Editorial | Open Access | Published 10th March 2021

Reflection paper on Good Manufacturing Practice and Marketing Authorisation Holders

The reflection paper on Good Manufacturing Practice (GMP) and Marketing Authorisation Holders (MAH) has been issued for comment . It focuses on the responsibilities where the MAH is different than the manufacturer. The paper states that the MAH responsibilities for GMP are scattered among EU GMP guidance. This reflection paper aims to collect these responsibilities into one document. Only GMP activities are within scope of this paper.

What was new for me was the realisation that, while manufacturing and testing sites have mandated licence inspections by the MHRA, where the MAH is a separate legal entity, the MHRA can inspect a MAH, if non-compliance is suspected. What is made clear is that while responsibilities can be delegated, the MAH remains accountable for tasks and actions outlined in this reflection paper. It must be kept in mind that a MAH does not need to have a manufacturing or site licence. The MAH can be a virtual “post box” and this has been a Brexit solution for a number of companies. MAH should ensure that even if duties are delegated that they still have “Quality Oversight” of the activities as although delegated the responsibilities still reside with them.

The reflection paper covers the MAH responsibility generating and maintaining the Marketing Authorisation (MA) and the responsibility for the accuracy of the content of the MA with a key section relating to communication to all parties regarding the content of the MA, within this responsibility the MAH must give the manufacturer access to the MA. Annex 16 has also made this absolutely clear, however, there must also be mechanisms in place to ensure that all concerned parties are aware of and implement variations.

The reflection paper outlines eight areas of GMP where the MAH is accountable. This is easy where the MAH is also the manufacturer. Where it might become blurred is where the MAH is a separate legal entity.

Outsourcing and technical agreements

As noted above, the MAH is accountable for all MAH tasks described in the paper, if any tasks are delegated, then a Quality Agreement in accordance with EUGMP Chapter 7 must be in place. This includes the responsibility for annual product quality reviews, reference /retention samples and manufacturing in accordance with relevant guidance.

While document retention activities may be delegated to the manufacturer, and this needs to be part of a quality agreement, the MAH remains accountable for document retention. This includes all the reports e.g. clinical trial, validation and stability documents that support the marketing authorisation (MA).

Audits & qualification activities

The MAH is accountable for the quality and compliance of all parties who contribute to the MA e.g. API sites, manufacturing sites, testing sites and the QP declaration that confirms the GMP compliance of all sites.

Communication with manufacturing sites and competent authorities (e.g. MA dossier information, variations, regulatory commitments, etc.)

This aspect of the MAH communication has been the most frustrating for me as a QP. In this reflection paper, as in Annex 16, it is stressed that the manufacturing site must have access to the dossier. This is often difficult for a Contract Manufacturing Organisation (CMO) but can be difficult also where the MAH is also the manufacturer. Electronic systems that give the Regulatory Affairs teams secure access to the dossier can and do exclude QA/QPs. I worked in a company once as a QP where we had to give “Reg Affairs” 2 days notice of the section we wanted to review as part of batch release. This was impossible and batch release stopped as a result of this.

Product Quality Reviews (PQRs)

The reflection paper makes it quite clear that the MAH is accountable for the PQRs. The Manufacturer, if different from the MAH, must provide the PQR data, review and assessment within the terms of a quality agreement. The MAH must also review and assess the data in relation to any CAPA that may be required. The MAH may need to collate information from several different CMO’s and should be assessing and determine the suitability of the CMO’s data, in the case of “virtual” MAH’s the experience to review and assess the data maybe limited, however Quality Oversight remains part of the MAH’s responsibility.

Quality defects, complaints and product recalls

Again, both the MAH and the manufacturers must have processes in place for complaints and recalls. But again, the MAH can delegate responsibilities via a Quality Agreement, but remains heavily involved and must be party to any reported quality defects and any resultant product shortage.

Maintenance of supply of medicinal products

The MAH has an obligation, that in holding a MA, it also holds a commitment to supply. The MAH must report any real or predicted shortages to the relevant competent authorities. There is also an obligation to request permission to suspend, withdraw or not to renew a MA.

Continual improvement activities

The MAH must have a process improvement system and a change control system. There are obligations to review the PQR for process improvements. The MAH variation process needs to be via change control where the change impact is assessed. In addition is the article 23 (Directive 2001/83/EC) obligation for the MAH to keep up to date with both regulatory and technical advances.

Falsified Medicines Directive (FMD)-related responsibilities

The MAH is accountable for compliance with Falsified Medicines Directive (FMD) 2011/62/EU and the related Delegated Regulations (including the Safety Features Regulation 2016/161). While the MAH can delegate the management of the serialisation data, the MAH remains accountable.

This reflection paper is a welcome collation of MAH responsibilities – especially where the MAH and the manufacturers are different legal entities.

The paper states:

“…the ultimate responsibility for the performance of a medicinal product over its lifetime, its safety, quality and efficacy, lies with the marketing authorisation holder”.

The reflection paper does not seek to separate out MAHs but to help all stakeholders to align their systems to facilitate compliance of the medicines placed on the market and to ensure the availability of high quality, safe and effective medicines.

I 14 January 2020 EMA/457570/2019, GMP/GDP Inspectors Working Group, Reflection paper on Good Manufacturing Practice and Marketing Authorisation Holder