This year’s meeting started with a discussion on the role of the European Pharmacopoeia in the use of modern rapid microbiological methods.
Emmanuelle Charton, EDQM, provided an overview of the history and objectives of Chapter 5.1.6, as well as other chapters within the Ph. Eur. that encourages the use of rapid or alternarive microbiological methods. For example, Ph. Eur. 2.6.12 and 2.6.13 states that alternative microbiological procedures, including automated methods, may be used, provided that their equivalence to the Pharmacopoeia method has been demonstrated. Chapter 2.6.7 states that nucleic acid amplification techniques (NAAT) may be used as an alternative to one or both of the other Mycoplasma methods after suitable validation. Chapter 2.6.27, Microbiological control of cellular products, also allows the procedure to be carried out manually or using an automated system.
Next, Hans van Doorne, University of Groningen, provided preliminary results from a questionnaire that was sent to the industry and to European Licensing Authorities (via National Pharmaceutical Authorities; NPA) with respect to the existing Chapter 5.1.6. The questionnaire asked if the current chapter is appropriate and whether a revision is necessary. Because the enquiry is ongoing, the MMM working party has not finalized any decisions, and the Ph. Eur. Commission has not discussed the results, only preliminary information was provided during this presentation.
Question: Which compendial and non-batch release methods have been replaced by alternative/rapid methods?
Response: RMMs are currently used in place of the compendial tests for sterility (2.6.1), microbial enumeration (2.6.12), specified microorganisms (2.6.13), Mycoplasma (2.6.7) and the standardization of suspensions. RMMs are also used for purposes other than batch release, including in-process control, real time release of pre-filtration bioburden, environmental monitoring, trouble shooting, microbial identification, antimicrobial assays and WFI testing.
Question: What do you consider as the strengths of the chapter?
Response: In general, the chapter applies to any new method not described in the pharmacopoeia, it is easily understandable and applicable, and it provides a road map for approval of rapid methods in the EU.
Question: Do you consider the validation example useful
Response: Both the NPA and industry considered generally view the example useful; however, it is difficult to understand and should be more aligned with the rest of the chapter. Additionally, because the section is confusing and conflicts with the previous sections, USP 1223 and PDA TR#33, it can be removed without loss of clarity.
Question: Would you favour having more examples?
Response: Most respondents stated yes. It would be helpful to provide validation examples for the main RMM technologies, and should be aligned with what is normally described in an FDA comparability protocol. Examples could also be provided where the results obtained by the new method differs significantly from the compendial method. Examples of sterility test validation was also requested, in addition to more examples on the use of statistical methods under a variety of conditions.
Question: What do you consider the weaknesses of the chapter?
Response: There is no global harmonization with other published documents (USP 1223 and PDA TR#33). It is also too prescriptive, and microbial identification methods should be separated from true rapid methods. There were also questions raised about the equivalence between the chapter and EN ISO methods.
The presentation concluded with some rationales for a revision. There is a need to address the use of alternative methods with Process Analytical Technology (PAT) concepts. Next, there needs to be a clearer distinction between methods for isolation and detection vs. methods for identification. Furthermore, there should be more distinction on the discriminative power of identification methods (Genus vs. species), an improvement and expansion of the example section, and terminology should be harmonized with international standards.
I rounded out the first session with a discussion of industry perceptions that have prevented or delayed many companies from validating and implementing RMMs. Some of these perceptions include (a) little or no regulatory guidance, acceptance or understanding of RMMs, (b) we will see things we have never seen before and our products will be at risk, (c) we will have to change our acceptance levels or specifications, (d) there is no clear guidance on validation expectations, and (e) we will realize little or no return on investment. Each of these perceptions were thoroughly discussed and dismissed, and I provided guidance on how the current worldwide regulatory framework actually encourages the qualification and implementation of RMMs.