RMMs and the Regulatory Environment

Introduction
International Conference on Harmonisation (ICH)
U.S. Food and Drug Administration (FDA)
European Medicines Agency (EMA)
Australian Therapeutic Goods Administration (TGA)
Japanese Pharmaceuticals and Medical Devices Agency (PMDA)
Regulatory Perspectives on Changing Acceptance Levels and Specifications

Changing Acceptance Levels and Specifications

Regulatory agencies will generally accept a change in a manufacturing or testing process if the change has been proven to be equivalent to or better than the system currently in place. However, some non-growth-based technologies, especially those that do not rely on the growth of microorganisms (e.g., viability or spectroscopic systems), may provide a higher count or microbial recovery as compared with conventional methods. From a regulatory perspective, this is one of the most challenging aspects of working with RMMs, because Regulatory Affairs and Quality organizations have a very difficult time grasping the possibility that:

We may be "seeing" things we haven't in the past,
the RMM measurements may be different than what we have been used to historically, such as fluorescent units or relative light units, as compared with colony forming units (CFUs), and
we won't be able to meet the existing specifications or acceptance levels and/or we may need to change our levels to reflect the data generated by the new RMM.

A number of regulatory representatives have commented on these concerns both in print and during speaking engagements at international forums on rapid methods and pharmaceutical microbiology. For example, Dr. Brenda Uratani (CDER, FDA) provided guidance on modifying acceptance levels during her presentation at the 2007 PDA Global Pharmaceutical Microbiology Meeting. She indicated that the FDA expects higher counts will be recovered when using RMM technologies, especially if the methods are more sensitive than conventional methods, and that a GMP evaluation of the new method and the results must be driven by good science. The example she provided was for active air monitoring in an ISO 5 area, where the current 1 CFU per cubic meter specification may be changed, because this specification was originally based on a less sensitive, agar-based method.

In the 2006 Hussong and Mello paper, "Alternative Microbiology Methods and Pharmaceutical Quality Control," these FDA microbiologists addressed the use of new microbiological methods, environmental monitoring, and changing acceptance levels. They provided the following position:

"If data are to be compared over time, then test methods must remain the same, which is fundamental to trend analysis. However, to accelerate data collection, methods must change. Some changes will be insignificant (and test method validation may show no difference), and some will change data greatly. Often, new methods rely on a completely different body of information; some may be direct measurements, some indirect. In either event, previous acceptance criteria may not be applicable. Therefore, implementation of newly developed, or more rapid, microbiology methods may also require establishment of new acceptance criteria. Ultimately, trending of data may be lost in order to bridge the gap between "old" and "new" data analysis."

Finally, Paul Hargreaves (MHRA) presented an overview of revisions to EU Annex 1 during the 2008 PDA/EMEA conference. During his discussion on continuous monitoring, Hargreaves stated that more excursions are found as all events are now being monitored, and that alert limits and out-of trend limits may need to be revised when implementing continuous monitoring. Although these discussions did not focus on viable particle monitoring, Hargreaves did infer that the majority of the pharmaceutical industry has not introduced 21st Century technologies for the counting of microorganisms, and that a future revision of EU Annex 1 may consider specific requirements in this area.

More recently, Hargreaves made a statement at a 2009 PDA RMM regulatory meeting following a question from the audience on this subject:

Comment: "If a RMM does not provide CFU counts but provides a new measurement (a fluorescent unit), and you have demonstrated equivalence between the two methods, and the difference in counts are relatively small (historically zeros on an active air sampling plate vs. 1 or 2 counts using the RMM), we can't use the CFU spec of zero any more because the RMM does not provide CFU data."

Hargreaves Response: "In this case it is appropriate to change the limits as long as you have documentation and a rationale for making the change."

At this same meeting, Hargreaves explained that since most organisms won’t grow on agar plates, it is expected that newer, more sensitive methods will obtain higher counts than traditional methods. Therefore, limits can be changed as long as an appropriate rationale is provided, and the rationale is explained to the inspector.

Summary

Based on the comments provided by these regulators, if it is demonstrated that a RMM recovers a higher number of microorganisms as compared with a conventional method, a correlation between the new and the old data must be well understood in order to justify any changes to existing specifications and/or acceptance levels. Therefore, discussions with the relevant regulatory authority can assist with the development of an appropriate change control strategy when modifications to existing recovery levels may need to be considered.