GMP Trends 2021/2022
The year 2021 was again characterised by pandemic-related limitations. Not only the pharmaceutical industry but also the authorities worldwide were hit by home-office requirements and travel restrictions. Many important activities had to be carried out online - as still is the case. This also applies to audits, inspections and batch releases. And Brexit has caused some necessary changes and adjustments, too. Nevertheless, the authorities have not only been occupied with the pandemic. There have been some publications concerning other topics, too. The following article summarises some of the highlights.
EU: Further Extension of GMP and GDP Certificates
The European Medicines Agency (EMA) announced in conjunction with the heads of Medicines Agencies (HMAs), and the European Commission already in April 2020 that due to pandemic-related safety measures, travel restrictions and the associated limitations on inspections expiring GMP and GDP certificates as well as temporary manufacturing, import and wholesale authorisations would be extended until the end of 2021. When the deadline expired many of the restrictions persisted, however, even if some of the inspection activities had been resumed. Therefore, the relevant validities have been extended once more.
As a consequence, a revision of the "Notice to Stakeholders: Questions and answers on regulatory expectations for medicinal products for human Use during the Covid-19 pandemic" was published in September 2021 (now in version 4)1.
For sites in and outside the EU and the European Economic Area (EEA), the certificates are automatically extended until the end of 2022. But there are also exceptions:
- restrictions on the validity period are stated in the clarifying remarks of the GMP certificate
- the issuing/regulatory authority finds itself constrained to adopt measures affecting the validity of the certificate.
Remote Audits/ Distant AssessmentsWhen the GMP requirements and regulations were developed and introduced nobody imagined that there could be a pandemic or something similar. Distant assessments or also remote audits as we have come to understand them - for instance with direct video or audio communication - have so far neither been made a subject of discussion nor have they been regulated. The EMA has developed a questions and answers document already in 2020 which discussed at least remote assessments by the authorities. In 2021 there were publications of further authorities:
- PMDA: The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) has published an English version of the "Procedure for Remote Inspection as a part of compliance inspection on drugs and regenerative medical products"2. The document describes the concrete procedure of a remote inspection, explains the procedure with the required documents and illustrates the expectations concerning video conferencing systems.
- FDA: The FDA has published a Guidance for Industry3 addressing this topic. Anybody hoping that the FDA would carry out remote assessments having the same status as an inspection on site or a comparable status sees himself deluded. Even in the title "Remote Interactive Evaluations" the words inspection or audit are avoided. A footnote contains the explanation that a remote interactive evaluation does not conform to the legal definition of an inspection. In the end, such a remote interactive evaluation is complementary to an inspection. The procedure described is very similar to a virtual inspection. It is possible to carry out livestreaming walkthroughs of the facility as well as interviews.
After the publication of the above-mentioned Guidance the FDA has updated its questions and answers document "Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-19 Public Health Emergency"4 which explains some of the measures which have to be taken if the authorities cannot carry out an on-site inspection of the facility.
- EDQM: "Innovation overcoming Adversity". That is how the European Directorate for the Quality of Medicines & Health- Care (EDQM) has entitled a publication on real-time remote GMP inspections of API manufacturers during the COVID-19 pandemic5. The EDQM is satisfied with the results of its study. A number of minor and major deficiencies could be identified even if the inspectors were not on-site.
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Based on quality risk-management principles remote inspections are supposed to become part of EDQM's inspection programme. They will be carried out in the case of travel restrictions or if the safety of the inspectors cannot be guaranteed. With a corresponding GMP-compliance history real-time remote GMP inspections will also be possible. Remote inspections will not be deployed for the assessment of aseptic manufacturing operations.
- ICMRA: The most interesting document, however, was developed by a working group of the International Coalition of Medicines Regulatory Authorities (ICMRA). The document is entitled: "Reflections on the regulatory Experience of remote Approaches to GCP and GMP regulatory Oversight during the COVID-19 Pandemic"6. The working group was headed by the British MHRA and comprised inter alia representatives of the FDA, the EMA, Health Canada, Swissmedic, HPRA, the PEI and the WHO. It could be seen that a variety of terms have been used, such as "remote evaluation," "remote assessment", "remote inspections", "desktop inspection", and "distant assessment".
The risk management processes and hybrid approaches considered are very interesting, including the experiences with different types of digital means, such as visual technology. These considerations can offer valuable support to the pharmaceutical industry concerning its own approaches. The paper also describes problems, challenges and limits and how they can be addressed.
Although it is a reflexion paper its cumulative experiences offer a valuable insight in the way the regulatory authorities have handled the official monitoring, inspections and assessments during the pandemic.
Following intensive negotiations the negotiators of the European Union (EU) and of the United Kingdom (UK) have agreed on a provisional Trade and Cooperation Agreement on 24 December 2020. Until the end of the year, all remaining EU member states had given their approval on the agreement and its provisional application. The approval of the European Parliament followed a little later.
What is the document's content?
Primarily, it covers an economic partnership and trade regulations. It stipulates exemption from duty for goods that comply with the relevant rules of origin. Further topics are services, professional qualifications, environmental and energy issues, freight transport as well as regulations on social security or research and development.
There are only few provisions which are directly dedicated to medicinal products and the associated requirements. Even though there is an annex (TBT-2: Medicinal products) it mainly refers to cooperation, recognition of inspections, exchange and recognition of official GMP documents and the establishment of a working group - but to nothing which could change the situation communicated by the European Commission, the EMA and the MHRA in the last year. It is not a mutual recognition agreement (MRA) as many hoped. For instance, it does not cover mutual recognition of batch testing nor mutual recognition of batch certification and release of medicinal products. This means that for medicinal products imported from the UK, batch certification must be carried out a second time according to EU GMP by an EU-based Qualified Person (QP).
In the meantime, the MHRA has updated or newly developed a number of requirements. The guidelines in the areas of marketing authorisation and pharmacovigilance, for instance, were updated. This can all be found on the MHRA website.
The United Kingdom has also unilaterally established transitional provisions. EU batch testing will still be recognised in the UK, for example. Deadline for this transitional provision was 31 December 2022 so far. The British government has published a "Letter to medicines and medical products suppliers" well ahead of this deadline in which it has been extended. The letter states word-forword: "the continued recognition of EU/EEA batch testing will not be ending on 1 January 2023".
The Protocol on Ireland and Northern Ireland – there remain issues to be clarified
Northern Ireland's role always was very important during the Brexit negotiations. It was especially the EU's goal to avoid a hard border on the Irish isle.
The result was the so-called Protocol on Ireland and Northern Ireland. But the situation still is and remains complicated and there were a number of successor documents. At the end of January, the European Commission published a notice with the title "Application of the Union's pharmaceutical acquis in markets historically dependent on medicines supply from or through Great Britain after the end of the transition period" (2021/C 27/08). This document contains a good summary on the movement of medicinal products.
Later on, the European Commission has put forward a so-called "balanced package of measures"7 to address some of the most pressing issues related to the implementation of the Protocol on Ireland and Northern Ireland. The EU is trying to find "creative solutions" with this balanced package. In the end, the solution for medicinal products consists in the EU changing its own rules so that "regulatory compliance functions for medicines authorised by the UK for the Northern Ireland market, in accordance with the Protocol, may be located in Great Britain, subject to specific conditions ensuring that the medicines concerned are not further distributed in the EU Internal Market". Following this, the Commission has published details in so-called "non-papers" in order to be able to advance the procedure.
The EU accepts inspections by the MHRA
The EMA has updated its questions and answers document8 on the implementation of the Protocol. Of interest are especially the question and answer no. 14.3 ("How will the manufacturing and import authorisations, GMP certificates and GMP non-compliance statements for sites in Northern Ireland be issued and made available and will the same apply to GMP certificates issued by the UK authorities for sites in other locations?"). Here it was added or clarified that according to the provisions of the earlier agreement between the EU and the UK both sides shall recognise the outcomes of GMP inspections carried out by the other party. The EU will continue to accept national documents of the British authority such as GMP certificates and inspection reports issued for sites located in Great Britain for the purpose of confirming GMP compliance in the context of regulatory submission and/importation requirements. The same applies to inspections in third countries. The GMP certificates issued can be submitted at least as supporting information for regulatory submissions.
Investigational Medicinal Products in Clinical Trials
At the end of April, the EMA confirmed that the EU-portal and the database for clinical trials (Clinical Trial Information System, CTIS) are fully functional now. This means that the Clinical Trials Regulation (EU) No 536/2014 has been applicable since 31 January 2022 (there will be a subsequent transition period of three years during which the contents of the Clinical Trials Regulation as well as the current legislation on clinical trials apply). The aim of this Regulation is to harmonise the registration and surveillance procedures for clinical trials on EU level.
The European Medicines Agency (EMA) has published two drafts for guidelines on the quality requirements concerning investigational medicinal products (IMPs):
- Quality documentation for IMPs (small molecules)9
- Quality documentation for biological IMPs (large molecules)10
According to information from the EMA the documents have to be seen in connection with Clinical Trials Regulation (EU) No. 536/2014 (CTR). Comments could be sent to the EMA until 31 August 2021.
WHO publishes further GMP Standards for the Pharmaceutical Development
In the light of the need for a fast development of medicinal products for the treatment of COVID-19 the World Health Organization (WHO) has published new good manufacturing practices for investigational products11 and new good manufacturing practices (GMP) for development batches12 for comments already in 2020.
After consolidation of the comments received and the review of the responses revised versions of the two documents have been published for a second round of public consultation. The deadline for comments ended on 31 August 2021.
EMA Reflection Paper on GMP and Marketing Authorisation Holders
In January 2020, the European Medicines Agency (EMA) published the draft of a so-called reflection paper with the following title: "Good Manufacturing Practice and Marketing Authorisation Holders"13 and encouraged comments from interested stakeholders. Later in the year, the final document has been published. It is about GMP responsibilities applicable to marketing authorisation holders. As not all marketing authorisation holders (MAH) are manufacturers at the same time and have a manufacturing or import authorisation (manufacturing/import authorisation holder, MIAH) this document aims at clarifying the different responsibilities and their practical importance for marketing authorisation holders. The final aim was to summarise the responsibilities described at various sections in relevant guideline documents such as the EU GMP Guideline or in Directives in one document and to explain them if necessary.
New FDA Director
With the inauguration of the new US-President Biden the previous Commissioner Stephen M. Hahn resigned from his office. On 20 January 2021 Dr Janet Woodcock was appointed Acting Commissioner. Dr Woodcock can look back on a long career at the FDA. She was Director of FDA's Center for Drug Evaluation and Research (CDER), inter alia.
EU-Switzerland: Mutual recognition of medical devices ceased to apply
The Mutual Recognition Agreement (MRA) between the EU and Switzerland has so far allowed medical device manufacturers from the EU and Switzerland to access the respective markets based on the Directives on medical devices applicable until now. At the end of May, the European Commission then announced the following: "EU-Switzerland: Mutual recognition of medical devices ceased to apply"14. This was linked to the new Medical Devices Regulation (Regulation (EU) 2017/745 which entered into force on 26 May 2021). In the course of the negotiations the EU had always made clear that in the absence of a deal on the Institutional Framework Agreement between the EU and Switzerland, an update of the MRA, including the medical devices chapter, could not be considered. On 30 March 2021 the EU proposed to Switzerland a limited modification of the Mutual Recognition Agreement providing for a transitional validity period. The proposed modification was not agreed, however. As a result, not even existing Swiss certificates of conformity or existing certificates issued in the EU remain valid.
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EUDAMED - Database for Medical Devices
On 26 May 2021, the day the Regulation (EU) 2017/745 on Medical Devices became applicable, the European Commission published a questions and answers document on the date of application of the EU-regulations on the safety of medical devises, inter alia on EUDAMED. This database for medical devices will provide an overview over all medical devices available in the European Union. It will integrate different electronic systems with information about medical devices and related companies (e. g. manufacturers).
We have been expecting the following two documents for some time now:
- Annex 1 of the EU GMP-Guidelines "Manufacture of Sterile Products"15
- Annex 21 of the EU GMP-Guidelines "Importation of Medicinal Products"16.
Annex 1: A second draft was published in February 2020 as targeted stakeholder consultation. Deadline for submitting comments was 20 July 2020. Targeted associations were invited to comment on certain still critical points. Altogether, comments from 52 different industry organisations, associations, and individuals were submitted. Actually, the final version of the document is assessed by PIC/S and the WHO. Approval and publication are expected for the first quarter of 2022.
The time lines for implementation will be interesting. Will it be 12 months in general? Or 24 months for specific topics? This remains to be seen.
Annex 21: The first draft was published for commenting in March 2020. Approximately 200 comments from 17 stakeholders were received. The final document was published on 16 February 2022 and will come into operatio on 21 Augustn 2022.
The annex is addressed to manufacturing import authorisation (MIA) holders who import human or veterinary medicinal products from outside the EU/EEA. Medicinal products are finished or intermediate medicinal products, and bulk products (according to the Directive 2001/83/EC). Advanced therapeutic medicinal products (ATMPs) are not included. The scope was a matter of dispute among EMA's GMDP IWG, and the European Commission for a long time. A point of discussion was whether the fiscal importation ("the product physically remaining in the EU when ownership is transferred to countries outside the EU/EEA) should be included in this annex. In the final document it is not included (anymore). Reimport activities and products without marketing authorisation in the EU/EEA intended to be exported directly aren't covered, either.
About the Author
... joined CONCEPT HEIDELBERG as Operations Director and is in charge of the areas Quality Assurance and Management GMP, Qualified Person.
5 EDQM and real-time remote GMP inspections of API manufacturers during the COVID-19 pandemic: innovation overcoming adversity | EDQM - European Directorate for the Quality of Medicines – https://www.edqm.eu/en/edqm-and-real-time-remote-gmp-inspections-api-manufacturers-during-covid-19-pandemic-innovation
8 Questions and answers to Stakeholders on the implementation of the Protocol on Ireland/Northern Ireland (EMA/520875/2020): https://www.ema.europa.eu/en/documents/other/questions-answersstakeholders-implementation-protocol-ireland/northern-ireland_en.pdf
9 Requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials | European Medicines Agency (europa.eu) – https://www.ema.europa.eu/en/requirements-chemical-pharmaceutical-quality-documentation-concerning-investigational-medicinal
10 Requirements for quality documentation concerning biological investigational medicinal products in clinical trials | European Medicines Agency (europa.eu) – https://www.ema.europa.eu/en/requirementsquality-documentation-concerning-biological-investigational-medicinal-products-clinical
13 Reflection Paper on Good Manufacturing Practice and Marketing Authorisation Holders_final version July 2021 (europa.eu) – https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-good-manufacturing-practice-marketing-authorisation-holders_en.pdf
14 EU-Switzerland: MRA for Medical Devices no longer valid - GMP Navigator (gmp-navigator.com) – see https://www.gmp-compliance.org/gmp-news/eu-switzerland-mra-for-medical-devices-no-longervalid