Validation Requirements for Medical Device Manufacturing Controlled Environments

By: Scott Mackin
December 2004

Industrial sterilization and contamination control are critical in medical device manufacturing. This article reviews sterilization standards, FDA requirements, and critical factors in controlled environments.

Challenges Facing Manufacturers—Just What is Required ?
Having assisted scores of medical device manufactures in designing, implementing, and maintaining both their sterilization and environmental monitoring programs, we have found that the biggest challenge for the manufacturer is determining just what exactly is required. Device manufacturers have historically been forced to piece together a strategy which is coherent and defensible by choosing bits and pieces from an array of different standards, guidance documents, and corporate policies. For anyone other than a device manufacturing veteran, the task is daunting, and often times, no concrete program is implemented. Frequently, when programs are implemented, there is little confidence in their practicality or regulatory muster. When production operators do not buy into the value of the program, it often transitions to a system of documenting control failure rather than a program which demonstrates continued control and compliance.
Typically, larger companies will already have solid programs in place for commissioning new production areas, continued monitoring, and sterilization validation. Addi tionally, since many of these companies are experienced in considering and satisfying a melee of regulatory environments in order to market their products globally, their programs tend to be more comprehensive.
Particulate Characterization: Viable vs. Non-Viable
Since the early days of Federal Standard 209 (FS 209), requirements for testing air cleanliness and/or assigning cleanliness classes to clean zones, using measured levels of non-viable particulates, have been well defined. Initially, microbiologists and regulatory professionals struggled to draw some correlation between the levels of non-viable particles and viable particles present in the environment but a general consensus was reached acknowledging that no direct relationship could be defined.
Determining just what satisfies the microbial sampling requirement called out in many standards is often an ambiguous matter, especially in Class 10,000 (ISO Class 7) and 100,000 (ISO Class 8) areas. Since FS 209 has been sunset, the ISO 14644 series of documents have taken its place. ISO 14644 [1] is currently recognized as the worldwide standard for designing and validating controlled environments. The drafting of the ISO 14698 series of documents has provided manufacturers with concrete guidance in setting up the microbial portions of their programs. Still, the ISO 14698 (microbial) document stops short of providing a definitive method for determining just how much microbial sampling is sufficient. Many manufacturers elect to utilize the same calculation for their microbial sampling that is set forth in 14644 to sample for non-viable particulate. Even so, this still leaves the questions of what sample locations in the environment are most critical and what type of organisms (aerobic, anaerobic, fungal) must be recovered. This is open to interpretation and written justification must be provided in the overall environmental monitoring plan. Unfortunately, as sterilization validation programs rely more and more upon bioburden control and monitoring, this missing piece becomes even more critical.
Sample Plans: Written Justification vs. Selecting Sample Frequencies and
Volumes from Menus

Regulatory folks would almost always prefer to defer to a table or calculation for determining these parameters. When they are not available, the manufacturer must design their environmental monitoring scheme by identifying critical sampling areas such as product contact or manufacturing activities. The tendency is to err on the side of over-sampling. At first glance, this sounds like an easy solution but for many manufacturers it is simply not feasible from a cost or manpower perspective. The expense associated with purchasing, validating, and maintaining sampling equipment, supplies, and training personnel is often prohibitive especially because many sampling schemes and/or control parameters are verified somewhat infrequently, such as quarterly or semi-annually as set forth in ISO 14644 [2], especially in Class 100,000 (ISO Class 8) areas.
Validation: Controlling Cost and Validation Data
Before a room is commissioned, draw a flow chart that outlines which data is required for validation, and what the source for the data will be. Vendor coordination, responsibilities, and agreements need to be clearly defined and documented to avoid costly retesting. For example, during HEPA filter installation, most vendors will scan the filters and seals for leaks. This data is part of what is required in order to assign an ISO class designation to an environment; be sure to identify exactly what each vendor’s responsibilities are, what data they may or may not be generating, and whether it should be included in your qualification documentation. This can save both time and expense. ISO 14644 [3] offers an overview of important parameters of performance. It also provides guidance including requirements for start-up and qualification. Keeping the project on a timeline also helps to get your cleanroom online on time and to coordinate testing and equipment installations to coincide with the three ISO occupancy states.
Sterilization Method Selection: Coordinating Both Programs
The method of selecting the most appropriate sterilization method should not only be product material specific (gamma vs. EO) but should also be specific to the level of bioburden on the product and within the facility. There seems to be a growing awareness among device manufacturers that there is an important relationship between their environmental monitoring and sterilization programs. It comes down to bioburden and control of that parameter. This is especially true given the rising popularity of using the VDmax method for sterilizing products. In fact, ISO 11137 [4], 11737 [5], 13409 [6], and TIR 27 [7] all refer to the need to have in place an environmental monitoring program.
The push to use VDmax [8] initially involved mostly larger, well established companies. These were manufacturers with plenty of historical data regarding the normal ranges of environmental and product bioburden. It was easy to document justification for using the newer method. Experienced manufacturers could feel confident that the programs they already had in place were sufficient to support product bioburden control, reducing the potential of verification dosing failures. These days, we are seeing more and more start-ups and component manufacturers using the VDmax method on new product validations.
Impact on Cost
The use of VDmax significantly reduces the amount of product required during quarterly dose audit testing, which reduces the cost of testing. This makes the method especially attractive to start-up manufacturers. However, the method is not always the best fit for everyone, especially for companies without experience in controlling bioburden. AAMI TIR 27-2001 [7] clearly states that this method cannot be used when the estimated average bioburden for product is >1000 cfu. Cost and/or product savings can also quickly vanish during quarterly audits if problems due to high bioburden are encountered. It’s important to remember that the verification dose is performed at an SAL [9] of 10-1, and on a statistically smaller sample set. An influx of undetected resistant organism can ultimately result in retests, if not revalidation to another method, even in situations where the bioburden count itself did 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 a couple of examples of how we see manufacturers do this.
Critical Factors
There are a number of other factors which are an integral part to any bioburden control that are not always obvious to manufacturers.
Raw Materials: Precautions should be taken to ensure that external bioburden does not travel into the 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 reduce or eliminate cardboard and paper products from the controlled environment.
Personnel Activities and Hygiene: There should be written and posted procedures for support of operations regarding proper gowning, hand washing, and of course basic microbiological principles involved in minimizing contamination from manufacturing personnel and their activities. Concepts as simple as where to stand while performing a particular function can have a major impact both on product and environmental bioburden. Training documentation should be in place for all personnel who will work in the manufacturing area. For example, it is common to require manufacturing personnel to execute some type of gowning validation, using touch plates or swabs, before they are deemed competent to work in the controlled environment.
Housekeeping: Similar to personnel hygiene, there should be written and posted procedures and training documentation. Close attention should be paid to cleaning materials such as mop heads and disinfectants, frequency of cleaning, and documentation of cleaning activities.
Unfortunately, there is not yet a single reference document for manufacturers to rely upon to design, validate, and demonstrate room class compliance. It’s not likely that one will be drafted any time soon. As anyone who’s been involved in the validation and monitoring process knows, the task would be monumental. The ISO 14644 series and the ISO 14698 documents have eased the task enormously and are indispensable resources for manufacturers of terminally sterilized products. The key is to bear in mind at all times that it’s really all about bioburden. We must step back and look at the manufacturing process, people, and environment as a whole when drafting our validation programs. By defining traffic patterns and identifying and limiting product and personnel contact areas, we can attain a solid understanding of bioburden. 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.
1 ISO 14644, Cleanrooms and associated controlled environments: Part 1: Classification of air cleanliness
2 ISO 14644, Cleanrooms and associated controlled environments: Part 2: Specifications for testing and monitoring to prove continued compliance with ISO 14644-1
3 ISO 14644, Cleanrooms and associated controlled environments: Part 4: Design, construction and start-up
4 ISO 11137: 1995, Sterilization of health care products: Requirements for validation and routine control—Radiation sterilization
5 ISO 11737-3:2004, Sterilization of medical devices: Microbiological methods: Part 3: Guidance on evaluation and interpretation of bioburden data
6 ISO/TS 13409:2002, Sterilization of health care products: Radiation sterilization: Substantiation of 25 kGy as a sterilization dose for small or infrequent production batches
7 AAMI TIR27:2001: Sterilization of health care products: Radiation sterilization: Substantiation of 25 kGy as a sterilization dose—Method VD max
8 VDmax: Maximum acceptable verification dose for a given bioburden and verification dose sample size.
9 Sterility Assurance Level: The probability of a microorganism being present on a product unit after sterilization
Scott Mackin is Manager of Technical Sales at MicroTest Laboratories Inc., 104 Gold Street, P.O. Box 848, Agawam, MA 01001. He can be reached at 413-786-1680 or at

No comments: