A WHITE PAPER

ENVIRONMENTAL MONITORING AND CERTIFICATION IN CONTROLLED ENVIRONMENTS

Meeting Regulations and Achieving Effective Microbial Control for Pharmaceutical and Medical Device Manufacturers
By Steven Wieczorek Supervisor, Environmental Sciences Microtest, Inc.

A WHITE PAPER

ENVIRONMENTAL MONITORING AND CERTIFICATION IN CONTROLLED ENVIRONMENTS

Meeting Regulations and Achieving Effective Microbial Control for Pharmaceutical and Medical Device Manufacturers ABSTRACT
Programs that meet regulatory compliance standards for industrial sterilization and contamination control are critical to the manufacture of pharmaceuticals and medical devices. This report reviews the key elements of a best-practices environmental testing program, including U.S. FDA requirements, sterilization standards, proper certification and validation processes, and other critical factors in maintaining controlled environments. Where relevant, this paper examines how these challenges may be met with the assistance of an up-to-date testing laboratory.

Steven Wieczorek

WHAT IS REQUIRED?
In attempting to meet regulatory demands from sources such as the U.S. FDA and the European Pharmacopoeia, the greatest challenge for medical device and pharmaceutical manufacturers may be determining what exactly is required for compliance. How must they design, implement, certify, and maintain correct sterilization and environmental monitoring programs? For parenteral manufacturers, environmental control parameters in U.S. regulations are stringent. The collaborative effort between the Office of Compliance in the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), and the Office of Regulatory Affairs (ORA) offers guidance for industry with the evolving document Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice.1 While the primary focus of the guidance is on cGMPs in 21 CFR 210 and 211, considerable attention is also given to environmental control. In addition, USP <1116>, Microbiological Evaluation of Clean Rooms and Other Controlled Environments,2 offers guidance that can be used as a framework for developing personnel training and environmental monitoring programs. This chapter also reviews guidelines, equipment, and statistical methods that have been adopted as industry standards. The PDA document TR13, Fundamentals of a Microbiological Environmental Monitoring Program, is also a mainstay, offering solid guidance to all categories of manufacturers. Environmental monitoring poses problems for all pharmaceutical and medical device manufacturers. They must attempt to assemble a unified, justifiable strategy by choosing bits and pieces from an array of different standards, guides, and corporate policies. It can be extremely difficult and time-consuming for them to create and implement a concrete, systematic environmental monitoring program. Even when some sort of homegrown program gets designed and implemented, frequently there is little confidence on the part of important internal constituencies in its chances of passing regulatory inspection, or in its practical application. For instance, production operators uninformed about program rationales may chafe at new gowning procedures or seemingly arbitrary prohibitions on bringing in music players or consuming food or drink at the workbench, while upper management may question added costs. This lack of understanding and cooperation from all parties caused by an inadequately designed and implemented program negatively impacts the chance of program success. In turn, program failure has unfortunate consequences for efficient, ongoing, profitable manufacturing and production. In Europe, the situation is somewhat clearer, but still evolving. U.S.-based or multinational manufacturers who wish to market medical device or pharmaceutical products in the European Union must meet the requirements set forth in the EU GMP Annex 1.3 Some requirements are substantially the same as those found in the U.S.; others differ.

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In both jurisdictions, regulatory demands are essentially moving targets. Statutes and standards change over time often on a quite rapid basis. Manufacturers who wish to remain in full compliance must stay current on evolving regulations worldwide. Unfortunately, researching, creating, carrying out, and constantly updating total environmental testing programs is not something all manufacturers are prepared to do. Many lack the internal resources required in staffing, training, experience, time, and effort. A number of manufacturers large and small have looked outward for help, to contract testing organizations. This category is exemplified by Microtest Laboratories. A leader in biological testing since 1984, the company provides a wide portfolio of laboratory testing and consulting services. Its built an unparalleled reputation for advanced technology, scientific expertise, process flexibility, proven quality, and responsive service all at competitive prices. The companys trained microbiologists and other specialists possess vast experience in designing, implementing, and ensuring the success of testing, monitoring, and certification for a comprehensive range of controlled environments. Instead of trying to manage a project patchwork of different testing vendors themselves, manufacturers working with Microtest get the industrys simplest, most turnkey solutions. Clients report that Microtest often makes a critical difference to their business, ultimately enabling fast, safe product release and quickest time to revenue.

VIABLE VS. NONVIABLE PARTICULATES

Under ISO 14644-1,4 cleanliness classes are assigned to clean zones using measured levels of nonviable particulates. Microbiologists and regulatory professionals cannot determine any definitive correlation between levels of nonviable and viable particles present in the environment. However, because of the relative ease and practicality of continuous monitoring for nonviables, this remains the approved method for real-time assessment of environmental control. Determining what satisfies the viable microbial sampling requirements given in many standards is often ambiguous. There are no commonly accepted levels of environmental bioburden. This is due to the large number of widely differing industries, manufacturing processes, and specific sub processes to which these regulations must apply. There are a few guidance organizations that are actively researching viable limits with plans of creating a general set of limits based on industry and ISO classification. The EU Annex 1 provides some guidance in relation to viable limits and acceptance criteria. Some facilities opt to reference this guidance document and utilize these limits in their environmental monitoring programs even though they may not be manufacturing product going overseas. Establishing limits for each manufacturing process and facility that can be applied and tested to, is a critical step in maintaining a controlled environment. Once these limits have been established, they should be evaluated periodically and adjusted accordingly, if required, typically every 12 months; after a years worth of trended data can be reviewed. Outliers are typically not included when setting alert and action limits as they can negatively impact accurate limits from being generated. ISO 14644 is currently recognized as the worldwide standard for designing and validating controlled environments. (Note: at publication time, this standard was under review, with possible changes pending.) Additionally, the ISO 146985 document series has provided manufacturers with some concrete guidance in setting up the microbial portions of their programs. However, it stops short of providing a definitive method for determining just how much microbial sampling is sufficient. Written justification for the manufacturers choice of standard to meet must be provided in the overall environmental monitoring plan. In an audit situation, regulators will make sure a given program has been designed to meet an appropriate standard; they then evaluate whether that program has met that standard. In essence, is the controlled environment designed to do the right thing? And does it successfully perform as designed? For example, many manufacturers elect to utilize the methodology set forth in ISO 14644 to sample for nonviable particulates. This still leaves open the question of what sample locations in the environment are most critical, as well as what type of organisms (aerobic, anaerobic, fungal) must be recovered. Unfortunately, as

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sterilization validation programs more and more rely upon bioburden control and monitoring, this missing piece becomes even more critical. Microtest differentiates itself from other recognized compliance vendors by offering both nonviable and viable air and surface sample testing of controlled environments. The company utilizes state-of-the-art testing equipment and materials. For example, its newest laser particle counters allow 1 full cubic meter of air to be tested for nonviable air particulates in only 10 minutes! Over many years and many clients, Microtest has collected and analyzed volumes of data that correlate environmental bioburden, product contamination, and sterilization efficacy. The companys off-site environmental services group has encountered virtually every type of manufacturing scenario imaginable. From Class 5 fill/ finish lines to extruding, to nonwovens, to packaging its clients benefit from Microtests understanding of program development for cleaning, qualifying, monitoring, and training in any environment.

SAMPLING PLANS
A number of highly trained, veteran Microtest microbiologists, chemists, quality assurance (QA) experts, clean room specialists, and project managers have worked in the pharmaceuticals and medical devices manufacturing fields themselves. Perhaps as important, others have years of experience working for the U.S. FDA or other agencies regulating those industries. In addition, company specialists regularly review new regulations, upcoming standards, and other important literature in the field, while also attending conferences, seminars, and workshops discussing current and future developments, technologies, methodologies, and regulations. Most manufacturers have limited experience involving only occasional audits by regulators. Due to its large number of clients and long history in the field, Microtest has assisted numerous clients in getting through the audit process. Finally, Microtest has confronted and resolved numerous environmental challenges on its own turf. The company maintains its own commercial aseptic processing suites, producing both clinical products and commercial drugs for manufacturers on a contract basis. These suites are located in their own FDA/DEA-registered and ISO 9001:2000certified contract testing and manufacturing facility at company headquarters in Agawam, Massachusetts. All the above qualifications help Microtest design and oversee thorough, efficient, well-documented environmental monitoring programs. These in turn help ensure straightforward, successful audit experiences. For instance, when it comes to sampling practices, regulatory agencies almost always prefer to rely on a standardized table or calculation for determining frequency and volume parameters. These provide a comfort factor. During an audit, its reassuring (for both regulator and client) when the manufacturer can point to a sampling document filled out according to established industry practices. The sampling scheme should identify critical areas of product contact or manufacturing activities. Volume requirements may vary considerably with the manufacturing application; Microtest specialists can suggest appropriate ranges based on the specific case. Questions of frequency also vary with application, and even to a certain extent with industry: pharmaceutical manufacturers face stricter requirements than medical device makers. However, even the latter must beware of undersampling. This is true even though many sampling schemes and/or control parameters are verified somewhat infrequently, such as quarterly or semiannually as set forth in ISO 14644.6 One category of problems often encountered is seasonal. Factors as subtle as staffers dry skin in winter, or outside pollen blooms in spring and fall, can greatly affect the yeast, fungal, or bacterial bioburden transported into the manufacturing environment. In addition, infrequent sampling can make it much harder to pinpoint exactly when a specific contamination occurred, and thus more difficult to identify and eradicate the source. Microtest can assess each unique environment and operation to determine the frequency of testing best suited to the individual site. Obviously, this is an area where the expense associated with purchasing, validating, and maintaining sampling equipment, plus buying supplies and training personnel, often would be prohibitive for even a larger manufacturing facility. Microtest offers an attractive opportunity to draw on resources and expertise that are too expensive to staff internally.

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VALIDATION MANAGEMENT
Microtest has developed innumerable monitoring programs, internally and for clients, that pass regulatory muster in a cost-efficient manner. Each new project can thus emulate the best practices learned in a hundred other similar efforts. However, each environmental plan is closely customized to the precise needs of each unique new manufacturing process and facility. ISO 146447 offers an overview of important parameters of performance. It also provides guidance including requirements for startup and qualification. In broad outline, initially, both as-built and at-rest testing must be accomplished. HEPA systems and other filtration measures must be tested in operation. Disinfection and HEPA procedures must be demonstrated to be under mandated control. Finally, three consecutive operational phases must be run, with the maximum planned number of personnel present in the area, performing, for example, simulated filling operations. In these initial phases, vendor responsibilities and agreements need to be clearly defined, managed, and documented to avoid costly retesting. For example, certification of newly constructed clean room facilities must be approached with special rigor. Sometimes manufacturers or builders attempt to certify their own work. This sends up an instant red flag for regulators. Veterans in the field have encountered cases where a facility supposedly certified to ISO Class 6 turns out to fall well short of the associated requirements. Entire production runs are threatened if audits find environmental contamination due to improperly built and inadequately certified facilities. Microtest offers reputable, objective third-party certification that both manufacturers and regulators can trust. Maintaining a clear understanding of regulatory requirements and managing vendor activities effectively shortens project timelines, reduces expenses, and accelerates production. ISO 14644 offers manufacturers only a broad overview of important performance parameters, with some guidance on requirements for startup and qualification. Microtest is able to streamline the entire process by combining expertise with a wide range of services. Unlike some vendors, it also stays with each project until any and all problems are resolved. The company offers a tried-and-true approach that minimizes the time and stress involved with project management and completion..

STERILIZATION PROGRAMS
Coordinating multiple programs to select the proper sterilization method is probably the most common example of how environmental control can impact other efforts in an organization. Selecting the most appropriate environmental monitoring and terminal sterilization programs must be a function of product materials (for example, a given material may be more suitable for sterilization by gamma rays than by ethylene oxide exposure). It should also take into account the level and nature of both the environmental and product bioburden. Indeed, theres a growing awareness among device manufacturers of the important relationship between their environmental monitoring and sterilization programs. This is especially true given the rising popularity of the VDmax method8 for sterilizing products. In fact, ISO 111379 and TIR 3310 all refer to the need to have an environmental monitoring program in place. The VDmax method for sterilization validation and control was developed by major companies in the industry. These large, well-established manufacturers had voluminous historical data regarding the normal ranges of environmental and product bioburden. It was easy to document justifications for using VDmax, since they could review long-term trends and had a good understanding of what could be considered a state of control. Experienced manufacturers could feel confident that the environmental programs they had in place were sufficient to support product bioburden control, reducing the potential of verification dosing failures. Today, more and more startups and component manufacturers use this preproven method on new product validations.

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COSTS
The above example of VDmax program integration reduces the amount of product required during quarterly dose audit testing, which in turn cuts the annual cost of product release testing. This makes the method especially attractive to startup manufacturers. However, the method is not always the best fit for every manufacturer especially companies with limited experience of controlling bioburden. AAMI TIR 33-2005 states that this method cannot be used when the estimated average bioburden for product is greater than 1000 colony-forming units (cfu). Cost and/or product savings can also vanish quickly during quarterly audits when problems due to high bioburden are encountered. Its important to remember that the verification dose is performed at a sterility assurance level (SAL)11 of 10-1, and on a statistically smaller sample set. An influx of an unobserved resistant organism can ultimately result in retests, if not revalidation to another method, even in situations where the bioburden count itself does not increase over historical levels. This makes understanding the nature of the typical bioburden as important as the levels themselves. Trending seasonal bioburden variations and identifying in-house isolates are two examples of how to gain this understanding. For situations such as these, Microtests qualification of its identification equipment has proven invaluable. It is currently one of the few testing laboratories in its field to maintain not one but two advanced MicroSeq DNA sequencing systems by Applied Biosystems for microbial identification. The result is perhaps the fastest, most cost-effective identification results in the industry an obvious advantage in resolving environmental excursions and maintaining control.

CRITICAL FACTORS
A number of other factors factors not always obvious to manufacturers, but earning top-of-mind awareness from Microtest specialists are integral parts of any bioburden control. Raw materials: Precautions should be taken to ensure that external bioburden does not travel into production areas along with components and materials. These materials should typically be removed from their original shipping containers, cleaned, and stored for staging in controlled areas within or adjacent to manufacturing suites. For example, every effort should be made to eliminate cardboard and paper products from the controlled environment, since these often prove major vectors for fungal spores. Process flow should be clearly defined and qualified. Adhering to the plan helps in avoiding surprises and dealing with unknowns. Personnel activities and hygiene: Procedures should be written and posted to mandate proper gowning, handwashing, and other basic microbiological control methods to minimize contamination from manufacturing personnel and their activities. Microtest is well-experienced at performing smoke studies to correlate airflow concepts as simple as placement of equipment and personnel with the risk of product contamination; visuals from those smoke studies can be used in protocols for personnel training. Training documentation should be in place for all personnel working in the manufacturing area. For example, it is common to require manufacturing personnel to correctly execute a gowning validation, using touch plates or swabs, before they are allowed to work in a controlled environment. An understanding of what types of house garments are appropriate to the specific activities and environment is important as well. This issue can impact cost and operator performance in addition to environmental control. Housekeeping: As with personnel hygiene, procedures and training documentation should be written and posted to regularize housekeeping methods. Close attention should be paid to cleaning materials such as mop heads and disinfectants, as well as to frequency of cleaning and documentation of cleaning activities. Microtest has worked with most commercially available disinfectants in cleaning, disinfectant validation, and challenging inhouse isolates. The company also has long experience providing clients with cleaning efficacy studies, disinfectant rotation programs, and use-dilution expiry protocols. General training: Even personnel whose work may be directly affected by microorganisms often have difficulty conceptualizing their presence. Microbiology is a science whose individual objects of study are out of sight and

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therefore out of mind. A general microbiology training course can be extremely valuable for operators, technicians, and others whose duties may bring them into controlled environments. Awareness is the key to control.

THE BENEFITS OF EXPERIENCE

Almost by definition, Microtest provides a level of problem-solving expertise thats hard to find within internal manufacturing staffs. The companys environmental specialists deal exclusively with testing programs every day, across a wide range of facilities and applications that face a vast array of environmental challenges. They cultivate a well-trained eye for troubleshooting thats simply impossible to develop on a single site. They know where to look for possible contamination vectors, from the staffs personal belongings to inadequately screened raw materials or supply containers to hidden flaws in heating, ventilation, and air conditioning systems. (The company even offers environmental monitoring of a facilitys compressed gas lines unexpected but not uncommon sources of contamination.) Microtest testing inspections, procedures, and equipment quickly and efficiently discover, identify, locate, and help resolve environmental challenges with unmatched speed and efficiency.

CONCLUSION
Unfortunately, there is no single reference document that U.S. manufacturers may rely upon to help them design, validate, and demonstrate room class compliance. Nor, given the monumental scope of the task, is it likely that one will be drafted anytime soon. However, the ISO 14644 series and ISO 14698 documents have eased the task considerably, and are recommended as valuable resources for all manufacturers. Manufacturers should step back and look at the manufacturing process, people, and environment as a whole when drafting validation programs. Defining traffic patterns and identifying and limiting product and personnel contact areas can help attain a solid understanding of microbial control. Microtest Laboratories offers reliable, accurate programs for testing of product bioburdens; viable aerobic, anaerobic, or fungal microorganisms; and nonviable air particulates. The companys expertise at characterizing, controlling, and understanding environmental bioburden levels and trends are the cornerstones to defining and implementing a solid environmental monitoring program which fully supports sterilization validation and release activities.

References 1. Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practices 2. USP <1116>, Microbiological Evaluation of Clean Rooms and Other Controlled Environments 3. Volume 4: 2008, EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 1: Manufacture of Sterile Medicinal Products 4. ISO 14644-1: 1999, Cleanrooms and associated controlled environments: Part 1: Classification of air cleanliness 5. ISO 14698-1: 2003, Cleanrooms and associated controlled environments: Part 1: Biocontamination Control General Principles and Methods 6. ISO 14644-2: 2000, , Cleanrooms and associated controlled environments: Part 2: Specifications for testing and monitoring to prove continued compliance with ISO 14644-1 7. ISO 14644-4: 2001, Cleanrooms and associated controlled environments: Part 4: Design, construction, and start-up 8. VDmax: Maximum acceptable verification dose for a given bioburden and verification dose sample size 9. ISO 11137-1:2006 Sterilization of health care products Radiation Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices 10. AAMI TIR 33:2005 Sterilization of health care products Radiation Substantiation of a selected sterilization dose Method VDmax 11. Sterility Assurance Level: The probability of a microorganisms being present on a product unit after sterilization

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About Microtest Microtest is a leader in testing services and contract manufacturing for medical devices, pharmaceuticals, and biotechnology. The company was founded in 1984. Its expertise and flexible processes enhance product safety and security, speed time to market, and minimize supply chain disruption. Mictrotests unique single-source capability to provide testing and manufacturing solutions allows the company to support a full pharmaceutical or medical device product release. Facilities in Agawam, Massachusetts, U.S.A. include state-of-the-art aseptic manufacturing areas; analytical chemistry, microbiological, and virological laboratories; Class 100 clean rooms; onsite steam and ethylene oxide sterilization, plus depyrogenation capabilities; purified water systems; and voice/data systems.

About the Author With experience in hands-on regulatory microbiology and contract laboratory operations since 2001, Steven Wieczorek leads Microtests environmental testing, monitoring, and certification groups. Mr. Wieczorek holds a B.S. degree in microbiology from Springfield College, Massachusetts. He can be reached at 413-786-1680, extension 199, or by e-mailing swieczorek@microtestlabs.com.

www.microtestlabs.com 1-800-631-1680 1-413-786-1680 fax: 1-413-789-4334 Microtest Laboratories, Inc. 104 Gold St P.O. Box 848 Agawam, MA 01001 Microtest is a trademark of Microtest Laboratories, Inc. All other brands may be trademarks of their respective holders. 2008 Microtest Laboratories, Inc. All rights reserved. Printed in U.S.A. 0850025 11/08

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