Good Manufacturing Practice and the Marketing Authorisation Holder
Question: When does a marketing authorisation holder have to comply with GMP? Answer: When it is also a manufacturing authorisation holder. The European Medicines Agency's Reflection Paper on this topic does not really add the clarity it promises.
Introduction
In January 2020 the European Medicines Agency (EMA) published a draft Reflection Paper entitled Good Manufacturing Practice and the Marketing Authorisation Holder inviting comments from stakeholders. The European Qualified Persons Association (EQPA), a not-for-profit organisation representing Qualified Persons (QPs) across the EU and beyond, duly provided comments on behalf of its membership. The aim here is not to discuss those comments but to consider the regulatory basis for many of them and in so doing, add a little clarity, something the Reflection Paper fails to do.
What is a Reflection Paper?
Let's start by explaining what a Reflection Paper is. Documents published by EMA fall into a number of defined categories depending on their intended purpose. The following is extracted from the Procedure for European Union Guidelines and Related Documents within the Pharmaceutical Legislative Framework. Published by EMA 18 March 2009:
"A reflection paper may be developed to communicate the current status of discussions or to invite comment on a selected area of medicinal product development or a specific topic. It can provide a framework for discussion or clarification particularly in areas where scientific knowledge is fast evolving or experience is limited. A reflection paper does not provide scientific, technical or regulatory guidance, but may contribute to future development of such guidelines, or related document."
So a number of objectives can be fulfilled. In this case there was clearly an objective to invite comment on the topic in question. Another stated objective was to provide clarity. If there were other objectives they were not so evident except, ironically, the provision of guidance, which it is not supposed to do. This often happens with Reflection Papers and is rarely questioned. Aside from the fact that some of the content may be useful to marketing authorisation holders (MAHs), it also gives them an idea as to how the regulators are thinking and a chance to formulate their own position before further developments ensue.
The Current Regulatory Situation
Before considering the content of the Reflection Paper it would be worthwhile studying what the EU regulatory framework actually says about GMP responsibilities of the MAH. For convenience this article restricts itself to the rules applicable to marketed medicinal products for human use although there is no doubt that its overall conclusion would be the same for veterinary products.
Directive 2001/83 defines "manufacturer" as the holder of a Manufacturing/ Import Authorisation (MIAH), something not to be overlooked. It lists GMP compliance as one of the obligations of the same. Directive 2003/94 lays down the principles of GMP, which are specifically addressed to the MIAH. Directive 2001/83 also obliges the MIAH to only use active substances that have been manufactured in accordance with GMP. Regulation No. 1252/2014 defines GMP principles for active substances and is also addressed to "manufacturers", but in this Regulation the term is defined as manufacturer of active substance intended for human use.
At no point is there any obligation on MAHs to comply with GMP. Directive 2001/83 does require a MIAH to be nominated by the MA applicant in order for the application to be valid and once the MA is granted, for it to remain valid. There are however, some specific obligations for MA applicants and MAHs that are "GMP-related" and these are mentioned in the Reflection Paper. Nevertheless, the EU GMP interpretive guidelines still mention roles and tasks for the MAH, as does the new dedicated GMP guidelines for Advanced Therapy Medicinal Products (ATMPs). It is welcome therefore that the authorities appear to agree that clarification is necessary.
The MAH can nominate a representative in other member states but EU legislation does not define a role for such. The Reflection Paper considers that some of the GMP-related tasks, which it identifies for MAHs, might be delegated to these local representatives although the MAH would retain ultimate responsibility.
Finally, it should not be forgotten that pharmaceutical development activities are out of scope of Directive 2001/83, so are not subject to the holding of a MIA, nor subject to GMP.
Discussion
The observant will have noticed that the Reflection Paper's title is GMP and the MAH, not GMP for the MAH, as it is sometimes called. This is not the trivial observation it may first seem. It is tacit acknowledgement of the truth of our own regulatory analysis above. The Reflection Paper proceeds nevertheless to identify several apparent GMP responsibilities for the MAH. In many cases a supposition is made that the MAH has inferred responsibilities or tasks. The end result intended or otherwise, appears to augment the responsibilities of the MAH and thereby diminish the responsibilities of the MIAH in this regard.
Recommendation
Berlin, Germany4/5 December 2024
Root Cause Analysis
On the positive side, it is useful to explore roles that the MAH can play in partnership with the MIAH in ensuring GMP compliance. To this end the Reflection Paper contains a very useful chapter entitled "The role of the MAH in facilitating compliance with GMP and the Marketing Authorisation".
We will now proceed to discuss each of the topics for which the Reflection Paper identifies or suggests GMP responsibilities or tasks for the MAH.
1. Outsourcing and Technical Agreements
The Reflection Paper treats manufacture carried out by a party other than the MAH is an outsourced activity by the MAH and presupposes that GMP rules on outsourcing are applicable to the MAH. This might appear to be reasonable and logical but as already shown, those rules are addressed to the MIAH, not to the MAH. They apply to anything outsourced by a manufacturer and, particularly relevant here, anything contracted-in by a manufacturer. Certainly the MAH, as owner of the product, will seek to establish a commercial contract with the manufacturer but this is not the same as the contractual arrangements envisaged in Chapter 7 of the GMP Guide, although it would be good practice for the latter to be cross-referred to in the former.
It is the MIAH that is responsible for establishing the contractual arrangements envisaged in GMP Chapter 7, which are drawn up to ensure GMP is complied with and, in particular, in conformance with the MA. The MIAH needs to have access to relevant and current MA details including open parts of any linked Certificate of Suitability of the European Pharmacopoeia (CEP) or Active Substance Master File (ASMF). Not only is conformance to the approved dossier a fundamental GMP principle but is also subject to batch-wise certification by the Qualified Person (QP) of the MIAH. GMP obliges the contract giver to qualify the contract acceptor. The MAH cannot realistically be expected to do this. Under EU law, GMP competence is not a pre-requisite for holding a MA but engaging a MIAH whose MIA is valid and appropriate for the product in question is.
Some MAHs may also be MIAHs and so would be capable of, and authorised to undertake, GMP functions. In such a case there is a joint responsibility to establish the contractual arrangements and to ensure that respective responsibilities are clear to avoid gaps and conflicting overlaps.
2. Audits and QP Declarations
The "QP Declaration" is the accepted vehicle for fulfilling article 8(3)(ha) of Directive 2001/83 designed to assure the authorities that any active substance manufacturer mentioned in MA submissions has been audited and complies with GMP. The Reflection Paper finds much to say on this topic despite concluding, correctly, that the audits and declarations are the responsibility of the MIAH, not the MAH. The MAH (or applicant as appropriate) is only responsible for filing the declarations alongside relevant MA submissions as needed.
3. Communication
Considerable weight is rightly dedicated in the Reflection Paper to the importance of communication involving MAH, MIAH, and, where relevant, the holder of a CEP or ASMF as well as the Regulatory Authorities. Clearly this is important for a variety of reasons and several examples are given in the chapter on communication in the Reflection Paper.
4. Product Quality Review
The Reflection Paper identifies Product Quality Review (PQR) as a significant example of a GMP responsibility of the MAH. Chapter 1 of the GMP Guide does indeed mention the MAH in this context.
"The manufacturer and, where different, marketing authorisation holder should evaluate the results of the review and an assessment made as to whether corrective and preventive action or any revalidation should be undertaken, under the Pharmaceutical Quality System..."
The MAH should of course have an interest in the contents of the PQR but the GMP aspects of the PQR are the responsibility of the MIAH. It holds the technical competence, the manufacturing experience and the Pharmaceutical Quality System (PQS) which enables corrective and preventive action to be identified. The EU GMP Guide should be read with the broader regulatory context in mind and so it is evident that the MAH's role here is to act on the assessment of the MIAH and execute any implication for the MA filing if needed. There can be more than one MIAH involved in the manufacturing chain of a product, possibly including the MAH, and so all MIAHs concerned have collective responsibility for ensuring PQRs are done drawing from all relevant inputs, including from manufacturers in Third Countries. By facilitating timely and appropriate communication between all parties and by sharing information that it holds such as the current MA filing status, the MAH can ensure satisfactory execution of PQRs.
5. Product Defects, Complaints, Supply Restrictions and Recalls
PQRs have their place and make life easy for Inspectors but their importance should not be overstated. A GMP-compliant facility with a well-designed and functioning PQS better serves the MAH and, more importantly, patient safety by identifying issues and dealing with them as they occur rather than belatedly through the PQR.
Chapter 8 of the GMP Guide on product defects and recalls does cover some activities that in practice are often carried out by the MAH, although it does not explicitly acknowledge this. Firstly, complaints from the market are normally received by the MAH who is obliged to refer anything that appears to be quality-related, including suspected falsification, to the MIAH with a request to investigate. The MIAH's investigation should be conducted in accordance with GMP and aim to identify the root cause, determine the full extent of the issue and propose potential corrective and/or preventive action, which might include recall. MAH input may be needed for appropriate risk-based decision-making and ultimately the MAH is responsible for interaction with the relevant competent authorities for the MA. If market action is needed the MAH often initiates that action and looks after market communication. The role of the MIAH might be limited to technical support for those tasks but often has a direct role in receiving returned product and monitoring the effectiveness of any recall. Contractual arrangements and good communication channels are vital in the handling of defects and recalls.
The MIAH has an obligation to notify the MAH of any manufacturing- related issues that will impact supply. This in turn enables the MAH to fulfil its legal responsibilities in notifying the regulatory authorities in this regard. The Reflection Paper advises MAHs to carry out proactive and detailed risk assessments of their manufacturing, regulatory and supply chain processes, and work to address any identified weaknesses in those areas. Much of this is better suited to the competences of the MIAH.
6. Continual Improvement and Scientific Advances
Quality issues are not only identified through market complaints but also by the MIAH as it applies GMP throughout the product's lifecycle identifying potential improvements, preventive/corrective actions and possibly the need for market action. Communication between MIAH and MAH is important here to ensure productrelated improvements can be made in line with the affected MA dossiers or whether the MAH needs to develop a strategy for filing of variations first. The Reflection Paper introduces another unreasonable expectation for MAHs to monitor the performance of its manufacturing contractors and makes a rather unusual suggestion that PQRs be used for this purpose. Similarly, there is a suggestion in the Reflection Paper that MAHs should keep abreast of new GMP developments. To what end? This is a matter for the MIAH. MA applicants are expressly told to avoid GMP aspects in MA submissions.
Both MAH and MIAH have responsibilities for ensuring manufacturing processes keep abreast of scientific advances. One would however expect the MIAH to be best placed to monitor relevant advances and raise these with the MAH as needed in view of any impact on the MA.
7. Ionising radiation
Annex 12 of the GMP Guide The use of Ionising Radiation in the Manufacture of Medicinal Products makes 3 superfluous references to the MAH and the Annex would not be any less useful without them.
8. Reference and Retention Samples
Annex 19 of the GMP Guide, Reference and Retention Samples, specifically states that the retention of these samples should be covered in the agreement with the MAH. There is no argument here but remember that it is the responsibility of the MIAH to establish the agreement with the MAH not the other way around. The Reflection Paper draws attention to guidance given to MAHs by Annex 19 in the case of closure of the MIAH, which is helpful. In order to ensure continued access to reference and retention samples in such a case the MIAH is normally responsible for delegating storage to another MIAH but the Annex recognises that this might not always be feasible and so concludes that the MAH may need to step in to find an alternative MIAH.
9. Document Retention
The Reflection Paper considers document retention as the MAH's responsibility, which is confused and misleading but in fairness is partly due to a lack of clarity in Chapter 4 of the GMP Guide (Documentation).
The MIAH is responsible for keeping batch documentation and any other documentation generated by it as part of its GMP-regulated activities.
The MA applicant/MAH does have data retention obligations in the case of data used in support of the MA. As pointed out earlier, pharmaceutical development is not subject to GMP or the holding of a MIA according to EU law.
Ongoing stability studies, as distinct from the studies submitted in the MA application, are GMP-regulated activities as is commercial scale process validation and so the MIAH performing these activities should retain the records.
Bearing in mind the potential role of the MAH in relation to continued storage of reference and retention samples in the case of closure of the MIAH it might be reasonable to draw an analogy with document retention. This scenario is not mentioned in GMP Chapter 4 and the Reflection Paper is silent on the topic.
Advanced Therapy Medicinal Products
There are more "GMP responsibilities" for the MAH in the Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products than in the rest of Eudralex Volume 4. Only one or two of them mirror references in the main GMP Guide. Many of these new references are puzzling and clarification in the Reflection Paper would be helpful so it is curious that the Reflection Paper excludes them from discussion. It is no secret that GMP inspectorates regard the stand-alone GMP guidelines for ATMPs as a form of heresy, which might explain a reticence to comment on them in this Reflection Paper.
MIAH or Manufacturer?
In this article use of "MIAH" has generally been deliberately favoured over the term "manufacturer". Pharmaceutical supply chains have become increasingly complex and globalised over recent decades and so there is a heightened need for clear understanding of responsibilities. A marked distinction should always be made between a manufacturer with a MIA and a third-country manufacturer even though both are commonly regarded as "manufacturers" holding the same obligations. They are not. The former is an EU-based entity with legally binding GMP responsibilities and subject to strong regulatory supervision. The latter may, or may not, be subject to similar conditions but not EU rules or jurisdiction. The MIAH, who imports a product, is responsible for GMP oversight of the third country manufacturer on behalf of the MAH. It is not a direct responsibility of the MAH. The initial draft of the long-awaited Annex 21 of the GMP Guide did not really materialise into the expected wake-up call for importers. If the next version is a considerable improvement it could prove helpful to MAHs seeking to source from third countries.
Inspections of MAHs
According to the Reflection Paper, not only does the MAH have GMP responsibilities, but it can also be inspected to ensure compliance. This might have caused anxiety, panic and confusion but is it really true? Yes, partly. According to Directive 2001/83, inspections can be carried out at the premises of the MAH. Looking deeper we can see that article 111.1g (d) permits inspections of the MAH in connection with its pharmacovigilance obligations. Beyond this the stated overall purpose of inspections is, to ensure that legal requirements governing medicinal products are complied with. We have already established that GMP rules are not addressed to the MAH so, whatever the outcome of an inspection of the MAH, there is no basis on which action could be taken against it for failing to comply with GMP. Action, for example to suspend, vary or revoke the MA, could however be taken for failure to fulfil any of the MAH obligations explicitly stated in the directive, some of which are "GMP-related". MIAHs should probably worry more about inspections of the MAH as it is conceivable that these might reveal shortfalls in the performance of their own obligations.
Other than inspections in connection with pharmacovigilance, inspections of MAHs are quite rare in EU. It is possible that there are member states with national legislation that exceed EU requirements but that is not something a Reflection Paper published by EMA could be expected to take into account.
Conclusions
At the start of this article it was pointed out that the Reflection Paper gives insight into the thinking of the regulators. The line of thought appears to be that since the MAH has ultimate responsibility for the product it follows that it must be responsible for GMP compliance. As we have seen EU legislation is constructed so that the MAH is obliged to engage an authorised manufacturer and it is the manufacturer to whom the GMP directives are addressed. That is not to suggest that MAHs should not be proactive and vigilant in ensuring that their products are manufactured in compliance with GMP but EU law does not require a MAH to have any demonstrable GMP competence. Many MAHs are also MIAHs and therefore do have the competence and authorisation to share GMP responsibilities with another MIAH engaged to manufacture or import its products, subject to carefully drawn up contractual arrangements to avoid duplication or gaps. On the other hand many MAHs are little more than a registered office somewhere in the EU.
ICH Q10 describes a PQS that is applicable across the entire lifecycle of a product and therefore goes beyond GMP. The PQS concept is also referred to in ICH Q12 (Lifecycle Management) where it becomes clear that the MAH should operate its own PQS in order to realise the aims of Q12. When looking at the Reflection Paper it can also be seen that a PQS would be necessary to effectively carry out the "GMP responsibilities" that it identifies. Nevertheless ICH Q10 and ICH Q12 remain optional for MAHs in EU.
Recommendation
22/23 January 2025
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Arguably, where the MAH does not hold a MIA it should not be undertaking any GMP-regulated tasks at all, including those MAHs that are part of a multi-national corporation with GMP expertise based outside of EU, which it draws upon. In truth there are gaps in the general understanding of what GMP tasks are subject to the holding of a MIA, which is a topic for perhaps another Reflection Paper. In the meantime, since a MIAH must always be in place, it must take control when engaged by a MAH that proposes to carry out some functions without a MIA. It should view this as outsourcing of its own GMP tasks and must therefore satisfy itself that it can rely on the MAH resources involved. This is the reverse of what you might expect after reading the Reflection Paper and possibly also what often happens in current practice.
Directive 2001/83 reveals a number of responsibilities of the MAH that are related to GMP activities, for example in connection with quality defects, some supply interruptions and some aspects of MA dossier maintenance. The Reflection Paper could summarise these in more understandable and concise way and should avoid placing GMP obligations onto the MAH but emphasise the role of the MIAH and on how the MAH and MIAH should work together.
It would be interesting to see a similar Reflection Paper regarding the GMP responsibilities of the Sponsor of clinical trials.
This article is taken from the EQPA Newsletter. All other articles in the EQPA Newsletter are only available to EQPA members.
About the Author
David Cockburn
... is a member of the European QP Association Board.
