RMMs and the Regulatory Environment

Introduction
New! Recent Policy Changes for Advanced Therapy Medicinal Products (ATMP, gene and cell therapy)
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:

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:

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.

The CFU vs. New RMM Signals

RMMs that do not rely on the growth of microorganisms may recover a higher number of organisms when compared to conventional growth-based methods. As such, there has been some debate on whether non-colony-forming-unit (CFU) signals, such as a fluorescent unit, can be compared with the traditional CFU.

USP <1223> addressed this potential challenge. The chapter states that attempts to use statistics to compare the CFU results to signals arising from biochemical, physiological, or genetic methods of analysis may have limited value because the different methods used cannot be expected to yield signals that could be compared statistically in terms of mean values and variability. As such, the chapter concludes the CFU cannot be used as acceptance criteria and it is the user’s responsibility to propose values (supported when necessary by scientific literature) that they can demonstrate are appropriate for the alternative method.

However, the chapter contradicts this position in its Equivalence section. Specifically, the section on Option 3 (Results Equivalence) states, "[r]eports on the use of alternative non-growth-based methods have shown that they may produce significantly higher cell count estimates than a growth method that reports outcomes in CFU. In this case, the analyst could use a calibration curve showing a correlation between the two methods in the product specification range."

If you experience a situation in which a non-growth-based RMM provides a greater recovery than a conventional growth-based method, but the results are still within the acceptable specification or acceptance level, then no changes to the specs may be necessary. However, if the RMM provides a significantly greater recovery in which the CFU spec would not be met, it may be possible to correlate the RMM signal to the control CFU counts and statistically justify a change in the specification to match the new signal and new recovery levels. Note that a sufficient amount of data may be needed to justify this change and discussions with regulatory authorities may be warranted, especially ion the new specs would impact a previously-approved product submission.