Rapid Microbiology – What Is Truly Possible?
Microbiology
William H. Fleming III, Ph.D. MedImmune, LLC
What is the Desired State?
Going forward, the regulatory agencies would like pharmaceutical and biopharmaceutical manufacturers to have a complete understanding of the drug substance and drug product manufacturing process. This will enable the release of drug substance and drug product as long as the manufacturing process stays within the design space throughout the manufacturing process. To accomplish this it will be necessary to use automated in-process testing, either in-line, on-line, at-line or in the lab to accomplish this task. Ultimately, the goal is to perform less testing at the end of the manufacturing process, as is currently the case. Will the microbiology community be able to step-up to reach this goal?
Issues
As detailed by Michael Miller (1), there are many issues that impact a Microbiologist's ability to purchase, validate and put into use a rapid microbiology method (RMM). It will be necessary to conduct a risk analysis on each new proposed RMM to answer the following questions: 1) Is the rapid method compatible with the current microbiology process and the knowledge of the manufacturing process? A risk analysis should be used to answer the following regarding this
question: where in the process is the best point to take samples that will provide meaningful data in regard to the design space; the resources required to take the additional sample; what samples may be eliminated due to the implementation of the RMM; 2) What Vendor support will be available after the purchase? It is imperative that the vendor be able to supply IOQ documentation for the instrument and its applications. Hopefully, the vendor has been in direct contact with an individual company, industry group, consultant or a combination of all three to help them develop the appropriate documentation. Continuing vendor support and upgrades for the software that controls the instrument is also a key to the implementation of a RMM. It should be noted that a good resource for the validation of a RMM is PDA TR 33 (2). This document is currently under revision and will be released once the enhanced version has been approved by the PDA. Finally, it will be necessary that the vendor's service program allows a 99% uptime for the instrument. Service will need to be able to fix a broken instrumentwithin 24 hours of the initiation of the service call. 3) How to deal with the perception that a sophisticated RMM instrument requires a highly trained operator? This is definitely an issue that needs to be addressed prior to the implementation of a RMM. The vendor will need to be able to supply training and certification or have an external resource
that can supply this training. Each Microbiologist will also need to determine the time required, following training, to allow the Analyst(s) to gain consistency and reproducibility in the operation of the RMM instrument. Finally, for instruments based upon flow cytometry and
mass spectroscopy, there will be a need for interpretation of the data when the algorithm used by the instrument is unable to analyze the data correctly. The Microbiologist will need to determine who will provide this additional expertise. 4) How often will it be necessary to run the instrument? RMM instruments based upon flow cytometry and mass spectroscopy will need to be operated on a regular basis. The Microbiologist will need to determine the schedule for running samples of control microorganisms in between running samples for analysis. 5) What is the Return on Investment (ROI) for the implementation of the RMM? For all in the biopharmaceutical arena, this has been and will continue to be a key to the implementation of new technology. Each Microbiologist is encouraged to work closely with colleagues in finance to obtain data that can be used to develop a successful ROI based upon each company's template for this process. 6) Will there be an effect on the cost of goods sold (COGS) with the implementation of an RMM? This can be a key consideration in developing the project to implement an RMM. If the implementation of the RMM results in a reduction in the component allocated for the laboratory testing in the calculation of the COGS for the drug product(s) manufactured at the site, this makes a solid case for the purchase and implementation of the RMM. 7) What are the costs associated with implementation of a RMM? The Microbiologist will need to consider the following: the time required to implement and validate a RMM, the training costs associated with a RMM. and the ongoing costs of maintaining the RMM instrument. 8) What if the RMM is more sensitive than the current technique? The FDA is clearly aware that a RMM may be more sensitive than the current method. Brenda Uratani, Ph.D., Consumer Safety Officer, CDER, made the following
statement at the 2007 PDA Global Pharmaceutical Microbiology meeting: "The FDA expects that higher counts will be recovered when using the new RMM technologies, especially if the methods are more sensitive than the conventional methods. GMP evaluation of the new method and the results (i.e., higher counts) must be driven by data and good science." Clearly, it is up to the Microbiologist to design a validation protocol that provides the data that shows that the new method is equivalent to or better than the current method. Based upon this data and discussions with the FDA, new limits may be required upon the introduction of an RMM. 9) What is the Regulatory Environment for RMM? It is clear that the Agency is pushing for the implementation of RMM by industry. In the guidance on sterile drug products produced by Aseptic processing (3) it states, "other suitable microbiological test methods (e.g. rapid test methods) can be considered for EM, inprocess control testing and finished product release testing after it is demonstrated that the methods are equivalent or better than the traditional methods (e.g. USP)"....
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