For the past two years, I have published a rapid micro methods series in each issue of European Pharmaceutical Review (EPR), with topics ranging from technology and scientific reviews, regulatory acceptance and validation strategies. In the 5th issue of 2011, EPR published a 3-article supplement that focused on RMMs, with papers from FDA's Bryan Riley, Baxter's Youwen Pan, and one of my regular series articles, this time focusing on nucleic acid and gene amplification technologies. Today, I would like to provide an overview of Dr. Riley's paper.
A Regulators View of Rapid Microbiology Methods. Bryan S. Riley, Ph.D. Senior Review Microbiologist, CDER, FDA. European Pharmaceutical Review. 2011: 16(5), 59-61.
Dr. Riley offers a powerful viewpoint on RMMs from the FDA microbiologist's perspective. Dr. Riley writes that there are numerous RMMs that are based on the growth of microorganisms as well as faster methods that do not rely on growth (and in some cases, results in real-time). He discusses various phases of rapid method implementation: technology selection, validation and regulatory communication and filing.
The first phase of selecting a RMM is to determine your user requirements. These can include time to result, whether a qualitative or quantitative methods is required, sensitivity and sample handling. It is critical to fully understand what you need the rapdi method to accomplish.
Once you have selected the rapid method, it must be validated for its intended use. Users can follow the validation guidance as provided in PDA Technical Report #33, USP chapter 1223 and Ph. Eur. chapter 5.1.6. Each of these documents describes the basics for validation, including validation parameters and acceptance criteria that might be appropriate for each parameter. And while it is important that each validation parameter be addressed, the user may not need to perform all of the work themselves. For example, ruggedness and robustness are better suited to be performed by the RMM vendor. However, the vendor can also provide additional validation test data, either by providing the data directly to the end user or by submitting the data to the FDA within a Drug Master File (DMF). In the latter, the end user would have to provide test data not covered in the DMF, as well as product-specific data associated with the RMM.
One of the validation parameters that has generated much discussion within the industry is Specificity. Here, the RMM should detect a wide range of microorganisms. but because it is unrealistic to expect the RMM to detect every possible microorganism, a combination approach is typically utilized. First, a panel of pharmacopoeia organisms can be used (e.g., see the challenge organisms required for method suitability tests in USP <71> and Ph. Eur. 2.1.16). Here, a representative of each major group of microorganisms would be covered, such as Gram positive and negative bacteria, spore formers, anaerobes, yeast and mold. Next, the user should use environmental isolates, or organisms that would pose a challenge to the RMM (e.g., slow growing organisms such as P. acnes when validating a growth-based RMM).
Another validation parameter that has caused much discussion, especially when validating a RMM for sterility testing, is the Limit of Detection (LOD). Because the conventional sterility test is, in theory, supposed to detect a single cell, Dr. Riley states that it stands to reason that the validation of a rapid sterility test also demonstrates that the proposed method has a LOD at, or very near, one microbial cell. However, there are significant technical difficulties in reproducibly inoculating a RMM system with a single, viable microbial cell. Therefore, end users have applied several approaches to deal with this issue, and these approaches have been accepted by the regulatory agencies. For example, a number of users have used serial dilutions of microbial suspensions, where the dilutions are taken down to less than one CFU in the test sample. The sample is then evaluated in the RMM. In some cases, the sample is tested in parallel by both methods, and the results from the RMM is compared with the results from the compendial method to determine if they are equivalent. In other examples, the RMM results can be used to determine a most probably limit of detection.
Even with all of the guidance for validating rapid methods, and the fact that the implementation of RMMs has slowly increased over the last few years, Dr. Riley explains that RMM usage is still the exception rather than the norm. The industry continues to question whether regulatory agencies accept RMMs and what they need to do to validate these methods. For these reasons, Dr. Riley recommends that firms communicate with the relevant regulatory authorities during the planing phases of RMM implementation to discuss validation strategies and regulatory notification requirements.
There are also regulatory filing mechanisms that can simplify the RMM implementation process. For example, the FDA allows the use of a Comparability Protocol (CP), which is a detailed written plan that demonstrates that a post approval change does not adversely affect product quality. In terms of RMMs, the CP is a validation protocol to demonstrate that the RMM is suitable for its intended use. The CP must be approved before it is used; therefore, it must be part of an original FDA product submission (e.g., NDA) or a prior approval supplement.
Dr. Riley also explains the advantages of using a CP. First, because the CP is reviewed by the FDA, deficiencies in the validation plan can be corrected prior to performing the studies, eliminating the need to repeat some or all of the testing. Next, a firm that follows the validation studies and meets the acceptance criteria as specified in the CP, a reduced reporting category can be used to notify the FDA that the method is being implemented (e.g., a Changes Being Effected [CBE-0]). Finally, the same CP can be used to subsequently validate the same RMM for additional products or samples, as long as the CP acceptance criteria are met. In this case, the same approved reduced reporting notification method can be used.
Dr. Riley concludes that as our understanding of RMMs continues to grow, the process of selecting, validating and gaining approval for RMMs should become easier and faster. To read the full article, please visit the RMM Supplement of the European Pharmaceutical Review.
good information, thanks
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