USP 797: Compliance and testing

By Douglas Theobald, CFM

Prior to getting started, let me say that the last article in this series, “Compliance and Documentation,” was, as I stated, in no way comprehensive. It is always challenging to provide in depth coverage of the various elements of discussion in the limited space available. I have had several individuals from as far as South America contact me requesting more information on the subject, which I have gladly provided. I encourage you to contact me if you are part of that group. There is more information and I am happy to share it with you. Now, in continuation, we will address the critical aspect of testing controlled environments.

A double standard?

The certification procedure of today's controlled environment is somewhat confusing. This is due in large degree to the number of companies that continue to test their facilities along Federal Standard 209 E guidelines as opposed to the newer ISO 14644 guidelines instituted in 1999. The reason why can be seen by a simple comparison of the two standards as they are written. Many people, including professionals, conclude that the Federal Standard 209 E was simpler and more easily understood than ISO 14644. Ralph Kraft, President of R. Kraft, Inc., Rochester, N.Y., is a friend and business associate of mine. We had a discussion about how the testing process plays out “in the real world.” I told you last time that you were in for a treat; here's what we discussed.

We will not take you through a list of comparisons with charts and graphs; however, we do recommend that it is good practice for you to review the methods and standards on your own. As professionals performing testing and certification while planning our approach to the airborne particle counting portion of the certification, we feel that it is best to go through the calculations of each guideline (FS&ISO) with the client and offer him the choice of the number of sample locations for the area being tested. For example, Fed 209 E calculates to a minimum of twelve sampling locations for a controlled environment, whereas ISO calculates to a minimum of nine locations. The typical approach is to provide a minimum of three one-minute, one-CFM (28.3 liters) samples per location as a benchmark for airborne particle sampling for better statistical reliability, in the same way laminar air flow workstations (LAFW) and isolator barriers must be tested. The testing is to be performed every six months and after any repairs, renovations or relocation.

The air sampling should not only include a test of particles per cubic foot or per cubic meter of air in the controlled environment (depending on whether you are using Fed 209 E or ISO standards); there should be testing for the number of viable organisms as well.

Can I get a witness?

Providing witness plate sampling and surface sampling on an accepted grid pattern and testing frequency within the controlled environment for volatile and non-volatile microorganisms is an excellent enhancement to controlled environment certification. In fact, this is a required portion of compliance testing for FDA, USDA, and USP facilities. This microorganism sampling should be done on a more frequent and routine basis than the airborne particle counting. The USP guideline specifically calls for the use of sterile nutrient agar plates, or witness plates. According to the first supplement of USP-NF 797 Environmental Monitoring, testing should be performed “in locations judged by compounding personnel to be the most prone to contamination during compounding activities.” These witness plate tests should be performed in controlled environments, LAFWs and Isolator barriers every month for low- to medium-risk areas and every week for high-risk areas. Areas where air turbulence is prevalent are also critical areas to test.

Set it up

Witness plates should be placed in predetermined locations throughout the controlled environment, including the buffer and ante areas, LAFWs and Isolator barriers. The exposure time to the environment is a minimum of one hour to allow the microorganisms to settle from the environment onto the surface of the medium. The plates are then covered and allowed to incubate for a period of forty-eight hours. Once the incubation time has elapsed, it is time to count the number of colony forming units (CFU). This count can be used as a baseline. If the CFUs are acceptable, the typical action limits may be approximately 50 percent above baseline for high- to medium-risk environments and 100 percent above baseline for low-risk environments. If the counts are not acceptable as a baseline, a thorough review of the integrity of the environment, procedures and personnel practices is warranted. While performing audits of controlled environments, we usually find that resolving the issue of unwanted contamination is a matter of gaining control and training personnel.

Back to the plan

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We spoke briefly before about documentation. It is necessary to have a documented plan for testing, types of tests, frequencies and action limit responses in place. The compounding personnel should be trained in the procedures of testing even if they do not directly perform the tests, as this lends to a better understanding of the critical nature of the environment and process. The personnel must understand the resulting data from the tests that are performed. We recommend that technicians have access to the analysis of the regular reports and are encouraged to review them. The environmental monitoring program for USP 797 is more focused upon the results of frequent microorganism sampling in a dynamic condition than on airborne particle counting for the cleanroom environment. Although these tests may seem to be overkill or tedious, they are essential for maintaining the ability to provide a safe product. The most critical elements for the success of a controlled environment are good housekeeping and personnel discipline. Enough cannot be said for ongoing training and retraining of personnel to assist in maintaining optimal operational efficiency in a controlled environment. We will focus on these important issues next time as we discuss personnel training as it relates to performing in a controlled environment.

Douglas Theobald is a consultant and general manager with Controlled Contamination Services LLC (San Clemente, Calif.). He can be reached at [email protected].


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