Introduction

Like their U.S. counterparts, European regulators have been supporting the industry to validate and implement RMM technologies. During the 2009 PDA European Conference on Implementing RMMs, Dr. Riccardo Luigetti (Scientific Administrator at EMA’s CHMP/CVMP Quality Working Party (QWP) and member of the EMA PAT Team) stated that RMMs clearly have the potential to be used to support Quality by Design (QbD), and that the introduction of such methods are supported by the EU regulatory competent authorities. During the same conference, Paul Hargreaves (Technical Manager, U.K. Medicines and Healthcare Products Regulatory Agency; MHRA) viewed the implementation of alternative microbiology methods as a positive step in improving the quality of medicines and patient safety, and has actively encouraged the industry to implement these technologies for many years. Additional points raised during his presentation included:

• MHRA is more than willing to discuss RMMs, review validation protocols and discuss possible uses ranging from screening tests, bioburden and even sterility testing,
• RMM suitability will be subject to scientific assessment, and
• the use of RMMs will require the employment of qualified microbiologists who are able to understand the basis of the techniques used.

Revision to Annex 1

On February 20, 2020, the European Commission published its latest draft revision to Annex 1, "Manufacture of Sterile Medicinal Products" of the EU Guideline for good manufacturing practice for drug products and drug substances, was published. Of note were significant changes associated with the implementation and use of RMMs and in particular, the use of rapid methods for environmental monitoring. The draft was finalized and went into effect on August 25, 2023. You can read more information about the revision and its impact on the use of rapid methods on our Annex 1 Revision page.

Challenges Associated with RMM Implementation and Type Variations

Historically, individual member states have approved RMMs for routine use. However, many of the tools provided by the FDA did not exist within the EMA. Additionally, there was no equivalent to the FDA Comparability Protocol in Europe, and companies had no formal process for submitting a RMM validation strategy for review and approval prior to the initiation of the actual testing plan. For some companies, it has taken almost 18 months for their RMM validation dossier to be reviewed and commented on by numerous member states, thereby extending the time for RMM implementation. Furthermore, for those RMMs intended to replace existing microbiology methods that have been incorporated into Marketing Authorisations, the filing of multiple Type Variations has been required for each product and facility, instead of being managed under a single Comparability Protocol, which is the strategy that many companies have used in the U.S. Therefore, the EU process of RMM implementation had historically been both time-consuming and costly.

Fortunately, significant regulatory policy changes were introduced in 2010 which paved the way for a friendlier and simpler strategy for RMM implementation within Europe. We will explore a number of these changes below.

EMA Quality Working Party (QWP) and The Use of RMMs for Purified Water Analysis

In 2005, a Question and Answer discussion on the regulatory consequences of implementing an alternative method for rapid control of microbiological quality of WFI and Purified water was developed by QWP in cooperation with the GMP/GDP Inspectors Working Group (GMDP IWG). The discussion was adopted by the Committee for Medicinal Products for Human Use (CHMP) and the Committee for Medicinal Products for Veterinary Use (CVMP) committees. Guidance on this topic is currently published on EMA's Quality of Medicines Questions and Answers page.

Specifically, the EMA answered the following question: "What is the regulatory consequence of implementing an alternative method for rapid control of microbiological quality of water for injection and purified water?" The answer is as follows:

• "According to European Union legislation, pharmaceutical manufacturers are required to use European Pharmacopoeial standard water in the manufacture of medicinal products.
  
  The European Pharmacopoeia (Ph. Eur.) has recently introduced a chapter making reference to the acceptability of rapid microbial methods to replace the standard Pharmacopoeial methods provided appropriate validation has been performed.
  
  Following discussions at the QWP and the ad hoc good-manufacturing-practice inspectors' group, it is suggested that the introduction of such methods might require specific review to ensure that the appropriate validation steps have been followed and that the water continues to meet the Ph. Eur. specifications. Since, in the case of water, the validation will not be product specific, it is suggested that a company could request the supervisory authority to carry out a specific site inspection. The performance of such an inspection would be at the discretion of the supervisory authority and could involve a pharmaceutical assessor where necessary.
  
  Since it is expected that the water will continue to meet Ph. Eur. specifications, if tested, no change to dossier requirements* (variations) would be involved and therefore no regulatory impact on individual products would normally be anticipated."

EMA Revised Variations Regulation

On January 1, 2010, new revisions to variations regulation 1234/2008 went into effect and apply to variations to a Marketing Authorisation granted in a Mutual Recognition / Decentralized Procedure and to Community or Centralized authorisations. The new variations regulation introduces a number of features such as annual reporting for minor type IA changes, type IB by default and implementing new procedures such as "work-sharing" and "grouping of variations" aiming to reduce the workload for both competent authorities and applicants. With the review of the variations regulations (new variations regulation 1234/2008) and the release of Directive 2009/53/EC3 for changing the legal basis of the variations regulation, the way towards the last major change has been cleared: all authorized medicinal products, including those authorized at the purely national level, will now be subject to the same criteria for the evaluation, approval and administrative handling of changes, regardless of the procedure under which those medicines have been initially authorized. These changes were previously outlined in the 2007 public consultation paper, "Better Regulation of Pharmaceuticals: Towards a simpler, clearer and more flexible framework on variations." More importantly, the changes will have significant impact on the way RMMs will be implemented in Europe, and this was the focus of a full-day meeting hosted by the PDA on September 21, 2009 in Frankfurt, Germany.

Three European regulators served as panelists during this meeting (Paul Hargreaves, MHRA inspector; Dr. Gustavo Marco, MHRA reviewer; and Dr. Riccardo Liugetti, EMA and PAT team member. They agreed to dedicate a discussion forum to practical questions about the implementation of RMMs in Europe, as the process appeared to not be well understood by the pharmaceutical industry at that time. Specifically, it was understood that the industry maintained the following perceptions:

• Implementing RMMs is a complex regulatory scenario
• It can become very costly, if variations to Marketing Authorisations are involved
• The time horizon to get approval for implementation might be unpredictable, especially if the product or products concerned possess heterogeneous Marketing Authorisations
• Discussions with regulators on scientific and practical questions seem not to be endorsed before a formal application is submitted, leaving the risk of missing aspects crucial to the authorities and related delays to the applicant.

Type Variations

There is a new opportunity for scientific dialog with regulators through the EMA Scientific Advice (SA) procedure. This is available for all products regardless of the application procedure used. The SA procedure is used for scientific issues concerning quality, non-clinical and clinical aspects relating to the proposed future development of the medicinal product and focuses on general strategies. The SA procedure is also used during the early stages of product development but is not intended to offer a pre-review of data in support of a MA application. Therefore, a firm may ask for advice on their RMM validation and implementation strategies. The SA procedure applies to the entire EU; however, individual national authorities may require additional discussions in addition to the advice received under this procedure. The SA is not legally binding and can be contradicted once the application is under official review; however, you will receive an official document from the EMA SA working party. The SA procedure is also subject to a fee. The SA working party includes representation from all member states. Finally, if you ask for SA you may be invited to the EMA for a discussion meeting and there may be an opportunity to ask for further clarification following receipt of the SA letter.

Post Approval Change Management Protocol (PACMP)

As previously discussed, the EMA did not have a policy in place that allowed for the review and approval of a RMM validation plan prior to conducting the actual validation studies. Historically, the evaluation of a proposed variation was performed as a whole, meaning that the planned studies, methods and acceptance criteria were simultaneously submitted with the testing results. If questions arose by any of the competent authorities, the submission may have been delayed due to additional testing requirements. However, in early 2011, the EMA introduced significant changes to the management of RMM reviews that should make the validation and approval process much more predictable and in-line with processes currently used by the FDA. The new process, which is very similar to FDA’s comparability protocol, is called the Post Approval Change Management Protocol (PACMP).

In this new, two-step process, a change management testing protocol is first submitted as a Type 2 Variation. Commission Regulation (EC) No. 1234/2008 (‘the Variations Regulation’) and the “Commission guideline on the details of the various categories of variations” (‘the Classification Guideline’) defines a Type II variation as a ‘major variation’, which may have a significant impact on the Quality, Safety or Efficacy of the medicinal product. The protocol should include the overall testing strategy, such as the planned studies, acceptance criteria and methods. Prior to submitting the PACMP, a firm may also discuss their testing strategies with the EMA under the Scientific Advice procedure. Once the protocol is approved, the submitting company will perform the testing as specified in the protocol.

The second step of the PACMP process involves submitting the resulting data (assuming they have met the protocol’s acceptance criteria) as either a Type 1A or 1B Variation. The decision as to whether the data is submitted as a Type 1A versus a Type 1B variation is determined at the time of protocol review and approval.

Type IA variations are considered as minor variations that have only a minimal impact, or no impact at all, on the quality, safety or efficacy of the medicinal product, and do not require prior approval before implementation. If the data is submitted under a Type 1A variation, the company can immediately implement the rapid method, similarly as what the FDA would consider under a CBE-0. The EMA also refers this implementation strategy as the “Tell and Do” procedure.

Type IB variations are also considered as minor variations, but is neither a Type IA variation nor a Type II major variation. In fact, when one or more of the conditions established in the Annex to the Classification Guideline for a minor variation of Type IA are not met, the concerned change may be submitted as a Type IB variation unless the change is specifically classified as a major variation of Type II. Specific supporting data for Type IB variations will depend on the specific nature of the change.

Type IB variations must be notified to the National Competent Authority/EMA by the Marketing Authorisation Holder (MAH) before implementation, but do not require a formal approval. Furthermore, the MAH must wait a period of 30 days to ensure that the notification is deemed acceptable before implementing the change. The strategy is considered as a “Tell, Wait and Do” procedure, and is similar to FDA’s CBE-30.

The most apparent difference between the EMA’s PACMP and FDA’s Comparability Protocol is that the former requires the submission of the test data. In any case, this is still a much more desirable RMM validation process than what companies were required to follow in the past. The introduction of the PACMP is a welcomed addition to the EMA’s other policy changes, and will greatly simplify the validation and implementation of RMMs within the EU.

EMA's Perspectives on RMM Validation

European Pharmacopoeia Chapter 5.1.6, as well as PDA TR#33, are the guidances that should be used when validating RMMs in Europe (please visit our Validation Page for detailed information regarding Ph. Eur. 5.1.6). The regulators have stated that the chapter does not need to be followed exactly; however, all deviations from the guidelines should be clearly stated and reasons provided.

The Quality Expert Report is the document used to convey the information from the RMM validation studies. In general, this report should be written by a quality expert, such as a microbiologist, an expert in the field of RMMs or a relevant technical person working in the pharmaceutical industry. The expert's CV should be included in the report and deviations from RMM validation guidelines, such as Ph. Eur. 5.1.6, should be explained. The documentation requirements should also include a description of the actual technique, including the application principle, the primary validation, risk-benefit analysis, validation of the equipment, validation of the actual test method, a comparative study against the pharmacopeial method, and the RMM system's detection principle, as provided by the vendor. Additionally, it is helpful if references to the application principle has been described in a peer-reviewed journal. Finally, performance claims made by the RMM vendor should be confirmed by the applicant, as appropriate.

The primary validation should include a characterization of the principle of detection using a panel of challenge microorganisms. The vendor usually conducts these studies. If confidential information by the vendor is to be used, it is possible for the vendor to provide this information directly to the competent authority. Currently, there is not a formal process for the vendor to submit a document similar to an FDA Drug Master File (DMF); however, they can provide the same type of information informally. If the data by the vendor is not confidential, it should be provided in the primary validation package submitted by the applicant. After the primary validation has been approved and it is used for a particular product, there is no need to submit additional approvals for future users; they only need to provide a link to the primary validation approval. If in doubt, make certain that your strategy is discussed with the relevant competent authority.

A risk-benefit analysis should include a discussion of the limitations of both the RMM and the compendial method and a comparison of these should be included. More specifically, the potential weaknesses of the RMM should be identified and fully discussed.

The equipment validation should include the Design Qualification (DQ), Installation Qualification (IQ) and Operational Qualification (OQ) including compliance with Annex 11 (computerized systems). The actual data is not needed in the application; however, it does need to be available during inspection. The full Performance Qualification (PQ) validation report does need to be included. The PQ demonstrates that the method has been validated for its intended use and this is performed using actual product. Additionally, the method must be comparable to test results characterized in a model system as evaluated by the vendor. Robustness is usually performed by the supplier; however, the actual data must be included.

Comparability with the compendial method must then be demonstrated: the RMM must be shown to be at least equivalent to the compendial method. Furthermore, the specific characteristics of the microbial methods should be described, such as the use of specific equipment or method variability. The use of compendial test strains, in-house (environmental) isolates and stressed or slow-growing organisms is recommended during these studies.

It is highly recommended to have discussions with the EMA, relevant competent authorities and/or the local inspectorate, especially if it is determined that a formal change will not need to be submitted (this will, of course, depend upon the RMM's intended application, such as an in-process microbiology test and/or whether the method intended to be replaced is already in a marketing Authorisation). Additionally, because the EMA does not currently recognize the FDA’s Research Exemption strategy, it is important to understand what the EMA and/or local inspectorate’s expectations are with regard to generating data in a manufacturing environment. Therefore, a meeting with the appropriate EMA regulators is warranted and this should occur very early in the implementation planning phase.

Summary

The EMA has implemented sweeping and much anticipated changes in their policies with regard to the validation and implementation of RMMs. Regulators have expressed their desire to have continued discussions with the industry in order to enhance their knowledge of newly introduced technologies, and to have an opportunity to encourage the use of RMMs in support of QbD principles and patient safety..