The Chairs of the USP, Ph. Eur. and JP provided their perspectives on the current and future state of rapid methods and plans for revisions to existing monographs and information chapters.
Dr. James Akers, USP Expert Committee, explained that any new United States Pharmacopoeia referee method must be very broad in application and suitable for use with the vast majority of monograph product. Furthermore, new candidate methods must not be from a patented, single-source technology. It is also critical to be clear on the distinction between QC quality control release testing versus in-process testing and monograph requirements. Therefore, companies that desire to submit a RMM for inclusion in the USP as a referee test must take these points into consideration. USP 1223 was developed to provide guidance on the implementation/validation of alternative methods, and this chapter should be used to support the use of a RMM as an alternative to a compendial test. To clarify, RMMs and alternative methods are already allowed under USP 62, as long as they are appropriately validated. Finally, the USP is looking to the industry to comment on the existing chapter 1223 in order to support future revision processes in this area. This will be discussed in further detail in a subsequent session tomorrow (check back for my blog covering this session!).
Dr. Han van Doorne, Ph. Eur. Expert Committee, stated that the General Notices section of the European Pharmacopoeia and Chapters 2.6.12 and 2.6.13 state that alternative methods may be used as long as they have been shown to be equivalent to the existing compendial methods. Chapter 2.6.27 states that automated systems may be used for the control of cellular products (e.g., for the daily observation of sterility). A separate chapter on the use of nucleic acid technologies for the detection of Mycoplasma (2.6.7) is also available, and Ph. Eur. 5.1.6 was developed to provide guidance on the validation of alternative microbiological methods. Dr. van Doorne then discussed the committee’s plans to revise Chapter 5.1.6. They would like to add more information on Process Analytical Technology (PAT), a better distinction for methods for isolation and detection, and for microbial identification. The examples at the end of the current chapter should be improved and expanded to include the validation of ID methods. However, these examples will not appear in a future revision of the chapter, but rather, it will be published as a separate white paper in PharmEuropa. The future revision of this chapter will also include updates to technologies and applications and a greater explanation of DNA-based methods. Finally, he discussed a survey that was sent to the industry asking what companies would like to see in a revision of Chapter 5.1.6. Questions included the following: what applications have been approved for use with RMMs, do you use RMMs for testing other than batch release, would you favor more validation examples, what are the strengths and weaknesses of the existing chapter, did the chapter facilitate applications to regulatory bodies, do you consider the chapter example (Annex) useful, and what compendial methods have been replaced by a RMM.
Dr. Tsuguo Sasaki, Japanese Pharmacopeia Expert Committee, PMDA, described two new RMM chapters that are now part of the Japanese Pharmacopoeia. These include Chapter 22 (Rapid identification of microorganisms based on molecular biological methods) and Chapter 33 (Rapid enumeration of bacteria based on a fluorescence staining method). He then provided some examples of where RMM validations were not at a level that was accepted by the Pharmacopoeia. For example, an ophthalmic manufacturer submitted a validation package for a RMM with a shortened sterility test (2 weeks for the compendial method to a 1 week incubation followed by ATP bioluminescence technology). The company validated the system using soybean casein digest medium instead of a medium that would recover more stressful or injured microbes. For this reason, the submission was not approved. Dr. Sasaki then presented data demonstrating that micro-colonies of a particular organism developed on R2A medium but not on TSA (this is one reason why the original submission was rejected). Therefore, the company would be required to go back and investigate the most appropriate media for this purpose (for a strategy that has already been approved by the FDA, EMA and MHRA, please see my earlier post describing this type of validation by Jennifer Gray at Novartis).