Editorial and PHSS News

Editorial By Kay O'Hagan, Tecmac

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

PHSS News - Chair of The PHSS

Dear Readers

2020 was an unprecedented year for the world as well as the PHSS, presenting us all with unforeseen changes and challenges. Our events programme was significantly impacted in 2020 and we will continue to adapt as we move through 2021. Our dedicated team continues to deliver a range of virtual webinars, conferences, and forums. James Drinkwater and Di Morris, have been outstanding with their efforts in 2020 regarding Annex 1, and the commenting process. The focus and persistence in ensuring that PHSS members and industry have had the opportunity to contribute and collaborate. They even found time to deliver excellent update webinars in July and September.

  • July: PHSS Annex 1 related to Barrier Technologies Webinar
  • September: PHSS Annex 1 Qualification (including Classification) of Cleanrooms and Clean air equipment.

In mid-September we hosted our Virtual Annual Conference, support by valued partner UCL, engaging with over 60 delegates each day. The conference discussed key challenges in manufacturing and aseptic processing of Biological and Advanced Medicinal Therapeutic products (ATMPs), Day 1 hosted presentations from Kelly Balsom, Advent Bio, Michael Schenk, Imperial College London and Stuart Curbishley, Head of Business and Process Development for ATMP’s (University of Birmingham). All providing their valuable insights on how they have managed to continue through the recent and dynamic fast changing months. Day 2 hosted presentations from MHRA, talking about changing landscapes and VMIC again providing very topical insights into How to build a facility for all processes, as well as how VMIC was established. We hosted our annual QP forum in early November, with presentations from, Kate Hogg, Clee Pharma and Di Morris, Astrazeneca, discussing Working in Radio Pharmaceuticals and its challenges and Aseptic Manufacture audit findings. We continue to focus on membership and industry engagement as begin 2021, in order to ensure we are providing access to relevant, topical and informative events. For more information on all our events please visit the PHSS website https://phss.co.uk/events/event_list.asp and follows us on social media.

Member benefits I would like to take the opportunity to highlight just some of the fantastic benefits of being a PHSS Member, we provide:

  • Exclusive access to monthly regulatory update synopsis,
  • Opportunities to participate in Special interest group collaboration and networking to help generate practical guidance
  • We are a voice for all stakeholders in the industry including suppliers and customers
  • Access to an extensive document library including white papers, Impact papers, and process discussions

Thank you finally to all our valued members, partners, and industry collaborations for your invaluable support in these challenge times. On behalf of PHSS Please keep safe and well. Jenni Tranter, Chair of PHSS – Pharmaceutical & Healthcare Sciences Society.