The validation of a rapid sterile transfer port (RsTP) system used in barrier filling lines

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Pharmaceutical Technology , 05/01/2003 27 5
The validation of a rapid sterile transfer port (RsTP) system used in barrier filling lines: an improved strategy for materials handling in the pharmaceutical industry. Tingley, Stephen *~|~*Baloda, Suraj *~|~*Belongia, Brett *~|~*Liepold, Gerhard *~|~*
COPYRIGHT 2003 Advanstar Communications, Inc.

Material transfer into Class A filling environments is one of the most common causes of aseptic processing failure. The authors in this paper review the challenges and options for material transfers, including a new UV light-based technology. **********
Material transfer into Class A filling environments has been identified as one of the most common causes of aseptic processing failure. Traditional filling facility design layout has placed the filling machine in a Class B environment. Process operations require that sterile materials be transferred across the B environment to the Class A filling area. Keeping such a filling line supplied with components requires numerous operator interventions that present a contamination risk.
In recent years, the development of barrier-isolator filling lines has made the challenge of supplying components to filling lines even more difficult. The most recent FDA draft concept paper on aseptic processing recognizes that it is not necessary to place a barrier-isolator inside a Class B environment provided that a validated materials-handling process is used. This article reviews the challenges and options for material transfers, including the validation of a new UV light-based rapid sterile transfer technology that reduces the risk of contamination from multiple material transfers into the Class A environment. By sterilizing the interface between the Class A and Class C environments, this system provides a secure method of material transfer and allows barrier-isolator lines to be placed in the significantly less costly Class C environment. This system, the rapid sterile transfer port system (RsTP), features a 3-min UV sterilization cycle that provides validation at!
the point of transfer. The UV light-based system design is more robust, reliable, and easily validated than previous applications of UV sterilization in the pharmaceutical industry.
The challenges of sterile material transfer
The heart of any liquid parenteral final fill-and-finish operation is the filling machine. The filling machine is a conveyor system responsible for bringing empty sterilized containers, glass vials, and syringes from a sterilization tunnel and delivering sterile filled and sealed parenteral dosage formats to a packaging line.
Certain dosage forms such as naked glass syringe barrels must be assembled before the drug solution is filled. Before the filling step, a sterile hypodermic syringe needle is assembled onto the glass syringe barrel, and the container is sealed closed. Rubber closures, in this case plunger tips, are delivered by a hopper-feed system.
The critical filling operations are identified as those in which sterile liquid, containers, and components are exposed to the environment before sealing. These operations are conducted in highly controlled Class A environments.
A recent Parenteral Drug Association (PDA) survey identified material transfer as a significant contributor to aseptic processing failure (Table I). In an 8-h shift, it is typical to supply 10,000 to 100,000 components to the filling area. The number of components transferred at any one time can range from 2000 to 5000, and a typical filling run of 100,000 containers would require an average of 20-50 transfers. Each time a transfer is made, there is an increased risk of elevated microbial challenge to the filling environment. Obviously, the more transfers that must take place, the greater the practical risk. Operators are the single-largest source of microbiological contamination within the aseptic filling core.
Current practices in managing sterile material transfer
There is a broad range of current practices and product technologies for managing sterile material transfer processes. The material transfer process depends largely on the details of facility design and manufacturing philosophy, which can be illustrated by two extreme examples: filling operations contained within a Class B cleanroom and those contained in a barrier-isolator filling operation.
Filling operations in the Class B cleanroom. In the first example, a Class B cleanroom uses wipe-and-pass methodology as the presterilized components are transferred from a Class C area into the Class B environment (see Figure 1). The primary concern with this transfer is to avoid contamination of the Class B room with particles or microorganisms. Wipe-and-pass transfer techniques using a small chamber between the staging area and the cleanroom are often implemented. An operator in the staging area removes a layer of protective packaging and/or wipes the external surface of the packaging with a cleaning and sanitizing agent. Once completed, the operator places the package in the chamber for passage to the cleanroom. An operator inside the cleanroom removes the transfer container containing the package and places it on a captive trolley.
[FIGURE 1 OMITTED]
The transfer container moves across the cleanroom to the Class A filling area. The challenge associated with this second transfer is double. The Class B environment has contaminated the external packaging of the components, so in transferring the sterile components, the operator again has to remove a layer of packaging and/or wipe down the external surface of the transfer container with a cleaning or sanitizing agent. The next task is to get the sterile components inside the Class A filling environment without compromising the sterility of the components or the environment immediately surrounding them. The component packaging cannot be opened in the Class B area because this would compromise the sterility of the components. Therefore, the operator has to partially enter the Class A environment. In some processes, the operator stops the filling operation, cuts open the container packaging, and replenishes the component feed hopper. By entering the Class A environment, the o!
perator is in close proximity to the sterile components and sterile liquid dispense heads, risking contamination. By bringing the nonsterile transfer container into the Class A environment, the operator also increases the microbiological challenge to the aseptic filling process.
Wipe-down procedures are subjective and, hence, are difficult to validate. Transfers of this type rely on quality operator training and accurate execution of standard operating procedures (SOPs). Risk increases with the number of transfer steps and the complexity of each. Each planned operator intervention must be included in the validation and re-validation of the media fill protocol. Sterility failure can be catastrophic; even failure during a media fill will result in significant extra work and lost production time.
Barrier-isolator filling operations
In the second example, barrier-isolator filling lines that have rapid transfer port (RTP) technology are used for the transfer of sterile materials. RTP technology uses a flexible or solid container to transfer the sterilized components. These containers must still be transferred from the staging area into dose proximity with the isolator. The materials are then transferred from the Class B environment to the isolator.
Alpha-Beta RTP systems are a two-component port system. The Alpha component is a stainless steel port that is set into the wall of the barrier and sealed by a plastic door. The Beta component is a stainless steel flange attached to the transfer container and sealed by a plastic door. Neither door can be opened unless the two components are docked together. The exterior door faces the room environment and is exposed to contaminants. However, the port-docking process seals the two nonsterile door faces together, which minimizes the risk of external contamination (see Figure 2).
[FIGURE 2 OMITTED]
The primary benefits of barrier-isolator systems that use RTP technology include the following:
* Operator manipulations are managed only through an isolator glove port.
* The need to introduce packaging materials into the isolator environment is eliminated.
Because of the primary benefits that RTP technology offers, it is widely considered to be state-of-the-art for a filling environment.
One significant limitation of RTP technology is that the transfer is aseptic rather than sterile. For the port to open, the canister cover must pass through the port opening. This opening action is facilitated by a small mechanical clearance between the outside diameter of the canister cover and the inside diameter of the port. This small exposed ring (termed the ring of concern) could contain contaminants. This risk was illustrated in 1995 by the Barrier User Group Symposium using the "toner test" in which copy machine toner was applied to the docking surfaces of the canister and port. The canister was docked to the port and the door was opened. When the port door was opened, two lines of toner were visible. One line appeared at the interface of the canister and port flanges, and the other line appeared at the interface of the port door and the canister cover (1). It is normal practice for the ring of concern to be sanitized with alcohol before starting a transfer to redu!
ce this risk.
Sterile materials handling, isolators, and future process design
Pharmaceutical manufacturing is increasingly requiring more process security, which includes minimizing or removing operator intervention in the process. This approach has increased regulatory and industry support for barrier-isolator filling line installations. This trend brings new challenges such as how to design component supply processes to feed a barrier filling line that ensures minimal risk and regulatory acceptance. FDA's preliminary concept paper, "Sterile Drug Products Produced by Aseptic Processing Draft" evidences this trend. Relevant conclusions of this concept paper include the following:
* Barrier-isolator filling lines appear to offer an advantage over classical aseptic processes.
* A Class 100,000 (Class C) background is appropriate for most manufacturing situations.
* The ability to maintain integrity and sterility of an isolator is affected by the design and use of the transfer ports.
A reasonable conclusion is that well-designed secure transfer port systems, which are vigorously validated, will facilitate the use of isolator filling lines in Class C environments. One solution for executing such a strategy is the RsTP. The major benefit of such systems over RTP systems is that the transfer is sterile rather than aseptic, and a sterile transfer interface is easily validated.
Overview of RsTP systems
One sterilizable transfer port uses the Alpha-Beta double-door design and addresses the ring of concern by integrating dry-heat sterilization into the Alpha port (see Figure 2). An electric heater is installed in the port flange, which heats this area to >200 [degree]C in 3 min. This temperature is maintained for 30 s followed by a 3-min cool down period. The double door is opened and a shield is moved into place. The purpose of the shield is to prevent damage to the components by the heated edges of the port.
More recently, a new UV light-based RsTP system has been introduced. This system is a double-door system, but does not depend on a mechanical rotating interlock. Operation of this RsTP system is simple. A filled, sterilized container is directly docked to the UV port (see Figure 3).
[FIGURE 3 OMITTED]
A simple molded collar, integrated into the flexible transfer container, is pushed into place and locked by a cam-and-pin system. The operator starts the 3-min UV sterilization cycle by pushing a button. This system uses flexible bags as the sterile transfer container. The components are sterilized inside sealed transfer containers using either gamma or autoclave sterilization.
Although the FDA preliminary concept paper "Sterile Drug Products Produced by Aseptic Processing Draft" leads us to a conclusion that RsTP systems are valuable tools in aseptic processing, it should be noted that in the concept paper, FDA questions the use of UV light as an acceptable sterilizing technology for transfer port technology. The authors of this article believe that a thorough review of UV science, past application, and rigorous validation of this technology is merited. The rest of this article is dedicated to a discussion of UV suitability, repeatability, and validatability as it applies to a UV light-based RSTP system.
Mechanism of ultraviolet sterilization
The biological effects of UV light and the mechanisms of action are well understood (2-5,8-10). The bactericidal effect of a low-pressure mercury UV lamp is a direct result of its emission wavelength intensity and the absorption by the bacterial cell's nucleic acid (4-5). The absorption of germicidal UV light interferes with the replication of DNA and RNA and consequently disrupts the normal cell function necessary for survival. Nucleic acids show maximum LTV absorption at wavelengths between 260 and 265 nm (11) with most nucleic acids showing a rapid decrease in UV absorption in the region of 290-315 nm (2).
UV irradiation has long been used as a fairly selective tool for causing cell damage. Understanding the effect of UV irradiation on the vital cellular processes also led to observation of the recovery of previously "dead" cells. The term photoreactiration describes this recovery of cells rendered nonviable by UV irradiation. It has been observed that the viability of irradiated Streptomyces griseus was increased 10-fold following storage for 1-2 days. Subsequent studies demonstrate that exposure to visible light was in part responsible for the photoreactivation. Experimentation showed that exposure of UV-irradiated suspensions of S. griseus to visible light resulted in an increased recovery of viability from 100,000- to 400,000-fold (3). The following three repair mechanisms may occur, depending on the organism:
Photoreactivation or photoenzymatic repair. DNA photolyase, activated by absorption of light between 300 and 500 nm, found in microorganisms and plants, is capable of binding and splitting dimmers (4). Exposure to light within 2-3 h after UV irradiation is required for recovery (7).
Excision repair. Found in most organisms, this repair mechanism is independent of the presence of light. Repair involves cleaving and excision of damaged DNA by nucleases followed by the synthesis of new DNA strands by means of a DNA polymerase (3,5).
Postreplication repair. Damaged DNA is replaced with a parental DNA sequence from either multiple replicate DNA or complementary DNA strands (3-5).
The cellular capacity for viability recovery may partially explain apparent discrepancies in laboratory results with respect to the use of UV light as a sterilizing source (3). This should be considered during validation study design.
Factors contributing to the success of UV sterilization
UV light has been widely used to control microbiological contamination (6). The most notable limitation has been the ability to develop applications where UV light can be reliably harnessed to provide sterilization that can be validated for use in the pharmaceutical industry.
Germicidal use of UV light has been implemented in the health industry for more than 60 years. In most of these applications the action of the UV light has been termed as sanitization or disinfection and rarely as sterilization. The major reason for this dichotomy rests with the choice of application. In almost every documented use of UV light for microbiological control, the target subject has been large in size or volume or distant and diffuse with respect to the UV source. Shechmeister provides an overview of how UV light has been used to sanitize air, surfaces, and water in the hospital, laboratory, and beverage manufacturer settings (6). In each of these applications the UV source has typically been mounted on walls or encased in quartz glass placed around the transport pipes (12). In these applications the intensity of the UV radiation, hence the killing power delivered to the target, is diminished. The distance between the sterilization target and the UV source, the!
presence of moisture, and particulate contamination combine to reduce the effectiveness and predictability of the UV dosage (13). These factors make sterilization unlikely and validation difficult.
UV sterilization in RsTP technology
The sterilization performance and validation of an RsTP system incorporating a UV sterilization source can be directly attributed to the design of the UV source and RsTP/barrier interface as an integrated system. The critical design characteristics of such a system must provide a consistent delivery of a known intensity of 254 nm of UV light.
The UV RsTP has been designed to meet these criteria. It consists of a sterilization port and a sterile transfer container (see Figure 4). The sterilization port is installed in the barrier--isolator wall and is sealed from the outside environment by an internal door. This door houses the UV sterilization source. The components to be transferred are sterilized in the transfer container bags by gamma, autoclave, or ethelene oxide sterilization.
[FIGURE 4 OMITTED]
In isolator applications, the port is sterilized by opening the UV door and inserting a plug in the open port. All internally exposed areas and the UV door are decontaminated during the vapor-phase hydrogen peroxide sterilization cycle of the isolator. The control systems of the port and isolator are linked, ensuring a full decontamination cycle has been completed. Once all the hardware is sterilized, the transfer system is ready for use.
A number of safety features, including a series of interlocks and alarms, prevent the inside of the isolator from being exposed to the outside environment by the premature opening of the door. Similarly, the UV sterilization cycle is closely monitored and alarmed and is stopped should an alarm condition occur. In such an event, the door cannot be opened. The sterile transfer container is removed from the port, and the alarm condition is corrected. Only at this stage can a new transfer cycle be initiated.
Designing a UV light sterilization interface for validation
Validation of the sterilizing capability of UV light was conducted by a direct microbiological challenge. To meet the validation requirement, the design of the RsTP system needed to ensure:
* a consistent level of energy output from the UV light source
* a consistent level of UV radiation at the sterilization site
* a consistently low bioburden level at the sterilization site.
Ensure a consistent level of energy output from the UV light source. The effectiveness of the mercury vapor lamp decreases as the temperature of the lamp increases. The temperature of the low-pressure mercury lamp rises because infrared (IR) light is produced along with the UV light. As a result, the longer the lamp runs, the more IR is produced, resulting in greater heat output. This lowers the intensity of the 254 nm UV and converts some of the UV light to wavelengths outside the effective range for sterilization. To address this, critical design features have been enhanced, thereby enabling the UV source to run at 40-45[degrees]C, its optimum temperature for maximizing the UV output.
Consistent UV intensity is key to the reproducibility and validation of the UV sterilization process. Consistency can only be achieved if the UV lamps are functioning correctly. A lamp-monitoring circuit integrated into the starter design monitors the amount of current drawn by each lamp, which ensures functionality of the UV source. Any change would equate to a reduction in UV intensity and generate a system alarm.
Ensure a consistent level of UV radiation is present at the sterilization site. UV light intensity decreases with distance from the source. The Inverse Square Law is often used to compute the intensity of light at any distance from a lamp but is inaccurate in the near field where most of the germicidal effect occurs. Other models such as the radiation view factor equation provide a more accurate prediction of LTV intensity at short distances (15). This is one of the key reasons why the use of UV in this application is significantly different than in other disinfection applications. In other applications performance was compromised because the UV source was far away from the sterilization target. In the sterile transfer application, however, the UV source is placed very close to the transfer collar interface to be sterilized (0.185 in./4.699 cm). By tightly controlling the dimensions of the transfer container collar and its position in the port and only allowing the sterili!
zation cycle to begin once the collar is locked into place, a consistent distance is maintained between the interface and the sterilization source.
Shadowing can also reduce the effectiveness of a UV sterilization system and make validation more difficult. Shadowing occurs when the UV rays are blocked or obstructed by foreign objects such as particulates or crevices. The profile of the transfer container collar of the RsTP is designed to minimize the effects of shadowing. In addition, a removable collar cap protects the collar face from scratches or particles that may collect on the collar face. Manufacturing the transfer collars in a Class 1000 environment further minimizes particulate contamination.
Ensure a consistently low bioburden level at the sterilization site
A low bioburden at the site of sterilization is ensured in the following four ways:
* Design of the collar interface: A tightly fitting protective cap that permits gamma or autoclave sterilization covers the entire transfer collar interface surface.
* Manufacturing practice: A Class 1000 molding environment minimizes bioburden contamination before sterilization.
* Presterilization of the transfer interface collar: The transfer interface collar is autoclave or gamma-sterilized along with the components.
* On-site SOPs: The protective cap is only removed inside a Class C/B environment, seconds before it is docked into the UV RsTP. Risk assessment studies have concluded that a 5-min exposure in a Class C room would result in a maximum contamination rate of 92 cfu on an exposed 100 mm (79 cm2) interface collar (16).
Validating UV light sterilization in the RsTP system
For any sterile transfer system to be of value to the pharmaceutical industry, its functionality must be validated in terms readily understood by the industry and acceptable to regulators. In determining an acceptable validation standard for sterile transfer, the starting point has to be the application. The purpose of the RsTP system is to create a sterile transfer interface between a Class A environment (barrier-isolator) and the surrounding Class B or C environment. In looking for an acceptable standard of sterility, the obvious candidate is the sterility assurance associated with autoclave sterilization. The expectation is that an autoclave cycle is capable of sterilizing a microbiological challenge of 1 x [10.sup.6] cfu, giving a theoretical assurance of a sterility level of 1 in 1,000,000.
Scientific data suggests that Tobacco Mosaic Virus (TMV) has a high resistance to UV, requiring a dose of 440 mWatts/[cm.sup.2] to achieve a 100% kill, although Bacillus anthracis spores require a dose of only 46 mWatts/[cm.sup.2] to achieve sterility. In the validation process, the total dose delivered by the UV sterilization source of the RsTP during a 90-s cycle was at least 1000 mWatts/[cm.sup.2], which is more than twice the minimum required dosage for TMV. The cycle requiring validation had a duration of 180 s, ensuring a larger dosage than is required for sterilization.
The sterilizing capability of the UV cycle was validated by a direct microbial challenge. This bacterial challenge was inoculated directly onto samples of low-density polyethylene (LDPE) material used to manufacture the transfer interface collars. An approximate concentration of [10.sup.6]-[10.sup.7] spores of Bacillus pumilus (ATCC 27142) was used. Complete sterility of the LDPE collar interface was shown after a minimum UV exposure of 45 s (see Table II).
Photoreactivation is considered an essential component of the sterilization validation protocol. To assess the sustained lethality of the UV irradiation dose associated with the RsTP sterilization cycle, a validation protocol was developed that would assess the ability of UV-irradiated organisms to repair themselves through photoenzymatic and dark repair mechanisms. The possibility of photoenzymatic repair (photoreactivation) was excluded by exposing irradiated organisms to monochromatic and broadband light. Similarly, the possibility of excision (dark) repair mechanisms was excluded by incubating irradiated organisms in the dark. Photo protection with preceding illumination was not investigated as it was considered that the inoculation organisms were already exposed to light before irradiation, and any recognized benefit would have been included in the original sterilization validation (2).
The study using B. pumilis was conducted three times on separate days and 36 gamma-irradiated 2 in. x 2 in. LDPE slides were tested with an inoculum size approximately ranging from 1.2 x [10.sup.6] to 1.6 x [10.sup.6] spores in 40% alcohol. Each slide was exposed to UV light for 180 s. For enumeration of the recovered bacteria following the UV exposure, four exposed slides were incubated in 100 mL of trypticase soy broth (TSB) at 30-35 [degrees]C for 14 days. Furthermore, two procedures were used to test for photoreactivation. In the first procedure, 16 slides were placed in glass petri dishes and stored under fluorescent light (light intensity: 500 [+ or -] 40 lux) for 7 days at 2-8, 20 [+ or -] 1, 24 [+ or -] 1, and 35 [+ or -] [degrees]C. In the second procedure, another set of 16 slides were incubated for 7 days in the dark followed by 7 days of exposure to fluorescent light (light intensity: 500 [+ or -] 40 lux) at the following temperatures: 2-8, 20 [+ or -] 1, 24 [+!
or -] 1, and 35 [+ or -] [degrees]C. The results showed that all 36 slides exposed to UV light for 180 s were sterile, indicating that B. pumilus spores did not undergo photoreactivation after exposure to UV light.
Conclusion
RsTP systems offer potentially significant benefits to the pharmaceutical manufacturer over existing aseptic RPT systems. The most notable benefit is a decreased risk associated with component transfer to a high-speed filling line. With the older aseptic transfer port systems, operator intervention is required several times each hour to feed more components to the filling line. With each successive transfer, there is a small but real risk of an increased microbiological challenge to the filling area, either from the operator or from the transfer process.
Until recently, the only available sterile transfer system was based on old mechanical Alpha-Beta RTP technology and dry-heat sterilization. Now, UV light has been successfully developed, validated, and used as a sterilizing source for a new rapid sterile transfer process. To make UV sterilization practical, the design of the transfer port interface has been optimized from a complex Alpha-Beta flange system to a simple docking collar and door assembly. The simple design of the one-piece molded collar facilitates using UV sterilization. Logistical problems associated with the cleaning, repair, tracking, and replacement of the beta flanges and their gaskets have been eliminated by the implementation of a single-use one-piece molded collar interface.
Thus, by addressing one of the most common causes of aseptic processing failure--material transfer into the Class A filling environment--RsTPs facilitate the development of more-secure materials handling processes. In addition, these improved processes permit the placement of isolators in less costly, less environmentally controlled areas, thus reducing capital investment and running costs.
<pre>
Table I: Top causes for aseptic processing
failure (PDA Industry Aseptic
Processing Survey 2001)

* Personnel contamination

* Nonroutine activity

* Aseptic assembly

* Human error

* Mechanical failure

* Airborne contaminants

* Improper sanitization:
surface contaminants

* Material transfers:
failure of 0.2-[micro]m filter
failure of HEPA

* Improper sterilization.

Table II: Microbial Challenge Data

Exposure CFU
Inoculum (HDPE) Ave. Conc. time (s) Per Slide % Recovery

Bacillus subtilus 5.6 x [10.sup.6] 60 0 0.0%

Bacillus pumilus 6.3 x [10.sup.6] 180 0 0.0%

Bacillus 6.8 x [10.sup.6] 60 0 0.0%
stearothermophilus

Deinococcus 4.5 x [10.sup.6] 60 0 0.0%
radiothurans

Pseudomonas 7.5 x [10.sup.6] 60 0 0.0%
aeroginosa

Staphylococcus 7.7 x [10.sup.6] 60 0 0.0%
epidermidis </pre>
References
(1.) Sterilizable Rapid Transfer Port for Pharmaceutical Isolators Joint PDA/ISPE Conference on Advanced Barrier Technology, 1995.
(2.) Harm, Walter, "Biological Effects of Ultraviolet Radiation," Cambridge University Press, 1980.
(3.) Kelner, Albert, "Effect of visible light on the recovery of Sterptomyces griseus condia from ultraviolet irradiation injury," Proceedings of the National Academy of Sciences, 35 (2), Feb, 1949, pp. 73-79.
(4.) Wang, Shih Yi, "Photochemistry and Photobiology of Nucleic Acids," Volumes I and II, Academic Press, 1976.
(5.) Hader and Tevini, "General Photobiology," Pergamon Press, 1987.
(6.) Shechmeister, I.L., "Sterilization by Ultraviolet Irradiation," Disinfection, Sterilization, and Preservation, 4th Edition, Seymour S. Block, 1991, pp. 553-565.
(7.) Wright, H.B., and Cairns, W.L., "Ultraviolet Light," Trojan Technologies Inc Technical Bulletin #52, 1998.
(8.) Lehninger, A.L., Nelson, D.L., and Cox, M.M., The Principles of Biochemistry, 2nd edition, Worth Publishers, NY, NY, 1993, pp. 330-345.
(9.) Groocock, N.H., "Disinfection of drinking water by ultraviolet light," J. of the Institute of Water Engineers and Scientists, 38 (20), 1984, pp. 163-172.
(10.) Schenck, G.O., "Ultraviolet Sterilization," Handbook of Water Purification, Chichester: Ellis Horwood Ltd.; 1981, pp. 530-595.
(11.) Cohn, A., "The UV-Tube as an Appropriate Water Disinfection Technology: An Assessment of Technical Performance and Potential for Dissemination," Master's Project for The Energy and Resources Group, 24 May 2002, pp. 12-17.
(12.) Srikanth, B., "The application of UV technology to pharmaceutical water treatment," European Journal of Parenteral Sciences, 3 (4), 1998, pp. 97-102.
(13.) Melgaard, N.L. and Haas, P.J., "Continuous Production UV Sterilization Transport Applications," Journal of Pharmaceutical Processing, November 1997, pp. 3-8.
(14.) Stockdale, D. and Nase, R.S., "Ready to Use Stoppers: A Novel Outsourcing Alternative," Pharmaceutical Engineering, March/April, 2002, pp. 52-54.
(15.) Kowlaski, W.J. and Bohnfleth, W.P., "Effective UVGI System Design through Improved Modeling," ASHRAE Transactions, 106(2), 2000, pp. 4-13.
(16.) Bergin, Brian, Eurostar Technology Limited, Bredbury UK, "SafePass UV Transfer Process Risk Assessment."
Stephen Tingley is the director of biopharmaceutical marketing in the BioPharmaceuticai Division of Millipore Corporation, Bedford, MA, tel. 781.533. 2559, steve_tingley@millipore. com. Suraj Baloda, PhD, is the group manager for process microbiology and sterile applications, and Brett Beiongia, PhD, is the applications engineer consultant for disposable product technology applications R&amp;D in the BioPharmaceutical Division, both at Millipore. Gerhard Liepoid is the managing director at GL Tool, Livingston, NJ.
Stephen Tingley, to whom all correspondence should be addressed.

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