The GMP Update 2023/2024
A lot has happened in the GMP environment in 2023. The following article summarizes some selected highlights. You will find changes in the area of clinical investigational medicinal products in the next issue.
Europe
Revision of EU drug legislation
On April 26, 2023, the European Commission presented the proposal for the revision of EU drug legislation. The changes are to be laid down in a directive and a regulation1.
Specifically, Directive 2001/83 (Directive 2001/83/EC of the European Parliament and of the Council of November 6, 2001 on the Community code relating to medicinal products for human use) and Directive 2009/35/EC are to be replaced. The proposal for the new Regulation 726/2004 (Authorization of medicinal products and establishment of the European Medicines Agency) is intended to replace Regulation 141/2000 for orphan drugs and Regulation 1901/2006 for medicinal products for paediatric use, but also introduces a number of new and adapted regulations.
The European Commission's proposal aims to make EU drug legislation more agile, flexible and adaptable to the needs of patients and businesses in the EU.
Key elements of the proposal include creating a single market for medicines, reducing administrative burdens, promoting innovation and competitiveness, addressing medicines shortages, ensuring environmental sustainability and tackling antimicrobial resistance. The reform also proposes a minimum period of eight years for the regulatory protection of innovative medicines, which can be extended on the basis of certain criteria. In addition, the Commission wants to intensify the fight against antimicrobial resistance (AMR).
Planned changes with GMP relevance:
An important change with GMP relevance are the amended requirements for the qualification of a Qualified Person (QP), which were previously regulated in Article 48 of Directive 2001/83/EU. These can now be found in an annex to Directive 2023/132 (Annex III).
Facilitation with regard to the "Written Confirmation": Member States may waive the requirement of the "Written Confirmation" within the validity period of the GMP certificate (Art. 158 of Directive 2023/132).
Remote inspections: Facilitation for inspectorates regarding remote inspections and risk-based approaches to inspection frequency.
Another focus is on the security of supply of medicinal products. This is to be addressed in the new regulation (Art. 116 ff). The proposal contains provisions for the monitoring and management of shortages and critical shortages of medicinal products.
Recommendation
7/8 May 2024
Audit Trail Review for Computerised Systems in Analytical Laboratories - Live Online Training
COVID-19 flexibilities in the GMP/GDP environment terminated
The EMA, the European Commission (EC) and the Heads of Medicines Agencies (HMA) have decided to phase out the exceptional regulatory flexibilities for medicinal products that were introduced during the COVID-19 pandemic2.
EU and MHRA extend validity of GMP and GDP Certificates
The validity of GMP and GDP certificates had already been extended until the end of 2023. The GMP/GDP inspectors' working group has now decided to continue the extension of the validity date until 2024 or until the completion of the next on-site inspection, whichever comes first, unless otherwise stated in the document3.
In the meantime, competent authorities will carry out risk-based monitoring of sites, either through on-site inspections or remote assessments, and depending on the outcome, they may continue to issue, withdraw or restrict GMP and GDP certificates, whichever is appropriate.
The UK MHRA has also decided to continue the extension of validity until 2024.4
Remote certification/confirmation of batches by the QP
The EMA has published new questions and answers on remote batch certification/conformation by the Qualified Person (QP).
However, there are no clear, uniform provisions. Instead, the decision is left to the competent national authorities.
It states: "Remote batch certification / batch confirmation could be allowed if accepted by the national competent authority where the authorised site is located. (...) In order to determine what requirements apply, manufacturers should consult with their national competent authority."
However, if accepted by the national competent authority, expectations are defined and a number of points should be taken into account.
Questions and answers on chapter 7 of the EU GMP guidance document
The European Medicines Agency EMA has updated its Q&A and discusses the Chain of Contracts, a construct in which one or more parties (sites/companies) act as signatories in a chain of contracts. This inserts one or more separate legal entities between the client - e.g. the manufacturing authorization holder responsible for QP certification - and a contract manufacturer. The relevant GMP activities are subcontracted via one or more levels.
EMA Reflection Paper on the use of artificial intelligence (AI) in medicinal products
In July, the EMA published a "Reflection Paper on the use of artificial intelligence (AI) in the lifecycle of medicines". The comment period ran until 31.12.2023. It is important to read the document in the context of the legal requirements and the overarching EU principles on AI, data protection and medicines regulation. A key principle is that it is the responsibility of the applicant or marketing authorization holder to ensure that all algorithms, models, datasets, etc. used are fit for purpose and comply with ethical, technical, scientific and regulatory standards.
New EMA Guidance on shortages of medicinal products
The EMA has published a document entitled "Good practices to ensure continuity in the supply of human medicines, prevent shortages and reduce their impact"5.
The document contains recommendations for marketing authorization holders, wholesalers and manufacturers on how to avoid supply bottlenecks for human medicinal products and how to deal with these bottlenecks. It emphasizes the importance of proactive measures and identifies common reasons for shortages. The document serves as a guideline and does not represent an exhaustive interpretation of legal obligations. It was developed as part of the HMA/EMA Task Force on the Availability of Authorized Human and Veterinary Medicinal Products, focusing on actions to be taken by key stakeholders in the supply chain. It discusses the roles and responsibilities of the various stakeholders, including marketing authorization holders, manufacturers, wholesalers, national competent authorities, the EMA, national healthcare providers, healthcare professionals and patient representative groups.
"Toolkit" for shortages of medicinal products
The EMA has published a so-called "MSSG Toolkit on recommendations on tackling shortages of medicinal products", a guide for the MSSG to facilitate the identification of recommendations on critical shortages of medicinal products.
The MSSG is the Executive Steering Group on Medicines Shortages and Safety established by Regulation (EU) 2022/1231. It is tasked with providing advice and recommendations on how to deal with critical shortages of medicines in the EU, particularly in the event of major incidents or public health emergencies. The MSSG can propose actions at Union level or for Member States, marketing authorization holders and other stakeholders. The MSSG is supported by a working group of national competent authorities, the SPOC Working Party on Medicines Shortages (SPOC WP), which monitors and reports events that could lead to medicines shortages. More information can be found here: MSSG Solidarity Mechanism.
EU Commission Strategy Paper with measures to combat medicine supply shortages
The European Commission has adopted a package of measures to prevent and mitigate shortages of critical medicines in the EU6. The reform of pharmaceutical legislation announced in April 2023 includes a bundle of measures aimed at increasing security of supply and overcoming supply bottlenecks in the long term. This communication complements the reform of pharmaceutical legislation.
The most important measures planned are:
- Establishment of a voluntary EU solidarity mechanism
- A Union list of critical medicines
- Flexibility in regulation
- EU guidelines for the procurement of medicines in the interest of greater security of supply
- Joint procurement at EU level of antibiotics and therapeutics against respiratory viruses
The Commission is also planning on setting up an alliance for critical medicines ("Critical Medicines Alliance"), which is due to start work at the beginning of 2024. This alliance will focus on a specific number of critical medicines where the risk of shortages is highest and the impact on healthcare systems is greatest.
MRA: EU-US agreement on recognition of GMP inspections for veterinary medicinal products
At a meeting of the EU-US Trade and Technology Council, the US and the EU agreed to mutually recognize the results of GMP inspections for veterinary drug manufacturers. This means that veterinary medicinal products manufactured in the EU can now be exported to the USA and marketed there without the EU manufacturers having to be inspected by a US authority beforehand, and vice versa. Nevertheless, the authorities can reserve the right to carry out GMP inspections in certain cases despite the agreement. Further details can be found on the EMA website7.
FDA
FDA signs MRA with Switzerland
The FDA has signed a Mutual Recognition Agreement (MRA)8 on the mutual recognition of good manufacturing practice for medicinal products with Switzerland.
This enables both authorities to use each other's GMP inspections and their results in order to avoid duplicate inspections. The FDA has already concluded an MRA with the European Union and one with the United Kingdom. The MRA with Swissmedic covers not only human medicinal products, but also veterinary medicinal products.
Recommendation
7/8 May 2024
EU GMP-/FDA-compliant Sampling - Live Online Training
FDA now also covers regions with risk factor
The FDA has updated one of its internal manuals9 and added a risk factor for establishments in countries with a history of violations. This is nothing more than a risk factor for a region or an entire country. Previously, individual criteria, such as the quality history of the respective site, site type or the time since the last inspection, were mainly used.
ICH
ICH Q9 Guideline Quality Risk Management published as revision 1
In January 2023, the revision of the guideline10 reached stage 4 and went into implementation. A concept document11 set out the direction of the changes in 2020.
The concept document identified four areas where the current application of QRM could be improved:
- A high degree of subjectivity in risk assessments and QRM results
- Inadequate management of supply and product availability risks
- Lack of understanding of what constitutes a formality in QRM work
- Lack of clarity on risk-based decision making
The now published revision contains guidance on each of these four topics.
A detailed analysis can be found here: The new ICH Q9 Revision on Quality Risk Management becomes Effective as of 23 July 2023: A Detailed Analysis - GMP Compliance (gmp-compliance.org).
The ICH also provided a set of slides12 that gives an insight into the revision. On 29 slides, the set describes the background of the revised guideline, its objectives and its implementation.
In addition, an ICH Q9 training package was developed and made available on the ICH website13.
Final versions of the Q2(R2) and Q14 Guidelines adopted
On October 31 and November 01, 2023, an ICH Assembly Meeting was held in Prague. At this meeting, the final texts of the ICH Guidelines Q2(R2) "Validation of Analytical Procedures" and Q14 "Analytical Procedure Development" were adopted after the drafts of March 2022 had each received around 3000 comments.
ICH Q2(R2) describes the aspects to be considered in the validation of analytical procedures in the context of marketing authorization applications and the parameters necessary for the validation of various analytical methods. The scope of the revision of ICH Q2(R1) also includes principles of validation related to the analytical use of spectroscopic or spectrometric data (e.g. NIR, Raman, NMR or MS). ICH Q14 addresses the scientific basis for the development, change management and submission requirements of analytical methods. The new guideline is intended to improve communication between industry and regulatory authorities and facilitate more efficient, science-based and risk-based approval and post-approval change management of analytical methods.
Further information on the two guidelines can also be found on the ICH website.
PIC/S
Annual Report
In August, the PIC/S published an annual report on the year 2022. At 46 pages, the report is relatively extensive and contains two annexes. A summary of the report can be found on our GMP news page.
EDQM
New procedure for CEPs
The EDQM (European Directorate for the Quality of Medicines & HealthCare) adopted the document "Management of CEP guidelines and operational documents for the CEP procedure" in late 2022 and published it on its website in early 2023. This document explains the new process for the preparation of supporting documentation relating to CEPs (Certificate of Suitability of Monographs of the European Pharmacopoeia). The focus is on three types of documents14:
- Guidelines for the CEP procedure
- Specification documents
- Administrative documents and instructions
It should be highlighted that a review procedure, which can be public or only for a specific target group, has now been introduced. This should help to increase the transparency of the processes, to communicate and announce updates and changes promptly and to provide an opportunity for comments.
U.K./ Brexit
"Windsor Framework": a new agreement for Northern Ireland
The European Commission and the government of the United Kingdom (UK) reached an agreement on special arrangements for Northern Ireland at the beginning of 2023 (the so-called "Windsor Framework")15. Part of this is also a possible solution for medicinal products. In this regard, "Regulation (EU) 2023/1182 of the European Parliament and of the Council of 14 June 2023 laying down specific rules for medicinal products for human use to be placed on the market in Northern Ireland and amending Directive 2001/83/ EC" was published in the Official Journal of the EU.
Here are some important aspects:
- Centrally authorized products (CAPs) in the EU can no longer automatically be placed on the market in Northern Ireland. A marketing authorization from the MHRA will be required.
- The MHRA can allow the import of medicinal products from Great Britain to Northern Ireland by wholesale authorization holders (even without a corresponding manufacturing authorization).
- Verification by the wholesaler is no longer required: "Wholesale authorization holders are not required to verify medicinal products under Article 1(1) of this Regulation in accordance with Article 80(1)(ca) of Directive 2001/83/EC".
- The requirements of the EU Falsified Medicines Directive (FMD) and the associated Delegated Regulation (EU) 2016/161 in relation to safety features for medicinal products are repealed for Northern Ireland. This means that packages placed on the market in Northern Ireland may no longer bear EU safety features on secondary packaging (features must be completely removed or covered). See also the relevant MHRA document.
- The packaging of all medicinal products placed on the market in Northern Ireland must clearly state "UK only".
Switzerland
Swissmedic launches its own GMDP database
As with the EudraGMDP database of the EMA (European Medicines Agency), the Swiss Medicines Agency Swissmedic will launch a SwissGMDP database, which will list the GMP and GDP certificates of every company in Switzerland that holds a valid Swissmedic manufacturing authorization.16 These SwissGMDP certificates contain all approved activities, i.e. in contrast to the EudraGMDP, the GDP activities and Swiss-specific GMP activities of Swiss companies are also listed in the certificates. On this SwissGMDP, all companies, authorities and persons can very easily view the GMP/GDP status of a company.
Document on the interpretation of Annex 1
On October 1, Swissmedic published a document on the interpretation of Annex 1, which is intended to make it easier for users to understand17. However, it refers to the revised Annex 1 of the PIC/S GMP Guideline (PE 009) on the manufacture of sterile medicinal products (which in turn is based on the revised Annex 1 of the EU GMP Guideline).
This technical interpretation focuses on some of the most important changes of the revision and covers aspects that were already included in the previous version of the guideline and that have repeatedly raised questions. This technical interpretation is intended to reflect the general opinion of the Swiss inspectorates on these topics and to assist in the inspection of manufacturers of sterile medicinal products.
Outlook
The European Medicines Agency EMA has published a new version of the "3-year work plan for the Quality domain" for the period January 2021 - December 2023. The plan will be prepared by the GMP/GDP Inspectors Working Group (GMDP IWG) as part of the planned revision after two years in March 2023. It also includes some updated timeframes for the revision of GMP requirements. Here is an overview:
| Document | Proposed change | Scope |
| GMP Guide: Chapter 4 (Documentation) | Final version of the amended chapter on data integrity | Q1 2026 |
| GMP Guide: Annex 11 (Computerised Systems) | Final version of the amended Annex in rela-tion to data integrity | Q1 2026 |
| Guidelines on GMP specific to ATMPS | Review with regard to the new Annex 1 Manufacture of sterile medicinal products | Q4 2024 |
| GMP Guide: Annex 15 Qualification and Validation | Review with regard to new technologies in equipment, products and processes. On the basis of the LLE recommendations, it must be examined whether the scope can be extended to APIs. | Q2 2024 |
| GMP Guide: Annex 16 Certification by a Qualified Person and Batch Release | Following on from the LLE recommenda-tions, consideration should be given to re-vising the annex to provide additional guidance on batch traceability. | Q4 2024 |
| GMP Guide: Annex 4 (Manufacture of Veterinary Medicinal Products Other Than Immunological Veterinary Medicinal Products) | Review of comments received during the stakeholder consultation on the concept paper. | Q4 2024 |
| GMP Guide: Annex 5 (Manufacture of Immunological Veterinary Medicinal Products) | Review of the comments received during the stakeholder consultation on the con-cept paper. | Q4 2024 |
| GMP Guide: GMP for Novel Veterinary Medicinal Products | Submission of a final text to the European Commission. | Q4 2023 |
| GMP Guide: GMP for Autogenous Veterinary Vaccines | Submission of a final text to the European Commission. | Q4 2023 |
| GMP and Marketing Authorisation Holders | Revision of the paper in line with the rec-ommendations of the Nitrosamines LLE also with regard to an appropriate quality agreement with manufacturers. | Q4 2023 |
| ICH Q13: Continuous Manufacturing | Support EU members of the Expert Work-ing Group (EWG) in developing the guide-line. | Q4 2023 |
| VICH: GMP for API’s for Veterinary Medicines | Support EU members of the Expert Work-ing Group (EWG) in developing the guide-line. | Q4 2023 |
| VICH: Other Q Guidelines for Veterinary Medicines | Support EU members of the Expert Work-ing Group (EWG) in future adaptations of existing ICH Q guidelines such as Q9/Q10 to veterinary medicinal products. | Q4 2023 |
| Implementing Act: GMP for Veterinary Medicinal Products | Scientific advice to the European Commis-sion on GMP standards to be included in a regulatory act on GMP for veterinary me-dicinal products. | Q4 2023 |
| Implementing Act: GMP for active substances for Veterinary Medicinal Products | Scientific advice to the European Commis-sion on GMP standards to be included in a regulatory act on GMP for veterinary me-dicinal products. | Q4 2023 |
About the Author
Wolfgang Schmitt is Vice President at CONCEPT HEIDELBERG and organises and conducts courses and conferences on behalf of the ECA Academy in the areas GMP Systems and Compliance, Qualified Person and GMP-Auditing. He is also Administration Manager of the European QP Association and Member of the Board of Directors of the European GMP-Auditor Association.
Notes:
1 https://ec.europa.eu/info/law/better-regulation/have-your-say/initiatives/12963-Revision-of-the-EU-general-pharmaceuticals-legislation_en
2 https://www.ema.europa.eu/en/news/phasing-out-extraordinary-covid-19-regulatory-flexibilities
3 https://www.ema.europa.eu/en/human-regulatory-overview/research-and-development/compliance-research-and-development/good-manufacturing-practice#ema-inpage-item-10391
4 https://mhrainspectorate.blog.gov.uk/2023/12/11/gmp-gdp-certificates-validity-period-extended/
5 https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/good-practices-industry-prevention-human-medicinal-product-shortages_en.pdf
6 https://www.gmp-compliance.org/gmp-news/eu-commission-strategy-paper-with-measures-against-medicine-supply-shortages
7 https://www.ema.europa.eu/en/news/progress-eu-us-mutual-recognition-agreement-inspections-veterinary-medicines
8 https://www.fda.gov/media/164511/download
9 MAPP "Understanding CDER's Risk-Based Site Selection Model" (5014.1 Rev. 1)
10 https://database.ich.org/sites/default/files/ICH_Q9%28R1%29_Guideline_Step4_2023_0126_0.pdf
11 https://database.ich.org/sites/default/files/Q9-R1_Concept%20Paper_2020_1113.pdf
12 https://admin.ich.org/sites/default/files/inline-files/ICH_Q9R1_Step_4_Presentation_2023_0314.pdf
13 https://www.ich.org/news/ich-q9r1-quality-risk-management-training-materials-now-available-ich-website
14 https://www.edqm.eu/en/-/management-of-edqm-cep-documents-edqm-introduces-a-consultation-phase
15 Press Release EU Commission: https://ec.europa.eu/commission/presscorner/detail/de/ip_23_1268
16 https://www.swissmedic.ch/swissmedic/en/home/humanarzneimittel/bewilligungen_zertifikate/authorisations/swissgmdp.html
17 https://www.swissmedic.ch/dam/swissmedic/en/dokumente/bewilligungen/inspektorat/-smi-ti-25e_interpretation_gmp-annex_1_2022.pdf.download.pdf/I-SMI.TI.25e_Interpretation_GMP_Annex1.pdf
