RAPID METHODS SUPPLEMENT
which RMM they are considering and how they proposed to use the RMM as well as how they planned to validate the RMM for its intended use. Regulators have provided feedback regarding the firm’s proposals and also asked questions to familiarise themselves with the RMM before they were required to formally assess the validation and implementation of that RMM. Regulatory filing requirements have also been discussed during these meetings so that firms know how to properly notify regulators when they want to implement the RMM. These meetings have been useful for both regulators and industry and some form of communication with the relevant regulatory authority is recommended for firms that have not had significant experience validating and implementing a RMM. There are also regulatory filing mechanisms
that can simplify the implementation of RMM. The FDA has a type of regulatory submission called a Comparability Protocol (CP). The CP is based on 21 CFR 314.70(e)10
and there is also a
draft guidance that provides background information related to how to use a CP11
. Simply
put, a CP is a detailed written plan to demon - strate that a post approval change does not adversely affect product quality. Therefore, a CP for a RMM is a validation protocol to demonstrate that the RMM is suitable for its intended use. A CP must be approved before it can be used, therefore it must either be part of an original submission (e.g., NDA) or a prior approval supplement. There are three features of a CP that make it
useful for implementation of a RMM. The first advantage of a CP is that it allows the FDA to review and approve the validation protocol before the applicant performs the studies. If the FDA finds any deficiencies in the validation protocol, the applicant can correct them prior to performing the studies and thus avoid having to repeat some (or all) of the studies. The second advantage of using a CP is that after the CP has been approved and the firm performs the validation studies and meets the acceptance criteria, a reduced reporting category can be used to notify the FDA that the method is being implemented. For example, if a RMM is going to be used for product release testing, implementation of a RMM would require a prior approval supplement. If a CP is used, the reporting category for implementation can be reduced to a Changes Being Effected supplement (CBE-0). The third advantage of a CP
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is that an approved CP for validating a RMM can subsequently be used to validate that RMM for additional products/samples. As long as the RMM is suitable for the product / sample and the validation acceptance criteria are
between potential RMM users and regulatory authorities while the
“There has been communication
firms are considering RMMs and planning validation studies”
met, the RMM can be implemented for the additional product / sample and implement - ation can be reported using the approved notification method (e.g., CBE-0). CP’s have been successfully used for RMM approval and implementation for multiple products by several pharmaceutical firms. A CP for RMM validation typically contains
the following items: A description of the RMM and how it works Background information regarding why the applicant selected the proposed RMM
A detailed validation protocol including acceptance criteria and any statistical analyses that will be performed
A proposed reporting category to notify the FDA that the method has been validated and use of the RMM is being implemented (typically a CBE-0)
RMM can be beneficial for pharmaceutical manufacturing. However, it is important that firms clearly understand their user requirements when selecting a RMM. Selecting a RMM that is not suitable can lead to much frustration and
REFERENCES
1. ICH (2005) Q2(R1) Validation Of Analytical Procedures: Text And Methodology. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use
2. Parenteral Drug Association (2000) Technical Report 33 – Evaluation, Validation and Implementation of New Microbiological Testing Methods
3. European Pharmacopoeia (2008) 5.1.6 Alternative Methods for Control of Microbiological Quality. European Directorate for the Quality of Medicines & HealthCare (EDQM) of the Council of Europe
4. United States Pharmacopeia/National Formulary. (2011) Chapter <1223> Validation of Alternative Microbiological Methods. USP 34-NF 29: The United States Pharmacopeial Convention, Inc.: Rockville. MD
5. Code of Federal Regulations, Title 21, Sec. 314.420. Drug Master Files. US Government Printing Office, Washington DC
6. Food and Drug Administration, (1989) Guideline for Drug Master Files
7. Gray, J., Staerk, A., Berchtold, M., Mercier, M., Neuhaus,
G., and Wirth, A. (2010). Introduction to a Rapid Microbiological Method as an Alternative to the Pharmocopoeial Method for the Sterility Test. Amer. Pharm. Rev. 13(6):88-94
8. Smith, R., Von Tress, M., Tubb, C. and Vanhaecke, E. . (2010). Evaluation of the ScanRDI as a Rapid Alternative to the Pharmacopoeial Sterility Test Method: Comparison of the Limits of Detection. PDA J Pharm Sci and Tech. Vol 64(4) pp 356-363
9. Verdonk, G.P.H.T, Willemse, M.J., Hoefs, S.G.G., Cremers, G., and van den Heuval, E.R. (2010). The Most Probable Limit of Detection (MPL) for Rapid Microbiological Methods. J. Microbiological Methods. Vol 82. pp 193-197
10. Code of Federal Regulations, Title 21, Sec. 314.70. Supplements and other changes to an approved application. US Government Printing Office, Washington DC
11. Food and Drug Administration, (2003) Draft Guidance for Industry, Comparability Protocols — Chemistry, Manufacturing, and Controls Information
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wasted time. In addition, overcoming the hurdles of regulatory approval can seem overwhelming and discourage the potential RMM user. However, regulatory authorities around the world have demonstrated a willingness to approve these methods under the right circumstances. Validation of a RMM is a critical step in gaining regulatory approval and there are several sources of guidance regarding RMM validation. Nonetheless, to avoid potential delays in regulatory approval, it is suggested that firms communicate with the appropriate regulatory authorities during the planning process to discuss validation strategy and regulatory notification requirements. Applicants considering RMMs for products regulated by the FDA may want to consider using a CP, particularly if they wish to use the same RMM for multiple drug products. Over the last 10 years, the number of RMM users has slowly but steadily increased as pharmaceutical firms, RMM vendors and regulators learn more about how RMM work, how to best use them and how to validate them for their intended use. As our understanding of RMMs continues to grow, the process of selecting, validating, and gaining approval for RMM should become easier and faster.
BIOGRAPHY
Bryan S. Riley, PhD, is a Senior Review Microbiologist in the Center for Drug Evaluation and Research at the FDA. Prior to coming to the FDA in 1998, he directed a clinical microbiology laboratory. During his time at the FDA, Dr. Riley has been deeply involved in
the regulatory assessment of rapid microbiology methods.
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