions.com; www.bfksolutions.com.
Dr. David Albert has over 25 years of medical device related experience. David has been at NAMSA for 10 years serving as a Corporate Staff Chemist, Manager of the Chemistry Department and most recently as a Senior Scientist. Prior to joining NAMSA, he served as a Senior Scientist at Anatrace, Inc. where he supervised research and development projects involving new and existing medical devices. His primary expertise is in the areas of pharmacology and biochemistry. He can be reached at dalbert@namsa.com.

Speeding Up the Patent Process

2011-01-16T01:56:00.001-08:00

John B. Durkee, Ph.D., P.E.

IF YOU'RE IN "BIG PHARMA," doing biomedical research in a company or a university, or are a patent attorney, there is an ongoing debate about which you're knowledgeable and probably involved. The issues are far more significant than the one of usual concern — how to speed up the patent process.

Beware the Troll
A "patent troll" is an "accident lawyer" or "ambulance chaser" who practices in the area of patent law. These are lawyers and investors who buy cheaply or assume control over paper patents, mistakenly granted largely to failed companies. Intel's chief patent counsel has stated that a "patent troll" purchased a patent for about $50,000 which infringed all of Intel's microprocessors from the Pentium II onwards, and that they were seeking $7 billion in damages.
Is this "good" because it is an example of initiative and free enterprise? Or is it "bad" because it limits the reward which drives the development process?
Got the Flu?
Roche, a Swiss firm, owns the patents for manufacture of the medication called TAMIFLU (oseltamivir phosphate) which can be used within 48 hours from the onset of Avian flu (H5N1) symptoms. The core problem is that the number ofglobal citizens greatly exceeds the capacity of Roche to produce the medication.
Some countries are considering an approach based on "eminent domain" where they use information in Roche's published patents to enable firms in their country to produce the medication for their citizens without permission of Roche.
Is ‘breaking the patents’ "good" because it shows how governments can protect their citizens in a time when crisis is perceived? Or is it "bad" because it is simple theft of property (intellectual property)?
Congress Weighs In
Congressman Dennis Kucinich has a proposal to eliminate drug patents. He would direct about $25 billion in taxpayer money (about what "Big Pharma" claims to spend on research) to government-backed research organizations — socializeddrug research.
Incidentally, the same argument has been made about exploration for oil and production of gasoline after Exxon and other firms posted "monster quarters" with record earnings in the fall of 2005.
Is this "good" public policy or arrogant confiscation?

Who Decides?
Where should funds for research, today, generally produced by profits from previous work, be spent?
One might think, from patent actions, that drug research should be done to aid bald male persons who are impotent and overweight rather than seeking (as does Bill Gates' foundation) treatments for malaria or AIDS in countries with poor economies.
If Congressman Kucinich's proposal became law in the U.S., would the direction of nearly all medical and pharmaceutical research be established by the beliefs of the political party currently in power? Is that "good?"
Or is that “bad?” Congress currently allocates hundreds of billions of dollars of resources. U.S. citizens accept and enable that outcome, so it must be "good." Right?
Who Knows What?
Patent attorneys don't have perfect or complete knowledge of the art they rule. Who does? Those involved in the art submit their knowledge in briefs attached to current patent applications. The USPTO maintains a web site where the application, drawings, and knowledge submitted by supposedly knowledgeable persons are collected (http: //www.priorart.uspto.gov). The process is called a Wiki ("what I know is"). It's no relation to the Hawaiian Wikiwhich means "quick," "fast," or "to hasten."
Who judges the validity of this information, which may have been submitted by a competitor? Is such a submission a "good" or a "bad" action?
If you're not participating or lobbying in this debate, your firm may be blind-sided. Good blogs and web sites on this topic are http://promotetheprogress.com/, http: //weatherall.blogspot.com/, http://patentlaw.typepad. com/patent.
John Durkee is an independent consultant specializing in critical cleaning for contamination control. Author of the forthcoming book Management of Industrial Cleaning Technology and Processes, to be published in 2006 by Elsevier (ISBN 0-0804-48887). Contact him at PO Box 847, Hunt, TX 78024 or 122 Ridge Rd. West,Hunt, TX 78024; 979-417-7707; Fax 612-677-3170; or jdurkee@precisioncleaning.com

Developing a Cleanroom Disaster Prevention Plan

2011-01-16T01:54:00.003-08:00

Jan Eudy

How does one prepare, respond, and recover a cleanroom operation from a natural disaster?
Question: I am a production supervisor working in an ISO Class 7 cleanroom in Florida. Our cleanroom has not been affected by the hurricanes in Florida in the past but I have been assigned to write a disaster plan for the clean-room. How does one prepare, respond, and recover a cleanroom operation from a natural disaster?
It is wise to develop a disaster prevention plan and a disaster recovery plan now, when you don’t need it, in order to reduce the financial impact and ensure a quick recovery, should a disaster occur. I assume you are a member of a cross-functional team that is developing a comprehensive disaster plan for the entire facility and you have been given the responsibility and authority for the clean-room. I will focus only on the prevention, response, and recovery as it pertains to the cleanroom operations. However, to be successful, the plan for the cleanroom operations should be incorporated into the overall masterplan.
The source of the disaster can be from nature (i.e. tornado, hurricane, earthquake, flood, etc.) or man-made (i.e. power outage, terrorist attack, uncontrolled wildfires, etc.). A disaster plan should be a documented, comprehensive planthat addresses three key areas:

-Prevention of the disaster
-Response to the disaster
-Recovery from the disaster

Prevention of the Disaster
The focus of this section of the plan should be on the importance of being prepared to continue operations in any unplanned event for the welfare of the customer and the employees. One can use routine quality system audits to spot a crisis waiting to happen. Performance of a failure mode analysis and evaluation will produce a plan to keep the impending crisis from happening. A crisis management team can implement and execute procedures and policies designed to continue operations in the event of a disaster. If not already in place, your facility should install security systems, back-up generators, fire protection systems, and contract for data back-up and document storage off-site. Additional planning should include both internal redundancy of equipment and back-up facilities within your company that follow the samepolicies and procedures in the case of a severe disaster.
Response to the Disaster
Your facility should already have developed an emergency response group and plan in the event of a fire and perform routine fire drills. From this groupyou can build a strong cohesive disaster response team to train all employees how to respond to a disaster, such as a procedure for evacuating the cleanroom in the event the disaster occurs while the facility is in operation, and how to preserve the product. Additional information should be given to eachemployee such as:

-Contact information of key people
-Contact information of media disseminating information regarding status of the facility
-Contact number (preferably an 800 number) for employees to call for assurance that they are needed at work and will be safe

Recovery from the Disaster
Your approach to recovery depends upon the nature of the disaster and the extent of the damage. Therefore the disaster prevention/response/recovery plan should address all types of potential events that could stop production. The recovery plan for the cleanroom should tie into each scenario. In order to write the disaster recovery plan for the cleanroom, one must know every detail of the operation of the cleanroom just as one must know every detail of the business for writing the master plan. This information is usually found in the validation documentation (Installation Qualification, Operation Qualification, Performance Qualification) performed initially on the cleanroom and subsequent routine (daily, weekly, monthly, quarterly, semi-annual, and annual) quality testing. The personnel and process flow charts, procedures, and controlled documents are good references for information. The most recent certification of the cleanroom can provide the basis for the recovery plan framework. The parameters and specifications from this documentation are used to determine when full recovery has been achieved. The Institute of Environmental Science and Technology recommended practice, IEST-RP-CC006.3, Testing cleanrooms, is a good resource for information to aid in writing a recovery plan for your cleanroom. Other recovery plan documentation and testing requirements are being developed in IEST working Group 41, Recovery Plan Following Disaster Disruption. This working group, chaired by Mike Dingle is meeting at the IEST Fall Conference, November 5 – 8, 2006. The working group discusses and documents thebest practices from a variety of different disciplines and companies.
Jan Eudy is Corporate Q.A. Manager for Cintas Cleanroom Resources.

Fire-Resistant Foams For Pharmaceutical And Semiconductor Cleanrooms

2011-01-16T01:53:00.001-08:00

Ron Partridge

Fluoropolymer foams are high performance closed-cell foams based on polyvinylidene fluoride (PVDF) that bring new materials solutions to the life sciences and semi-conductor industries. Both industries require the use of ultra-high purity materials with low smoke generation and outstanding flame and chemical resistance. For many years, fluoropolymers, such as PVDF and its copolymers, have been successfully used for fluid handling and packaging systems. The introduction of new fluoropolymer foams fills a gap by adding flame retardant and chemically resistant insulation materials.

Molded fluoropolymer foams¹

LIFE SCIENCES
Today’s pharmaceutical industry uses the latest technologies to develop and manufacture medicines that dramatically improve the quality of life and increase life expectancy. The cost to develop, produce, pass FDA approvals and deliver these drugs to consumers can be as much as $800 million per new medicine. The financial impact is very large if production of these medicines is slowed or shut down due to fire or smoke damage. Even the slightest delay in production can result in significant losses.
New, sophisticated medicines are made using advanced manufacturing technologies and materials. High technology, “clean-room” environments often contain polymeric sheet and polymeric foam for insulation. These are used to create lightweight structures, partitions, chemical wet benches, and pipe and ducting insulation. These environments may also include wiring, flexible non-metallic conduit for fiber optic cables, as well as process control and automation wiring.

Foam sheet and tubes 1

SEMICONDUCTORS
The semiconductor manufacturing environments require the use of materials with excellent chemical resistance, purity, and low smoke generation in the event of a fire. PVDF polymers are commonly used because of their high purity and low smoke generation, and are widely used by the semiconductor industry to supply high-purity water to chip manufacturing operations. They are also used in the fabrication of wet benches. Since most chemicals do not alter PVDF, it has been adopted by the chemical process and pulp and paper industries for vessel lining and piping systems. PVDF is also characterized by its strength, toughness, and long-term resistance to both UV and gamma radiation.
In addition, PVDF is used to insulate data communications, fiber optic, fire alarm, and control cables because it will not easily propagate a fire and produces minimal smoke when burned. The excellent fire performance properties of PVDF allow for the installation of wire and cable products in building air-handling spaces without the need for metal conduits.
In order to limit the risk due to fire and smoke, Factory Mutual (FM), Underwriters Laboratories (UL), ASTM, and other testing agencies have developed fire-testing methods to characterize the fire performance of materials. It is generally recognized by these agencies that the best testing methods are full-scale tests or scaled-down versions that take into account where and how the product will be used. These test methods often use solid sheets, mounted horizontally or vertically, which are then exposed to a heat source and/or direct flame. These test methods are also used for testing polymeric foams, wire, and cable, and characterize performance by measuring flame spread and smoke generation as the polymer burns. In the case of wire and cable products, the cables are laid side by side in a closed chamber called a Steiner Tunnel (ASTM E84/NFPA 262/NFPA255) and fire performance is again characterized by flame spread and smoke generation. There are a number of nationally recognized testing laboratories that can performthese tests.
Many polymeric materials will readily burn and produce large amounts of smoke, as well as contribute significant fuel load, should a fire occur. However, fluoropolymers, especially PVDF, prevent and minimize fire hazards. PVDF is a pure polymer and is inherently flame retardant without additives. PVDF is characterized by:

High auto-ignition temperature
Low caloric value
Self extinguishes when a direct flame is removed
Minimal fire propagation and minimal smoke generation
Resistance to most chemicals, including typical sterilization methods
High purity
UV and gamma radiation resistant
Toughness and cut-through resistance

PVDF closed-cell foams can be obtained in continuous sheets and in a variety of thicknesses. The foams can be easily thermoformed, cut, and machined to produce complex shapes. PVDF foams can also be laminated to other sheet materials, such as PVDF sheets, to produce lightweight panels, partitions, and enclosures.
These PVDF foams are extremely flexible, can be ther-moformed into complex shapes, or transformed into tubes. The thickness, density, and flexibility of the finished foam can be controlled to suit a specific application. Densities as low as 30 kg/m3(0.03 g/cm3) have been obtained, representing a 60-fold reduction in specific weight. They can be used in cleanroom areas where good thermal insulating properties and high levels of flame retardance with low smoke generation are required. Recent FM 4910 exploratory testing has resulted in a Fire Propagation Index (FPI) of 3.0 and a Smoke Development Index (SDI) of 0.1. These preliminary results indicate that PVDF foams are capable of meeting the stringent requirements for cleanroom materials. Complete FM 4910 listings will be completed in the near future.
Specific PVDF resins and resultant closed-cell PVDF foams have been tested and passed the following fire performance standards. Fire testing and fire science is a very complicated area, and the results of fire performance testing can vary widely due to the test method used. However, the following standards (Table 1) are recognized as being the most stringent and best replicate of real-world, full-scale fire scenarios.
PVDF CLOSED-CELL FOAMS TEST RESULTS
Factory Mutual FM 4910
Exploratory FM 4910 testing has been completed and the results are shown inTable 2.
ASTM E84/UL 723
Surface burning characteristics of certain foam grades have been tested accordingto method ANSI/UL 723 (ASTM E 84 -01) used for the classification of buildingmaterials. ASTM E 84 test results are reported as Flame Spread Index (FSI) andSmoke Development Index (SDI) (Table 3). Results less than 25/50, respectively,indicate that the material has very limited combustibility and offers the highestlevel of fire performance other than a non-combustible (non-organic) material.

In order to pass these higher smoke release requirements, specific grades of LS foams with “LS” signifying low smoke have been developed. An SDI less than 50 is very difficult to achieve for a foamed polymeric material in the ASTM E 84/UL 723 test. These LS foams are useful for the insulation of air conditioning ducts, steam pipes, and other process components. In addition, the thermal conductivity of foams is very low which makes them ideally suitedfor insulating applications.
SUMMARY
By selecting materials used in controlled environments with the best fire performance characteristics, risks to life, property, and revenue can be dramatically reduced. Reduction in risk should also translate into reduced insurances rates. Closed-cell foams offer excellent fire-, chemical, and temperature-resistance characteristics and can be manufactured to produce solid sheets, insulation foams, complex shapes, and wiring insulation. PVDF closed-cell foams provide new options for engineers designing cleanrooms for the semiconductor and life sciences industries. Their excellent fire resistance characteristicsand low smoke generation should soon result in the listing of these productsas FM 4910-approved materials.
See MSDS for Health & Safety Considerations. Kynar® PVDF is a registered trademark of Arkema Inc. ZOTEK®F is a registered trademark of ZotefoamsPLC in the UK.
Reference
1. www.zotefoams.com
Ron Partridge is a Business Development Engineer in the Technical Polymers group at Arkema.Ron is responsible for Kynar® PVDF, foams,rotomolding,rotolin-ing,and wire and cable business development.He has roughly 20 years experience in the polymer industry in sales,busi-ness development,technical service and R&D.He has worked for Arkema for the last three years.He received his BS degree in Chemistry and Materials Science from The State University of New York in 1984.Hecan be reached at 215-419-7874;e-mail: ron.partridge@arkemagroup.com
Arkema is involved in vinyl products, industrial chemicals, and performance products.

Human Factors Engineering Applied to Controlled Environments

2011-01-16T01:50:00.001-08:00

Edmond Israelski, Ph.D.

Human Factors Engineering (HFE) is a discipline originating in World War II that includes in the design process data about human capabilities and limitations, as well as methods from the behavioral sciences to make products and processes,safe, effective, efficient, and usable.
The flow chart summarizes the systematic and scientific methods to design products or processes, such as controlled environments. At the core, HFE is a user-centered design, where, from the beginning of design, users are included. The HFE process starts with a very thorough understanding of the context of use, that is, the task flows, the user profiles, and the use environment. The process proceeds to quantification of risk and usability to iterative design using prototypes and simulations. Designs are then evaluated for usability using analytical techniques such as expert reviews and cognitive walk-throughs, followed by quantitative task-based usability testing. Usability testing is done one-on-one, where user performance is observed and recorded as they perform essential and critical tasks. Usability testing is done early as the design is iterated and then at the end to validate the design to see that usability objectives can be met and risk is reduced as much as is practicable.
Throughout the HFE process, user data is obtained to iterate both the design and the formal risk analysis, as appropriate. The end result is a process that is effective, efficient, safe, and satisfying for its users, since they have been at the forefront during the design process.

Edmond Israelski, Ph.D. is Human Factors Program Manager, Corporate Regulatory and Quality Science at Abbott. He has been practicing human factors engineering for many years in the design of a wide variety of products. He can be reached at Abbott, 100 Abbott Park Road, Abbott Park, IL 60064; 847-936-1131;ed.Israelski@abbott.com; www.abbott.com.

Powder Metallurgy: Problems of an Economically Friendly Technology

2011-01-16T01:45:00.003-08:00

Dr. D.D. Radev

This article is devoted to powder metallurgy (PM) and the peculiarities of that branch of materials science. The technological and economical advantages of PM methods compared with traditional metallurgical processes for production of metal products are discussed. The main stages of PM technology, namely the processes of powder production, shaping, and densification of the end bodies, and the effects of these operations on both human health and the environment are also discussed. In that respect, the methods of metal powder production are viewed in more detailed. There are several methods for metal powder production and features of these methods that determine the set of physical, chemical, and technological properties of the powders. That relationship is demonstrated using scanning electron microscopy (SEM). Toxicity and other harmful properties of certain metal powders with numerous practical applications are also discussed.
POWDER METALLURGY METHODOLOGY
Powder metallurgy (PM) is an industrial method for obtaining metal or metal-like powders, molding semifinished goods from powders, and manufacturing particles from them by a thermal process, called sinter-ing. The sintering temperature is below the melting temperature of the main component in the powder mixture. Because of the similarities between methods for ceramic (shaping – thermal treatment) and PM (molding – sintering) production, the end bodiesproduced by PM are also called metalloceramics. The term “powder metallurgy” soundsprovocative or at least suspicious on the pages of a publication when the authorwants to propagandize the achievements of a technology, the first step of whichis metal or ceramic powder production. Could a technology be connected with powderproduction and its processing in a way that is friendly to both environment andhumanity, especially when our every-day practice shows that metallurgy is a mainnatural pollutant? We want to show here the achievements of a technology thatis not only economically profitable but environmental favorable.
HISTORICAL PERSPECTIVE
The first historical example for industrial applications of PM is the chiseling of high-quality platinum (Pt) coins by intaglio. The method was developed by Sobolevski and Liubarski in Russia and practiced from 1826 to 1844.1The first modern powder metallurgy product was the tungsten (W) filament of electric light bulbs, developed in the early 1900s. During this time, the production of materials and products was closely related to the achievements of the necessary technological conditions, primarily the realization of high temperatures and the reliability of the corresponding equipment and materials. Although the process has existed for more than 100 years, over the past quarter century it has become widely recognized as a superior way to produce high-quality parts for a variety of important applications. This success is due to the privileges that the PM process offers over other metal-forming technologies (such as forging and metal casting), advantages in material utilization, shape complexity, and near-net shape dimensional control. These, in turn,yied benefits of lower costs and greater production versatility.
ENVIRONMENTAL IMPACT
PM is closely connected with technologies that determine its relationship to environmental protection. Obtaining and manipulating solids in powder state is an essential feature of PM. If PM is limited to the production of metal or metal-like powders, it would be just a part of metallurgy and could not be a progressive, technologically, and economically attractive method combined with metallurgy, materials science, and metalworking. Elimination (in most cases) or at least minimization of machining of the end article leads to economic advantages. As more than 97% of the starting materials reach the finished product, powder metallurgy is a process that conserves both energy and materials. Elimination of scrap losses, which directly reflects on environmental protection, is another privilege of the PM method, providing many possibilitiesto create waste-free and environmentally friendly processes.
ADVANTAGES AND APPLICATIONS OF PM
PM could use wastes obtained by other traditional metallurgical processes. The utilization of copper oxides obtained after cable production is a good example. This simple technology allows the burning of engine oil, presented as an impurity, to obtain pure fragile copper oxide flakes. After milling of copper oxide and reduction with hydrogen (H2) at 450 °C, one obtains pure copper (Cu) powder of very high quality that is suitable for use in the electrical industry for production of copper-graphite brushes. Controlling the parameters of the processes of milling and reduction (type of mill, milling conditions, time, and temperature), one could obtain Cu powder with defined chemical, physical, and technological properties. In this example, another advantage of PM is demonstrated — the creation of composite materials from physically and chemically different (as copper and graphite) components. Very often, PM is the only technology able to lead to the production of materials and articles with specific properties, such as self-lubricating bearings, hard alloy cutting tools from tungsten carbide (WC)-based alloys, magnet materials, copper-graphite brushes for electric engines, catalysts, and hydrogenstorage materials for hydrogen economics, among others.

Figure 1 presents an SEM image of boron carbide (B4C) particles. This material is directly and dramatically connected with human body protection. Dense plates from B4C powders find numerous applications in the military for anti-bullet protection. Dense B4C pellets find applications in nuclear energy as neutron-absorbing material, thus controlling peaceful nuclear reactions. PM is the only method for producing this superhard material.² In some cases, the conversion of a cast or wrought component to powdered metal provides a cost savings of 40% or higher. To produce a part for a contemporary reactive jet, weighing 0.45 kg, by a traditional metallurgical technology requires 8.6 kg of molded metal; the PM technique requires only 2.95 kg of the metal. Machine parts produced by PM are maintained very close to dimensional tolerances. That is very important for lowering costs. PM allows strict control on technological parameters, such as pressing, sintering temperature, etc. The combination of chemical (purity, presence of oxygen layers or impurities, etc.), physical (particle size and size distribution, surface area, etc.), and technological (fluidity, pressability, and sinterability) properties of starting powders are responsible for the behavior of PM articles during the processes of their shaping and densification by pressing and sintering. This determines the importance of the route for metal powder production. There are different industrial methods for this as all are responsible for the specific set of properties that is the “calling card” of the powder. It is customary to subdivide the methods of metal powder production into physical-chemistry and mechanical. The first method is based on deep chemical and physical transformation of the composition and structure of the starting material. Reduction, electrolysis, and thermal decomposition are base methods in that group. The “snow balls” of B4C shown in Figure 1 are obtained by so called plasmo-chemical synthesis.
The second type of method transforms starting material into powder without a change in composition. Dispersion of the metal melts and milling in different apparatuses are good examples. Interaction of certain metal powders with water and hydrogen (e.g., Al powders) makes water pulverization very dangerous. Strict measures to prevent hydrogen accumulation and its explosion should be taken. Figure 2 shows an SEM image of molybdenum (Mo) powder with a mean particle size of approximately 200 µm obtained by ball milling. Morphological peculiarities reveal products with low technological properties (pressability and sinterability). Sometimes, metal powder production is a contradiction of technological and work safety viewpoints. Low temperature reduction of metal oxides, in order to obtain fine-grained metal powders that lead to high sinterabili-ty, may result in products with pyrophoric properties. These powders, in contact with air, tend to self-ignite. The burning proceeds at very high speed and very high temperatures. Iron (Fe) and cobalt (Co) powders, which find numerous applications in PM, are good representatives of these materials. Strict safety measures should be taken during manipulation and storage of fine (< 10 µm) and ultrafine (< 0.5 µm) Fe and Co powders. Organic liquids, vacuum techniques, and an inert atmosphere of argon (Ar) are used to protect such powders from self-ignition.³

NICKEL POWDERS
Figures 3 and 4 show SEM images of nickel (Ni) powders obtained by hydrogen reduction of nickel oxide at 800°C and thermal decomposition of nickel carbonyl [Ni(CO)4], respectively. Differences in morphological properties of these powders obtained by different methods are obvious. Nickel powders find numerous applications in many branches of industry: production of specialsteels, superalloys, and alloys with controlled expansion (named Kovar), shape-memory alloys, Ni-La hydrogen accumulation alloys, dental alloys, implants, etc.
Being technologically attractive for specialists and curious for readers, these particles could be harmful and dangerous for human health. Nickel is an allergic agent and may cause different dermal effects. It is estimated that as many as 10–20% of women and 1–2% of men have been sensitized to nickel. The mechanism of nickel penetration by skin is based on the dissolving of pure metal by sweat. It is advisable not to wear cheap jewelry and to always demand a test for nickel allergy from your dentist if nickel-containing alloys for metal-to-ceramic dental constructions are used. Nickel also has carcinogenic effects and may cause throat or lung cancer. That is why very strict precautions should be taken when developing Ni powder metallurgy. These measures should include human and environment protection and strict observation of the corresponding standards for nickel dust concentrationsin the air of work places.
There are many materials that can be toxic but are safe to use when handled in the right way and exposures kept at acceptable levels. Wearing protective clothes and respiratory masks as well as strict control of dust levels in the air are necessary to minimize the risk of inhaling nickel or nickel-containing powders.
CONCLUSIONS
Based on materials science knowledge, PM is a very flexible and versatile technology. Newer methods and cheaper high-quality materials appear as a result of PM R&D activities. In that respect, we can show a metal injection molded (MIM) technique whose products have shown constant progress over the past several years. Strong markets for MIM products include tools, medical parts,electronics, firearms, etc. Spark plasma sintering (SPS) is a new process for obtaining fully dense, high-quality materials in a short time frame, thus retaining a fine-grained structure in the product. Recently, new methods for obtaining nanostructured and nanosized metal powders, alloys, and compounds, such as mechanochemical synthesis, self-propagating high-temperature synthesis (SHS), and combinations of these methods with thermal synthesis, have drastically changed the technological design for metal and ceramic powder synthesis.⁴ After intense mechanical treatment in high-energetic mills, such as attritors and planetary mills, certain metal powders acquired pyrophoric properties.^5,6 In the presence of oxygen, some mechanically induced interactions proceeded by explosive kinetics. That is why very strict safety measures, including the use of protective inert atmospheres, glove-boxes, etc., should be observed when working with mechanically activated metal powders. PM supplies the industry with low-cost production of precision, high-performance materials and products and no other metalworking process can match its competitive advantages. Could it be friendly to the environment? It all depends on us.
References:

Schatt, W. et al. Pulvermetallurgie, Sinter-und Verbundwerkstoffe.“ Veb Deutscer Verlag Fur Grundstoffindustrie, August 1977.
Ghosh, D. et al. “Dynamic Indentation Response of Fine-Grained Boron Carbide.” Journal of the American Ceramic Society, June 2007.
US Patent, No 4030913, 1977.
Radev D. et al. “Mechanically Activated Self-Propagating High-Temperature Synthesis of Nanometer-Structured MgB2.” Physica C, January 2005.
Radev D, and Klissurski D. “Properties of TiB2 Powders Obtained in a Mechanochemical Way.” Journal of Alloys and Compounds, April 1994.
Radev D. “Pulvermetallugie des Titans.“ Metall, January 1998.

Dr. D. D. Radev is at the Institute of General and Inorganic Chemistry, Bulgarian Academy of Science, “Acad. G. Bonchev” str., Bl.11, 1113 Sofia, Bulgaria. He can be reached at ddradev@gmail.com.

Document Integrity In The Life Sciences: An Industry At Risk

2011-01-16T01:44:00.001-08:00

Dirk Karsten Beth

Document integrity and security are critical to ensure compliance and approval for life science companies. Amazingly, the industry has chosen systems that put their documents at risk of loss, tampering, and regulatory penalties.
It might surprise many both inside and outside the industry to discover that critical documents, even those containing sensitive information such as patient data and test results, are routinely transferred from sponsor to CRO to consultant and back via unsecured e-mail. E-mail can be misdirected to the wrong people inside the company, sent to competitors, and can easily be read by any hacker.
Additionally, the same organizations often use loosely guarded systems such as network file shares to store and manage documents. A network file share does not provide version control, document locking, and minimal access control. With so many people working on a document, one is never sure who has the latest version leading to wasted time and resources tracking down the correct version.
Organizations who believe that they are using best practices may be unwittingly at risk. Some document management systems, including the largest and most expensive, have significant security flaws that are rooted deep within their aging architectures.
THE UBIQUITOUS NETWORK FILE SHARE
It seems like a great place to start. The collaboration tool of choice. The network file share. A single place where everyone stores their documents — and gives everyone access to those documents. Yet again, it is a risky decision. Imagine a disgruntled employee who has access to that share who decides to alter it, steal it, or wipe it out. Even with routine backups, the user still has broad access to other peoples work. The loss in productivity and resources adds up quickly. For example, if ten peoples’ work is stored on theshare and a days worth of data is lost, that is ten man days of work lost.
Network file shares also allow for corruption. A user could manipulate others work with little or no evidence of tampering. What prevents a manager, who has a project at stake, from opening completed documents and changing data to meet their needs? If this is discovered by a regulatory body, all data would be considered suspect and cost a life science company significant delays andfines, as well as lost revenue and corporate reputation.
THE E-MAIL ATTACHMENT
E-mail has become the communications platform of choice for today’s business, including the life sciences space. The vast number of participants collaborating in the development of life science products makes e-mail even more important.Is there any other way to comu-nicate with such speed and ease?
E-mail is a critical business tool that clearly is not going to be replaced any time soon. However, the use of e-mail and the security policies chosenwill have a major influence on business processes. The role of an attachment and how it is handled is extremly important and impacts security and regulatorycompliance.
E-mail is bounced from server to server across multiple Internet Service Providers before it arrives in the inbox. During its travels outside of your corporate firewall, it is unsecured. Using this mechanism to transfer critical documents puts those documents and the company at risk. Proprietary information may begiven up and patient data exposed.
An additional issue with e-mail, primarily if it is used for collaboration, is the inability to identify who is in poss-esion of a document and whether any alterations to the data have been made. Muddying the water further, several people may be making changes or updates to multiple versions of a document simultaneiously. Imagine being put in charge of producing a single, updated master document.
Life science companies of all sizes feel that their IT staff has a handle on this e-mail situation. E-mail may be secure for intra-office transfer but inevitably documents need to be accessed by others outside of the corporate firewall. There is only one way to deal with the problem; do not allow sensitive or mission critical documents to be e-mailed.
So what system should replace e-mail for the transfer of documents? A Web-based document management system that is made selectively available to the users who need access to documents. A port is opened, a user is created on the system. The document management system allows the user to access the document and tracks when the user has it checked out, creates a version when he checks it back in, and ensures that no one else is updating the same document while it is checked out. A full audit trail is maintained all the while.
This provides a richly managed collaboration in a regulatory compliant framework that shows who has what document and version, what changes were made, and digital signatures for approvals. Also, providing check-in and check-out functionality to eliminate simultaneous changes.

DOCUMENT MANAGEMENT DOES NOT A SECURE DOCUMENT MAKE
It is generally believed in the life science world that all regulatory and compliance issues go away when a document management system is implemented, preferably the most expensive system with untold rewards. And why should this misconception not be believed? The regulatory bodies almost promotethis idea.
Most of these systems do not do all of the things required for the life science industry out of the box. Rather they require a significant amount of configuration during implementation to meet those needs. This implementation will eithersucceed or fail to make a company more impervious to compliance issues.
The truth is that a document management system, if implemented correctly, can significantly improve the regulatory landscape of a company and at the same time yield significantadditional business benefits.
There are several issues with either the document management system or the implementation that can put a company at regulatory risk. Those include misunderstood requirements, poor or delayed execution, or a system that cannot be validated.
A significant architectural flaw is that some legacy document management systems still store managed documents on the file system. Making the documents as susceptibleto tampering, corruption, and malice as a network file share.
This flaw can be traced back to a time when there was no other way to solve the problem. Today’s modern database systems make this problem surmountable but legacy systems whose code base is dated are unable to change.
While it is true that this specific file system can be significantly secured from user access, those files could still be manipulated by an IT staffer either under coercion or self-directed contempt. The end result is that not only all of the company’s data is suspect, but their expensive document management system is suspect as well.
A robust document management system stores documents inside a database, where they are absolutely secured against download or change without an audit trail. In fact, they are no longer documents — just binary data. In some cases, this data is even encrypted. In the eyes of a regulator, imagine which system will emerge as a better choice.
INDUSTRY IS NOT AN ACADEMIC ENVIRONMENT
The development of life science products is often so closely tied to research that even workers inside a sponsor perceive the environment as academic. Most employees come out of an academic world and may not be accustomed to a regulated environment.
Leaders in the life science space should educate employees on the critical differences of working in industry versus academia. Systems are put in place not to complicate the process of science but to yield the eventual benefits of that research.
The data the researchers and others in life science companies create is critical to the process and to the eventual success of the company. It is imperative that the integrity and security of that data is maintained. Without vigil a company faces many perils:

Regulatory risks, fines, and delays
Extended or failed due diligence from investors, purchasers, and out-licensing partners
Patentability and patent defense issues
Situations have led to firings and criminal prosecution of C-level individuals

SUMMARY
Document integrity is critical to many regulated industries; however, the life sciences do not have the issue as well in hand as its counterparts. Not only is it a requirement for the industry to ensure document and data integrity as well as security, but it makes good business sense. It requires peoplewithin the organization to be vigilant but can return heavily for that investment.
Dirk Karsten Beth is President of Mission3, Inc., a software company that provides solutions to the life science industry. He can be reached at Mission3; 5060 N. 40th St., Suite 209; Phoenix, AZ 85018; 602-957-2150 ext. 503; dbeth@mission3.com; www.mission3.com.

Auditing: Resources For Managing Vendor Oversight

2011-01-16T01:42:00.003-08:00

Thomas Menighan, RPh, MBA

Chris Ward

In preparing to write this article for Controlled Environments, we looked at audits of vendors, like software developers and automated processes, and to distributor audits for supply chain integrity. A common thread in successful audits is the maintenance of sound audit practices, standards, and guidelines.
TO WHAT PURPOSE?
Auditing serves several purposes that are adapted to the application as necessary. Goals and results should be shared across the enterprise to help solve problems evident in all areas of pharmaceutical manufacturing and distribution. Regardless of what is being examined or audited — a system, facility, or software process — the resources available, such as the data, people, auditors,or experts, can be similar and many can be used in nearly all situations.
Audits are conducted to meet FDA guidelines to insure that manufacturers maintain appropriate due diligence and inspection of processes, environments, vendors, suppliers, and others whose products, work, and expertise goes into the manufacture of regulated products.
For example, in 1996, the FDA challenged the industry to establish a standard way to assess the structural integrity of acquired computer software and to lower overall costs to the industry. In 1997, a task force was formed to assess the integrity of and develop a guideline for auditing acquired commercial off the shelf (COTS) software. Under the umbrella of the Parenteral Drug Association’s PDA’s Computer Validation Interest Group, the PDA along with the FDA,members of the user community from the pharmaceutical and medical device industries, and the software developers themselves came together to create and publisha guideline for auditing the acquired computer software and services.
The objectives of this task group were focused on the specific application of software in the manufacturing process. These objectives were also very similar to those that any group consisting of professionals from any sector of the industrymeeting to establish standards might have. They include:

To define and demonstrate (through simulation and field testing) a process for supplier audits and qualification in a way that promotes standardization and simplification
To meet regulatory expectations for the structural integrity of acquired software and computer products in general (regardless of where in the manufacturing process they were applied)
To satisfy customer needs for information as supporting procurement, systems engineering, and computer validation
To lower costs to both the pharmaceutical companies and suppliers.¹

With regard to the latter point, costs of audits within the industry have increased dramatically and pharmaceutical companies may incur costs (internal and external) upwards of $750,000 per year to perform, manage, and archive audits. Examples exist that show reductions in cost greater than 50% through the use of a central repository. Such a repository for technology process audits was created by the PDA and is now known as the Audit Resource Center (ARC).
DEVELOPING THE AUDIT PROCESS
In the process of developing the published audit process, the task force performed research, used experience from supplier audits, and drafted a common practice to meet the needs of the industry. The needs assessment came from the users’ agreement that auditing practices used throughout the industry were cumbersome, duplicative,and inconsistent.²
The task force of industry professionals continued working after the publication of the report by the PDA (Technical Report 32 or TR-32) to monitor, maintain, and upgrade the process. Today, this group is known with the PDA as the Audit Guidance Advisory Board (AGAB). The AGAB now guides the development of technical reports for auditing and reviews the relevance of the documents, recruits committees of technical experts, and revises, expands, and broadens the guidelines as needed. The first iteration of this new guideline was published in 2001 and was revised in 2004. The current document is under review and publication of a new broader guideline is expected in the coming year.
Anyone who manufactures products that are regulated by the FDA must conduct due diligence of their vendors, typically in the form of audits. In this environment, those vendors who produce equipment that utilizes software or suppliers who develop software itself have to be audited; a well-accepted process that isoften used is TR-32.
Quality audit procedures are all driven by observation. Observations are made either by an external auditor or by the company’s technical expert who insures that inspection of the proper elements is done to current standards or by internal quality teams whose responsibility it is to report to managementon the status of the environment whether static, dynamic, or resting.
Other guidelines and standards exist to support professionals in their auditing, examination, and inspection of manufacturing processes and technology such as cleanrooms, controlled environments, and product pedigree in the chain of custody. Standards are developed by organizations that include members who work in the industry and governing bodies such as the U.S. FDA and the EuropeanMedicines Agency (EMEA).
The need for diligence is not unique to manufacturing of pharmaceuticals and devices. Companies also face challenges in distribution, both internal and throughout the external supply chain typically consisting of pharmaceutical wholesalers. Early in this decade, a significant increase in the incidence of counterfeit and diverted drug products and devices got the attention of industry stakeholders and led to a series of very significant changes. These changes included the publication of “Recommended Guidelines for Pharmaceutical Distribution System Integrity” by the Healthcare Distribution Management Association (HDMA) and the National Association of Boards of Pharmacy (NABP) Model Rules for distributors, which calls for strengthening of the Prescription Drug Marketing Act (pedigree) and related state laws, as well as changes in the business model between manufacturers and distributors (fees for serviceagreements).
AUDIT GUIDELINES
Today, the changes in the supply chain landscape continue. While no audit standard has been formally adopted, NABP created an inspection process that may be used by state boards of pharmacy for inspecting distributors (Verified Accredited Wholesale Distributor or VAWD) and the HDMA’s Recommended Guidelinesserve as a metric for at least one private audit firm.
GAMP 4, Good Automated Manufacturing Practices, is used as an audit guide for many manufacturing processes such as controlled environments where computer products and software are not the primary processes being examined. GAMP 4 has also been enhanced, refined, and restructured like the TR-32 to reflect current regulatory expectations and good practice.
Professionals from the Americas and Europe contributed to the production of GAMP 4 which is intended for suppliers and users in pharmaceutical manufacturing and related healthcare industries. This guide draws together key principles and practices and describes how they can be applied to determine the scope and extent of validation for different types of automated systems.
Benefits of this standard to industry users and suppliers echo those of the TR-32 and others include:

Cost benefits, aiding the production of systems that are fit for purpose, meet user and business requirements, and have acceptable operation and maintenance costs
Increased understanding of the subject and introduction of a common language and terminology
Reductions in cost and time taken to achieve compliance systems
Clarification of the division of responsibility between user and supplier

While GAMP addresses a broad range of issues related to validation of systems, another document that can assist cleanroom operators in maintaining 21 CFR Part 11 compliance is the joint PDA/ISPE publication “Complying with 21 CFR Part 11, Electronic Records and Electronic Signatures,” a companion document to GAMP 4.³
International standards and the groups that develop, maintain, archive, and promote them are the background for auditing within the regulated environment. Consideration must be given to adjunct drivers in the industry that help us conduct not only audits but daily performance, inspection, and maintenance of various processes.
ICH, or the International Conference on Harmonization, along with ISO 9001 standards, govern certain critical elements of the manufacturing process and how they are conducted. The American Society for Quality has been instrumental in supporting the industry and professionals who perform the operation, maintenance, inspection, and management of any systems within the industry.
ISO, the International Standards Organization, is a network of the national standards institutes of 155 countries, on the basis of one member per country, with a Central Secretariat in Geneva, Switzerland, that coordinates the system.
Between 1947 and the present day, ISO published more than 16,000 International Standards. ISO’s work program ranges from standards for traditional activities, such as agriculture and construction, through mechanical engineering to medical devices and the newest information on technology developments, such as the digital coding of audio-visual signals for multimedia applications.⁴
ISO is accepted in many industries and now has entered the pharmaceutical industry in manufacturing as well as software developers that service the industry.
AUDIT EXECUTION
Audits have historically been executed by compliance personnel in pharmaceutical companies who possessed a basic knowledge of software or other processes. These knowledgeable individuals used methods and checklists common to auditing physical processes and checking paper trails. Much of this was based on written regulation for good manufacturing and clinical practices, but was not alwayssuited for technology processes.
Audits conducted by independent auditors to a standard are valued by industry as a way to “certify” that a vendor or company has followed the proper procedures and their work or products have been through a third partyreview and is credible.
Training, qualification, and certification have become the basis for developing personnel and teams that can execute audits with the latest standards from governing organizations and professional associations like PDA, ISPE, ASQ, and others.
The PDA and ASQ both train professionals and qualify or certify them to conduct quality examinations for their companies, for clients independently, and audit the manufacturing and technical processes discussed here. This training is essential to furthering the standards employed and to the industry acceptance and adherence to standards and regulations from governing bodies like the FDA.
The rationale for developing industry standards is to systemize this process and to qualify auditors based on the standard developed by a sanctioning body, such as the PDA or others.
TRAINING
The PDA Training and Research Institute (TRI) exists for those who want to advance their careers in Quality Assurance, Quality Control, Manufacturing, Training, Regulatory Affairs, Validation, Engineering, or Information Technology; the PDA TRI has courses designed to fit many specialized needs. It is approved by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education.⁵The American Society for Quality has developed several training and certification courses relevant to this discussion. Someexcerpted from the ASQ Web site are:

Biomedical Auditor - CBA
Quality Auditor - CQA
Quality Engineer - CQE
Quality Technician - CQT
Software Quality Engineer - CSQE⁶

Other organizations that train or qualify auditors, maintain credentials, or set standards for these professionals are listed below with their Web sites:

International Register of Certified Auditors or IRCA http://www.irca.org/home.html
International Personnel Certification Association http://www.ipc.com
RABQSA http://www.rabqsa.com/
European Commission on Enterprise and Industry (Pharmaceuticals)
http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-4/pdfs-en/anx11en.pdf

RESOURCES
Third party participation in the audit process creates some distinct advantages. A third party resource can be a credible source for information, participation by technical experts, overview from sanctioning bodies, and resource extensionfor valuable and scarce internal resources.
One such resource to auditing is a central repository for audits and reports on audits that can be shared across the enterprise and throughout the industry by both a customer and their vendor in an effort to strengthen a vendor relationship, reduce time and cost associated with the auditing process, and provide quality controlfor documentation.
Many organizations may have processes and even specific software for managing audit data and reports. Like internal audit systems and those personnel managing them, they may be subject to the individual needs of groups within the companyor department and not meet a standard or include standard practices.
The same bodies that develop and maintain standards also devise ways to help maintain the integrity of the reports and information that is produced by an audit in an effort to make it acceptable to multiple stakeholders with theorganization or across the industry.
One such entity was created by the PDA’s task group and is the ARC that is managed under the supervision of the Audit Guidance Advisory Board. This entity provides audit reports to industry and partners with suppliers of software products to facilitate audits and track the global supply of available auditsand qualified auditors who conduct them.
CONCLUSION
One of the goals of examining audit resources in this article is to provide an overview of processes and procedures for auditing in the regulated environment and also to show the breadth and depth of the standards to which those involvedin the discipline are and should be held.
We often look into the detail of that which we are endeavoring to examine to find gems of data that we need to complete reports and manage a process or state of the system. Many times we need to start at a meta-level to understandthe system and make observations about that before examining the details.
This article is intended not to be an exhaustive journey through the history, development, or practice of technical auditing within the regulated pharmaceutical industry, but to shine some light on the resources available within particular sectors and perhaps provide a perspective or broader picture on a critical issue that consumes many hours for all of the professionals who spend careers dedicated to the pursuit of quality.
References

Auditing of Suppliers Providing Computer Products and Services for Regulated Pharmaceutical Operations. Technical Report No. 32, Release 2.0, Vol. 58, No. 5, September/October 2004.
Carney, David; Greenawalt, Harvey; Grigonis, George; Oberndorf, Patricia. Case Study: Computer Supplier Evaluation Practices of the Parenteral Drug Association (PDA) Carnegie Mellon Software Engineering Institute, May 2003.
GAMP 4, Good Automated Manufacturing Practice (GAMP) Guide for Validation of Automated Systems. Thomson TECHSTREET. 01 Aug 2007 www.techstreet.com.
Overview of the ISO System. 12 Sep 2006. International Standards Organization. 31 Jul 2007. www.iso.org.
About PDA Training and Research Institute. Parenteral Drug Association.
28 Jul 2007
Auditing and ISO Solutions, Quality in Manufacturing. American Society for Quality. 04 Aug 2007. www.asq.org.

Chris Ward is the Director of the Audit Resource Center for SynTe-gra and is responsible for business development and management of the ARC database of software process audits. He is a member of the American Chemical Society and has served as President of the Board of Directors, Vice President and Chair of various committees for the Asthma and Allergy Foundation of America. He can be reached at SynTegra LLC, 12800 Middlebrook Road, Suite 220, Germantown, MD 20874; cward@syntegrallc.com.
Thomas E. Menighan, RPh, MBA, is the President of SynTegra, LLC, and leads development and delivery of a full suite of operational and regulatory compliance services for pharmaceutical and biotechnology companies from product discovery to distribution. He is a past President of the American Pharmacists Association (2001–2002) and is currently a partner in Pharmacy Associates, Inc. He can be reached at tmenighan@syntegrallc.com.

Auditing: Resources For Managing Vendor Oversight

2011-01-16T01:42:00.001-08:00

Thomas Menighan, RPh, MBA

Chris Ward

To define and demonstrate (through simulation and field testing) a process for supplier audits and qualification in a way that promotes standardization and simplification
To meet regulatory expectations for the structural integrity of acquired software and computer products in general (regardless of where in the manufacturing process they were applied)
To satisfy customer needs for information as supporting procurement, systems engineering, and computer validation
To lower costs to both the pharmaceutical companies and suppliers.¹

Cost benefits, aiding the production of systems that are fit for purpose, meet user and business requirements, and have acceptable operation and maintenance costs
Increased understanding of the subject and introduction of a common language and terminology
Reductions in cost and time taken to achieve compliance systems
Clarification of the division of responsibility between user and supplier

Biomedical Auditor - CBA
Quality Auditor - CQA
Quality Engineer - CQE
Quality Technician - CQT
Software Quality Engineer - CSQE⁶

Other organizations that train or qualify auditors, maintain credentials, or set standards for these professionals are listed below with their Web sites:

International Register of Certified Auditors or IRCA http://www.irca.org/home.html
International Personnel Certification Association http://www.ipc.com
RABQSA http://www.rabqsa.com/
European Commission on Enterprise and Industry (Pharmaceuticals)
http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-4/pdfs-en/anx11en.pdf

Auditing of Suppliers Providing Computer Products and Services for Regulated Pharmaceutical Operations. Technical Report No. 32, Release 2.0, Vol. 58, No. 5, September/October 2004.
Carney, David; Greenawalt, Harvey; Grigonis, George; Oberndorf, Patricia. Case Study: Computer Supplier Evaluation Practices of the Parenteral Drug Association (PDA) Carnegie Mellon Software Engineering Institute, May 2003.
GAMP 4, Good Automated Manufacturing Practice (GAMP) Guide for Validation of Automated Systems. Thomson TECHSTREET. 01 Aug 2007 www.techstreet.com.
Overview of the ISO System. 12 Sep 2006. International Standards Organization. 31 Jul 2007. www.iso.org.
About PDA Training and Research Institute. Parenteral Drug Association.
28 Jul 2007
Auditing and ISO Solutions, Quality in Manufacturing. American Society for Quality. 04 Aug 2007. www.asq.org.

Integrating Business Continuity as Part of Strategic Planning

2011-01-16T01:40:00.003-08:00

Bikash Chatterjee

Much is written about the components of an effective strategic plan and how best to develop one. The headlines, filled with debates on pandemic preparedness and potential terrorist threats, highlight the need to define and align key communication and business corridors in the event of a catastrophe. From this debate, Business Continuity Planning has emerged as a central component to overall corporate well-being that all sectors of business recognize.1But with the globalization of our business practices comes greater probability for business disruption, as organizations attempt to align cultures, languages, and customs into cohesive business entities.
Previously, we discussed how current FDA and ICH guidance — and the push to manage risk — has triggered a shift in thinking in terms of product and process development in many business sectors. Yet, despite the use of time-proven methodologies, such as Balanced Scorecards and Strategy Maps for strategic planning, many organizations have not integrated Business Continuity Planning into their overall strategic thinking. While no one hopes for a disaster, defining the problem and taking steps to keep your organization in business can make the difference between surviving to fight another day and becoming a casualty. This column takes a deeper look at laying out a Business Continuity Plan for your organization.

ELEMENTS OF A BUSINESS CONTINUITY PLAN (BCP)
To develop and manage an effective Business Continuity Plan (BCP), we’ve isolated four major activities, each of which focuses on key elements that drive your business (Figure 1).
Business Impact Analysis (BIA)
The first step in moving toward an effective BCP is to conduct a Business Impact Analysis (BIA), based on your organization’s long-term strategic goals that accounts for the key elements of your organization. A BIA will help you focus on identifying the effect of non-specific events on your businessprocesses and customers.
This analysis should not be done in a vacuum. You may integrate this activity with other analysis tools such as a SWOT (Strengths, Weakness, Opportunities, and Threats), Johari window, and market analysis exercises to ensure all critical aspects of the business are addressed.
Consider the categories listed below when calculating your organization’s risk in the face of a catastrophic event. As you evaluate each category, study the possible risk to each organizational element, estimate the maximum time allowable to recover, and analyze the cost of being out of operation. From this analysis, you can articulate a recovery roadmap and set milestones as part of the tactical rollout. While this constitutes the “heavy lifting” of the exercise, the basic components of any organization can be distilled intothe following seven elements:

Facilities
People
Communication (IT)
Supply Chain
Equipment
Vital Records/Documentation
Intellectual Property

1. Facilities: Identify points of failure within the facility’s design and infrastructure. For instance, if the facility is an aseptic operation, what would be the impact of a breach to the sterile core? Is there a geographically separate facility available that could support the products manufactured in the facility?
2. People: Most pharmaceutical and biotech operations require a highly specialized workforce. What would the impact be if this workforce were disrupted and were not available to support manufacturing (as in the case of Hurricane Katrina)?
3. Communication: More than ever, our industry’s nerve center revolves around its information infrastructure, particularly given the industry’s use of contract manufacturing (CMO) and research (CRO) organizations to support clinical and commercial programs. What would the impact be if these communication ties were lost, or worse, if data were lost? How quickly could the communication corridor be replaced? How will you handle the change management requirements?
4. Supply Chain: The supply chain feeds the organization’s revenue engine. Procurement, warehousing, material handling, and distribution require visibility into the current production stream and forecasted demand stream. Configuration management considerations for all components are central to ensuring quality and regulatory compliance. So what would the impact be in the case of disruption? The availability of qualified alternate suppliers may be critical to ensuring ongoing operations.
5. Equipment: Many processes require customized equipment to support operations. Often Biotech processes, even those with identical fermentation and purification equipment, do not behave the same way when transferred to alternate equipment. What would be the impact of repeating process development studies on new equipment?
6. Vital Records/Documentation: Documentation is the cornerstone of our quality management system. Our internal process and external process (recall, adverse events, etc.) are predicated on access to these documents. An inability to recover critical documentation may not put only future products in jeopardy, but also product currently in the field. The roll-through impacts of withdrawing critical therapies cannot support the current regulatory requirements can greatly affect your business as well as the customers that rely on these products.
7. Intellectual Property: Socio-economic issues, such as pandemic outbreaks, may be raised if an organization is unable to provide the therapies required to support customers who depend on them. For that reason, you may need multiple manufacturers with available capacity to make your product. In such cases, how will you ensure your rights are protected?
Risk Assessment (RA)
The Risk Assessment (RA) phase consists of prioritizing the identified business disruptions based upon severity and likelihood of occurrence, and will have a profound impact on the effectiveness of the final BCP. If the threat scenarios you develop are too narrow, then the resulting BCP may not adequately protect the organization from an undesirable business interruption. The RA should analyze all risks to the business, including its employees, customers, and investors/shareholders: in short, assess all entities which would be affected by a business disruption. If your organization has a legacy BCP, you shouldcompare it against your updated risk assessment summaries.
During the RA, business process and business impact assumptions will be stressed using different threat scenarios, based upon severity and likelihood of occurrence. The result is a series of outcomes, some that have straightforward mitigation requirements and some that require a more involved business continuity plan. Threat scenarios should address both the business disruption and probability of occurrence, ranging from low-impact, high-probability threats, such as a brief power outage, to high-impact, low-probability threats, such as an earthquake or a terrorist attack. While high-probability threats may at first seem like the higher priority, it is the low-probability threats that are the more complex for which to prepare. A balanced perspective in preparation will be essential to avoid following the path of least resistance. When assessing the probability of a threat, the RA should consider geographical location (floodplain, access to water for processing) and proximity to critical infrastructure (power stations, points of national interest, airports, etc.). There is no mandatory toolset required to do this analysis. Classical risk analysis tools such as a Failure Modes and Effects Analysis (FMEA), Fault Tree Analysis, or your own organization’s proprietary analysis methodology may all be used in the assessment. At the conclusion of the exercise, the RA should summarize and prioritize the threatsto the organization’s ability to meet its strategic initiatives.
Risk Management
Now, with a clear picture of the prioritized threats to the organization, the next step is Risk Management itself, which involves developing a business continuity plan to describe the steps necessary to mitigate risk. A wellwritten BCP documents the strategy, policies, and procedures required to maintain, recover, and stabilize critical business operations after a business disruption. While it is impossible to consider all threats to a business’s operation, your plan should be flexible enough to adapt to changing threat scenarios. Your detailed BCP will describe the crisis management organization structure including decision-making and plan-execution processes such as financing,resource management, and communication platforms.
Risk Monitoring
The final step establishes a program that ensures your plan remains relevant as your organization grows Review this plan on an annual basis to ensurethe policies and procedures reflect the current needs of the company. It is prudent to have the plan reviewed by an external consultant or auditor who is experienced both in your industry and in the establishment of BCPs. A word to the wise: choosing a BCP auditor from outside the regulated life sciences industry may add risk to your assessment given the unique regulatory and process constraints associated with manufacturing drug products. Finally, update your plan to reflect changes in key personnel and organizational structure. A BCP Process flow-down chart is shown in Figure 2 and contains all four elements of theprocess we’ve described.

CONCLUSION
A clearly articulated BCP forms the foundation for business performance and is strategic to the long-term health of your organization. As pharmaceuticaland biotech companies leverage contract organizations around the world, interdependence between each piece of the business model increases. An organization’s inability to progress against these strategic objectives can have a profound effect on the organization and its shareholders. More importantly, in the event of life-sustaining therapies, it can have a huge impact on society and the population at large. By following the four phases necessary to develop a comprehensive BCP, an organization can pursue the opportunities presented by emerging countries in terms of manufacturing and clinical expertise aswell as mitigate global threats to their business operations.

1. Recently, the SEC implemented NASDAQ’s rule 3510 and 3520,and the New York Stock Exchange implemented rule 446 specifically to ensure business continuity in the event of an unplanned business disruption, such as a terrorist attack.

Bikash Chatterjee is the president of Pharmatech Associates, Inc. He has been involved in the bio-pharmaceutical, pharmaceutical, medical device and diagnostics industry for over 20 years. His expertise includes site selection, project management, design, and validation of facilities for both U.S. and European regulatory requirements.

Exhausting Your Options

2011-01-16T01:39:00.000-08:00

Kenneth J. Fisher

Facilities and purchasing managers can achieve positive results for fire safety and occupant health and safety while capturing cost efficiencies through green system material selection.
Semiconductor industry facilities and purchasing managers who are key decision makers for systems and materials selection need to rethink and broaden their approach in selecting, specifying, and purchasing an industrial fume exhaust duct system. By broadening their perspective and taking into consideration the long-term value, the best in “green” class fume exhaust duct systems will ultimately deliver the rewards of reducing waste and improving system sustainability.
The robust fume exhaust duct systems approved for the semiconductor industry are containment systems with specialty lining consisting of a fluoropolymer coating or a composite. The fluoropolymer and composite lining’s purpose is to protect the duct containment system from corrosion and chemical attack by the volatile chemicals, toxic fumes, and corrosive vapors. These fume exhaust duct systems transfer the contaminated air produced by the semiconductor manufacturing process to fume abatement scrubber systems. The abatement scrubber systems are typically water sprayed across numerous filaments that wash toxic exhaust air to a clean state before the clean air can be dischargedin to the atmosphere.
The semiconductor industry is known to be extremely progressive and continually changing, relentless in the pursuit of new designs and best inclass practices. The saying, “the only thing thatremains the same is change” fits the industry perfectly. We often reador hear news of an excitingleading edge technology in chip design which reduces manufacturing costs and improves deviceperformance. The result from the implementation ofthis technology is a win-win providing efficienciesand performance which typically benefit both thecompany and the ultimate end consumer.
Facilities systems and operations are not as intense or multifaceted as the manufacturing systems which produce a DRAM or flash memory. However, the search for new technologies and the best in class practices related to facilities systems and operations are an aggressive and an ongoing effort because they too can have a positive influence on a semiconductor company’s bottom line. Facilities systems and their continual 24 hours a day, 7 days a week operation become a part of the company’s long term expense budget. Facility managers are tasked to evaluate, align, and implement cost reduction initiatives on their site to closely match what other industry leaders set as the benchmark for best practices.

MATERIAL ADVANCEMENTS
Taking a deeper look in facilities systems and operations, and specifically a more comprehensive assessment of the fume exhaust duct systems, we find new a new set of system challenges and rewards. The new challenge for facility managers is to define and implement their company’s progressive approach to be a responsible industry leader pushing for and supporting the green movement in search of sustainable fume exhaust ductsystems. The rewards are the reduction of waste, reductionof energy use, and cost efficiencies while buildingenvironmentally friendly system awareness and acceptance.
Improved material chemistry advancements in fume exhaust duct systems over the years have facilitated positive results for fire safety, occupant health and safety while at the same time providing cost efficiencies.
FIRE SAFETY
The importance of the continual development of standards, testing, and audits ensure that the fume exhaust systems meet or exceed occupant health and safety requirements. The industry has the progressive involvement of FM Approvals, a nationally recognized testing laboratory that certifies industrial and commercial products and services that support property loss prevention. FM Approvals continues to be the dominant organization in setting the highest mark in the development of the testing and certification of fume exhaust duct systems for the semiconductor industry. FM Approvals Standard 4922 (FM4922), “Approval Standard For Fume Exhaust Ducts or Fume and Smoke Exhaust Ducts,” (available at www.fmapprovals.com) is the criteria all suppliers mustmeet or exceed in order earn FM Approvals’ certification which indicatesthat such equipment meets the highest property loss prevention standards in thesemiconductor industry.
FM4922 evaluates fume exhaust ducts for their performance in regard to fire spread on the inner and outer surface of the duct, and suitability of the duct to be used for smoke removal. FM4922 is an extremely stringent test for any supplier to pass. When you consider what is at stake, occupant safety and the ever increasing cost of a semiconductor fabrication facility now in the billions of dollars, you can understand why the test is necessary and why the test has gained global acceptance.
INNER COATINGS
Fume exhaust duct suppliers invest heavily in their fabrication and coating application operations, their quality controls, and continual training of team members on best practices to produce a product that will pass the stringent FM4922. Fume exhaust suppliers continually explore and develop new processes and technologies to enhance their existing systems’ performance to keep pace with changes of the semiconductor industry. There are numerous statistics on the various grades of the different fume exhaust duct inner protective linings ETFEs (Ethylene – TetraFluoroEthylene) and ECTFEs (Ethylene – ChloroTri- FluorEthylene) and composites making up the FRPs (Fiberglass Reinforced Plastic) used by the different fume exhaust duct suppliers. These statistics can be presented in a manner to show one fume exhaust system is superior over the other, and yet when the truth be known, there are more partial system failures due the improper installation of the fume exhaust systems then there are partial failures with fluoropolymer coatings or composites that make up the systems.
The reality is, even though FM Approvals provides the highest of standards and the most rigorous testing for fume exhaust duct systems in the semiconductor industry, and the fume exhaust duct systems suppliers invest heavily in their operations, people, and R&D to produce a best in class system which meets or surpasses FM4922 — this is not enough. The reason it is not enough is because FM Approvals and fume exhaust suppliers are not the decision makers who ultimately design, specify system type, and purchase the best in “green” class system for a specific fume condition. Nor will they be ultimately responsible for the system maintenance long-term, the rework of the system, and at some point the disposal of the installed fume exhaust systems.
CHOOSING A GREEN FUME EXHAUST SYSTEM
Facility and purchasing managers in the semiconductor industry have an excellent opportunity to leverage their technical knowledge, evaluate and prioritize initiatives, and pursue their final selection of a fumeexhaust duct system that promotes and produces greenrewards.
Here are just a few green points to consider when selecting a best in “green” class fume exhaust system:

What are the impacts to the environment when the system is manufactured for use?
Where is the fume exhaust system manufactured and what is the travel distance, cost, and impact?
Is the system easy to install, retrofit, and remove?
Are there environmental impacts to an occupied space during system install?
Is the system impacted by ultraviolet light?
Can the fume exhaust duct be field cut and installed to meet a special length requirement without damaging the integrity of the protection surface?
Does the system require additional system support protection systems, e.g. fire sprinklers, etc.?
What system maintenance is required long-term and at what cost?
Can the system be reused for fume exhaust?
Can the system be reused for other exhaust systems?
What percentage of the system can be reused?
Can the system be easily packaged and stored for reuse?
Can the system be recycled?
What percentage of the system can be recycled?
Are their special hazardous material disposal requirements after system is removed from operation?

Evaluating and recognizing the positive economic potential associated with selecting a fire safe, green fume exhaust duct system is an affirmative step forward for facilities and purchasing managers responding to the semiconductor industry’s challenge to push forward in search for the best in “green” class system sustainability, performance, and the reduction of system waste.
Kenneth J. Fisher Sr. is Director, COR*Guard with 17 years experience in Semiconductor Industry Facilities Engineering, Construction, and Planning. He has 8 years experience in Fluoropolymer coated stainless steel fume exhaust duct. COR*Guard is a supplier of stainless steel industrial fume exhaust duct system, PRIME*GUARD, for the Semiconductor Industry. He can be contacted at Ken@corguard.net; www.corguard.net.
Dyneon LLC, a 3M Company and one of the world's leading fluoropolymer suppliers with operations and representation in more than 50 countries offers a wide selection of advanced fluoropolymer materials. Dyneon has developed COR*Guard's ETFE coating system meeting the stringent requirements for corrosion and fire resistance for acid laden fume ducts used in semiconductor industrial applications. DyneonT ETFE is a unique Dyneon copolymer of tetrafluoroethyleneand ethylene.

Ergonomically Speaking

2011-01-16T01:37:00.003-08:00

Bill Fleming

Operator interface systems for controlled environments are becoming more user-friendly.
In the past, ergonomics have not been a prime consideration for industrial designs. But, when industrial engineers and designers omit ergonomics from their plans, they compromise the safe and efficient operation of equipment in controlled environments, which leads to injuries, equipment damage, and costly retrofits.
Although ergonomics play an increasingly important role in the design of operator interfaces and computer systems, the U.S. government has left the implementation of ergonomic principles up to individual industries to regulate. To address workplace concerns, standards-based organizations have released practice guidelines and standards for ergonomics.
For example, the ISO 11064 (Ergonomic Design of Control Centers) international standard recommends a top-down approach to ergonomic controlled environment design that emphasizes functional demands. This approach recognizes that even if a controlled environment is well-designed, the overall system will fail if workers are overloaded, poorly trained, or straining to read illegible operator interface monitors.
With these guidelines available to industry, and with the U.S. Census Bureau reporting that half of all adults use computers in the workplace, more and more companies are discovering that ergonomically sound workstations and operator interface systems are more productive. That’s why the new modus operandi of industrial designers is to account for how operators and systems interface in the working environment.
Perhaps the most important questions in the design of controlled areas and their operator interface systems are, “What does the user want?” and “What is the user trying to achieve?” Each question and its answer will affect the design of a controlled environment and its systems, as well as impact the comfort and productivity of the operators slated to work in those areas.
DESIGN PRINCIPLES
Operator productivity and safety depend on the layout and design of the tools provided to the operators. As such, there are clear advantages to systems created with ergonomics in mind.
Operator interface systems must be able to accommodate a variety of users and their postures. Proper ergonomic design of a workstation takes into account an operator’s posture, movement, and visual comfort.
Posturing
In controlled environments, operators may be seated for long periods of time or be required to stand at a workstation. Operators who are sedentary may suffer from shift work fatigue and decreased alertness because sitting for long shifts reduces blood flow and promotes sleep. Some of the best operator interfaces relieve this fatigue by allowing a wide range of comfortable postures.
Variability in posturing can be achieved by using vertically adjustable workstations that allow users to sit or stand; integrating track balls and joy sticks for input devices; installing keyboards at optimal reach distances to eliminate extreme ranges of motion; and using ergonomically correct chairs that adjust to different heights. Additionally, workstations should be designed to consider eye height, elbow height, and eye-elbow height difference so as to not install components (such as keyboards) too high or too low.
Eye height ranges from 41 to 51 inches for seated workers and from 56 to 69 inches for standing workers, and elbow height varies between 22 and 28 inches for seated workers and 36 to 45 inches for standing workers. Whether seated or standing, the eye-elbow difference is the same. For the U.S. population, that difference ranges from just less than 19 inches (women) to slightly more than 23 inches (men).
Visual comfort
As industries see more and more process automation, operators are spending more time interacting with computer workstations. When these workstations are installed at incorrect levels, an operator’s visual comfort can be compromised by eye strain, neck strain, or a combination of both.
Designers can help prevent operator neck strain by situating workstation monitors at the proper gaze angle. The general recommendation is to place the monitor so that the top of the viewing area is at or slightly below the user’s horizontal eye level. This places the center of the screen at the ideal 15 to 20 degrees below eye level for most monitors.
In controlled areas where operators use several monitors at a time, screens are generally installed in a horizontal arc in front of the workstation. These monitors should be in a user’s direct field of vision. After a period of lateral eye movement, a person’s head will turn automatically when responding to eye movement, and this excessive head and neck rotation can result in strain and fatigue. A common way to prevent this problem is to situate keyboards and other controls in front of the monitors. Writing surfaces and storage spaces should be installed on the sides of these workspaces.
Monitor tilt also impacts visual and postural comfort. Screens that tilt forward increase neck, upper back, and visual discomfort compared to those tilting backward. An optimal tilt angle for monitors ranges from 5 to 20 degrees back from the vertical plane. Despite the chosen angle, care should be taken that ambient lighting does not cause screen reflection and glare.
NOISE AND LIGHT LEVELS
Operator interfaces are only as good as the environment in which they are installed. Due to their job specifications, operators can be subjected to high levels of stress, which also contributes to shift work fatigue.
Ambient noise, alarms, printers, and traffic through a controlled environment can distract operators and can interfere with communication during emergencies. By routing traffic away from operator interfaces and isolating other equipment from a controlled environment, plant designers can reduce ambient noise. In areas where noise can not be avoided, operator interfaces can be surrounded by acoustical treatments to pad sound levels.
The placement of ambient and task lighting in controlled areas must be considered when selecting an operator interface in order to prevent glare on monitors. Light levels impact alertness, and appropriate light levels are necessary to prevent eye strain. So designers must achieve a careful balance of ambient lighting and task lighting by which operators can successfully use controls. For controlled environments, ambient lighting in a range of 300 to 650 lux is adequate. Task lighting set at about 600 lux should shine on work surfaces.
All elements of operator interfaces should be integrated systematically and as early as possible in a controlled environment’s design phase. The design of the operator interface influences the layout of an operator’s workspace, the location of visual displays, and the size, shape and placement of workstations relative to those interfaces.
INTERFACE SELECTION
Reducing operator stress and enhancing alertness and productivity are the goals of properly selecting an ergonomic operator interface.
Selecting an ergonomic operator interface begins with a task analysis. This is a detailed study of how operators carry out parts of their jobs and how they interact with the equipment used to perform those jobs. Task analysis can include the following considerations: workload, corporate culture, situational awareness, and communication.
Designers also should consider environmental factors such as ambient noise and light levels, as well as the need to share space in the workplace. Interfaces may need to fold up, swing back and forth, or move up and down to allow other work to be performed with in the same footprint. Luckily, today’s manufacturers offer lines of ergonomically friendly designs that maximize controlled area design.

Vertically adjustable systems typically provide up to 30 inches of counterbalanced repositioning with rotational articulation. They can be attached to a wall, floor post, ceiling, or machine top.
Console systems are designed to provide improved process visibility.
In-wall stations fit into the confines of a shallow wall, minimizing the protrusion in to the controlled environment. Front door access permits interior access to internal components without compromising the wall seal.
On-wall stations mount directly to the wall via tabs or holes in the rear of the enclosure. They are suited for controlled areas where space is at a premium.
Mobile systems allow operators to bring the interface to the process, eliminating the need for multiple fixed stations. Mobile systems are suited for bulk product, batch pre-weigh or quality assurance applications, and they usually are outfitted with integrated weight scales, bar code scanners, and label printers.

Vertically adjustable operator interfaces offer a solid ergonomic solution, particularly when the operator is required to spend long periods of time at the interface. This configuration allows for easy adjustment between different-sized operators and precise positioning of the display. These interfaces also allow an operator to use the display for setup and subsequent repositioning up and out of the way during operations.
DON’T OVERLOOK COMPONENTS
Tools such as the touch screens, keyboards, and pointer devices are of great importance when designing operator interfaces, too.
Touch screens: Although touch screens are not used in all industrial applications, studies have shown that they are beneficial to operators. When under high levels of stress, some operators have difficulty using a mouse to find and click an icon on the desktop. Those same operators may have less trouble using their finger on a touch screen. The result is more touch screens appearing in high-security and high-stress controlled environment applications.
Touch screens also are the best choices for operator interfaces in hazardous areas. The most popular touch screen technologies include resistive, infrared, and SAW (surface acoustic wave).
Keyboards: A variety of different keyboards are available for operator interfaces. The best devices are built rugged to withstand harsh environments. For example, desktop keyboards may come in corrosion-resistant stainless steel or a durable ABS polycarbonate casing. Membrane mechanical keyswitch keyboards are completely sealed and easily cleaned, making them the preferred choice for harsh chemical environments.
Pointer Devices: A vast number of pointer options are also available for controlled areas. These include trackballs, glide pads, and stainless steel mice. The stainless steel mouse is a recent industrial innovation, and is NEMA 4X rated. The use of an industrial mouse provides operators with a familiar pointing device, which can improve comfort and efficiency.
Finding an operator interface system that considers all of these factors for multiple operators can be a tall order. Changes in controlled environment technology and a better understanding of ergonomics are changing operator interface systems. With more ergonomic systems and components available to industrial consumers, control room designers and engineers will be able to more realistically assess how operators work at their workstations and outfit them with the best systems to increase their comfort and productivity.
Bill Fleming has served STRONGARM, Inc. since 2001. His expertise is built on a 20-year career serving the manufacturing needs of pharmaceutical and other process companies. Fleming is a member of the International Society for Pharmaceutical Engineering. www.strongarm.com

Achieving True EH&S In Controlled Environments

2011-01-16T01:35:00.001-08:00

Matt Kopecky

What most organizations require is corporate-level, stringent process control.
Beyond the perennial concerns of profitability and competitive advantage, life science organizations have a number of responsibilities to carefully consider each day. Particularly in the area of environmental health and safety (EH&S), organizations must ensure the safety of their workers and test subjects, protect the community and environment from any hazards associated with production or development, adhere to governmental safety regulations, and maintain the integrity of their corporate brand. The complex manufacturing processes organizations have are designed to control the working environment to ensure quality production, high productivity yield, safety, compliance, and overall efficiency. However, sometimes the processes themselves are not flexible enough to guarantee these results.
Given these seemingly contradictory requirements, software vendors are developing solutions to address these issues. Today, there are modularbased software products on the market that promise to provide organizations with this level of support. However, these products often operate within the global organization as isolated, non-integrated technical systems that do little in terms of corporate centralization and process harmonization. Such programs fall short in perhaps the most critical element of EH&S. They fail to provide a holistic, macro view inside the inner-workings of the business to help ensure internal and external standards adherence.
This article will explore the myriad of business challenges manufacturers face, as well as current solutions many of them use today in an attempt to meet requirements. This piece will then discuss the adverse impact these ill-equipped “quality control” systems can have on the organization and what programs are available today to satisfy these complex requirements while maintaining a profitable, viable business and corporate image.
SAFETY CHALLENGES
Life sciences companies are at the forefront of advanced research and development and regularly work with new chemicals, processes, and manufacturing methods. These green-field approaches often lead to new discoveries that can offer a profound benefit to the world. Still, these innovative discoveries do also come with a certain amount of risk — i.e., potential harm to those performing these tests and the subjects of those experiments, as well as public safety in terms of potential environmental hazard. When a manufacturer identifies a weakness in the area of equipment, process, or chemical testing, it is imperative that the problem stops there before causing further damage. A centralized EH&S quality management system can help stop these potentially damaging developments in their tracks, across the organization. In turn, this will minimize the negative impact on all internal and external constituents.
For example, imagine if a clinical technician found a breakdown in a critical testing process in a cleanroom, and was unable to efficiently and effectively communicate this to his or her counterparts across the global life sciences organization. Unfortunately, this happens all the time. When such a problem occurs, the department affected is only equipped with the communication and safety documentation equipment necessary to inform those within earshot. Those employees working in similar facilities and testing environments across the world would never get the benefit of receiving the same critical information. It is quite easy to see how such a safety and drugdevelopment integrity problem could then propagate throughout a large, international company posing serious risks to all involved.
ENVIRONMENTAL/COMMUNITY HAZARD
Life sciences organizations work with dangerous materials on a daily basis and have strict policies and procedures with which to dispose of such waste safely. Nevertheless, sometimes the risks posed by these dangerous elements lie beyond the control of those tasked with handling them safely. Take for example a drug development services company that was using poorly constructed protective packaging to transport highly sensitive drug samples from one location to another. Workers noticed infiltration during transport that would compromise the viability of the sample. If this problem was not caught in time, the implications to a large study could be very serious causing delays, increased costs, and perhaps safety concerns. Now imagine this exact same process, under these very same conditions, was taking place across the company’s 36 other global facilities simultaneously — unbeknownst to those working closely with it. It is easy to see how problematic such a situation could become if not handled efficiently and properly in a centralized and standardized manner.
If this organization had an integrated environmental health and safety management system that consolidated and shared all such reporting across the company in a streamlined, centralized fashion, any problem could be reported, shared, prevented, and corrected before it ever becomes a widespread disaster. Without such a system, this type of problem could have a negative impact that could easily spiral out of control.
REGULATORY COMPLIANCE
In these high-risk industries, governmental regulatory compliance and reporting is a business imperative that cannot be left to manual processes and paper-based reminder mechanisms. These governmental checks and balances are put in place to ensure overall health and safety. In the U.S., agencies such as OSHA, EPA, and FDA require life sciences companies to document and report on all safety matters to ensure proper corrective and preventative action is taken.
If a firm neglects to update and file its air and wastewater permits, its leak detection and repair (LDAR) documentation, or its OSHA Form 300A (Summary of Work-Related Injuries and Illnesses), it leaves itself vulnerable to hefty penalties and could put its own staff and customers at risk for injury or death.
Centralization of such procedures and documentation management helps organizations remain diligent on all these matters. Without a central system, permits may not be filed on time, reports may not be submitted, forms may not be completed, and a company could be in violation of one or more safety regulations. Manufacturing organizations and their constituents cannot afford such neglect. A standardized, comprehensive EH&S system can provide businesses the protection they need to remain compliant, safe, and in control of critical matters.
BRAND INTEGRITY
Large, public organizations are under tremendous scrutiny to perform well these days—perhaps more than ever before. While safety performance and compliance can affect an organization’s financial results, anything negative that occurs in the safety area can put an organization’s brand reputation in jeopardy. This can have a serious, detrimental impact on its overall financial performance—not to mention the negative PR impact.
Chemical spills, soil, water, or air contamination that affect public safety can cripple a business’ integrity in the eyes of its stakeholders. The key to containing the negative impact on all parties is to manage these events early on at a company-wide level that is designed to stop a problem before it has an enterprise-wide domino effect.
A properly designed and configured, centralized, and integrated EH&S system provides organizations with a superior level of both regulatory compliance and brand/image protection. If such a mechanism is not in place, when incidents occur, they can snowball and adversely impact an entire organization. In serious, high profile cases these events can be severe enough in the eyes of the public and Wall Street to impact a business’ ability to raise capital, conclude business partnerships, expand market dominance, and could significantly affect shareholder value.
INTEGRATED, HOLISTIC, AND CENTRALIZED EH&S SYSTEMS
Centralized and integrated enterprise software systems are currently available on the market that can address these challenges. Their ability to harmonize, standardize, and enable corporate-level communication, visibility, and operational transparency is what makes them so effective. These same systems in turn also drive other bottom-line performance enhancements within the organization in terms of efficiency, cost reduction, process improvement, product quality, risk mitigation, and so much more.
Here is how these types of centralized systems work: The software system is installed at an enterprise level with certain corporate-wide rules and policies that are mandated across the business. At the departmental or geographic level, teams are able to customize the software to best fit their needs, while adhering closely to all corporate compliance requirements. This gives each office or department the ability to interact with the software in a way that makes the most sense for their specific business requirements and workflow demands while not interfering with company-wide regulations.
Since all relevant activities are entered into a single, integrated system, the organization is given both micro-level visibility down to small, day to day operations in any area of the business as well as macrolevel reporting and data aggregation to see the collective impact of such dispersed events.
Specifically, such systems afford a business the following types of benefits, and more:

Globalized harmonization around a common philosophy, approach, and goals
Standardized definitions and processes at the corporate and business level
Flexibility for site level variations
Automated workflow, reporting, and event tracking
Accountability assigning and tracking

The inclusive and automated enterprise software systems discussed in this article proactively deal with events that could negatively impact an organization in a diligent, accountable way while also working to make continuous environmental health and safety improvements that prevent such problems from ever occurring.
In the end, what matters most in the world of safety and security is that everything possible is being done to ensure overall well-being of all parties involved. When even the slightest preventable oversight or issue occurs, business reputation and even individual lives may be at risk. Organizations need to examine their global safety tracking and reporting systems frequently and make sure they are meeting current organization needs and regulatory requirements.
Matthew Kopecky is Product Manager at Sparta Systems, Inc. Mr. Kopecky held numerous analyst and development positions at Johnson & Johnson Corporate before joining Sparta Systems in 2004. Mr. Kopecky spent his first years at Sparta implementing TrackWise systems at life sciences organizations as a Product Specialist and has been a key contributor and manager with the company’s Solutions Architecture team. www.sparta-systems.com

Controlled Environments in Canada

2011-01-16T01:33:00.003-08:00

Rob Nightingale

Government initiatives provide leadership and other benefits to the pharmaceutical and biotech industries.
Canada is a rather unique country. It draws its cultural and demographic experiences primarily from Western Europe and the United States, though in recent years the influence of Asia has also been prominent. As a result, Canada has tended to be less ideologically conservative than the United States, to the extent that some might claim socialist leanings. Regardless, Canadian governments take an active role in industry and are not usually as laissez-faire as its southern neighbors.
From a cleanroom or controlled environment perspective, the Federal and Provincial Governments both operate cleanrooms and promote technology based industries that dominate these environments. Both levels of government have continued to support research and development that promotes high technology discoveries and the resulting employment spin-offs. This support is multi-faceted, and can be either passive, including tax incentives for research and development, or hands-on, including both federally or provincially operated cleanrooms.
GOVERNMENTAL SUPPORT
The passive governmental support in Canada can also be divided into either federal or provincial factions, and as a result the methods dif differ substantially. On the federal level, government has enacted and supports industry-specific groups through Industry Canada, a division of the Ministry of Industry. Some of the groups promoted include Biote Canada, a portal to disseminate biotech news, financing, and technology transfer. Similarly, Industry Canada has also created the Life Sciences Trade Network. It provides information about target markets, intelligence about business opportunities, including assistance in trade fairs and missions in addition to other matchmaking events. In real terms, this consists of promotion and technical assistance at trade fairs such as BIO 2009, which will be held at the Georgia World Congress Centre in Atlanta, GA and is billed as the world’s largest, global biotechnology conference, and at MEDICA in Düsseldorf, Germany, representing Canada’s medical device manufacturing sector.
The federal government has also lead with progressive patent legislation and protection that has garnered growth for both major and smaller pharmaceutical manufacturers. These firms are supported through a government encouraged association called Canada’s Research-Based Pharmaceutical Companies (Rx&D), which is a national association representing over 50 research-based pharmaceutical companies in Canada. So as not to promote favoritism, the federal government also supports the Canadian Generic Pharmaceutical Association (CGPA). CGPA represents manufacturers and distributors of finished generic pharmaceutical products, manufacturers, and distributors of active pharmaceutical chemicals, and suppliers of other goods and services to the generic pharmaceutical industry.
TAX INCENTIVES
One of the most passive means used by the Canadian Government to support high technology based industries is through what are known as ITC tax credits, which are handed out through the Scientific Research and Experimental Development (SR&ED) Tax Credit Program. The SR&ED tax credit is an ongoing program that essentially allows a company to do experimental research, and deduct the hard and soft costs (capital equipment and overhead) from their annual corporate taxes, in addition to other capital expenditure write downs. The program is run through Revenue Canada, the equivalent of the IRS, and is audited by both financial and scientific officers to ensure authenticity of the research and tax claims. In 2007, the SR&ED tax program financed over C$6 billion in private sector research, or approximately 38% of Canada’s private sector research and development, according to Industry Canada findings. Approximately C$3.8 billion of the R&D investment included industries that use cleanrooms and controlled environments for their R&D and manufacturing processes. Provincial governments also support this tax, which allows a provincial tax benefit as well.
PROVINCIAL SUPPORT
Provincial support for cleanroom related industries has also taken an indirect and direct approach. They have supported private initiatives in life sciences, biotech, and nanotechnologies through provincial agencies such as Investissement Québec which provides a range of services including liaison to venture capital. In Ontario, through the Ministry of Economic Development and Trade, the provincial government has provided a range of resources including direct investment, as was the case this past year with an investment of C$10 million in Bioniche Life Sciences’s expansion of its Belleville, Ontario facility for a state-of-the-art vaccine manufacturing plant. Other provinces have demonstrated similar initiatives to promote life sciences and biotech among other critical manufacturing and R&D programs.
GOVERNMENT-OPERATED CLEANROOMS
The Canadian government also manages cleanrooms. Through the federally funded National Research Council, several cleanrooms provide research and technology development for programs such as the NRC-IMI Functional Nanomaterials group and the NRC Industrial Materials Institute, whose principal applications are dental and orthopedic implants as well as the production of medical device components. A unique federal-provincial collaboration has brought about the National Institute for Nanotechnology (NINT) in Edmonton, Alberta. The $52.2 million facility is designed to provide the optimal conditions for nano-scale research and to foster collaboration between researchers. The NINT facility has specialized spaces that include laboratories for chemical and biochemical synthesis and analysis of the material structure at the atomic scale; and a Class 1000 cleanroom for the production of nano-structured systems. The Government of Alberta provided $40 million for the building as a part of their commitment to the NINT initiative.
One of the lesser known government- run cleanrooms in Canada is the National Microbiology Laboratory (NML), located in the Canadian Science Centre for Human and Animal Health in Winnipeg, Manitoba. This modern state-of-the-art facility houses the NML’s Biological Safety Level 4 (BSL-4) containment laboratory, currently Canada’s only BSL-4 laboratory. As a maximum containment facility, the NML deals with the most serious human and animal pathogens and diseases, such as SARS, Ebola, and Lassa fever.
It is difficult to assess the benefits of the combined passive and active leadership of the Canadian governments in the area of controlled environments. Clearly, the passive means has lead to greater research and development spending, and a growing pharmaceutical and biotech industrial infrastructure, though some might contend that this has failed to spur growth in microelectronics related manufacturing. As for active participation, much of the same could be said, though there seems to be some glimmers in the fabrication of MEMS and CCD devices and new start-ups that are using the government initiatives to fund and assist in their development.
So what’s doing in Canada? Just keep looking for this column to find out.
Rob Nightingale is Director of Research and Development, Ameripride Services Inc., and Canadian Linen and Uniform Services, CleanStyle Cleanroom Division. He has 20 years of experience in human source contamination and cleanroom apparel processing, as founder and President of Cleanroom Garments™, with multiple cleanrooms supporting a vast array of cleanroom applications from aseptic fill operations, aerospace, and MEMS fabrication, to automotive paint spray operations. He is also a co-owner of several international patents for cleanroom soil removal processes. He holds bachelor and masters degrees in international relations from The University of Windsor, Canada, and is also a senior member of the Institute of Environmental Sciences and Technology.

Green Cleaning

2011-01-16T01:32:00.000-08:00

Barbara Kanegsberg

Green, environmentally-preferred, sustainable, biobased, safe — the terms are sometimes used interchangeably. However, their meaning and interpretation really depend on one’s viewpoint.
The following thoughts on green cleaning represent my viewpoint. I did, after all, volunteer to write this article; and, at this point I have been involved in precision and industrial cleaning activities for decades.
GREEN EVOLUTION
My own view of green cleaning has evolved; and will no doubt continue to change. About a generation ago, I became involved in (“was coerced into” might be a more apt description) industrial and precision cleaning as a consequence of the move away from ozone depleting chemicals, specifically CFC-113 (chlorofluorocarbon 113, popularly known under the trade names Freon or Genesolv) and TCA (1,1,1- trichloroethane). Both were considered relatively benign to workers; they were inexpensive, plentiful, and widely used in industry. Unfortunately, given their molecular stability, they reach the stratosphere, releasing chlorine free radicals that destroy the protective ozone layer.
Both were phased out of production under the Montreal Protocol; the phase-out presented an acute problem for industry. Typical precision or critical cleaning processes were straightforward; processes depended on repeated spraying, ultrasonic cleaning, and vapor phase degreasing with CFC-113 and/or TCA. Perhaps a bit of isopropyl alcohol might be used; a final rinse/drying step in acetone was popular. Aqueous cleaning was often consigned to industrial, rather than critical, cleaning applications.
As the availability of CFC-113 and TCA decreased and the costs increased, a wide variety of aqueous and solvent based cleaning chemistries became available. So-called “non-chemical” cleaning such as CO₂ snow and plasma cleaning were considered. It gradually dawned on many in manufacturing that cleaning is not a chemical, it is a process. In electronics, water-washable and so-called “no-clean” fluxes were introduced. Cleaning processes were tested and validated; crucial customer requirements were met; irrelevant customer requirements were negotiated away. The manufacturing world did not wither and die; it thrived.
IT’S NOT EASY BEING GREEN
We helped to protect the ozone layer. In fact, the U.S. EPA “Stratospheric Ozone Protection” award is proudly displayed in my office. Protecting the ozone layer, while necessary, was not sufficient. The concept of green still eludes us. The stakes are higher; the pathway to success is more complex.
Many of the chemicals that were initially instituted as replacements for ozone-depleters have themselves come under fire by safety and/or environmental regulatory agencies. We protected the stratospheric ozone layer, but often adopted substitutes that impact tropo - spheric (smog producing) ozone. Aqueous processes were adopted; but the impact of waste streams were either not understood or not adequately dealt with. As more studies were performed, issues of worker safety and neighborhood safety increased. With increasing regulatory scrutiny and given the costs to develop new cleaning chemistries, finding appropriate cleaning agents has become a challenge.
Environmental and worker safety regulations are becoming increasingly stringent. The “regulatory distress” of a given cleaning agent depends on a complex blend of local, regional, and national regulations. A given chemical may be either favored or essentially banned, depending on where you alight on this planet. Effective cleaning agents that can be readily adopted are decreasing, and may be sitespecific.
At the same time, manufacturers are faced with increasingly tough performance requirements. Mini - ature and micro-components as well as nano-based products all involve surfaces with exacting qualities and properties. Critical or precision cleaning activities have increased.
Perhaps in response to this complexity, there is a growing trend in some regulatory and industrial groups toward a more holistic view. The concept of cleaning operations that utilize principles of pollution prevention has been supplanted by the concept of sustainable cleaning processes. The concept of “cradle to cradle” is supplanting that of “cradle to grave” to describe manufacturing operations.
MEETING THE REGULATIONS
The reality is that the “command and control” regulatory approach is still the norm. Given limited technical and economic resources, many companies struggle to understand, interpret, and meet a complex and perhaps conflicting set of safety and environmental regulations.
Certainly, meeting or exceeding the regulations is necessary, but it is not sufficient.
The regulations are complex and ever-changing. A company may adopt what appears to be a sustainable, environmentally-preferred cleaning process, only to discover within a few years that their efforts are insufficient or even counterproductive.
VOCS
For many manufacturers, green cleaning has become using a specific chemical or group of cleaning agents, or avoiding a specific chemical or group of chemicals. For example, some manufacturers have adopted all aqueous processes; or they use acetone or some other VOC-exempt compound extensively.
Acetone?
Volatile Organic Compounds (VOCs) produce smog; but not all VOCs are created equal. While acetone has been declared “VOC-exempt” at the Federal level,¹ the exemption does not mean that acetone does not contribute to smog. It does, but at a rate below a threshold set by the EPA.
As a result of the exemption, acetone has been adopted extensively in areas of poor air quality. In terms of air pollution, in some locales it is treated essentially like water, so people use a great deal of acetone. Aside from issues of materials compatibility and flammability, this means that a great deal of acetone is emitted to the air. It is, in a way, like a reduced, but not zero, calorie cookie. If you eat enough of them, you can still gain weight. Emit enough acetone, and you still produce smog. Given the lack of availability of other VOC exempt options that are cost effective, reasonably aggressive, and volatile, my colleagues and I have observed significant increases in acetone use in cleaning.
Other approaches to VOC reduction
Other scenarios might reduce the current dependence on acetone for cleaning. All have pros and cons. Using smaller amounts of non-exempt VOCs may result in more effective cleaning, with less solvent usage, and less smog production. However, many local regulatory agencies take a dim view of this approach, preferring to show decreases in the amount of VOCs in their area. That is, reduction in the inventory of VOCs is used as a measure of how well the agencies themselves are doing.
Another possibility is to foster aqueous cleaning agents, with the VOC content “as applied” below a certain limit; this approach has been used in Southern California. In some areas and applications, the vapor pressure of the cleaning agent is considered. Not all agencies find this to be appropriate, preferring to effectively expunge non-exempt organic compounds from the list of options for industry.
Alternatively, there is the concept of relative reactivity, ² where the inherent smog-producing potential of all organic compounds is considered, whether or not these chemicals are in aqueous-based or solvent-based process materials or cleaning agents. There are some moves toward adopting relative reactivity, particularly in California. At the same time, there is some concern, particularly among formulators, that using relative reactivity might result in a recordkeeping quagmire. With the proliferation of spreadsheets and related programs others see those concerns as perhaps less relevant than, say ten years ago. And, there could be an option for suppliers to use either the VOC/exempt approach (an either/or, “line in the sand” approach), or to use the more detailed relative reactivity approach.
The bottom line is that perhaps inventive approaches to how government looks at VOCs could result in greener, more sustainable, and more productive cleaning processes.
TOXICITY
Cleaning chemicals have a specific job to do — to break chemical bonds that cause soils to adhere. Since many or most soils are organic, chemicals that are effective for cleaning can interact negatively with biological entities like people. It is therefore, no surprise that many of the most effective cleaning chemistries have toxicity.
One solution, adopted or favored by many regula - tory agencies, is to ban or severely restrict the use of many toxic chemicals. This can have, however, an analogous effect as the use of acetone to reduce VOCs. That is, manufacturers might be driven to use more of a less toxic material when the smaller amount of the toxic, appropriately contained, would be both cost effective and minimize the environmental footprint. The key phrase is “appropriately contained.” There are many ef fective containment processes, with controls, to allow usage with low risk to nearby workers or the community.
LOWERING THE ENVIRONMENTAL FOOTPRINT OF THE CLEANING PROCESS
So how do you do green cleaning? What follows are a few of my own suggestions that may lower the environmental footprint of your cleaning process and move the operation toward green, sustainable cleaning.
Do less cleaning
By this, I do not mean to promote leaving undesirable residue on the component. Quite the contrary. Time invested in planning the product and planning the assembly process can yield benefits in decreased need for cleaning.
Product design
In designing new products, it is typical to consider such factors as perfor mance, cost, miniaturization, and the nature of materials of construction. Historically, the ability to assemble the product and to avoid surface contamination has not been high on the list of requirements. I find it encouraging that designers are now asking to be educated in precision cleaning, contamination control, and surface quality. Designers are collaborating with those who will actually fabricate the product. They are learning about the physical and chemical properties and limitations of aqueous and solvent cleaning agents.
Companies with the goal of using water-based cleaning agents exclusively would do well to consider that the surface tension of aqueous cleaning agents limits the spacing of components, the population density of electronics assemblies. Aqueous cleaning agents have to be rinsed with water, so the surface tension of water has to be factored in. Coordinate the product design with the anticipated cleaning process. A process may be environmentally-preferred. However, an inefficient, inef fective cleaning process is not good for the environment; it is not good for product quality; it is not good for the bottom line.
What if the product has a configuration that makes aqueous cleaning impractical? I think it is prudent to understand this at the design stage and to factor in the cleaning equipment and environmental controls as part of the initial design review.
Greener soils and cleaning agents
A processing agent that is essential at a given point in the fabrication process eventually has to be treated as soil, or matter out of place. It needs to be removed to achieve a low-residue surface. It stands to reason that soils that are more readily-removed tend to be greener, in the sense that cleaning steps may be reduced or eliminated. The replacement of rosin flux with “noclean” or low-residue fluxes is an historical example of substituting a soil that decreased the need for defluxing (i.e. cleaning) of electronics assemblies. Certain solder fluxes leave a tolerable level of residue for many applications. For some applications, water or water with low level of additives is used to decrease the level of even the “no-clean” flux residue. Further, with increased miniaturization and higher performance expectations, critical cleaning of electronics assemblies is again becoming a fact of life. In such cases, green cleaning means designing and controlling processes in an effective manner.
Moving to water soluble metalworking fluids decreases the amount of cleaning — or not. While water soluble lubricants are inherently more readily removed by water, issues may arise as a result of machining in that the heat and forces involved in the machining process can change the metalworking fluid into something that is not readily soluble in water.
Biobased cleaning agents are being promoted as a green approach to cleaning chemicals. Biobased agents are derived from plants and are sustainable resources. However, it should be noted that the word “biobased” is not a synonym for “effective.” Some biobased agents are effective in a number of cleaning applications. However, they are primarily large molecules that can leave residues unless thoroughly rinsed. In addition, many biobased processes are VOCs. Further, the fact that a chemical is derived from a natural source, the fact that it may have been used at limited concentration for decades without apparent harm to the worker or the environment does mean we are “out of the woods” in terms of toxicity. Toxicity studies are important even for biobased materials. When plantderived chemicals are concentrated and then used in cleaning processes along with heat and force, we have to consider such issues as worker exposure, community exposure, and waste stream management. We have to consider impact on the local and global environment.
Green and document the supply chain cleaning processes
Assure that your suppliers clean the component or sub-assembly promptly. Prompt and effective cleaning by your suppliers minimizes adherent residue.³ With proper testing and documentation, you may be able to eliminate cleaning steps.
Requiring that your suppliers document the cleaning processes and demonstrate effectiveness of the processes can help green your own facility; and, based on experience, it will help you to produce a better quality product, decrease failures, and ultimately will save your company money.
There is a proviso. It is tempting for manufacturers of critical product for applications like medical devices or aerospace components to specify a level of cleanliness achievable only by using very aggressive and heavily-regulated chemicals. While such chemicals can be used in a non-emissive manner with minimal impact on employees, some smaller operations may not be in a position to invest in the appropriate cleaning systems. In my opinion, you are not being green if you require your suppliers to be irresponsible to their workers, their neighbors, or the environment. Instead, require that your suppliers and sub-vendors document that cleaning processes meet or exceed environmental and safety regulations.
IN-HOUSE CLEANING PROCESSES
Worker safety, local environmental concerns, and global environmental concerns
Green is not the same as safe. Initiatives involving worker safety and “green” chemistry may actually be at odds with each other. A chemical may be relatively benign in terms of the impact on the individual worker, but may have a long atmospheric lifetime, and therefore endanger the planet. As recent history illustrates, chemicals that do not impact stratospheric ozone (upper ozone, good ozone) may increase tropospheric ozone or smog, and vice versa.
You have to obey all applicable safety and environmental regulations, and this can be a challenge because regulations may impel you in conflicting directions. In addition, by corporate policy, you may be restricted to certain cleaning agents.
Consider the cleaning process, not just the cleaning agent
Based on my experience, you cannot be green and you cannot assure the safety of the worker based on selecting a supposedly safe and/or green cleaning agent.
You have to consider the process, the way the cleaning agent is used. Concentration, temperature, time, mechanical force, all contribute to the overall safety and environmental preferability of the process. Consider rinse steps, water usage, product rework rate. A supposedly green cleaning process that puts a high proportion of your product in the landfill may not be green for your purposes.
Put your cleaning process on a diet
To me, being truly green means minimizing the impact of your process on workers and on the environment. This does not mean re-using cleaning agents in a way that could potentially contaminate the product. However, consider such approaches as:

water conservation, recycling, and closed-loop processes
solvent conservation, in-process recycling, on-site recycling
well-contained systems
energy use reduction
design processes for containment
consider efficacy of cleaning

We have published or presented case studies illustrating the environmental, economic, quality, and worker safety benefits associated with containing the cleaning process.⁴ Reduction in energy usage, as it applies to cleaning and manufacturing processes, has great potential, particularly in the design of cleaning process equipment.⁵
Lean and Green
Lean cleaning ought to include green cleaning. Particularly in the current competitive and intense economic climate, the reality is that an inefficient, ineffective green cleaning process will not be widely adopted. It probably should not be adopted, not in any economic climate. Ideally, green and lean ought to be interchangeable; and at least some regulatory agencies are highlighting the connection. The EPA, in fact, offers “The Lean and Environment Toolkit.”⁶ In addition, the EPA Partnership Programs⁷ provide ways for firms, organizations, and individuals to team with the EPA to foster Green or Sustainable efforts. Most people are familiar with the “Energy Star” program due to home appliances with the label “Energy Star.” There are many more partnership programs, including “Labs21,” “Green Engineering,” and “Design for the Environment.”
Whether or not your company chooses to partner with a regulatory agency, the concept of lean and green cleaning should not be ignored.
GREEN REFLECTIONS
The concept of green cleaning will continue to evolve. Regulators explain what you have to do; and perhaps they provide guidelines as well. Because regulations will evolve, sometimes in a conflicting manner, the most reasonable approach to insulating against changing regulations is to adopt flexible processes, processes typically not dependent on a single cleaning agent. Characterizing and validating the cleaning processes and documenting acceptable residue levels will also help in coping with the need for the seemingly inevitable periodic process change, the change in response to the new regulations.
I have focused on only a few aspects of what “green cleaning” is or perhaps ought to be. Some of the many additional aspects of green cleaning include:

minimizing the compounds with long atmospheric lifetimes
replacing current ozone depleting compounds
optimizing the energy efficiency of the cleaning process
minimizing water usage
assessing environmental persistence in soil, water

In addition, those in manufacturing, those who develop and more importantly utilize cleaning technologies have every business, every responsibility, to provide input and guidance to help green cleaning evolve.
In my view, green cleaning is not about a green chemical. Any effective chemical, including a biobased chemical, is likely to have some sort of environmental or safety baggage. While many might argue the point, there are no ultimate green chemicals, any more than there are any “ultimate foods,” foods that alone contribute to health and happiness. (OK, perhaps dark chocolate is an exception.) Most cleaning chemicals can be used safely and with respect for the environment, under appropriate conditions.
Perhaps green cleaning will become more about the cleaning process, more about incorporating industrial cleaning, precision cleaning, critical cleaning — whatever we want to call it — into the overall manufacturing process. For the manufacturer, in determining green cleaning, it is critical to factor in worker safety, efficiency, process costs, and product quality. Green cleaning is a goal we will probably reach asymptotically, and I suspect that green cleaning may ultimately merge with lean manufacturing.
The author thanks Ed Kanegsberg for his critique and comments.
REFERENCES

EPA Exclusion of Acetone as VOC: www.epa.gov/EPA-AIR/1995/June/Day-16/ pr-752.html
Carter, William P. L., “Development of Ozone Reactivity Scales for Volatile Organic Compounds,” J. Air & Waste Manage. Assoc., 44: 881–899, (1994).
“Lean Cleaning with Your Global Supply Chain,” National Manufacturing Week, Half Day Workshop, September 24, 2007, Rosemont, IL.
“Case Study: Cleaning Process Prior to PVD of Critical Metal Substrates,” Bob Dowell, Plasma Technology; Steve Norris, Plasma Technology; Jim Unmack, Unmack Corporation; and Barbara Kanegsberg, BFK Solutions, Presentation and Proceedings, CleanTech03, Chicago, Il, March 2003
“Costs of Cleaning,” prepared for University of Massachusetts Lowell, Toxics Use Reduction Institute, presentation, CleanTech 2001, Rosemont, IL, May 2001.
“The Lean and Environment Toolkit,” EPA, www.epa.gov/lean/toolkit/index.htm
The EPA gateway for Partnerships Programs: www.epa.gov/partners

Barbara Kanegsberg, BFK Solutions, LLC, is a recognized independent consultant in critical cleaning, contamination control, and surface quality. “The cleaning lady” helps industry achieve high performance and cost effective processes that meet or exceed environmental and worker safety standards. Reach her at Barbara@bfksolutions.com.

Extending the Operational Excellence Paradigm

2011-01-16T01:30:00.003-08:00

Bikash Chatterjee

There can be no mistaking that we are entering a new era in the pharmaceutical and biotech marketplace. The escalation of the pharmaceutical emerging markets in India, China, and the remaining BRICK nations has changed the landscape from both a strategic and tactical perspective. It has even spawned its own buzz word, called the “Pharmerging” markets. The progression of these markets has put unmistakable pressure on pharmaceutical companies to reinvent the way they think about product development, clinical efficiency, and manufacturing performance.
In response, the established markets in the U.S. and Europe have embraced the principles of Operational Excellence as a catalyst for change. Big pharma has taken up the basic principles of Lean Manufacturing and Six Sigma as frameworks for driving business performance, with tangible results. While wholesale transformation may take decades to accomplish, public pressure together with market pressure from these Pharmerging markets are hastening the transformation, spawning a “survival of the fittest” business environment. While many large pharma organizations explore the potential for leveraging the low cost intellectual horsepower and low labor cost the Pharmerging markets promise, they have chosen to move forward cautiously in part due to their perceived difficulty in adopting the U.S. and European concepts of cGMP and also the risk exposure from quality management systems which are still maturing.
The question remains, is it possible to extend the benefits of operational excellence and its subsequent heightened business performance, to the principles of sustainability in this current competitive marketplace? I believe it is not only possible but also in an organization’s best interest to do so.
SUSTAINABILITY
What is sustainability? Sustainability is “meeting the needs of the current generation without compromising the ability of future generations to meet their needs.”¹ While the U.S. has historically been a powerhouse from a GDP perspective, it has been notoriously inefficient in how we feed our manufacturing engines. Across industries, only 1% of all of the raw materials we use actually end up in our final products.² Similarly, if China used the same amount of oil as the U.S. per capita, it would consume the entire world’s oil capacity of 83 billion barrels in just one year.³ Simply put, sustainability is the Golden Rule applied across generations, and it is easy to see how the principles of Lean can lead us toward sustainability initiatives. Originated by Taiichi Ohno to analyze processes within the Toyota Production System, Lean principles have evolved into a development philosophy that strives to identify and eliminate waste by concentrating on what is valuable to the customer.
In his landmark book “The Machine That Changed the World,” Jim Womack describes the five basic tenets of Lean as follows:

Value

Every company needs to understand what value the customer places upon their products and services. It is this value that determines how much money the customer is willing to pay for the product and services.

The Value Stream

The value stream is the entire flow of a product’s life-cycle from the origin of the raw materials used to make the product through to the customer’s cost of using and ultimately disposing of the product. Only by a study and clear understanding of the value stream and its value-add and waste can a company truly understand the waste associated with the manufacture and delivery of a product and/or service.

Flow

One very significant key to the elimination of waste is flow. Carefully designed flow across the entire value chain will tend to minimize waste and increase value to the customer.

Pull

Use a pull approach to ensure that nothing is made ahead of time, building up work-in-process inventory that stops the synchronized flow. A pull approach states that we do not make anything until the customer orders it, in order to achieve this requires great flexibility and very short cycle times of design, production, and delivery of the products and services.

Perfection

A lean manufacturer sets his/her targets for perfection. The idea of total quality management is to systematically and continuously remove the root causes of poor quality from the production processes so that the plant and its products are moving towards perfection.
How do these basic principles align with the philosophy of sustainability? Classically, Lean principles have focused primarily on discrete, measurable short term improvements which can drive long term corporate growth, i.e. the economic organizational customer. Sustainability tends to look at the long term benefits to an organization and like Lean, stresses the lifecycle approach to improvement. The Lean mantra of eliminating waste fits sustainability initiatives perfectly. Since it is much like Lean, both in concept and in practice, sustainability can be thought of as Lean extended to a much broader objective.
DRIVING SUSTAINABILITY TRANSFORMATION
While it would be wonderful to say the nobler long term goals of greater sustainability should be sufficient to drive change, the reality is our industry requires near term tangible benefits to catalyze a change in thinking. Three tangible benefits from pursuing an organizational strategy of sustainability are:

Reduced Operating Costs
Extending the concepts of Lean in terms of eliminating waste to environmental improvement will drive down operating costs. Waste removal, energy conservation, water management all drive down operating costs. Organizations attempting to operate in Europe are often confronted with the requirement to be ISO 14001 compliant. Shifting this requirement up to the development process can multiply its effectiveness exponentially as it integrates through the product development lifecycle.
Greater Consumer Satisfaction
It is difficult to debate the high profile nature of environmental issues facing the world today. Greenhouse gases and global warming are in the news on a daily basis. Any organization that embraces and advocates the merits of its sustainability program will garner public praise and position itself, all things being equal, as a higher quality supplier of product
Risk Reduction
Investing in business performance initiatives tied to sustainability provides both a moral and financial catalyst for change. As regulations and legislation evolve, they are migrating towards to escalating standards for both safety and environmental impact. Similarly, recognizing the heightened sensitivity to sustainability issues, some insurance organizations are punishing organizations that have no active sustainability programs in place because of the potential for litigation as policies change.

SUSTAINABLE FACILITIES
With a typical useful lifetime measured in decades, facilities are one of the largest investments an organization can make. Facilities require significant capital investment well in advance of proof of clinical efficacy, and yet they typically end up being the gating activity to moving your product to market. Applying sustainability requirements to the facility planning and design exercise is the perfect opportunity for an organization to add value to the overall product development process.
Extending the identification of waste not only to the processes within the facility but to the facility’s operation as well, will result in an operation which is flexible and cost efficient.
LEVERAGING OPERATIONAL EXCELLENCE
The framework for Lean facility design has been discussed in previous articles. Within this framework many of the analytical tools from Lean can be applied to include sustainability. When combined with the milestone-based project management structure of Six Sigma, an organization’s ability to begin the transformation to sustainability is almost seamless. For example, value stream mapping can easily include environmental considerations such as power consumption, waste generated, and utility requirements. Lean Kaizen teams which focus on rapid focused improvement of a problem can apply the same definition and improvement approach to environmental issues. Integrating root cause analysis techniques such as Kepner-Tregoe and the 5 Why’s, coupled with capable measurement tools can easily facilitate the optimization activities of both the product and its byproducts.
CONCLUSION
The application of Operational Excellence principles can easily be extended to include sustainability considerations for an organization. Doing so provides a competitive edge both in terms of business performance and reducing risk from shifting legislation. The Pharmerging markets are struggling to demonstrate their ability to consistently provide product which is safe and efficacious. Compounding these challenges is the ever-increasing scrutiny from the public and regulatory bodies around the globe regarding pressing environmental issues. Any organization that embraces both the near term benefits of improved business performance derived from Operational Excellence programs such as Lean and Six Sigma will have the added advantage from the long-term strength in terms of both profitability and social responsibility a sustainability strategy can provide.
References

The definition is from the Bruntland Commission Report, United Nations, 1987.
Ayres, R.U., Technology and Environment, Washington, D.C., National Academy of Sciences, 1989.
Langenwalter, G., “Life is Our Ultimate Customer: From Lean to Sustainability,” AME, Target Vol. 22, No. 1, 2006

Bikash Chatterjee is the president of Pharmatech Associates, Inc. He has been involved in the bio-pharmaceutical, pharmaceutical, medical device and diagnostics industry for over 20 years. His expertise includes site selection, project management, design, and validation of facilities for both U.S. and European regulatory requirements.

Kathy E. Harrington Curtis L. Harrington There are a number of critical timing issues that new product introducers should consider as they attempt to capture intellectual property rights and facilitate early sales. Generally, the drivers for an overall intellectual property (IP) protection strategy for a new product are (1) the existence of the one-year Paris Convention, which allows patent applicants to file in other countries within one year of the U.S. filing date; (2) the potential to attract foreign purchasers/licensees within the first one-year period after filing to allow others to provide the investment in foreign patents and the foreign licenses; and (3) the provision of a more rapid and, hopefully, more efficient license sale of the product. The term “product” as used here includes products, services, and hybrid situations involving both. There are a number of critical timing issues that new product introducers should consider as they attempt to capture intellectual property rights and facilitate early sales. It is understood that every product may warrant multiple or other critical time considerations in addition to those listed here. This analysis also assumes that the product has been finished, that production and unit costs are known for major quantities (such that a complete profitability profile of the product is presentable), and that the resulting numbers can easily justify moving production forward regardless of any sale, given that (a) the complete profitability profile will justify it, and (b) any perceived lack of willingness to continue the project will result in a “wait and see” strategy by a potential buyer. This analysis also assumes the timely filing of a patent before any disclosure is made. TIME PERIODS The time periods to be considered are centered around the patent filing date, and include: the period preceding the filing by more than two months (Phase I); the period preceding the filing by two months or less (Phase II - this is the time, on average, which should be allowed for a patent attorney to complete drafting a patent application); and the 11-month period following the filing (Phase III - the end of which leaves only one month to file foreign before the one-year deadline for foreign filing expires). During Phase I the following tasks should be completed: 1. Completely finish the product. This includes developing different versions, such as economy and luxury models, base and fully-accessorized models, permanent and disposable models, retail sales versions and imprinted give-away versions, and home and foreign country versions (taking into account possible peculiarities of foreign environments); addressing packaging issues, including individual and bulk sales packaging, sales display designs, racks and shelving, free-standing cardboard displays, and the like; and considering type and placement of any trademark name and other information on the product and/or packaging. 2. Complete a comprehensive business plan, taking into account production costs; packaging; overhead (including, at a minimum, patent insurance, corporate entity formation costs, product liability insurance, and inventory financing); costs associated with the product pipeline; foreign and domestic production costs; cost variations based on projected sales channels such as distributors and distributor programs, direct internet sales, and contract sales to catalogs; and costs of selling or manufacturing in foreign countries, including import/export efficiencies, tariffs, sea-container packing densities, and foreign tax effects of direct marketing or sales-agent licensing, just to name a few. A comprehensive and carefully detailed business plan including the above indicators (at a minimum) is a prerequisite to determining the true value of the product. Without this level of information, the value of the product simply cannot be known. 3. Gather all information needed to promote the product. Much of the information gathered will also be useful in activities directed toward selling the product to consumers and/or selling the product and associated intellectual property rights to another manufacturer. 4. Identify competitors, customers, and related entities. The identity of persons and organizations even remotely associated with the product should be recorded, including: (a) Product-related trade associations; (b) Product-related professional associations; (c) Related government branches, elected officials, and bureaucrats, including test organizations and standard-setting groups (local, state, and federal); (d) Related trade shows (very important for Phase III activities after filing); (e) All trade-related magazines, including paid and free subscriptions, trade sales, and trade-related product publications, especially those which may carry a news story relating to the product after the patent is filed; (f) All newspapers and magazines in any way related to the applicant or product, including those associated through geography or language, for example; (g) A list of product endorsers, particularly those who might endorse without compensation, and even local elected officials, comedians, radio personalities, and other public figures. [Note that efforts (4)(a) through (4)(g) should not be limited to home country or home language. Where the product admits to use anywhere, the entire world should be considered the potential market and the information database should be expanded accordingly.] 5. Integrate information gathered in items (1) through (4) to determine which markets to enter. Using all of the above information, make a list of why the product is better than others currently available, comparing all versions of the product (both highend and basic) to the next-best alternative. This information will be used by the patent attorney in drafting the case. To begin Phase II, submit all product information, especially the information outlined in (5) above, to the patent attorney and allow two months for the patent to be completed (both first and final drafts) and filed. In Phase II, you should fully prepare (but do not disclose or transmit) all media which could possibly be used to market the product immediately after filing. Prepare every sort of media kit, including long story/short story, color/black & white photos, drawings, diagrams, or videos, in short, prepare in advance every form of media which a potential publisher might want. Your new product or invention is only born once and you might be able to pick up free advertising if a publisher runs the story as a news/interest item. This exercise will also be good preparation for any scheduled trade shows. Trade shows should be scheduled during Phase III, only after the patent is filed, yet early enough to allow sufficient time to determine what foreign filings will need to be affected prior to the foreign filing deadline (one year from the U.S. filing date). Keep in mind that every truly good, new, and nonobvious invention is a news item. Each publication that showcases the product may save a thousand dollars or more in advertising costs. During Phase II, projected plans for Phase III should be finalized and ready for execution immediately after filing so that all time spent post-filing can be exclusively devoted to promoting and selling the product. Other tasks in Phase II include: 1. Setting up a limited liability corporation or C-corp for marketing and selling the product; 2. securing a source of product to meet sales activities; 3. contacting a patent insurance carrier to complete insurance application forms necessary to put protection in place immediately after filing; 4. ensuring that the sales entity purchases commercial product liability insurance; 5. selecting and applying for a fanciful, non-descriptive trademark after the entity filing for the sales entity is complete (including the home country and all foreign countries where the product is planned to appear, and taking into account the six-month trademark treaty which enables foreign filing within six months of home country filing); 6. ensuring that the sales entity registers for an internet URL (which may be the same as the trademark) intended to be used to sell the product; and 7. setting up the HTML files offline to allow the website to go live as soon as possible after any patents are filed (utility, design, or both). The primary goal is total preparedness prior to filing the patent so that, after filing, marketing and selling can begin as quickly as possible without delay or interruption. Filing the patent is a prerequisite for beginning Phase III; absolutely no activities in Phase III should take place until it can be established with certainty that filing has occurred. It may be preferable to devote a few days after the patent filing to secure a postal or computer filing receipt or other indicia of filing in hand. Once the patent filing can be established with certainty, begin Phase III: 1. Sell the product; 2. acquire floor space at trade shows which relate to the product; 3. send out the media kits/news release items to all magazines and newspapers world-wide, making certain to provide material in as many formats as possible to meet each publication’s requirements. In addition to article length, quantity and type of photographs and, video, consider foreign language translation versions; 4. follow up by phone with the publishers to push news release items submitted in (3) above; 5. where possible, provide product samples to publishers to further interest, either on demand or in media packets submitted in (3) above; 6. contact local media to ensure that they feature the product; 7. after securing trade show space and booth number, forward media kits to likely foreign licensees, local country distributors and other entities who may be interested in purchasing the product and IP rights - follow up to schedule meetings during the show and make sure to have sufficient booth coverage so that all appointments can be accommodated; 8. set up a newsletter by e-mail and regular mail announcing the product and highlighting its progress, including distributors, publications running news stories, and any other news tidbits, even including a grant of patent insurance when it occurs (design patents will likely be examined quickly; allowance and issuance are news-worthy announcements); 9. secure product endorsers and have news conferences and events where the endorsements are formalized (formalized endorsements are also newsworthy announcements for the newsletter in item (8) above); 10. arrange to test-market the product in retail stores which will allow for a display, possibly on consignment, and carefully record the sales per unit time, and the types of products sold; 11. at the trade show, be certain to a. get the product in the “new products” pavilion, b. meet with foreign licensees, sales agents and buyers and plan to close deals within six months after the filing of the design patents and ITU trademarks to enable foreign filing with the benefit of the U.S. filing date priority (which expires after six months); and 12. generally inject sales into each and every market segment possible—the interest generated by the time the trade show takes place will depend directly upon the market acceptances earned, the gross numbers of products sold, and the positive publicity and popularity surrounding the product. Curtis L. Harrington and Kathy E. Harrington are partners in the law firm of Harrington & Harrington, which specializes in intellectual property and its taxation. Curt is located at Suite 250, 6300 State University Drive, Long Beach, CA, 90815. He may be reached by phone at (562) 594-9784, by fax at (562) 594-4414, or by e-mail at curt@patentax.com. He is admitted to practice before the state bars of CA, TX, AZ, and NV; the U.S. District Court; the U.S. Court of Appeals, Fifth and Ninth Circuits; the U.S. Supreme Court; the U.S. Patent and Trademark Office; and the IRS. He holds a B.S. in Chemistry (Auburn Univ., 1974); M.S. in Chemical Engineering (Georgia Tech, 1977); JD (Univ. Houston, 1983); MBA (Univ. Oklahoma, 1985); M.S. in Electrical Engineering (California State Univ. Long Beach, 1990); and LLM in Taxation (Univ. San Diego Law School, 1997). He is specially admitted to practice before the U.S. Patent and Trademark Office and the IRS. Curt is also certified as a Taxation Specialist by the State Bar of California Board of Legal Specialization. He has technical reading proficiency in both Russian and Japanese. Special technology areas: electrical, mechanical, and chemical. Kathy is located at 355 S. Mt. Carmel Road, McDonough, GA 30253. She may be reached by phone at (770) 914-1413, by fax at (770) 914-1496, or by e-mail at kathy@patentax.com. She is admitted to practice before the state bar of Georgia, the U.S. Tax Court, and the U.S. Patent and Trademark Office. She is a graduate of Mercer Law School and also holds a B.S. in Electrical Engineering from Georgia Tech. She holds additional undergraduate degrees in both Physics and Nursing, and is currently working toward completing her Master’s in Taxation. She is a member of the Georgia Association for Women Lawyers, in which she served as Southside Chapter President and Statewide Membership Chair in 2007/2008, and in which she currently serves as Southside Chapter Immediate Past President. She is a member of the Taxation & Intellectual Property sections of the State Bar of Georgia, the Atlanta Bar Association, the Henry County, Clayton County, and Fayette County Bar Associations, and is a student member of the Georgia Society of Certified Public Accountants. Special technology areas: electrical and mechanical.

2011-01-16T01:28:00.001-08:00

Rob Nightingale

Canada has not been immune to the economic downturn of the past year. Even so-called recession proof industries have felt the effects of the decline, including pharmaceutical manufacturing. None of the business stories in Canada have had quite the affect on the psyche of high tech and cleanroom junkies as the demise of Nortel Networks, which filed for bankruptcy protection this past January. What was once the darling of the communications industry, and the anchor of the Canadian tech sector as Bell-Northern Research, is no more. During its court protection, it shed its most valuable assets to foreign suitors, namely Nokia Siemens Networks, and is thus no longer the Canadian tech giant. Some would argue that Nortel’s loss is a fatal blow to the Canadian advanced technology sector. Others disagree and believe that new innovation will replace the older supply chain paradigm of tech sector growth — and spawn high tech start ups that will fill the void of the demised tech icons. So where is this new innovation?
One could easily point to RIM, the Waterloo, Ontario company that produces the BlackBerry® wireless device which virtually launched the era of the smart phone. Though RIM has catapulted itself onto the high technology arena, it is not the research powerhouse that Nortel once was. RIM reported 2008 R&D spending at about $685 million versus Nortel, who spent $1.85 billion in R&D in 2007. RIM has spurred development of supply chain partners and has become the cornerstone of Ontario’s high tech transformation as the province transitions from the largest concentration of automotive manufacturing in North America to a technology and knowledge-based economy. That is a tall order for a region that has lost over 200,000 manufacturing jobs over the past few years. Other tech companies that have helped to fill the void in this region include COM DEV, a global leader in the engineering and production of custom-designed space hardware, and Dalsa, manufacturers of digital imaging and machine vision CCD and CMOS products for applications such as semiconductor and industrial inspection.
In other provinces, innovation has led to not only replacing some of the traditional economic generators, but has paved the way towards a new generation of manufacturing and technology. In British Columbia, Photon Control manufactures opto-electronic products in their cleanrooms and has become a world leader in optical sensing technologies. In Alberta, Dynamic Source Manufacturing, a Calgary-based electronics manufacture, has recently been certified to ISO’s medical standard 13485:2003 to provide medical device manufacturing.
Moving east across the country, the biotech and life sciences sector has flourished in Quebec. Home to the third-highest number of biotechnology companies of any province or state in North America (after California and Massachusetts), Quebec has a total of 75 life sciences- related companies employing over 2,100 people generating revenues in excess of $480 million according to recent information from Investissement Quebec. The Province of Quebec is also a leader in life sciences and biotech research with 68% of Canada’s prescription drug patents; 42% of Canadian investment in pharmaceutical research and development; 27% of private Canadian investment in biotechnology; and 32% of Canadian subsidies for peer review medical research, according to BIOQuebec, a quasi-governmental industry relations entity.
Though the Maritime Provinces make smaller contributions to the Canadian economy, Nova Scotia employs over 1,100 people in biotech industries with annual revenues of $181 million. One of the more surprising stories comes from the Province of Saskatchewan, famous for having the world’s largest source of potash. Saskatchewan now is home to almost 60 biotech firms, with revenues of approximately $100 million, according to Conference Board of Canada data.
A recent directory of Canada’s leading emerging companies lists almost 100 new firms dedicated to innovative technologies in areas ranging from stem cell applications, life sciences, biosciences, and molecular science. During a year of shrinking commodity prices, Canada has felt the global economic chill, as a primary exporter of energy, mining, and lumber products. However, innovative change is on the horizon.
An addendum to the previous column regarding government initiatives: On May 4, 2009, the Province of Ontario announced $100 million in new research funding to stem top scientists from fleeing to U.S. laboratories that will soon be saturated in stimulus money from the Obama administration.
Rob Nightingale is Director of Research and Development, Ameripride Services Inc., and Canadian Linen and Uniform Services, CleanStyle Cleanroom Division. He has 20 years of experience in human source contamination and cleanroom apparel processing, as founder and President of Cleanroom Garments™, and is also a coowner of several international patents for cleanroom soil removal processes.

Critical New Product Development

2011-01-16T01:26:00.001-08:00

Kathy E. Harrington

Curtis L. Harrington

There are a number of critical timing issues that new product introducers should consider as they attempt to capture intellectual property rights and facilitate early sales.
Generally, the drivers for an overall intellectual property (IP) protection strategy for a new product are (1) the existence of the one-year Paris Convention, which allows patent applicants to file in other countries within one year of the U.S. filing date; (2) the potential to attract foreign purchasers/licensees within the first one-year period after filing to allow others to provide the investment in foreign patents and the foreign licenses; and (3) the provision of a more rapid and, hopefully, more efficient license sale of the product.
The term “product” as used here includes products, services, and hybrid situations involving both. There are a number of critical timing issues that new product introducers should consider as they attempt to capture intellectual property rights and facilitate early sales. It is understood that every product may warrant multiple or other critical time considerations in addition to those listed here.
This analysis also assumes that the product has been finished, that production and unit costs are known for major quantities (such that a complete profitability profile of the product is presentable), and that the resulting numbers can easily justify moving production forward regardless of any sale, given that (a) the complete profitability profile will justify it, and (b) any perceived lack of willingness to continue the project will result in a “wait and see” strategy by a potential buyer. This analysis also assumes the timely filing of a patent before any disclosure is made.
TIME PERIODS
The time periods to be considered are centered around the patent filing date, and include: the period preceding the filing by more than two months (Phase I); the period preceding the filing by two months or less (Phase II - this is the time, on average, which should be allowed for a patent attorney to complete drafting a patent application); and the 11-month period following the filing (Phase III - the end of which leaves only one month to file foreign before the one-year deadline for foreign filing expires).
During Phase I the following tasks should be completed:
1. Completely finish the product. This includes developing different versions, such as economy and luxury models, base and fully-accessorized models, permanent and disposable models, retail sales versions and imprinted give-away versions, and home and foreign country versions (taking into account possible peculiarities of foreign environments); addressing packaging issues, including individual and bulk sales packaging, sales display designs, racks and shelving, free-standing cardboard displays, and the like; and considering type and placement of any trademark name and other information on the product and/or packaging.
2. Complete a comprehensive business plan, taking into account production costs; packaging; overhead (including, at a minimum, patent insurance, corporate entity formation costs, product liability insurance, and inventory financing); costs associated with the product pipeline; foreign and domestic production costs; cost variations based on projected sales channels such as distributors and distributor programs, direct internet sales, and contract sales to catalogs; and costs of selling or manufacturing in foreign countries, including import/export efficiencies, tariffs, sea-container packing densities, and foreign tax effects of direct marketing or sales-agent licensing, just to name a few. A comprehensive and carefully detailed business plan including the above indicators (at a minimum) is a prerequisite to determining the true value of the product. Without this level of information, the value of the product simply cannot be known.
3. Gather all information needed to promote the product. Much of the information gathered will also be useful in activities directed toward selling the product to consumers and/or selling the product and associated intellectual property rights to another manufacturer.
4. Identify competitors, customers, and related entities. The identity of persons and organizations even remotely associated with the product should be recorded, including:

(a) Product-related trade associations;
(b) Product-related professional associations;
(c) Related government branches, elected officials, and bureaucrats, including test organizations and standard-setting groups (local, state, and federal);
(d) Related trade shows (very important for Phase III activities after filing);
(e) All trade-related magazines, including paid and free subscriptions, trade sales, and trade-related product publications, especially those which may carry a news story relating to the product after the patent is filed;
(f) All newspapers and magazines in any way related to the applicant or product, including those associated through geography or language, for example;
(g) A list of product endorsers, particularly those who might endorse without compensation, and even local elected officials, comedians, radio personalities, and other public figures. [Note that efforts (4)(a) through (4)(g) should not be limited to home country or home language. Where the product admits to use anywhere, the entire world should be considered the potential market and the information database should be expanded accordingly.]

5. Integrate information gathered in items (1) through (4) to determine which markets to enter. Using all of the above information, make a list of why the product is better than others currently available, comparing all versions of the product (both highend and basic) to the next-best alternative. This information will be used by the patent attorney in drafting the case.
To begin Phase II, submit all product information, especially the information outlined in (5) above, to the patent attorney and allow two months for the patent to be completed (both first and final drafts) and filed.
In Phase II, you should fully prepare (but do not disclose or transmit) all media which could possibly be used to market the product immediately after filing. Prepare every sort of media kit, including long story/short story, color/black & white photos, drawings, diagrams, or videos, in short, prepare in advance every form of media which a potential publisher might want. Your new product or invention is only born once and you might be able to pick up free advertising if a publisher runs the story as a news/interest item. This exercise will also be good preparation for any scheduled trade shows. Trade shows should be scheduled during Phase III, only after the patent is filed, yet early enough to allow sufficient time to determine what foreign filings will need to be affected prior to the foreign filing deadline (one year from the U.S. filing date).
Keep in mind that every truly good, new, and nonobvious invention is a news item. Each publication that showcases the product may save a thousand dollars or more in advertising costs. During Phase II, projected plans for Phase III should be finalized and ready for execution immediately after filing so that all time spent post-filing can be exclusively devoted to promoting and selling the product.
Other tasks in Phase II include:
1. Setting up a limited liability corporation or C-corp for marketing and selling the product;
2. securing a source of product to meet sales activities;
3. contacting a patent insurance carrier to complete insurance application forms necessary to put protection in place immediately after filing;
4. ensuring that the sales entity purchases commercial product liability insurance;
5. selecting and applying for a fanciful, non-descriptive trademark after the entity filing for the sales entity is complete (including the home country and all foreign countries where the product is planned to appear, and taking into account the six-month trademark treaty which enables foreign filing within six months of home country filing);
6. ensuring that the sales entity registers for an internet URL (which may be the same as the trademark) intended to be used to sell the product; and
7. setting up the HTML files offline to allow the website to go live as soon as possible after any patents are filed (utility, design, or both). The primary goal is total preparedness prior to filing the patent so that, after filing, marketing and selling can begin as quickly as possible without delay or interruption.
Filing the patent is a prerequisite for beginning Phase III; absolutely no activities in Phase III should take place until it can be established with certainty that filing has occurred. It may be preferable to devote a few days after the patent filing to secure a postal or computer filing receipt or other indicia of filing in hand.
Once the patent filing can be established with certainty, begin Phase III:
1. Sell the product;
2. acquire floor space at trade shows which relate to the product;
3. send out the media kits/news release items to all magazines and newspapers world-wide, making certain to provide material in as many formats as possible to meet each publication’s requirements. In addition to article length, quantity and type of photographs and, video, consider foreign language translation versions;
4. follow up by phone with the publishers to push news release items submitted in (3) above;
5. where possible, provide product samples to publishers to further interest, either on demand or in media packets submitted in (3) above;
6. contact local media to ensure that they feature the product;
7. after securing trade show space and booth number, forward media kits to likely foreign licensees, local country distributors and other entities who may be interested in purchasing the product and IP rights - follow up to schedule meetings during the show and make sure to have sufficient booth coverage so that all appointments can be accommodated;
8. set up a newsletter by e-mail and regular mail announcing the product and highlighting its progress, including distributors, publications running news stories, and any other news tidbits, even including a grant of patent insurance when it occurs (design patents will likely be examined quickly; allowance and issuance are news-worthy announcements);
9. secure product endorsers and have news conferences and events where the endorsements are formalized (formalized endorsements are also newsworthy announcements for the newsletter in item (8) above);
10. arrange to test-market the product in retail stores which will allow for a display, possibly on consignment, and carefully record the sales per unit time, and the types of products sold;
11. at the trade show, be certain to

a. get the product in the “new products” pavilion,
b. meet with foreign licensees, sales agents and buyers and plan to close deals within six months after the filing of the design patents and ITU trademarks to enable foreign filing with the benefit of the U.S. filing date priority (which expires after six months); and

12. generally inject sales into each and every market segment possible—the interest generated by the time the trade show takes place will depend directly upon the market acceptances earned, the gross numbers of products sold, and the positive publicity and popularity surrounding the product.
Curtis L. Harrington and Kathy E. Harrington are partners in the law firm of Harrington & Harrington, which specializes in intellectual property and its taxation.
Curt is located at Suite 250, 6300 State University Drive, Long Beach, CA, 90815. He may be reached by phone at (562) 594-9784, by fax at (562) 594-4414, or by e-mail at curt@patentax.com. He is admitted to practice before the state bars of CA, TX, AZ, and NV; the U.S. District Court; the U.S. Court of Appeals, Fifth and Ninth Circuits; the U.S. Supreme Court; the U.S. Patent and Trademark Office; and the IRS. He holds a B.S. in Chemistry (Auburn Univ., 1974); M.S. in Chemical Engineering (Georgia Tech, 1977); JD (Univ. Houston, 1983); MBA (Univ. Oklahoma, 1985); M.S. in Electrical Engineering (California State Univ. Long Beach, 1990); and LLM in Taxation (Univ. San Diego Law School, 1997). He is specially admitted to practice before the U.S. Patent and Trademark Office and the IRS. Curt is also certified as a Taxation Specialist by the State Bar of California Board of Legal Specialization. He has technical reading proficiency in both Russian and Japanese. Special technology areas: electrical, mechanical, and chemical.
Kathy is located at 355 S. Mt. Carmel Road, McDonough, GA 30253. She may be reached by phone at (770) 914-1413, by fax at (770) 914-1496, or by e-mail at kathy@patentax.com. She is admitted to practice before the state bar of Georgia, the U.S. Tax Court, and the U.S. Patent and Trademark Office. She is a graduate of Mercer Law School and also holds a B.S. in Electrical Engineering from Georgia Tech. She holds additional undergraduate degrees in both Physics and Nursing, and is currently working toward completing her Master’s in Taxation. She is a member of the Georgia Association for Women Lawyers, in which she served as Southside Chapter President and Statewide Membership Chair in 2007/2008, and in which she currently serves as Southside Chapter Immediate Past President. She is a member of the Taxation & Intellectual Property sections of the State Bar of Georgia, the Atlanta Bar Association, the Henry County, Clayton County, and Fayette County Bar Associations, and is a student member of the Georgia Society of Certified Public Accountants. Special technology areas: electrical and mechanical.

Sorbent Solutions Ensure Moisture Management and Product Stability

2011-01-02T03:28:00.000-08:00

Adrian Possumato

Sorbents represent a class of active packaging components that can be used to guard against the effects of degradation, ensuring the integrity of packaged pharmaceuticals and other environmentally sensitive products. The author answers some common questions and discusses the benefits of active packaging to ensure product stability.
Q: What are some of the key threats to product stability?
A: Pharmaceuticals and other products are subject to a variety of degradation pathways that compromise safety and shelf-life. By far the greatest degradation is caused by hydrolysis and oxidation. There are a number of packaging components available to help maintain product integrity; however, determining the optimal solution requires a calculated analysis drawing on diverse areas of expertise.
It’s critical when determining a degradation-prevention program that manufacturers consider the whole manufacturing and packaging process, from the pharmaceutical formulation to the packaging environment and to the distribution chain. What might work in one part of the operation may not work at another end — solutions determined upstream may have unintended consequences downstream.
When developing the optimum package protection, the best approach to take is a multidisciplinary one that considers the knowledge and experience of packaging engineers, formulation chemists, analytical chemists, and the sorbent supplier.
Q: How do companies implement moisture management into their packaging?
A: Protecting a product from degradation is a critical component of manufacturing success, and packaging considerations are key. Choosing your packaging components requires careful strategy and considering the “big picture.” The bottom line is to consider the whole spectrum of factors involved in product degradation, and every aspect of upstream and downstream processing. Calculating these factors with a modeling system, supported by a knowledgeable partner, can lead to a more shelf-stable and safer product.
Q: Can a sorbent solution be customized to meet the specific demands of customers?
A: Certainly. As part of a systems approach, every aspect of moisture control can be customized to meet the needs of a customer. Packaging solutions must consider all facets of the manufacturing and development processes.
To optimize package protection for solid-dose formulations, pharmaceutical manufacturers need to employ a technique of moisture and oxygen ingress modeling to analyze the rates of degradation for a given pharmaceutical. Chemical degradation pathways can cause a loss of pharmaceutical potency after several weeks, whereas two to three years of shelf-life may be required depending on distribution channels. Modeling also determines steady-state levels of oxygen within bottles and moisture permeation across bottle walls, and material permeability.
As far as packaging is concerned, equipment can be customized to meet the needs of several markets. For instance, the pharmaceutical industry is driven by the need for positive placement verification. As such, several levels of verification can be provided to guarantee that the sorbent has been placed properly into the bottle, package, etc.
Q: What trends do you anticipate in the future for sorbent technologies?
A: Respiratory drug delivery systems that employ dry powder inhalation (DPI) devices are a significant new trend, offering clinical benefits, dosage control, and patient convenience. Integrating sorbent technologies into DPI devices will preserve the quality and safety of pharmaceutical formulations and ensure that the device functions accurately and effectively each time it is used. Because proper desiccation is an integral part of DPI device functioning, the choice of sorbent is crucial. Packaging components that respond to changes in the head-space of packaging relative to outside conditions provide an ideal solution. They regulate humidity levels within a DPI device without making contact with the dry powder and optimize conditions for drug delivery.
A new generation of desiccants — coated solid format (CSF) sorbents — is particularly well suited for DPI applications because they significantly increase the level of functional desiccation per unit volume. Through condensed density technology, CSF sorbents are able to deliver twice the moisture protection in the same dimensional space as a typical loose-fill desiccant. CSF sorbents can be made from silica gel, activated carbon, or a combination of both.
Overall, when evaluating the desiccation requirements for inhalation devices, pharmaceutical manufacturers should consider the interactions between drug formulation, device, and packaging. They must also consider all of the sources of moisture, including the plastic from which a device is manufactured and any inserts or other components of the package. It is only once these factors are taken into consideration, that manufacturers can make the best decision regarding the most appropriate sorbent technology for DPI applications.
Adrian Possumato is the global manager,pharmaceutical market with Multisorb Technologies,Inc.(Buffalo,NY).He works closely with drug innovators and generic pharmaceutical manufacturers to determine the best selection of packaged sorbents to stabilize pharmaceutical formulations.He has over 15 years of experience in the pharmaceutical and chemical industries.He can be reached at apossumato@multisorb.com,tel.908-849-3005,fax 908-849-3006.

Manufacturing & Processing - Compliance with GMPs During Development

2011-01-02T03:25:00.001-08:00

GMPs are necessary for the manufacture of biopharmaceuticals that are administered to patients enrolled in clinical trials. Gail Sofer, director of regulatory compliance at GE Healthcare, discusses the approaches for compliance in the areas of cell banking, cell culture and downstream processing.

GMP compliance is a legal requirement in most of the world, with increased emphasis on enforcement in the last several years. But what does GMP mean for clinical trial manufacturing?

Adherence to GMPs during clinical trial material manufacturing compensates for the lack of completely fixed routines, potential risks associated with cross-contamination, incomplete knowledge of product potency and toxicity, and lack of full process validation.1 In fact, process validation may be inappropriate during clinical production.2 Emphasis is placed on personnel training, which is especially critical when operators have come from R&D labs where creativity, rather than adherence to protocols, is encouraged.

Although full process validation is not appropriate (in fact, may be impossible) during manufacturing of materials for early clinical trials (for example, phase 1 and/or 2), certain aspects related to safety must be addressed. For example, as noted in the EU document, validation of the sterilisation processes is no different than for a licensed product. This means that sterility assays must also be validated, including assays for bacteriostasis and fungistasis. Viral safety should be assured as well as removal of other potentially harmful impurities. Stringent cleaning is required to minimise cross-contamination; but as noted in a FDA draft guidance, the use of disposables in early clinical manufacturing can facilitate conformance with CGMP³ (In the USA, a C is placed before GMP. GMPs should be current. Sponsors of a biotech product are expected to employ, where feasible, state of the art methods as they apply to patient safety.) Clearly, a graded approach for the implementation of GMPs is accepted by regulatory authorities as long as potential risks to patient safety are mitigated.

Important safety aspects for clinical trial materials:

Sterility
Cross contamination by products and process intermediates
Viral safety

Unit Operations

Cell banking, cell culture, recovery, and purification steps are unit operations used in the manufacture of biotherapeutics. The impact of each unit operation on the others should be considered early in development of clinical trial materials, with special focus on patient safety issues.

Cell Banking

ICH Q5D addresses cell substrates used to produce biotechnological products. Establishment of a two-tiered cell banking system - master cell bank (MCB) and working cell bank (WCB) - is expected for licensed products, but it is realistic to have only an MCB for early clinical studies provided there is sufficient material to expand into WCBs at later stages. Since a new MCB is considered a new product, it is important at even the earliest stages to ensure the integrity, quantity and back-up storage for the MCB.

Although the scope statement in ICH Q5D states that it provides recommendations on information that should be present in market applications, cell line characterisation is an essential activity for patient safety. Not only should cell banks be tested prior to entering clinical studies, even earlier screening for bacteria and fungi, mycoplasma, and virus is advisable to prevent having to replace MCBs that are found to contain adventitious agents during the characterisation studies - an activity that will almost certainly result in the need to repeat earlier (and expensive) studies such as toxicology. It is also important to keep in mind that new assays and findings of new viruses require companies to periodically review cell substrate characterisation.

Cell Culture

In a preliminary draft guidance, the FDA noted that during phase 3/pivotal studies, the stability of cells during growth should be validated. What happens if at this late development stage the cells are found to be unstable? Some companies have tried to change culture media to stabilise the cells, but this poses other risks such as alterations in product expression level, glycosylation or other post-translational modifications, and quantity and quality of host cell proteins. In reality, companies should perform a pre-study to understand if the cells will be stable under the process conditions. Companies want to obtain maximum productivity from cell culture processes and are, therefore, almost always continuing to optimise process conditions during clinical development. This has the potential to alter endogenous retrovirus expression, host cell protein expression, product modifications, and downstream processing.

Downstream Processing

The impact of a change in cell culture on downstream processing is not always obvious. Addition of an antifoam in cell culture caused increased leaching of Protein A from a chromatography column. Fortunately, the remainder of the downstream process was designed to provide a final product with sufficient Protein A removal. A change in bioreactor design caused increased cell death, which resulted in increased levels of DNA that needed to be cleared by the downstream process. A change in culture media can result in the need to redesign the downstream process to remove specific culture components. As noted above, retrovirus expression levels can be altered by changes in cell culture, notably by changes that significantly alter the metabolic state of the cells and/or rates of protein expression.4 An increase in retrovirus expression levels can require changes in the downstream process to ensure viral safety. Communication between upstream and downstream personnel is key to the design of a downstream process that will be suitable for the manufacture of clinical material.

Downstream processes are used to clear both known and potential viruses from the unprocessed bulk material derived from cell culture. Viral safety is an important issue that needs to be addressed prior to entering clinical studies, but there are different opinions around the world regarding how many viruses should be evaluated in a clearance study prior to phase 1 clinical trials. Attempts are now being made to provide guidance for companies wishing to enter clinical trials in the EU.5 For clinical trials of monoclonal antibodies in the USA, the Points to Consider provide guidance.

There is a lot to be said for designing a robust downstream process that can remove viruses within a specified range of conditions. This range of parameters defines the design space.7 Defining the design space requires robustness, also called characterisation, studies. These studies use statistical methods, such as DOE, to evaluate different parameters, their ranges, and their influence on product quality. In chromatography, the design space might include upper and lower limits for protein load, flow rate, buffer pH and conductivity. Determining the appropriate design space requires an understanding, derived from development, of why a unit operation is incorporated into the overall process.

Typically, in phase 3, processes are scaled up. Scale up usually requires some modifications, in the best case only minor ones. Understanding manufacturing's capabilities is an important element for successful scale-up. These capabilities should be considered during process development. Both production equipment and in-process controls should be evaluated. In many cases, in-process analysis capabilities are not the same at development and production scales. Once scale-up is verified and any necessary modifications made, process validation can be carried out. At this point in development, full compliance with current GMPs is required. Process validation, a GMP requirement, usually necessitates a combination of both small and manufacturing scales. Small-scale models must be demonstrated to represent manufacturing, if the data are to be meaningful and accepted by regulatory agencies.

In conclusion, it is important to keep in mind that a step-wise implementation of GMPs is accepted, but any elements related to patient safety should be implemented prior to clinical studies. Furthermore, as processes are optimised during development, some safety-related issues need to be reconsidered. This can include, for example, a repeat of viral clearance studies if the feedstream is modified during process optimisation in phase 1 and/or 2 clinical trials. The amount of risk to patient safety that is tolerated is determined by the disease which is being treated and, often, by local regulatory authorities. Getting regulatory input prior to submitting an application to begin clinical trials can be very useful.

References

EU GMP Annex 13. Manufacture of Investigational Medicinal Products; EU 07/03.
ICH Q7A, Good Manufacturing Practice Guide for APIs; November 2000.
US FDA. Guidance for Industry, INDs - approaches to complying with CGMP during phase 1; January 2006.
Brorson K et al. 'Impact of Cell Culture Process Changes on Endogenous Retrovirus Expression'; Biotechnol. Bioeng; 80(2002)257-67.
Brorson K et al. 'Viral Safety Evaluation of Biotech Products Used in clinical Trials'; PDA Letter, January 2006, pp12.
US FDA. Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use; February 1997.
ICH Q8 Pharmaceutical Development; November 2005.

Single-use Bioprocess Containers

2011-01-02T03:24:00.001-08:00

Economics of usage in Asia

Extensive adoption of single-use products in manufacturing has shown considerable cost reductions by limiting initial capital costs, utilities required and cleaning validation etc. Do they promise the same benefits in the Asian manufacturing scenario, where overall cost of production and labour are significantly lower than in the West?

Swapnil Ballal Head, Biopharmaceutical
Bulk Manufacturing,
Intas Biopharmaceuticals Ltd., India

Single-use disposables have become a common name in the biomanufacturing industry world over. All major companies related to equipment and filtration products are present in this domain. They are increasing their presence by introducing more products in the disposable / single-use format. Some of the well-known benefits are:

Lower capital investments
Cost savings in cleaning and sterilisation
Elimination of cleaning validation requirements
Speed of deployment and batch changeover
Flexibility of operating scales.

Increasing implementation of single-use technologies clearly indicates that their benefits are attractive to the users.

Drivers of single-use technology

More than 1,000 biotech-based new drug entities are in various pre-clinical and clinical phases. A large number of such leads are being developed by startups and small sized firms with one to four lead candidates in their development pipeline. Since manufacturing plants take years to be built and costs run into hundreds of million dollars, most biotechnology companies are reluctant to make investments to support a therapeutic candidate still undergoing clinical trials. They rely on Contract Manufacturing Organisations (CMOs) for facilities and production expertise. This allows them to focus their resources on product development and establish a proof-of-concept in clinical trials. Meanwhile, CMOs executing short-term production requirements benefit from the fast turnaround and flexibility offered by the single-use products while limiting allied activities like changeover and cleaning validation.

The operating dynamics in Asia are quite different from the developed markets. This is largely due to the business model of the Asian biopharmaceutical industry which is primarily based on biogeneric products, lower labour costs and low-cost operations. In a scenario where the CMOs not catering to the local market and very few innovations taking place in biotechnology, the benefits of single-use technology using bioprocess containers as a model in Asian scenario can be reconsidered.

Capital investments

Asia benefits from having a well-developed steel fabrication set-up for the production of customised GMP vessels and related fabrication. A large number of EMEA and US FDA plants in India and in other parts of Asia make use of such indigenous fabricators.

A 200-500 litres mixing tank for buffer preparation costs around US$ 50,000 in India, which includes a jacketed pressure vessel with Clean-In-Place (CIP) / Sterilize-In-Place (SIP) pressure ratings, magnetic agitator, pH and temperature controls. Fabrication costs for similar units in the West are one and half to three times higher. The difference in cost is mainly due to the overall lower operating costs and low-cost skilled labour and not necessarily due to the usage of lower quality components.

On the other hand, a 200-litre bag holder with jacket and magnetic stirrer would cost around US$ 40,000 to 60,000 depending upon the configuration selected. Additional accessories like tubing sealer, tubing cutter etc. would take the cost to US$ 90,000. pH, conductivity and temperature control requirements further increase the cost.

A. Sinclair & M. Monge showed that adopting a single-use Bioprocess Containers (BPC)-based manufacturing system could result in overall capital saving of about 20-40 per cent over the traditional Stainless Steel (SS) fixed tank set-up in US or Europe. The major difference in Cost of Goods (COG) is due to the reduction in capital charges, smaller size of utility systems and decreased manpower for Quality Assurance & Quality Control for a disposable-component-based concept plant.

With products like SS tanks, CIP / SIP skids and other customised engineering products and piping available in Asia at a cost that is less than 25-50 per cent that of the US and Europe, the difference in capital investment between a plant with BPC set-up and with fixed SS tank decreases to a near equal level, if not to a lower one.

Operating cost

The cost of cleaning and sterilising a SS fixed tank is directly related to the cost of utility required. While the reduction in absolute quantity of utility may look very significant in terms of volume, the cost of CIP and SIP operation may actually be only a fraction of the cost of the bag itself. The cost of generating purified water / WFI is in the range of US$ 6 to 10 for 1,000 litres. For the cleaning of a 200-litre tank with a highly unoptimised CIP cycle, requiring 1,000 litres of water, one would spend less than US$ 10 of utilities in each run, while a single 200-litres bag alone costs above US$ 250. A process using five bags each day working 150 days in a year would require US$ 187,000 worth of bags alone against US$ 7,500 worth of utilities for a fixed tank.

Elimination of cleaning validation requirement

Cleaning validation is portrayed as one of the biggest cause of stress for bio-manufacturers. The gap between practice and regulatory expectation has been decreasing over the years. As per ranking of total GMP deficiencies by EMEA between 1995 and 2005, cleaning validation comes at 23rd place with only 1.3 per cent deficiency attributed to the category of cleaning validation and only one critical deficiency out of 193 deficiencies cited during the period, indicating that regulators are satisfied with the approach and extent of cleaning validation.

Cleaning validation of buffer and process intermediate tanks consume additional resources over the set-up based on BPC. The cleaning of buffer tanks in itself is easier to validate since these are not expected to contact and contaminate the product and product carryover issues are minimal. Cleaning validation of intermediate holding tanks can be reduced by intelligent and judicious selection of worst case scenario and bracketing to minimise the number of runs required for validation.

The point being emphasised here is that the science of cleaning validation is well established and since one would require cleaning validation of other plant equipment like fermenters, chromatography systems and columns, the set-up for cleaning validation would anyway exist and, therefore, it would only be the case of increasing the scope of the cleaning validation.

On the other hand, the use of bags is most practical for contract manufacturers since it eliminates cleaning validation studies for a different product each time.

Additional validation requirements

The use of single-use disposable systems brings a whole new set of validation requirements, which are at times more complex in nature than cleaning validation, largely due to the limited knowledge base and regulatory exposure. These are compatibility testing, extractables and leachables testing, mixing efficiency testing, leak testing, endotoxin, short-term and long-term stability testing and sterility validation. These are generally product-specific. Though reduceable for similar buffers, they still require product-specific testing for each product and intermediate. The analytical methods involved range from pH, conductivity to LC-MS, GC & GC-MS based analytical tools. The cost of carrying out the same also needs to be factored. Moreover, major bag manufacturers use different resins and probably different moulding procedures and chemicals.

Table1: Cost of Goods Comparision - US/EU

Labour
Material
Indirect Material
Consumables
Capital
Total
Savings

Traditional
200.1
61.5
82.2
40.8
149.1
533.7
0%

Disposables Concept
154.4
57
74.2
76.3
83.7
445.6
17%

Adapted from: A. Sinclair and M. Monge, BioProcess International 3(9): s51-55 (October 2005)

Figure 1: Contribution of individual cost head to cost of goods - US / EU

Simple substitution is not possible as in the case of stainless steel tanks, thereby increasing the reliance on a single bag manufacturer.

Cost of Goods analysis

The Cost of Goods (COG) for any manufacturing process plays a decisive role in acceptance of the technology.
As shown in Table 1, COG comparison of a traditional steel vessel-based plant and a disposable concept plant indicates a saving of 17 per cent using disposable technology. Contribution of each major head is shown in Figure 1.

Considering a 30 per cent lower capital cost in Asia for traditional plants and 15 per cent for disposable plant (since disposables set-up is to be imported), it is seen that the savings using a disposable set-up are reduced to about 6.5 per cent (Table 2 and Figure 2). If import duties on the disposable components are added at the current rate of 30 per cent in India, the COG for a traditional plant would be lower than that of the disposables.

With the continuous increase in price of crude oil and that of the base plastic resin, operating cost of plants using plastics may keep on increasing, while a steel set-up once installed would not add significantly to operating expenses.

Table 2: Cost of Goods Comparision - Asia

Labour*
Material
Indirect Material
Consumables
Capital**
Total
Savings

Traditional
50.0
61.5
82.2
40.8
104.4
338.9
0%

Disposables Concept
38.6
57.0
74.2
76.3
71.1
317.2
6%

* Considering Asian labour cost in Asia to be 25% of US/EU
** Considering 30% lesser capital for traditional and 15% lesser capital for disposable plant in Asia

Decreasing the disposable products cost by about 30 per cent and eliminating import duties would make the scenario for adopting disposable products and technologies favourable. This cost reduction can be brought about by offering better pricing for Asian markets and by exploring the possibility of manufacturing such units in Asia itself.

Drivers for adopting single¬-use disposable containers in Asia

Users from the US and Europe whose revenue came from contract manufacturing were the early adopters of disposable technology. Adopting the technology brought immediate reduction in capital with quick turnaround time.

However, in Asia, the focus is still on the manufacturing of biologics for captive use. Since the market for such products is highly cost-sensitive, increase in the overall cost of the finished product is critical. Since many of these plants operate mono-product lines / set-up, the need for adopting BPC set-up may not be very high.

In situations where living organisms are handled, single-use products can ensure the safety of the product as well as the operators, and thus would find early acceptance.

Contract manufacturers in Asia would also find single-use products useful, though such manufacturers are limited in number as of now. Single-use products would also find their use in scale-up and development labs, which have limited set-up for tank processing, allowing them to process on a larger scale in an R&D set-up.

One of the areas where single-use disposables set-up can be of great interest is finished dose manufacturing. The existing fill-finish facility can be adapted to single-use set-up without disturbing the existing set-up, allowing manufacturers to have a greater degree of assurance as well as flexibility of scale.

In addition to the above, facilities which are limited in capacity due to utility limitations like Water For Injection / clean steam can benefit from use of the single-use bioprocess bags.

Conclusion

In the European and US scenario, there is possibly a clear capital investment benefit in adopting the single-use bags and tanks. The same may not hold true in most Asian countries, where steel fabrication and labour costs are low.

The decrease in efforts in carrying out cleaning validation of fixed system needs to be evaluated critically against the cost of additional validation related to compatibility of plastics with process fluids.

Potential adopters of single-use bioprocess vessels need to carry out a critical evaluation of economic benefits while selecting between fixed tank system and single-use system.

They should also perform a thorough cost-analysis on their own before singling out one option.

Scenario of a hybrid system with a fixed non-product dedicated set-up like buffer preparation, transfer and hold with single-use product contact can also be a good compromise between cost and flexibility while making full use of the advantages of single-use systems.

Acknowledgements: I wish to thank Mahesh Kodilkar of Intas Biopharmaceuticals Ltd. and Vishal Wagh, Director, adam fabriwerk, Mumbai for their valuable contributions.

Author Bio

Swapnil Ballal is currently heading India's only EU-GMP approved biopharmaceutical plant at Intas Biopharmaceuticals Ltd. Being associated with the Indian biotechnology industry for the past 12 years he is presently overseeing manufacturing of 4 bio-therapeutics products along with contract manufacturing projects. He joined Intas in 2000 and played key roles in the set up of the biotechnology and R&D divisions and the manufacturing plant for biologics. Prior to Intas, he worked for Wockhardt Research Centre. He received his MSc in Marine Biotechnology from Goa University and holds professional membership at PDA and ISPE.

References

1. Quantitative Economic Evaluation of Single Use Disposables in Bioprocessing: Sinclair A, Monge M, Pharmaceutical Engineering, 2002, Vol. 22,3, 20-34
2. Design Economics for USP Purified Water Systems, Andrew Collentro, MECO, Inc. Pharmaceutical Processing, Dec 2004
3. Good Manufacturing Practice: An analysis of regulatory inspection findings in the centralised procedure, EMEA/INS/GMP/23022/2007, January 2007
4. Implementation and Validation of Single Use Systems : Ian Sellick & Joe Dallapiazza, Pall Life Science, 2007
5. Andrew Sinclair and Miriam Monge:BioProcess International 3(9):S51-55 (October 2005)

A compliant IT environment with IT service management software

2011-01-02T03:23:00.003-08:00

IT can play a key role in cutting down the costs of production and helping biopharmaceutical companies maintain regulatory compliance. IT service management software can be an essential element in

David A Medina Chief Technologist
Worldwide Health & Life Sciences
Hewlett Packard, USA

As the complexity of the biotechnology industry increased, pharmaceutical companies have struggled to ensure that their IT organisations keep pace with the latest hardware and software applications. Yet, the need to maintain regulatory compliance while ensuring that an organisation’s IT infrastructure meet its ever-changing business requirements, is a significant challenge that industry faces today. Biopharmaceutical companies must deal with the regulatory pressures of cost-effectively maintaining a qualified IT infrastructure with validated business applications, while dealing with the business demands of managing and controlling an IT infrastructure through effective IT Service Management (for example: change control or incident management). IT service management software can help companies cost-effectively meet their needs in both of these arenas.

ITIL – A framework for compliant IT service management
Regulatory compliance is one of the critical elements in the pharmaceutical industry that drives a significant portion of IT spending. Consequently, proper IT service management plays a significant role in reducing company risk by maintaining compliance in a cost-effective fashion. One of the most effective methods of achieving IT compliance is by adopting a process management framework such as Information Technology Infrastructure Library (ITIL®). The ITIL framework is a proven and accepted model for regulatory compliance, especially since process requirements for a mature ITIL model are in line with FDA requirements.

By using ITIL as a framework and incorporating common enhancements to ensure FDA regulatory compliance, such as approval levels, record controls, and integrating risk management techniques, a pharmaceutical company’s IT department can cost-effectively maintain compliance. Adopting ITIL allows companies to measure, monitor and analyse processes that enable implementation, management and continuous improvement of their IT services and underlying infrastructure. ITIL also enables companies to better incorporate risk analysis and management in their procedures.

Many pharmaceutical companies are moving towards, or have adopted an ITIL-based approach to IT service management. However, due to the documentation required to demonstrate regulatory compliance, most pharma IT processes are paper-based and not easily accessible throughout the enterprise. As a result, there is a significant opportunity to reduce the cost of managing IT infrastructures while increasing the level of regulatory compliance. This can be accomplished by automating ITIL processes using IT service management software.

Driving consistent processes through automation
From the perspective of managing IT delivery, IT service management software can help ensure compliance through the integration of all IT processes. These software tools allow for the continuous flow and visibility of information. IT Service Management can provide a single, enterprise-wide platform for incident management, problem management, change and configuration management, release management and service level management.

IT Service Management will also reduce the cost of maintaining IT infrastructure in a compliant state by allowing for optimisation and stabilisation of existing processes and electronic management (authorisation and approval) of IT infrastructure management process and procedures. This will reduce the cost of IT Infrastructure compliance and qualification by eliminating much of the paper-based documentation and process / procedure approvals.

For example, in the realm of change control, IT management software with ITIL-based procedures can help streamline processes and approvals while reducing the risk of implementing unauthorised changes. Pharma companies can benefit from software that allows them to quickly implement standard processes throughout an enterprise, with proper approval controls and mechanisms, while maintaining 21 CFR compliant digital signatures, audit trails etc. The software should also be able to track all changes, allowing IT managers to look at the overall processes from a workflow perspective where they can evaluate and control the impact of system-wide changes. With IT Service Management, IT managers can easily manage all related tasks and actions in a change process, tracking action items through completion. From a compliance perspective, IT (and compliance) managers can more easily capture, and manage, exceptions and deviations.

Accelerating the validation process through automation
Another area where software can drive compliance as well as help to better manage the IT infrastructure is in the area of computer software validation. Processes and tools must be developed and implemented to maintain the software and hardware involved in FDA-regulated processes in a validated state. ITIL and IT automation software tools in combination with some specific enhancements, can help biopharmaceutical companies automate the processes around software validation in order to ensure that they are able to take advantage of the latest IT technologies, while lowering costs and risk and maintaining compliance with regulatory requirements for IT qualification and validation.

It should be recognised that computer software validation does make good business sense. It is less expensive to validate proper system functionality up front than to deal with inconsistent performance later. However, effective computer software validation must be an integral part of IT operations. The need to maintain applications in a validated state has encouraged some negative behaviours, such as:

• Reluctance to perform patches or upgrades because of need to revalidate applications
• Manual validation processes often result in out-of-date IT environments that can be very difficult and costly to maintain.

Leveraging test management and automation software will allow biopharma companies to improve their validation processes and reduce compliance risk through the automation of their current paper-based processes. These benefits include time and cost reduction, increased consistency and quality, repeatability and enhanced agility, and automatic report generation. The end result will enable companies to deploy application patches and upgrades more frequently keeping IT infrastructures technologically current and compliant. This can be accomplished by incorporating automated functional testing, automated performance testing, test management and monitoring managed through software automation tools into the process.

IT infrastructure software accelerates the validation effort by helping to automate elements of the validation process particularly Operational Qualification (OQ), Performance Qualification (PQ), traceability matrix and the summary report. The role of OQ and PQ in software validation is to assess the key metric of whether or not applications function according to their intended use. Regression testing helps assure that the functionality and performance of applications continue to meet expectations over time as changes occur to the system. However, manually maintaining a regression suite is costly and labour-intensive, and they must be re-run after patches or major software updates. These software tools reduce the amount of time devoted to OQ and PQ by automating and accelerating regression testing to dramatically reduce execution times while providing fixed and repeatable sets of tests. The result is that automated testing will reduce time, and costs in the areas of OQ, PQ, generating a Traceability Matrix and Validation Summary Report.

These tools also allow organisations to better incorporate a risk-based approach by allowing them to look at their integrated applications and focus on areas of the application that are critical to human safety. For example, should a company identify, through their risk-based analysis, an application that has a high-risk profile for drug safety; they can use them, in conjunction with a risk-based approach, to perform more rigorous testing on those application areas of highest risk.

Once a company completes its validation and automation, thereby improving its efficiencies and reducing the cost of initial testing, they can be further used to perform periodic testing. Good validation SOPs and IT processes also call for regulated companies to periodically test their IT environments. This is a perfect situation where biopharmaceutical companies can use automated testing tools for scheduling and conducting the required testing and save the results for later review and action. The use of these tools will allow an organisation to quickly and cheaply verify that their environment is in a validated state. Thus, management of an IT infrastructure becomes much more agile when companies can increase their testing to a more frequent basis through automation. The result is better assurance of a validated state and preparedness for validation audits as well as a better understanding of the operational status of their IT environment.

IT management and compliance through software automation
IT infrastructure software management tools can be a key weapon in the arsenal of pharmaceutical companies to help ensure both compliance and cost-effective management of their IT infrastructures. Many companies are discovering that deploying software tools for incident, problem, change and configuration, release and service level management as well as test management can actually help reduce compliance uncertainty and greatly streamline operations.

Properly deployed IT management tools and automation technology actually lowers compliance risk by enforcing standard policies and procedures to ensure a stable IT infrastructure. Coupled with ITIL practices these tools will allow organisations to evaluate and analyse their processes and procedures in terms of best-IT practices and their risk management profile. Validation processes are more efficient and effective with automation testing technology, which helps to ensure a thorough testing of validated IT environments. Automated tests reduce the time required for complex testing as well as ensuring their repeatability and consistency. The result is that organisations are able to better maintain an effective and available software environment that is current with the latest patches and upgrades.

Any life science organisation that is interested in the cost-effective, compliant management of its IT infrastructure can use IT Service Management software to help implement its ITIL service delivery strategies to positively impact the business in the highly- regulated environment of the pharmaceutical industry.

Author Bio

David Medina is responsible for the pharmaceutical and life science research segments in HP’s Worldwide Health & Life Science group. Prior to that he held leadership positions with Quintiles Consulting, Medical Manager, Dianon Systems, and Confer Software.

Cell-based Potency Assays

2011-01-02T03:23:00.001-08:00

Adhering to GMP standards

The means of measuring the biological activity of a new drug is of critical importance to its release. The process through which a manufacturer can achieve this measure should be clearly defined before pre-clinical studies are initiated. The quality and validation requirements of these studies are defined in a number of regulations but experience of interpretation of these guidelines is essential in establishing a regulatory-compliant assay.

Daniel N Galbraith, Head, Operations
and

Andrew Upsall, Head, In vitro Services
BioOutsource Ltd., UK

A biological measurement of the activity of a drug is perhaps the most critical step in the series of tests required for product release for both clinical trials as well as the market and plays an important role in the stability assessment of drug candidates. All drugs require a clearly defined specification for release; wherever possible, this should be in place at the pre-clinical stage in a basic format and made more stringent throughout the product life cycle leading to a clearly defined set of release tests that constitutes the marketing authorisation. Some of these assays are generic and can be very simple, such as a measurement of the pH of the material or the product appearance. However, others are product-specific and can be problematic and require significant scientific insight and thorough validation; the cell-based potency assays fall into the latter category.

Animal studies

Biological drugs seldom lend themselves to enzymatic reactions as a measure of biological activity. Insulin is perhaps the only biological which measures potency by enzymic reactions, therefore in vivo or in vitro measures of activity are the most popular choice. Animal studies have a number of distinct disadvantages when considering product release within a Good Manufacturing Practice (GMP) environment, not withstanding the industry's ongoing commitment to reduce the use of animal experimentation. Fundamentally, animal studies are typically performed to ascertain the Good Laboratory Practice (GLP) level of quality, rather than that of the GMP level demanded by the industry for other release tests. Animal studies are costly and time-consuming and are known to have a degree of variability raising questions about their effectiveness.

Measurements of biological activity can be performed in the following three ways:

• Animal studies in which a defined animal model demonstrates a measurable, physiological change in response to application of the drug.
• Cell-based assays that use a specified cell system, which on addition of the drug, demonstrate a measureable biological response.
• Enzymatic reactions where the biological activity of the drug can be measured by the accumulation of product following the chemical reaction facilitated by the drug.

Cell-based potency assays

Another method to measure the biological activity of a drug that is proving to be of interest to the majority of manufacturers is cell-based potency assays or bioassays. Cells are living entities, representing biological systems that possess many of the important in vivo characteristics that make them useful for measuring biological activity.

Cell-based potency assays possess a number of advantages over animal models. The most obvious is the cost, with cell-based assays typically reducing cost by 80 to 90 per cent when compared to equivalent animal studies. Initiation of cell-based assays can be achieved with greatly reduced time frames and the variation associated with animal studies is largely removed as the cells used are usually clonally derived and maintained within strict parameters. Therefore, the variability of response is reduced when compared to in-bred animal groups as well. For all these reasons and many more, cell-based potency assays have been the method of choice. However, these assays do require careful consideration when preparing them for use in the release of a drug product.

When considering a bioassay, the cells are universally regarded as the most important feature; without the cells responding in the characterised manner, the assay will never be of use for the release of the product. Cell-based potency assays typically start their life in the research and development section of a large pharmaceutical organisation or in an independent research organisation such as a University or Government Department. These facilities often do not comply to recognised quality system such as GLP or GMP and this presents a significant problem. Cells from these institutions may not have sufficient provenance to demonstrate the appropriateness of their usage for GMP and this can be a time-consuming endeavour to undertake. Ultimately, these tests will need to meet standard GMP requirements for product release for clinical trials (in the European Union) and for marketing authorisation in the rest of the world.

The next problematic feature that can hamper assay development and validation is the availability of information regarding the characterisation of the reference standard. Cell-based potency assays generally report a value relative to a standard drug batch, with every new batch measured against it. In this way each batch can be shown to be consistent with previous batches and the reference standard. The provenance of the reference standard is critical to every batch released and characterisation can be an arduous process. A successful approach employed by most manufacturers is to use one of the early production batches as the reference standard and obtain information during initial assay development. Issues can arise when, following the initial clinical trials, a number of process and formulation changes and improvements to the manufacturing process are implemented. This results in the reference standard no longer being an identical composition to the new batches of the product. Significant effects on the results of the bioassays can ensue and a new reference standard may be required to be established for the new product design. Whenever a new reference standard is created, a bridging study to show the comparability of the new and old molecules is required. This again can be a time-consuming and expensive work and may lead to project delays if not managed effectively.

Validation of assays

The next major hurdle, once the cells and reference standards are in place, is the validation of the assay to an International Conference on Harmonisation (ICH) standard that will also meet GMP requirements of the regulatory authority. The ICH sets out specific guidelines for all tests to be followed if they are to be used for the release of drugs. To meet GMP requirements, appropriate specifications and control of critical reagents and equipment must also be given full consideration. For example, the incubators used to grow the cells as well as the reagents used in the culture of the cells all require qualification and control. Reagents, such as foetal calf serum, should be considered as critical and even plasticware must be kept as consistent as possible to ensure the desired performance of assay.

To meet all the specifications in the validation guideline, cell-based potency assay may present many obstacles and also require considerable time and resources. The ICH Q2 guidelines describe a bioassay as a "Quantitative test of the active moiety in samples of drug substance or drug product or other selected component(s) in the drug product". The validation characteristics which should be considered are accuracy, precision, repeatability, intermediate precision, specificity, limit of detection, linearity and range.

The scope of the validation should include a number of assay runs to be performed by several operators to provide sufficient data from which appropriate conclusions can be drawn. The validation process should also focus upon critical assay parameters in all robustness experiments. Overall, the aim of the validation data set is to provide evidence for the appropriateness of the assay to have utility in the release of product.

Many organisations find that they have insufficient in-house resources to undertake the task of performing validation or batch release testing of product using these complex biopotency assays and often consider outsourcing to a Contract Testing Organisation (CTO). CTOs typically have experience, quality systems and suitably qualified equipment for successful assay validation and release of product to a GMP standard. Responsibility for stability studies, where the stability of the biological potency of several batches of the drug is measured over time, can also be transferred to these organisations. A major advantage of transferring an assay to a CTO is the provision of a back-up facility providing a critical aspect of the expected business continuity programme that can be utilised in the event of problems arising with the in-house testing programme.

Transfer of an assay to a CTO requires several stages to be considered. Quality and technical agreements need to be prepared where the individual responsibilities of both parties are defined and identified. Experience has shown that the important part of the agreements relate to critical GMP requirements such as responsibility for Out of Specification Results and Deviations to Protocols and these requirements should be clearly defined. Following agreement on documentation, "proof of concept" studies are performed to demonstrate that the cells used in the assay grow and respond in a consistent manner with the original (expert) laboratory. GMP compliance requires that the operators are suitably trained and it is often considered to be prudent for operators from the expert laboratory to conduct training for analysts of the receiving laboratory. Upon successful completion of these studies, a formal protocol should be initiated to establish conclusively that consistent results can be obtained between the laboratories. A technology transfer will then be performed, if transferring a validated assay or a validation study can be performed at the CTO.

The way forward

Cell-based potency assays are clearly seen as the way forward as methods to set the specifications for new drug products. These assays provide a clear and reliable indication of the activity of the drug and provide a consistent means of measuring this over time. These assays do however require a commitment of time and resources which may necessitate the use of outsourcing the work to a CTO. This endeavour should be carefully considered and the right partner to assist should be selected with care, ensuring that sufficient experience and resources are available. As biologic drugs become widely used, the demand for efficient release of drug to the market will also increase. Planning for this in a timely manner is a challenge to all manufacturers. However, the failure to do so will result in inevitable delays to release and eventually add cost to the bottom line.

Author Bio

Daniel Galbraith heads the Operations for BioOutsource Ltd., a GMP testing organisation which supports batch release of vaccines and biologics. Daniel comes to BioOutsource following experience heading departments in Covance Laboratories and MedImmune.

Andrew Upsall leads a team of scientists who support safety and potency testing for new biologics and vaccines. Andrew comes to BioOutsource following experience in a number of positions in the pharmaceutical industry.

Drug Reconstitution: Market Needs and Technical Challenges

2011-01-01T21:14:00.001-08:00

Graham Reynolds

Many reconstituted drugs are administered at home by the patient. Different technologies for reconstitution have gained approval and acceptance among pharmaceutical companies and their patients.

For patients who must manage chronic diseases — such as hemophilia, multiple sclerosis, rheumatoid arthritis, diabetes, and others — medication issues can present significant challenges regarding safety, ease of administration, cost, compliance, and other factors. Fortunately, continual advances and breakthroughs from pharmaceutical companies are delivering tremendous improvements in theform of more effective medications. However, these medications typically require frequent injections; depending on the nature of the disease and the patient’s individual condition, those injections could be weekly, daily, or even multipletimes a day.

In an effort to reduce health care costs and improve patient satisfaction, there has been a marked increase in patient self-administration of medications forchronic conditions. Many pharmaceutical companies are turning to home-deliveryand administration of these injectable medications, most of which are manufacturedand sold in lyophilized (or “freeze-dried”) form and require reconstitution,mixing, or transfer before administration. This reconstitution process can becomplex and introduce certain issues to consider.

WHY DO WE NEED RECONSTITUTION SYSTEMS?
Many new drugs, especially those developed by bio-pharmaceutical companies, are initially marketed in lyophilized form for two primary reasons: shelf-life and time-to-market. A lyophilized drug maintains its stability and potency over time, extending its shelf-life for prolonged storage. Some drugs marketed in lyophilized form may eventually be available as liquids, but lyophilizationprovides the fastest route to market for many drugs, and the only option forthose not stable in a liquid form.

These drugs — often packaged in a powdered form in vials —requirean additional preparation step prior to administration. That additional stepis the traditional reconstitution process. With traditional reconstitution, thereare two vials and one disposable syringe. One vial contains the lyophilized drugand the other contains the diluent (often water, but occasionally another liquid).The patient or caregiver must use the syringe to insert air into the vial containingdiluent, withdraw the diluent into the syringe, insert the diluent into the vial containing the lyophilized drug, mix the solution to create an injectable medication, and draw a measured dose back into the syringe for injection. Not surprisingly,this rudimentary reconstitution process presents several formidable challenges.

A Lack of Expertise – In most instances, reconstituted drugs are administered in non-clinical settings (typically at home) by patients or caregivers who are not trained health care professionals. While it’s far more convenient for patients who can avoid repeated trips to clinics and other facilities for routine injections, it can be a daunting experience to prepare and administer an injectable drug. Pharma companies need to ensure that the process is simple and safe.

Added Risks – Any drug that requires mixing presents complications and risks. For instance, a hemophiliac must be especially vigilant to prevent accidental needle sticks. There can be inadvertent contaminations or exposures to sometimes-toxic drugs (often resulting from so-called “spray-back”). And there’s a greater risk of inaccurate process — such as using improper concentrations, resulting in incorrect dosing.

Compliance Concerns – If the process is complicated, dosing accuracy may suffer. And if the process is difficult, unpleasant, or painful, it can become an impediment to patient compliance.

Waste – Pharmaceutical manufacturers often overfill the vial by as much as 35 percent to ensure that there is a sufficient quantity of the reconstituted drug to administer the correct dose. The overfill compensates for the inherent variability of the manual process, as well as the difficulty of removing the liquid completely from the vial. From the patient’s perspective, there’s a risk of mishandling or contamination that can necessitate throwing out very expensive drugs.

A number of newer, advanced products on the market can provide both professionals and non-professionals alike with safe, convenient, and easy-to-use systems for reconstituting and administering injectable drugs. These systems can be provided either as a total packaged solution or as components for specialized use.

Figure 1:
A vial adaptor is a low-cost solution to
improving the reconstitutionprocess.

Figure 2: A needle-less transfer device allows for pressurization and transfer of the diluent into the vial containing the hyophilized drug.

Many of the new reconstitution systems can be adapted to currently marketed drugs without the need to change manufacturing processes or packaging components such as vials, stoppers, and seals. They are offered as a total system that can be packaged with the filled drug vial and the reconstitution components. Such systems usually consist of a plastic device that joins the drug vial to the diluent container that can be a pre-filled syringe, vial, or infusion bag. Reconstitution devices can be sterile and fully supported by appropriate regulatory filings. To further enhance convenience, all required items to perform the reconstitution can be packaged together in a kit form. The following sectionexamines some of the leading reconstitution options.

SELECTING THE RIGHT RECONSTITUTION ALTERNATIVE
An advanced reconstitution system can add value to currently marketed and pipeline drug products. When evaluating various alternatives for advanced reconstitution, pharmaceutical makers should carefully consider various factors. Among thekey criteria are the following:

The type of drug – If it’s expensive or more toxic, there are implications for the type of reconstitution method you choose.

The diluent volume type – Different volumes will present you with a varying number of options.

The administration method – Is the drug to be injected subcutaneously,intravenously, or intramuscularly?

Linkage to secondary administration – If you need to connect (post-reconstitution) to a bag or auto-injector, certain options are more advantageous.

The competitive environment – Many drug makers use reconstitution and delivery as differentiators for products that may be approaching commodity status.

Time-to-market requirements – Reconstitution systems that use existing, approved packaging avoid the need for regulatory review.

Overfill issues – Systems that reduce the need to overfill vials with lyophilized medications are ideal for expensive pharmaceuticals.

Vial Adaptors
Vial adaptors — which provide quick, safe, and cost-effective transfer of the diluent — are a low-cost solution to improving the reconstitution process (see Figure 1). These systems connect a syringe of a diluent (either pre-filled or filled from another container such as a vial or ampoule) to a vial with a lyophilized drug and provide for quick and safe transfer from vials, allowing convenient, optimal quantity aspiration. The adapter snaps to the neck of the standard vial after the plastic button has been flipped off. A plastic spike pierces the stopper; needles are not used. The reconstituteddrug is transferred to a syringe by a luer connection. Vial adapters come in a variety of sizes as well as venting and inline filter options; an optional incorporated valve system maintains stability for multi-dose applications. One can even use different variations of the vial adapter to connect to other containers such as IV bags and cartridges (for subsequent insertion into apen system) as well as nasal or oral administration routes.

Vial-to-Vial Systems
Vial-to-vial systems offer a similar level of simplicity and cost-effectiveness through a double-adapter that connects to the top of each vial (lyophilized drug and dilu-ent). This is an ideal solution for connecting vials of different sizes. You can color-code the adapters (e.g., blue side is for diluent) and add particulate filters and venting if necessary/desired. This is a very easy process for patients and no needles are required to reconstitute the drug. For manufacturers, vial-to-vial systems are attractive because theynecessitate no changes to the vials they currently use.

Needle-less Transfer Devices
This is a more sophisticated form of vial-to-vial reconstitution (see Figure 2). This single-device model allows for pressurization and transfer of the diluent into the vial containing the lyophilized drug. The patient snaps on both vials. The diluent mixes with the powdered drug and the connectedsyringe draws in the reconstituted drug for administration.

Direct Connection to Vial
In some instances, pharmaceutical companies may opt to deploy a package in which the syringe is directly connected to a vial. The syringe is pre-filled with the proper amount of diluent and is directly attached to the vial duringthe manufacturing process. (The patient needn’t attach the vial.)

This replaces the use of the traditional aluminum seal. This approach requires fewer steps for the patient. He or she simply injects the diluent directly into the vial holding the powdered drug, gently mixes the solution, and draws a measured dose back into the syringe for injection. The disadvantage is that this does require a new manufacturing process for the drug maker. Some newer direct-connection systems offer more manufacturing flexibility by using vial adapters (to support standard vials and drug packaging) and a range of syringes or even auto-injectors.

Dual-Chamber Syringes
Dual-chamber syringes provide a lyophilized drug and diluent in a single unit. Reconstitution is achieved by pushing down on the syringe plunger, forcing the dilu-ent through a channel and into the second chamber where it mixes with the drug to create the injectable solution. The drug can then be injectedusing an attached needle or can be transferred through a luer connection. These systems provide a high level of end-user benefits. The pharmaceutical company, however, has additional challenges in terms of manufacturing and regulatoryrequirements because of the change in primary container.

ADVANCED RECONSTITUTION BENEFITS AT A GLANCE

Ease of Use – Advanced reconstitution systems
with well-engineered components and processes
introduce structure that simplifies their usage. For
instance, a simple locking adapter can snap onto the
neck of a standard vial, a plastic spike pierces the
stopper, and the reconstituted drug gets transferred
to the syringe by a luer connection. Such a simple
system is usable by non-health care professionals
without difficulty. That encourages patients to con-
form to their prescribed regimen.

Better Patient Compliance – Advanced recon-
stitution systems can package the precise amount of
diluent and drug with a properly sized needle in a
single kit. This helps improve dosing accuracy.

Improved Safety – Needle-free reconstitution can
help prevent accidental needle sticks. Calibrated
doses also prevent incorrect dilution or administra-
tion and accidental contamination or exposure.

Less Waste – Reduce the amount of overfill — a
significant factor for expensive drugs.

RECONSTITUTION SOLUTIONS PROVIDE MANY ADVANTAGES
By successfully addressing these challenges, advanced reconstitution systems can create a host of benefits for both pharmaceutical companies and theirpatients.

    * They are easy to use by patients and caregivers who aren’t health care professionals.
    * They help protect against drug spray-back and accidental needle sticks.
    * Many provide needle-less reconstitution and transfer.
    * Since they are more convenient, they encourage patients to comply with a dosing regimen, helping to improve patient outcomes.
    * They may help the pharmaceutical company reduce the amount of overfill in the drug vial because the system promotes the use of the entire drug in the calibrated dose.
    * They can reduce problems during the mixing process, such as foaming or incomplete reconstitution of the drug.

CONCLUSION
Reconstitution systems are especially beneficial for products that are used to treat chronic conditions that are administered in a home setting. Many systems are approved as medical devices by the United States Food and DrugAdministration and carry CE certification for European markets.

For the person administering the drug, whether a health care professional or not, advanced reconstitution systems can help promote safe and effective drug delivery and compliance with a dosing regimen. For pharmaceutical companies, advanced systems can differentiate products in the market. Since the dosing is accurate, manufacturers may be able to reduce the need for drug overfills.

One important consideration for pharmaceutical makers centers on the need to educate their users. Advanced reconstitution systems represent an important leap forward in usability and safety. However, it’s also undeniable that they introduce a level of change that is non-trivial to people who are not health care professionals. Manufacturers must assume the burden of ensuring that patients receive complete and clear training on using the new reconstitutionsystems.

The ideal time to evaluate systems for developmental drugs is during Phase II and Phase III clinical trials when the effectiveness of the delivery system can be evaluated. For currently marketed lyophilized drugs, systems are available that can be used without the need to change processing and filling lines or packaging components.

Graham Reynolds is the Vice President of Reconstitution and Transfer Systems of West Pharmaceutical Services,Inc.,101 Gordon Drive,Lionville,PA 19341.He can be reached at 610-594-2900; graham.reynolds@westpharma.com.

Key Considerations For Cleanroom Conveyors

2011-01-01T21:13:00.000-08:00

Mark Dinges

The case for modular conveyors
Cleanroom production lies at the heart of many of the world’s leading industries. These include pharmaceutical, medical, semiconductor and, if current events are any guide, solar power—now just beginning to emerge as a worldwide technological mainstay. The clean industrial environment can encompass the entire assembly/manufacturing process, leaving only packing and shipping to be done in a non-cleanroom area, or the manufacturer can isolate only certain facets of the process as a cleanroom environment. Increasingly, the trend has been toward the latter approach, due to cost savings and flexibility—a solar panel manufacturer, for example, may have production processes with cleanroom requirements ranging anywhere from Class 1 to Class 100,000. The simplest way to do this is to take a modular approach, in which each manufacturing step requiring a clean environment is treated as a self-contained process. Each process station can then be operated within the appropriate cleanroom specifications. In solar panel assembly, for example, wafer production, cell production, and module production all have different cleanroom requirements (Table 1). These requirements further vary within each production area, depending on the process.

The modular approach to cleanroom conveying offers numerous advantages for manufacturers such as increased flexibility, reduced costs, and the ability to take a more proactive approach to changes in technology or levels of demand.

The most logical approach to handling product within a clean modular-type assembly process is to use modular conveyors. Modular conveyors are commonly used in conjunction with standard cleanroom components, such as HEPA filters, cool zone sterilization, and hermetically sealed entry/exit gates to minimize the risk of product exposure to the environment outside each module. Modular conveyors, which are made from bolt-together components and aluminum framing, provide a high level of flexibility. In industries where production needs can suddenly change, or where sudden innovation is common (e.g., the solar industry), the modular approach helps manufacturers employ rapid and proactive methods to meet the demands of new developments.
Along with flexibility, modular conveyors can help manufacturers achieve the goal of cost savings through isolation of specific processes within cleanroom conditions. In the pharmaceutical industry, these processes can include ovens for dehydration of pharmaceutical solutions, pill compression, bottle filling, and sealed blister packaging. Depyrogenation of pharmaceutical glassware (e.g., vials, ampuls) is made more efficient through the use of a conveyor within a clean environment tunnel. The use of separate cleanroom areas within the same plant can also help prevent cross-contamination between pharmaceutical products and batches. The medical supply industry has applied similar, process-based cleanroom techniques to ensure sterile bandages, syringes, gauzes, razors, chemistry analysis kits, and surgical instruments. In the semiconductor industry, 300mm wafer fabrication has been isolated in environments so clean that even stray ions—as well as dust and organisms—must be prevented from contact with the wafer. The key in all these cases is that stringent cleanroom specifications need only be applied to the operations that need them—not to the entire manufacturing process.
The same concepts are taking hold in the emerging solar industry, where U.S. production is apparently ready for an enormous leap forward in response to demand. In Europe, where demand is already climbing and the solar industry is more established, modular conveyors are already commonly used in the production of wafer-based and thin modules. The use of a modular conveyor makes it easier to reconfigure the production process in response to (or anticipation of) future demands. Demand for solar power components in the U.S. is likely to increase soon—and so is the use of modular cleanroom conveyors.

The use of modular conveyors makes it easier to reconfigure the production process in response to (or anticipation of) future demands.

WHAT MODULAR CONVEYORS SHOULD DO
The most critical requirement for a modular conveyor in a cleanroom environment is, of course, its specification. Conveyors rated to class 100,000 are readily available, but for processes requiring true contamination control, class 100,000 is well out of range. Indeed, a truly sensitive process will require a vastly stricter specification (down to class 1 in some cases, such as semiconductor manufacture), while other processes in the same facility require only class 100 or 1,000. This wide range of cleanroom requirements can present a challenge in terms of conveyor system planning and layout. In addition to contaminants, a modular cleanroom conveyor must also protect materials from damage caused during the manufacturing process itself—including, potentially, the conveyor itself.
Modular conveyors should also be truly modular in design: Pre-assembled, and available in a wide variety of section lengths and widths appropriate to the application. Some applications require materials to travel several inches, while others require materials to be conveyed several feet, or even farther. Conveyor width is also crucial, especially in the solar industry. Conveyors must be able to accommodate a wide variety of size requirements, ranging from wafers the size of a CD-ROM to frameless, thin film panels that average 1100mm x 1300mm in size.

In the solar industry, production methods for processes such as stringing and lay up, vary greatly from one solar panel manufacturer to the next. As a result, solar industry requirements often generate a variety of custom conveying/material handling requirements.

Beyond the conveyor itself, all potential sources of environmental contaminants should be considered.

WHAT TO LOOK FOR—AND AVOID—IN SPECIFYING A CLEANROOM CONVEYOR
Both European and U.S. regulators have applied considerable resources to answering the question “What is ‘clean’?” The spectrum of U.S. cleanroom classes for typical manufacturing applications runs from class 100,000 (an environment with =100,000 particles of 0.5 micrometers in diameter per cubic foot) to class 1 (=1 particle of 0.5 mm/cubic foot). The European system is similar but is based on particle concentrations per cubic meter—ISO 9 is the least stringent standard and ISO 1 is the cleanest.
For some applications, a class 100,000 environment is clean enough. But most cleanroom processes require lower levels of contaminants than this—some solar manufacturing processes, for example, require less than a class 10,000 environment, and semi wafer production can have a class 1 to 100 requirement. The cleanroom rating of the conveyor should be at least as strict as any of the environments with which it interacts—and in many industries, that means class 10,000 or cleaner. Another aspect of conveyor specification to consider is technological changes that may require an upgrade in clean environment rating. In these cases it may be advisable to err on the side of caution and specify a higher cleanliness class.
On the other hand, over-specification can be wasteful and lead to unnecessary complications in a manufacturing process. Few industries require exceptionally clean conveying (e.g., class 1)—hard disk, computer chip, and semiconductor manufacturing are the exceptions. In some cases, a 100,000 clean rating will be appropriate. If a class 100 level conveyor is selected for a class 100,000 application, the result will be an unnecessary investment in technological features that are rarely if ever used, and which might slow down manufacturing processes (e.g., by requiring thermal sterilization between steps). The best approach is to consider not only current cleanroom requirements, but possible changes in the future. Will processes change? Is technology likely to advance? Will production demand increase? The answers to these questions will help determine clean specification decisions for modular conveyors both now and in the future.
Specification can also be complicated by the nature of the industry. In the semiconductor and computer hardware industries, processes have become fairly well established through decades of manufacturing experience. There is a “book” to consult when designing and implementing conveying solutions. In the solar industry, however, processes are still evolving. The production methods, for processes such as stringing and lay up, vary greatly from one solar panel manufacturer to the next. As a result, solar industry requirements tend to generate a variety of custom conveying/material handling requirements. The same plant may have twin-rail, single-chain, and contact-free magnetic conveying systems in close proximity—different solutions for different processes. The expected increase in demand for solar energy is likely to increase the level of standardization, but for now, designers should be prepared for customization requirements.
Finally, maintenance and upkeep must be kept in mind. Cleanroom conveyors must be readily accessible for cleaning, sanitation, maintenance, repair and other requirements. Maximizing accessibility helps reduce downtime and improve efficiency.

Cleanroom specialists can help develop an optimum approach for cleanroom conveying—including appropriate specifications—as well as for other aspects of clean manufacturing processes.

THINKING BEYOND THE CONVEYOR
A crucial area to remember in evaluating cleanroom conveyors is that the conveyor is only as clean as the environment in which it is operating. A conveyor rated to class 1,000 will only perform at that level if its environment remains class 1,000 rated as well. All potential sources of environmental contaminants should be considered along with the conveyor itself.
With this in mind, consultation with a cleanroom specialist is highly recommended. A number of firms provide consulting, design, planning, and installation (including modular systems) dedicated to cleanroom solutions. These specialists can help develop an optimum approach for cleanroom conveying—including appropriate specifications—as well as for other aspects of clean manufacturing processes.
MAJOR ADVANTAGES FOR CLEAN MANUFACTURING
The modular approach to cleanroom conveying offers numerous advantages for manufacturers. It can increase flexibility, reduce costs, and allow a more proactive approach to changes in technology or levels of demand. It should also be remembered that clean manufacturing can be an important facet of lean manufacturing. The right choice of conveyor(s) can reduce wasted material, improve efficiency, and increase productivity. Best of all, modular cleanroom conveying can better position manufacturers for future developments. As products continue to shrink in size—as is the case in many high-tech industries—the need for clean manufacturing solutions will continue to grow.
Mark Dinges is Product Manager, TS Conveyors for Bosch Rexroth Corporation, Linear Motion and Assembly Technologies, Buchanan, MI; www.boschrexroth-us.com.

Extrapolate To Production: Quality and Economics

2011-01-01T21:12:00.001-08:00

Barbara Kanegsberg
Ed Kanegsberg

Let us assume there is a promising prototype for a critical product, a prototype for which we have reached the “ah-ha” moment. Perhaps half a dozen have been produced and pilot tested. If the product is a medical device, biocompatibility testing or even clinical trials may have started.

Production is imminent. The product must be cleaned; and appropriate contamination control is a must. Extrapolating from one or two products in a beaker to production runs of thousands per day (or even thousands per hour) can be daunting, particularly when the need for controlled environments is anticipated (Figure 1).

PROTOTYPE DESIGN
First, look at the design. Determine where cleaning and contamination control issues are most likely to occur. Can you redesign the prototype to avoid these problems? Perhaps not, but it is worth consideration. In fact, many clients now factor in the concept of “design for cleaning.” It can be productive to invite your design engineers to tour an applicable fabrication facility and to involve design engineers in your production team.

WHEN TO CLEAN
The short answer is: right away — then shield the product from recontamination. In our experience, it is generally more productive to place the cleaning system so that the product requires as little transport as possible.

Products for many critical applications involve outside fabrication, often by a chain of complex, secretive suppliers. Moving from prototype to production can be an excellent time to demand or at least to negotiate, not just levels of cleanliness, but to actually specify the process in detail, including the cleaning chemistry. This practice has certain advantages, particularly in military and medical applications where specific cleaning agents or leachable agent residues must be avoided.

As a precaution, some groups elect to clean all incoming components. Because the appropriate cleaning process depends on the soils in question and because surface residue tends to become more adherent with time, it is preferable to work with the supply chain to pin down the cleaning process.

Perhaps, however, a critical link in the supply chain is recalcitrant, uncommunicative, and not readily replaceable. The most expeditious approach can be cleaning incoming product with periodic monitoring of contamination, perhaps by non-volatile residue (NVR) determination. Speciation of surface residue may also be needed where residue of a particular chemical or class of chemicals could be damaging to performance. In such a situation, to avoid having the recalcitrant link become the weakest link, it is probably prudent to continue the search for another supplier. If faced with the prospect of replacement, a recalcitrant supplier is likely to become more communicative.

CLEANING EQUIPMENT: MACRO OR MICRO
Particularly where funds for capital equipment are limited, there is a certain appeal to purchasing a single, large automated cleaning system that uses a single cleaning chemistry and to use that system throughout the process. Theoretically, given scrupulous control of process baths and process chemicals, a single cleaning system could be used for an entire fabrication process from initial cleaning through final assembly. Theoretically, with enough control and monitoring, it might be possible to clean a carburetor and an implantable medical device in the same cleaning system; however, we do not recommend the practice.

Even with a very robust and well-controlled cleaning system, there is always the potential for cross-contamination, for erosion, corrosion, and surface damage related to unexpected contamination of one product line by another. Keeping separate process lines for critical product and for critical stages of assembly is a more reasonable approach, especially where process soils from an earlier part of fabrication might contaminate product at a later stage.

In order to minimize work in progress (WIP), for most complex assembly and fabrications operations, it is better to invest carefully in the appropriate number of cleaning systems. This means determining sources of contamination, estimating soil loading at each stage, and then strategically adding the cleaning process at the correct time and the correct location.

EFFECTIVE USE OF CONTROLLED ENVIRONMENTS
Early on, decisions must be made as to which parts of production will be conducted in a cleanroom or a mini-environment. Determining where not to use a controlled environment is perhaps an even more important decision.

For one thing, cleanrooms and mini-environments are costly in terms of initial capital investment, consumables, monitoring, labor time for gowning, as well as ongoing employee education (training). In addition, just as access to the cleanroom should be restricted to educated personnel, entry of product to the cleanroom must also be carefully evaluated. To avoid the potential for cross-contamination, only critical product and sub-assemblies should be processed in a cleanroom environment and facilities and procedures for product transfer into and out of the cleanroom environment should be designed.1

AUTOMATION
On the positive side, automation reduces the labor involved with piece-by-piece cleaning. Automation also provides consistency; the process avoids operator- to-operator differences and reduces run-to-run variations.

Automation of a process needs to be carefully planned, including the decision of parameters to be monitored. The negative side of automation is that if an inefficient or incorrect process is automated, it will be inefficient or incorrect every time.2

If crucial parameters are not continuously or frequently monitored, a change in operating conditions (e.g. soil accumulation in a wash or soil removal bath) can result in an unacceptable amount of WIP being rejected before the changed condition is detected and ameliorated.

Finally, automated processes must not contribute to contamination. The hardware of the material handling systems must be designed to minimize particles and volatiles (Figure 2).

Automated systems are important to minimize WIP within the cleanroom and in general manufacturing areas (Figure 3). However, it is important to consider what happens at the interface. While at first glance it may seem efficient to use an in-line conveyor system to transport product from the general manufacturing area into the cleanroom, because of the difficulties in contamination control, the practice is not generally recommended.

WHERE TO CLEAN
Finally, the placement of process equipment must be carefully considered. Before automatically locating critical cleaning operations in the cleanroom, please consider that the cleaning process and the cleaning equipment can be a source of contamination. Mists, vapors, and re-deposited cleaning agent residue can re-contaminate product with particles and/or airborne molecular contamination. In addition, cleaning equipment in a cleanroom takes up valuable real estate. It often makes more sense to place the cleaning equipment proximal to the cleanroom, control the drying chamber, keep the clean and dry parts free of contaminants, transport them to the cleanroom, and perhaps do a brief, final cleaning within the cleanroom. Where cleaning equipment is used in the cleanroom, keep those parts of the equipment that generate particles and airborne molecular contamination (AMC) outside of the controlled environment.

WHEN, WHERE, HOW
Planning when, where, and how to clean is crucial to well-defined surface quality and for reliable contamination control. Plan the cleaning and manufacturing processes wisely. Define what constitutes general cleaning and what constitutes precision or critical cleaning for your application. Then, locate the cleaning systems where they will be convenient, effective, and not contribute to recontamination or cross-contamination.

References

1. B. Kanegsberg, E. Kanegsberg, and K. O’Donoghue “Contamination Control In and Out of the Cleanroom” Controlled Environments Magazine, Feb., Mar. (2009).
2. B. Kanegsberg and E. Kanegsberg, “Contamination Control In and Out of the Cleanroom” Controlled Environments Magazine, April (2007).

Barbara Kanegsberg and Ed Kanegsberg, “the Cleaning Lady and the Rocket Scientist,” are independent consultants in critical and precision cleaning, surface preparation, and contamination control. They are the editors of The Handbook for Critical Cleaning, CRC Press. Contact them at BFK Solutions LLC., 310-459-3614; info@bfksolutions.com; www.bfksolutions.com.