Jeanne Moldenhauer- Vice President, Excellent Pharma Consulting, Inc.
Background
More than twenty years ago, companies started introducing rapid microbiological methods (RMMs) to the industry. Some call these methods alternative microbiological methods. Rapid or alternative microbiological methods refer to techniques that enable faster and more efficient detection, enumeration, and identification of microorganisms compared to traditional methods. Note: Some companies choose to separate identification methods from this category, due to the differences in validation and implementation of these methods. RMM methods have the potential to reduce testing time, increase sensitivity, improve accuracy, and enhance overall efficiency in the analysis of microbial contamination in pharmaceutical, food, and environmental samples.
Salespeople came to companies promising sterility tests that took substantially less time than the 14-day test currently required. Other salespeople indicated that these new methods could have a more sensitive test method, for example single cell detection.
When these individuals were queried, it became evident that many did not have a good understanding of the regulatory and testing requirements that had to be met, prior to a pharmaceutical company’s ability to implement these methods. As a result, companies were slow to move to these newer methods. Additionally, RMM manufacturers drastically underestimated the time it would take to get their systems into full implementation at regulated companies.
As an individual in a company becomes interested in RMMs, they go to their management to get approval to purchase and/or investigate these methods. One of the first questions from management personnel is often some version of whether the regulators will accept these methods.
Contrary to common industry perceptions, the regulators have embraced RMMs. The use of RMMs supports quality and safety objectives of the regulatory agencies, as these systems may obtain more information on how the process is operating earlier in the manufacturing process. The regulators have requirements that testing be performed to verify performance and equivalence, or superiority of the methods when compared to traditional methods.
Hindrances to Acceptance by the Pharma Industry
Many individuals think that the regulators are the reason that RMMs are not yet used extensively.
Dr. Michael J. Miller published a great article on the regulatory acceptance of rapid methods. “After all was said and done, the participants came to a universal agreement that it really wasn’t the regulators who were not accepting RMMs, but rather it was primarily their internal departments like regulatory affairs. When pressed on their reasons, the following themes were disclosed why companies are still hesitant about implementing RMMs:”1
- ’A desire not to change approved regulatory dossiers or marketing authorizations”
- “A fear of new methods and in general, change”
- “Being too conservative and not open to thinking outside the box”
- “Perception that the cost of implementing RMMs and submitting variations to dossiers would be prohibitive”
- “Companies do not want their scientists talking with regulators.”
Major Issues with Perceived Lack of Acceptance by Regulators
At the time when RMMs were introduced, the regulatory group at companies was typically comprised of chemists, with few if any, microbiologists. The chemists in these company departments were not used to dealing with microbiologists. In general, when people do not know a topic well, they tend to be extra conservative. In talking to various people about validation conditions, there were concerns with how much data would be needed to convince regulators to allow implementation of these methods. Additionally, chemists are used to very tight controls and limits for chemistry methods. Most microbiology methods would have significant issues meeting these types of tight limits. In testing these parameters for RMMs, most often it is the conventional method which fails the validation criteria.
As stated earlier, many companies were concerned with “not knowing the expectations for a submission to the Agency for a new RMM.” In many cases, the concern was that an extensive validation strategy could be evaluated, and numerous studies performed, and the regulators would not accept or agree with the validation strategy that was used. This could result in significant costs to the company and delay the acceptance of the intended usage of the new technology. This one is also tied to a fear of loss of reputation by pushing for a methodology and major project which then is not accepted by the regulatory agency.
In general, microbiology budgets have very few pieces of equipment that are in the tens of thousands of dollars. Fear of the regulators not accepting your methods after spending such large amounts of money is also prohibitive to many potential users.
Applicability of RMMs in Pharma Companies
Today there are numerous RMMs available, several instantaneous methods for environmental monitoring methods, growth and instantaneous methods for water monitoring, a variety of potential sterility test methods, methods for conducting specific bioburden and other test methods, endotoxin test methods, and identification methods. Identification methods have been widely accepted and implemented in pharma, as the regulatory implementation requirements are quite different.
Often the focus has been on sterility testing, as most companies felt that this methodology had the highest potential to show a significant cost savings (avoidance) due to the elimination or reduction of the 14- day incubation time period.
Resources Available to Aid in the Development of Validation Requirements
Industry was one of the first to respond to support the use of RMMs by publishing guidance on the topic of selecting, testing, and evaluation of RMMs. The Parenteral Drug Association has published a technical report on this topic.2 Since then, this document has been revised and updated to include new information.3 At the time of writing this article, another revision to this Technical Report is in progress. Both the United States Pharmacopeia (USP)4 and the European Pharmacopoeia, called Pharm Europa (Ph. Europa)5 issued mono graphs on the appropriate validation criteria to be met for rapid or alternative methods.6 The Japanese Pharmacopeia also has requirements for RMMs.
Additionally, there are numerous articles published by a variety of early adopters of RMMs that provide guidance on validation of these methods. Dr. Miller has also published many articles referring to the comparison of different validation criteria, e.g., USP vs. Pharm Europa vs JP, or the comparison of compendial requirements to those in PDA’s Technical Report No. 33.
Comparability Protocols
A comparability protocol is a written agreement between the Regulatory Agency and the User Company. This document allows a company to submit a written protocol to the Regulatory Agency for review, prior to executing the work, to ensure that it will be considered acceptable if done in agreement with the prior approved protocol. This submission is accomplished as part of a pre-approval supplement to the product regulatory submission. This allows for the company to submit their protocol and know whether FDA will accept the data if you meet all the requirements of your testing protocol as specified in the Comparability Protocol.
One of the suggestions by The United States Food and Drug Administration (FDA) to address this type of concern was to allow companies to submit a “Comparability Protocol” to the Agency for rapid microbiological methods. The final guidance for the Comparability Protocol process has been issued. This would allow companies to receive feedback from the Agency prior to submission of data for review.
An advantage of using comparability protocols for the submission is that while the comparability protocol was submitted to the FDA as a prior approval supplement, the Agency generally allowed a significantly shorter regulatory path for implementing the change. Among the most attractive options were the equivalent to the Changes Being Effective – 0 Days (CBE-0), i.e., the company needed to notify the FDA that the change was completed and was being implemented.7
An example of the typical contents of a comparability protocol is included in Figure 1.
While this is allowed for the United States, comparability protocols are not applicable for other regulatory agencies., however, another regulatory pathway is open for approval of these methods.
Europe’s Alternative to Comparability Protocols
While Europe does not specifically have a program called Comparability Protocols, a new guidance document was issued entitled Guidance for Post Approval Change Management Protocols (PACMPs).8 While not specifically the same as the US document, it allows the user to submit their validation documents and obtain regulatory review and approval prior to implementation of the change.
The stated review times for prior approval supplements appear to be shorter than the corresponding approval times for the FDA, approximately two months versus four months.
Another potential option to gain information on the acceptability of a validation approach to rapid microbiological methods is the EMEAs Guidance for Scientific Advice.9 This procedure allows for review of validation approaches prior to conducting the testing. There is a charge associated with this service, but it can be useful in assessing whether it may be feasible for the company to pursue the validation methodology.
Early Adopters and Successful Implementation of Methods
Most of the early adopters of RMMs pursued rapid sterility testing for aseptically processed products. This was attractive to companies that already had implemented parametric release for their terminally sterilized products. Parametric release allowed for elimination of sterility testing and use of controlled manufacturing parameters to ensure product sterility. The first company to implement parametric release for terminally sterilized drugs was implemented in 1983.
The main technologies available for sterility testing are summarized in Table 1.
An ophthalmics company was the first to obtain FDA approval for a rapid sterility test of their aseptically filled drug products. This company predominantly had preserved products, lowering the risk of a potential non-sterile unit. This approval was obtained in four months from the date of the submission (i.e., equivalent to the expedited review time for submissions). No deficiencies were obtained for the submission package. This submission utilized a ScanRDI system. This approval required a Special Report (like a CBE-0) to be used to notify FDA of the implementation of the new testing method.
This submission was followed in short order by a company that manufactured generic drugs that were aseptically filled drug products. Like their predecessor, they had already implemented parametric release for terminally sterilized products and were using the ScanRDI. This submission was also approved four months from the date of the submission, with no deficiencies. It also required a special report be submitted for implementation.
Several compounding pharmacies wanted to implement rapid microbiological methods, as their products were frequently used in patients prior to the completion of sterility testing. Due to the high number of small product batch sizes, systems like the BacT/ Alert and the Bactec were desirable, due to the system designs, e.g., automated identification of sterility test positives, minimum change in testing methods, and ability to process many samples simultaneously. These systems were also routinely used in blood processing operations. Some of these pharmacies utilized comparability protocols, while others worked through FDA directly to review validation test plans.
Interactions with Regulatory Agencies During the RMM Implementation Process
The FDA has identified Dr. Bryan Riley in CDER, as an expert in RMMs. It is possible to request a meeting with Dr. Riley to discuss potential validation methods and to discuss your RMM strategy. Many find it useful to provide examples of test plans prior to the meeting.
Alternatively, a comparability protocol can be submitted for formal review and comment.
If there are discrepancies between the company and the Agency, it is useful to discuss what potential responses may mitigate the circumstances.
For European companies, it may be useful to ask for formal scientific advice in accordance with the established guidance. There is a charge for this service.
Conclusions
In the last twenty years, many improvements have been made in providing guidance to the validation and implementation of RMMs. Regulatory agencies have established procedures to obtain guidance and opinions on proposed validation strategies. Many company personnel have identified that it is really their own companies that are hindering the adoption of these new methods.
Take courage and try these methods out. They are worth the risk. In most cases, regulators are not the problem. We are!
References
1. Miller, M.J. (2017) The regulatory acceptance of rapid microbiological methods. European Pharmaceutical Review. 22(2). Downloaded from: The regulatory acceptance of rapid microbiological methods (europeanpharmaceuticalreview.com) on June 9, 2023.
2. PDA (2000) Evaluation, Validation and Implementation of Alternative and Rapid Microbiological Methods. Parenteral Drug Association. Bethesda, MD.
3. PDA (2013) TR33 Evaluation, Validation and Implementation of Alternative and Rapid Microbiological Methods, Technical Report No. 33. Revised 2013.
4. USP (2016) Validation of Alternative Microbiological Methods. United States Pharmacopeial Convention. US Pharmacopeia. . USP 39/NF34: 1616.
5. Ph. Europa (2017) Alternative Methods for Control of Microbiological Quality, European Directorate for the Quality of Medicines & HealthCare. Pharmeuropa; Chapter 5.1.6. Supplement 9.2
6. JP (2016) (The Japanese Pharmacopoeia, Seventeenth Edition (JP17). the MHLW Ministerial Notification No.64]http://jpdb.nihs.go.jp/jp17e/ JP17_REV_1.pdf (mhlw.go.jp)
7. Food and Drug Administration. Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information. Guidance for Industry. U.S. Department of Health and Human Services, Rockville, Maryland. 2016. http://www. fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM496611.pdf
8. European Commission. Regulation No 1234/2008 concerning the examination of variations to the terms of marketing authorizations for medicinal products for human use and veterinary medicinal products. 2008. http://ec.europa.eu/… and European Commission. Regulation No 1234/2008 concerning the examination of variations to the terms of marketing authorizations for medicinal products for human use and veterinary medicinal products. 2008. http://ec.europa.eu/health/sites/health/files/files/eudralex/ vol-1/reg_2008_1234_cons_2012-11-02/reg_2008_1234_cons_2012-11-02_en.pdf
9. European Medicines Agency. Human Medicines Research and Development Support. Guidance for applicants seeking scientific advice and protocol assistance. EMA/691788/2010 Rev. 7. 2014. http://www.ema.europa.eu/docs/en_GB/document_ library/Regulatory_and_procedural_guideline/2009/10/WC500004089.pdf
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