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Developing environmental monitoring programs for an ever-changing regulatory landscape: designing and implementing effective microbial control for medical device manufacturers.

It is critical that manufacturers of medical devices and pharmaceuticals meet and exceed regulatory compliance standards for industrial sterilization and contamination control. While there is no "one standard fits all" approach, there are key elements of a best-practices environmental testing program. They include U.S. Food and Drug Administration (FDA) requirements, sterilization standards, proper certification and validation processes, and other critical factors in maintaining controlled environments.

What's Required?

Meeting compliance requirements, while attempting to respond to regulatory demands from the FDA and European Pharmacopoeia, may be the greatest challenges manufacturers face. In the wake of this challenge, how will manufacturers design, implement, certify, and maintain correct sterilization and environmental monitoring (EM) programs?

For parenteral manufacturers, environmental control parameters in U.S. regulations are stringent. The collaborative effort between the FDA's Office of Compliance in the Center for Drug Evaluation and Research, the Center for Biologies Evaluation and Research, and the Office of Regulatory Affairs 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 also is given to environmental control. In addition, U.S. Pharmacopeia (USP) Chapter 1116, titled "Microbiological Evaluation of Clean Rooms and Other Controlled Environments," offers guidance that can be used as a framework for developing personnel training and environmental monitoring programs. (2) This chapter also reviews guidelines, equipment, and statistical methods that have been adopted as industry standards. Parenteral Drug Association document TR13, "Fundamentals of a Microbiological Environmental Monitoring Program," also is a mainstay, offering solid guidance to all categories of manufacturers.

While the establishment of a reliable environmental monitoring program is essential, it does present problems for all pharmaceutical and medical device manufacturers. With the lack of consistency stemming from different standards, guides, and corporate policies, it is difficult to create and implement a comprehensive environmental monitoring program.

When a manufacturer does design and implement a local program, it usually confronts a lack of confidence in its practical application or chances of passing regulatory inspection. For instance, production operators uninformed about program rationales may balk at new gowning procedures or 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. As a result, program failure has unfortunate consequences for efficient, ongoing, profitable manufacturing and production.

Future recalls generally can be avoided with proper planning and implantation.

In Europe, the situation is somewhat clearer, but still evolving. U.S.-based or multinational manufacturers who wish to market medical devices or pharmaceutical products in the European Union (EU) must meet the requirements set forth in the EU's Good Manufacturing Practice (GMP) Annex 1.3 While some requirements substantially are the same as those found in the United States, others differ.

With ever-changing jurisdictions and regulatory demands, statutes and standards continually are evolving. To stay in compliance, manufacturers must remain up to speed on the evolving regulations worldwide.

While keeping up with regulations is paramount for manufacturers, to do so properly would entail researching, creating, carrying out, and constantly updating environmental testing and procedures. The lack of resources such as staff, time, experience and effort usually hamper these efforts.

A growing number of large and small manufacturers now look for third-party contract testing organizations instead of trying to internally manage a patchwork of multiple testing vendors. Such an approach can provide a manufacturer with a simple, turnkey solution that can improve both safe product release and time to revenue. A thorough risk analysis program is paramount to developing a robust EM program.

Viable vs. Non-Viable Particulates

According to ISO 14644-1, cleanliness classes are assigned to clean zones based on the levels of nonviable particulates. (4) Currently, 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 non-viables, this remains the approved, real-time assessment of environmental control.

With a multitude of standards and guidelines, what is required for the microbial sampling requirements often is unclear. With differing industries, manufacturing processes, and sub processes, no industry wide accepted level of environmental bioburden has been developed. While no accepted level has been created, a few organizations are working to develop one based on industry and ISO classification.

Currently, with this lack of standards, some facilities are opting to reference EU Annex 1, which provides guidance in relation to viable limits and acceptance criteria. Even some facilities that do not manufacture products for overseas use these limits in their environmental monitoring. Risk profiling can be an effective tool to determine which areas to sample.

Establishing limits for each manufacturing process and facility that can be applied and tested is a critical step in maintaining a controlled environment. Once these limits have been established, they should be evaluated periodically and adjusted accordingly, typically every 12 months after a year's worth of trended data can be reviewed. Outliers typically are not included when setting alert and action limits as they negatively can impact accurate limits from being generated.

ISO 14644 currently is 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 14698 document series has provided manufacturers with some concrete guidance in setting up the microbial portions of their programs. (5) However, it stops short of providing a definitive method for determining just how much microbial sampling is sufficient.

As part of the overall environmental monitoring plan, written justification of the manufacturer's choice of standard to meet must be provided. If an audit is to occur, regulators will look to see if the appropriate standard matches up with the designated program, then evaluate if the program has met the standard. In essence, is the controlled environment designed to maintain an appropriate cleanliness level? And does it successfully perform as designed?

For example, many manufacturers elect to use 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 more and more sterilization validation programs rely upon bioburden control and monitoring, these missing pieces become even more critical. The FDA is concerned that sampling areas are not justified by statistical or sense rationale.

Manufacturers can partner with recognized compliance vendors that offer nonviable and viable air and surface sample testing of controlled environments. All testing is then performed under their Quality Systems Regulation (QSR)/GMP framework.

Sampling Plans

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, it's 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; environmental monitoring 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 manufacturers. However, even the latter must beware of under-sampling. 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 manufactures encounter is seasonal. These outside factors include staffers' dry skin in the winter or outside pollen blooms in spring and fall. The influx of outside contaminents greatly can 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 make it more difficult to identify and eradicate the source. Assess each unique environment and operation to determine the frequency of testing best suited to the individual site.

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 large manufacturing facility. Qualified testing organizations offer an attractive opportunity to draw on resources and expertise that are too expensive to staff internally.

Validation Management

ISO 14644 offers an overview of important parameters of performance. It also provides guidance including requirements for startup and qualification. (7)

First, to determine performance, both as-built and at-rest testing must be carried out. This entails testing the high-efficiency particulate absorption (commonly referred to more simply as HEPA) and other filtration systems, operation, and disinfection procedures. Additionally, three consecutive operational phases must be run, with the maximum planned number of personnel present in the area performing simulations of day-to-day duties.

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 immediate 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.

Maintaining a clear understanding of regulatory requirements and managing vendor activities effectively shorten project timelines, reduce expenses, and accelerate production. ISO 14644 offers manufacturers only a broad overview of important performance parameters while offering some guidance on requirements for startup and qualification.

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 also should take into account the level and nature of both the environmental and product bioburden. Indeed, there's a growing awareness among device manufacturers of the important relationship between their environmental monitoring and sterilization programs. Some bioburden microorganisms can cause recalls based on their resistance to the sterilization method.

This especially is true given the rising popularity of the VDmax method for sterilizing products. (8) In fact, ISO 11137 and Association for the Advancement of Medical Instrumentation (AAMI) Technical Information Report (TIR) 3 refer to the need to have an environmental monitoring program in place. (9,10)

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 have 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, an increasing number of startups and component manufacturers use this pre-proven method on new product validations.

The Costs

The integration of a VDmax program, as previously detailed, reduces the amount of product needed for 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 1,000 colony-forming units.

Cost and/or product savings also can vanish quickly during quarterly audits when problems due to high bioburden are encountered. It's important to remember that the verification dose is performed at a sterility assurance level of [10.sup.-1] and on a statistically smaller sample set. (11) An influx of an unobserved resistant organism ultimately can 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.

Critical Factors

A number of other important factors are integral parts of any bioburden control.

They include:

* Raw materials: Precautions should be taken to ensure that external bioburden does not travel into production areas along with components and materials. These materials typically should 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 clearly be 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, hand washing, and other basic microbiological control methods to minimize contamination from manufacturing personnel and their activities. Smoke studies can be performed to correlate airflow concepts. These can be as simple as identifying the proper placement of equipment and personnel to minimize the risk of product contamination. Video from those smoke studies also 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 and documentation of cleaning activities.

* 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 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.

Unfortunately, there is no single reference document that U.S. manufacturers may rely upon to help them design, validate and demonstrate clean-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 their processes, 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. This kind of risk analysis is critical to developing a robust EM program.


(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, Clean rooms and associated controlled environments: Part 1: Classification of air cleanliness

(5.) ISO 14698-1:2003, Clean rooms and associated controlled environments: Part 1: Biocontamination Control--General Principles and Methods

(6.) ISO 14644-2:2000, Clean rooms and associated controlled environments: Part 2: Specifications for testing and monitoring to prove continued compliance with ISO 14644-1

(7.) ISO 14644-4:2001, Clean rooms 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 microorganism's being present on a product unit after sterilization

Steven G. Richter, Ph.D. * Contributing Writer

Steven G. Richter, Ph.D., is president and chief scientific officer of Microtest Laboratories Inc. ( Richter founded Agawam, Mass.-based Microtest Labs in 1984 after a distinguished career at the U.S. Food & Drug Administration. Under his leadership, Microtest has provided the medical device, pharmaceutical and biotechnology industries with premier testing and manufacturing support. He can be reached at (413) 786-1680 or
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Title Annotation:Environmental Monitoring
Author:Richter, Steven G.
Publication:Medical Product Outsourcing
Date:Mar 1, 2014
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