Our Regulatory Affairs team have produced this article with the aim of summarising the key elements of the EMA Reflection Paper and the GMP-related responsibilities that apply to Marketing Authorisation Holders. The article also aims to assist our clients in interpreting these in relation to their own business.

Marketing Authorisation Holder GMP-related Responsibilities: EMA Reflection Paper

Annex 16 of the European Commission (EC) guide to GMP (hereafter referred to as the “GMP guide”) indicates that ultimate responsibility for the performance of a medicinal product over its lifetime, its safety, quality and efficacy, lies with the Marketing Authorisation Holder (MAH). However, MAHs are often not directly engaged in the manufacture of medicinal products and therefore their responsibilities in relation to GMP can be difficult to comprehend on initially reading the GMP guide and applicable legislation.

EMA Draft Reflection Paper

The EMA has recently published a draft reflection paper focussed on the GMP-related responsibilities that apply to all Marketing Authorisation Holders.

This is a useful document providing clarity as to the various GMP responsibilities as they apply to MAHs and provides guidance on what they mean for MAHs at a practical level.

The areas of GMP relevant to MAHs and discussed in the reflection paper are:

  • Outsourcing and technical agreements
  • Audits and Qualification activities
  • Communication with manufacturing sites and competent authorities
  • Quality defects, complaints and recalls
  • Maintenance of supply
  • Continual improvement activities

Delegation of GMP activities

Activities that are required to ensure GMP compliance can be delegated by the MAH to a manufacturer or other third party, however, the MAH retains the ultimate responsibility. When delegating activities, it is critical that the roles and responsibilities of each party are clearly defined, and within the GMP guide there are obligations to ensure any outsourced activities are described in writing. This would normally be delivered via a technical agreement which details the respective responsibilities of the MAH, manufacturer and any other third parties.

It is the responsibility of the MAH to ensure that the person or entity to whom any tasks or activity has been delegated, possess the required competence, information and knowledge to successfully carry out the outsourced activities.

It should also be noted that the level of MAH responsibility remains the same regardless of whether both the MAH and manufacturer are from completely separate unrelated companies or belong to the same overall group of companies and are separate legal entities. There are no reduced MAH responsibilities in the latter scenario provided in the GMP Guide.

Similarly, while relevant activities pertaining to GMP may be delegated by the MAH to a local representative in a member state, none of the MAH’s responsibilities in this regard can be delegated.

When delegating activities, communication is key. MAHs can facilitate compliance by establishing robust and documented two-way communication systems with manufacturing sites, Qualified Persons and any organisations relevant to the monitoring of post-marketing quality.

MAH Production of MedicinesKey considerations

The MAH’s GMP-related responsibilities are broad reaching. The following list is not exhaustive, but aims to provide guidance on some of the key considerations for an MAH when ensuring compliance:

  • Evidence of GMP compliance:
    When submitting a Marketing Authorisation Application, the MAH has responsibility to make sure that the proposed manufacturer(s) hold a valid Manufacturer’s Licence (MIA) and a valid GMP certificate or equivalent. There is also a requirement for a written confirmation (QP declaration) that the manufacturer of a medicinal product has verified GMP compliance of the active substance manufacturer(s) by conducting an audit to this effect. To ensure GMP compliance MAHs should consider a third party supplier audit process, and other qualification activities for all contracted third parties especially their drug substance and drug product manufacturers. This requirement stands for the entirety of the medicinal product life-cycle and the MAH must continue to confirm a manufacturer’s authorisation and GMP compliance throughout.
  • Regulatory Compliance:
    MAHs should ensure process and controls are in place to guarantee the registered Marketing Authorisation remains current. Changes to the approved dossier, specifically Modules 1 and 3 concerning product labelling and quality must be communicated in a timely manner between the MAH and manufacturer(s) to enable compliance with the MA. Supporting processes should also ensure all required changes to an MA are appropriately communicated to the competent authority and implemented within the required timelines. Likewise, there must be a process to ensure manufacturers communicate with the Marketing Authorisation Holder prior to making any changes to their manufacturing processes and the related controls. Regulatory compliance can be facilitated through a robust change management process. MAHs should also ensure that any updates to the GMP guide are incorporated at manufacturing site level.
  • Regulatory commitments:
    Regulatory commitments are agreed between an MAH and a relevant competent authority. The management of these commitments is critical to maintaining MA compliance. MAHs need to implement effective processes for communicating and tracking all commitments with the relevant manufacturing sites. Failure to implement a commitment risks significant MA non-compliance. The management of regulatory commitments can be anticipated to assume increased importance in the changing regulatory environment where there is a move towards greater flexibility in the area of post-approval change management. Such flexibility will rely on the pharmaceutical quality systems that MAH’s have in place.
  • Quality Systems:
    MAHs need to ensure they have documented systems in place to support GMP compliance management processes. The MAH systems include management both internally and also externally, with all manufacturers and third parties to whom activities are delegated. As previously discussed this includes the need for robust change management, commitment tracking and also processes for managing non-compliance.
  • Data integrity & document retention:
    Failure to implement robust control systems to assure the integrity of data pertaining to the MA can result in GMP non-compliance. MAHs must have systems in place that ensure the integrity and reliability of the data they, and their manufacturers and/or other third parties, use to discharge their GMP responsibilities. There must be assurance that data are reliable, complete and accurate with provisions in place to ensure the long term storage and retention of the data upon which an MA relies.
  • Delegation of activities:
    As discussed previously all delegated activities should be described in writing, normally via a technical/quality agreement detailing the respective responsibilities. In addition to those items discussed above, other factors that MAHs may wish to consider when authoring such agreements for outsourced and delegated responsibilities could include Product Quality Reviews (PQRs), Active Substance Master Files (ASMFs), the retention of samples, mechanisms to ensure product supply and the management of falsified medicines.
  • Falsified Medicines Directive (FMD)
    The FMD Directive introduced a responsibility for the manufacturer to inform the competent authority and the MAH immediately of information which indicates that a medicinal product within the scope of its manufacturing authorisation is, or is suspected of being, falsified. The MAH therefore also has a number of responsibilities related to FMD, one of those being the need to confirm the GMP status of the active substance manufacturer by means of GMP audits as discussed above.

The impact of non-compliance

The potential implications of non-compliance for MAHs are significant. Non-compliance with the various Marketing Authorisation Holder obligations, based on Article 116 of Directive 2001/83/EC, means a Marketing Authorisation may be suspended, revoked or varied by the competent authority.

In addition, under Article 111 of Directive 2001/83/EC and Article 80 Directive 2001/82/EC in situations in which there are grounds for suspecting non-compliance with the legal requirements laid down in these directives, including with the principles and guidelines of GMP, competent authorities will have the power to inspect the premises of the MAH.

How can S-cubed help you?

Team WorkingAs the MAH’s GMP-related responsibilities are broad reaching, and requirements will vary depending on multiple factors including the scope of outsourced activities, product type and complexity of the manufacturing/supply chain in place, S-cubed can support companies in further reviewing and assessing their GMP-responsibilities and whether these are satisfactorily managed to ensure compliance.

S-cubed is working with many client companies, including both MAHs and manufacturers, to ensure compliance with GMP-requirements. We can help through the establishment, review and/or update of Quality Management Systems, authoring and review of SOPs and procedures and Technical/Quality Agreements, conducting supplier audits and managing regulatory activities including product quality and labelling variations to ensure MA compliance.

S-cubed has extensive experience across all GxP areas and can support with ensuring an MAH fulfils their responsibilities for a medicinal product over its lifetime.

Any Questions

If you have any questions on this topic, please don’t hesitate to ask.  You can contact us through our website, via email (info @ s-cubed-global.com ), and telephone (S-cubed Ltd: +44 1235 77 22 60).