Introduction

In addition to the FDA and EMA, a number of regulatory authorities around the world have adopted alternative and rapid microbiological methods. In some cases, formal policies have been developed, and/or local pharmacopoeias have written chapters and guidance on validation and implementation.

However, there are regulatory agencies that may not recognize the use of alternative and rapid methods. For example, there could be a potential conflict when an alternative or rapid method is approved by one regulatory authority but not another. In this instance, products that are marketed in countries where new methods are not recognized may need to be tested using conventional or compendial procedures. As such, firms should develop appropriate strategies to accommodate the requirements by different regulatory authorities.

The following sections provide an overview of alternative and rapid method expectations for the rest of the world.

World Health Organisation

WHO's Annex 6, GMPs for Sterile Pharmaceutical Products, has been revised to include guidance on the use of rapid microbiological methods. The annex states, "The use of rapid microbiological methods to replace the traditional microbiological methods, and to obtain earlier results on the microbiological quality of, for example, water, the environment or bioburden, could be considered if appropriately validated and if a comparative assessment of the proposed rapid method is performed against the pharmacopoeial method."

Australian Therapeutic Goods Administration (TGA)

The Australian Therapeutic Goods Administration (TGA) has worked with the industry in supporting the validation and implementation of RMMs. During the 2010 PDA 5th Annual Global Conference on Pharmaceutical Microbiology, Dr. Vivienne Christ (Chief Microbiologist, TGA Office of Laboratories and Scientific Services) discussed her agency's policies and validation guidance that they follow with regard to rapid methods.

The TGA utilizes relevant sections in the Ph. Eur. and British Pharmacopoeia (BP) in that these compendia also allow for the validation of alternate methods. They also rely on the validation guidance from USP Chapter <1223>, Ph. Eur. Chapter 5.1.6, PDA Technical Report #33, and ISO 17025 (validation of non-standard methods), to name a few. From the legislative perspective, the TGA also turns to the TGA GMPs, which allows for other acceptable methods as long as they are shown to be equivalent to those in the GMP guide, as well as Annex 11 (computer validation) and Annex 15 (IQ, OQ, PQ). However, unlike other regulatory agencies, such as the FDA, the TGA only “quietly” embraces new technologies, and to date, they have not communicated a formal statement or policy.

The TGA views RMMs to be used in a wide range of applications, including finished product testing and in-process testing. Validation expectations include a DQ, IQ and OQ performed by the vendor, and the PQ (jointly performed by the vendor and user) and verification of the method using actual product. Testing on potential interfering substances should be performed, and for users intending to develop a matrix testing strategy (i.e., grouping products together), a justification for doing so should be provided. Furthermore, there is the expectation that equivalence or superiority to classical method is demonstrated, as well as the computer validation of software. For a qualitative method, the validation should address specificity, sensitivity, ruggedness, robustness, and equivalence. For quantitative tests, the user should demonstrate accuracy, precision, ruggedness, robustness, equivalence sensitivity, linearity, and specificity.

Japanese Pharmaceuticals and Medical Devices Agency (PMDA)

The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) has also supported the implementation of RMMs, and several approvals have already been realized, including those for rapid sterility testing. During the 2010 PDA 5th Annual Global Conference on Pharmaceutical Microbiology, Dr. Tsuguo Sasaki (GMP Expert, Office of Compliance and Standards) discussed his agency's policies and validation guidance that they follow with regard to RMMs. The PMDA will work with companies in the development of RMM strategies for use in Japan. For example, in a number of cases, it may not be possible to detect microorganisms in stressed environments, such as purified water and reverse osmosis test samples. Therefore, it is hoped that more rapid and continuous monitoring methods are developed for microorganism detection in pharmaceutical-grade water systems. In the past, the PMDA followed a similar strategy for reviewing RMM validation submissions as the U.S. FDA currently does. However, it would be appropriate to have the relevant conversations with the PMDA prior to initiating any RMM validation and implementation strategy, as expectations may have changed with the introduction of RMM chapters within the Japanese Pharmacopoeia. The Japanese Pharmacopoeia has published the following chapters related to the validation and use of alternative and rapid methods:

• Rapid Microbial Methods
• Rapid Identification of Microorganisms Based on Molecular Biological Method
• Rapid Counting of Microbes using Fluorescent Staining
• Bacterial Endotoxins Test and Alternative Methods using Recombinant Protein-Reagents

Additional references to the use of alternative and rapid methods have been included in the following JP chapters:

• QC of pharmaceutical manufacturing water
• Microbial evaluation of processing areas
• Sterility, Microbial Limit, Antimicrobial and Preservatives Effectiveness test
• Raw material acceptance test

For example, the 4.06 Sterility Test and 5.02 Microbial Limit Test chapters have been revised to state, "[a]lternative microbiological procedures, including rapid methods, may be used, provided that they give a result equal to or better than that of the Pharmacopoeial methods."

The chapter on Preservatives-Effectiveness Tests (G4-3-170) now includes the following, "[a]lternative microbiological procedures, including an automated method, may be used for the products of Categories I and II, if they give a result equal to or better than that of the Pharmacopoeial methods."

And the chapter on the Quality Control of Water for Pharmaceutical Use (GZ-2-172) now states, "[t]o adopt a rapid microorganism detection technique, confirm in advance the microbial counts obtained by such techniques are equivalent to those obtained by incubation-based monitoring techniques."

Indian Pharmacopoeia Commission

The Indian Pharmacopoeia has developed a guidance document on approaches to the use of alternative microbiological methods for qualitative, quantitative and identification tests. The document is for information only and is not an official requirement. The scientific principles and validation strategies presented are generally based on the recommendations provided in USP <1223> and Ph. Eur. 5.1.6.

Chinese Pharmacopoeia Commission

The Chinese Pharmacopoeia published Chapter 9201: Guidelines for the Validation of Alternative Microbial Detection Methods for Pharmaceuticals. It provides guidance for determining whether methods can be used as alternatives to compendial microbiological testing method for pharmaceuticals. The chapter states that some methods have the potential for real-time monitoring to take corrective measures early in production and to guide GMPs, and that validation of the methods is required, which should be proved to yield results equivalent to, or better than, the results generated by the compendial method.

Other Agencies and Compendia that are Developing Guidance

Brazil, other LATAM countries and Korea are currently working on guidance documents for the validation and implementation of alternative and rapid methods. When formal guidance is published, we will update this page as information becomes available.