FAST BREEDERS: RAPID MICROBIOLOGICAL METHODS (RMM)
Currently the microbiological tests and controls as part of the pharmaceutical manufacture often still take as much time as the classic microbiological methods for germ cell culture, reproduction and identification. In biopharmaceutical development and production, though, they increasingly gain in importance.
Especially the time needed for incubation and the following, sometimes quite complicated identification are an enormous cost factor. For one reason this is due to the personnel needed, for the other it is the time delay for releasing the product. In addition, with regard to in-process controls several days waiting periods for receiving results are also unsatisfying. This situation especially applies to cell or tissue based products which frequently have to be implanted or administered within 72 hours. For that reason the use of Rapid Microbiological Methods (RMM) is almost indispensable in this case.
Under this aspect the development in the area of microbiological rapid methods progressed tremendously in the past couple of months. This advance is a result of the major contributions due to the increased interest from the industry side as well as the system manufacturers' efforts. However, authorities and other pharmaceutical organisations also have been facing this challenge and already provided a number of guidances relating to alternative methods - including
USP
- USP <1225> "Validation of Alternative Methods"
- USP <1223> "Validation of Alternative Microbiological Methods"
PDA
- PDA Technical Report #33 "Evaluation, validation and Implementation of new Microbiological testing methods"
Recommendation
Berlin, Germany5-8 November 2024
Contamination Control Strategies & Workshop Risk Assessment in Contamination Control
FDA
- FDA Guidance for Industry - Growth-based rapid microbiological methods for sterility testing of cellular and gene therapy products (Draft-2008)
European Pharmacopeia
- Ph Eur. 5.1.6.: Alternative methods for control of microbiological quality
- Ph Eur. 2.6.27.: Microbiological control of cellular products
The enormous attendance at a conference on this subject in Berlin, Germany, end of last year showed the tremendous interest in RMM. The commitment on the industry side to implement RMM also became obvious in a lecture by Elizabeth Young from Baxter in the US. Young is involved in a worldwide project to introduce RMM. For that purpose Baxter analysed the demand in their facilities all over the world and recorded operating conditions. Opportunities for applying rapid methods would be colony count, for monitoring the environment and for biological indicators. The facilities indicated that they would prefer a not destructive system. The collected data were used to derive a comprehensive catalogue with requirements, which was then compared against available systems.
Decision Matrix
Nine technologies were evaluated against 11 criteria:
- Destructive/Non-destructive
- Presence/Absence or Enumeration
- Cost of Equipment
- Cost per Test
- Mechanism for Detection
- Summary of System
- Maximum Volume of Sample
- Detection Limit
- Throughput
- Time to Result
- Stage of Development
To make a selection from the systems available, a decision matrix was developed using various evaluations, on the one hand taking into account factors for the Possibility of Success (POS) like technical investment, validation efforts, acceptance on the authority side and other uncertainties. On the other hand financial factors for the "Return of Investment" (ROI) were also considered - like acquisition costs, operating costs, time, risk of loss of a batch and reduced time for batch release.
This process resulted in a decision for the Growth Direct System, providing the results alike the classic methods in KBE (cfu). However, only the further course of this project will show whether and how RMM can be implemented across the corporate group.
Novartis Pharma in Switzerland and Bayer Schering in Berlin, Germany, are also applying microbiological rapid methods, as reported by Jennifer Grey respectively Petra Merker. Novartis established a new sterility test for a product in 2008, submitted the comparability protocol relating to USP Chapter <17> including a validation master plan at the Food & Drug Administration (FDA) - and received the authority's authorisation. The competent authorities in Switzerland also received the appropriate documentation, and in 2009 validation data are supposed to be submitted to the European Medicines Agency (EMEA).
As part of an interlaboratory comparison at seven pharmaceutical manufacturers Bayer Schering also gained experience with the validation and implementation of a "Real Time PCR System" from Biotecon. This system was supposed to be tested for its comparability with the classic biochemical methods. Using a 16s sequencing (reference method) the results were controlled in the six participating companies.
The interlaboratory comparison also included experiments on reproducibility and precision or results, considering accuracy criteria within a lab and for processing in different labs. Again, the results showed a high consistency, especially regarding reproducibility and precision of an analysis within a lab.
In the area of cell and tissue based products RMM also increasingly gain in importance, as emphasised by Gary du Moulin from Genzyme in the US and Uta Schurig and her colleague Melanie Störmer from the Paul-Ehrlich-Institute, Germany's regulatory agency for sera and vaccines. These applications will become more important with the increasing meaning of cell and tissue based products. In these cases, not only costs and time are important aspects, but also the products' short storage lives require a rapid microbiological release.
Recommendation
Berlin, Germany5-7 November 2024
Contamination Control Strategies
Three years ago, the European Compliance Academy (ECA) established the RMM Working Group to accompany the fast-paced advancements of microbiological rapid methods. Today, this group unites more than 200 members from almost 40 nations, as Dr Sven Deutschmann from Roche Diagnostics and the group's Chairman confirmed at the conference. The group's latest service is a database for searching systems available on the market using criteria like analysis method, application area etc. This database was introduced last May. According to Dr Deutschmann it is also planned to introduce further "Best Practice Papers" with users' experience in applying and validating RMM. Alike the database, these papers will be published in the members' area on the ECA website.
Author:
Axel H Schroeder
CONCEPT HEIDELBERG
