GMP Update 2024/2025
A lot has happened in the GMP environment in 2024. The following article summarizes a few selected highlights. Changes in the area of IMPs can be found in a separate article.
Europe
EMA publishes ICH Q14 Guideline "Analytical Procedure Development" - Step 5
On January 26, 2024, the European Medicines Agency (EMA) published the new ICH Q14 Guideline "Analytical Procedure Development" as Step 5. It has been in force since June 2024.
The guideline describes scientific and risk-based approaches for the development and maintenance of analytical procedures suitable for assessing the quality of active pharmaceutical ingredients (APIs) and medicinal products. It applies to new or revised analytical methods used for the release and stability testing of commercial APIs and medicinal products (chemical and biological/biotechnological).
EMA recommendations to strengthen the supply chains of critical medicinal products
On April 23, 2024, EMA published a list of recommendations for strengthening the supply chains of medicinal products included in the Union list of critical drugs.
These measures have been developed by EMA's Medicinal Shortages Steering Group (MSSG) and aim to secure the availability and supply of critical drugs whose supply chain has been identified as vulnerable. The recommendations are made on a case-by-case basis, taking into account the vulnerabilities of the supply chain and the individual characteristics of the medicinal product. A summary of the measures is available on our news page.
Question and answer document on the QP's role in supply chain traceability
EMA has published a question and answer document on its website "Guidance on good manufacturing practice and good distribution practice: Questions and answers" under "EU GMP guide annexes: Supplementary requirements: Annex 16". It focusses on the documentation of the traceability of the supply chain of APIs and medicinal products. This question addresses how documentation systems for the traceability of an API and a medicinal product can be established and maintained to support QPs in fulfilling their legal obligations during batch certification and release.
Updated question and answer document on combination products
A question and answer document published by EMA on the subject of combination products focuses on quality-related issues relating to these products during marketing authorization. The latest additions date from summer 2024 and are in fact revision 4 of the original document. Changes are marked as "Rev" or "New". The entire document can be accessed on the EMA website. As a special service, EMA also offers a version with change tracking so that you can follow the amendments directly. However, due to the many changes from the previous version, the document is difficult to read.
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FDA
Q2(R2) and Q14 guidance documents published
After the ICH and the EMA had already made the documents available for download in December 2023 and January 2024 respectively, the FDA has now also announced the availability of the two Guidances for the Industry titled "Q2(R2) Validation of Analytical Procedures" and "Q14 Analytical Procedure Development".
FDA Inspections
The FDA has published its annual "State of Pharmaceutical Quality" report for fiscal year 2023, which aims to provide a comprehensive look at the US drug supply chain. The report provides an overview of key quality data, trends and surveillance activities related to pharmaceutical manufacturing.
The report covers various aspects including:
Quality monitoring programs and their effectiveness in monitoring the pharmaceutical market
Data on pharmaceutical manufacturers, their products and cases of post-marketing quality defects
Information on import alerts, recalls and warning letters to manufacturers
New approaches to improving pharmaceutical quality
Number of inspections:
The number of drug quality assurance inspections conducted by the FDA increased from 548 in 2022 to 776 in 2023; this is the highest number of inspections since the beginning of the COVID-19 pandemic. In the same period, the number of inspections covered by MRAs increased from 144 in 2022 to 187 in 2023.
ICH
ICH Q3C: New version of Guideline for Residual Solvents published
The ninth revision of the "Impurities: Guideline for Residual Solvents Q3C(R9)" has been available on the ICH website under "Quality Guidelines" since the late April 2024. This version contains revisions and adjustments in section 3.4 Analytical Procedures.
EDQM
Indication of manufacturing sites in CEP
Since June 1, 2023, "identification numbers" have been mandatory for all companies named in the CEP dossier. Together with the names and addresses of the respective companies, these are then listed on the CEP. In March 2024, the document "Unique identification of manufacturing sites linked to CEP applications, using SPOR OMS and GPS coordinates" was updated and revised and published in revision 4 on the EDQM website in April. In this revision, it was specified that the data provided for the manufacturing sites in the CEP must match the data contained in the SPOR/OMS database.
Further information on the document can be found on the EDQM website1.
New chapter "Quality of Data" published for comments
A draft of the new chapter "5.38. QUALITY OF DATA" has been published in the Pharmeuropa section on the EDQM's website and had been open for comments (among several other new drafts) until December 31, 2024.
The draft of the new chapter refers to data that is generated, collected or used as part of quality control and highlights its increasing importance in relation to the quality assessment of medicinal products.
New guideline for sterile substances published
In November, the new guideline "Content of the dossier for sterile substances (PA/PH/CEP (23) 54)" was published on the EDQM (European Directorate for the Quality of Medicines & Health-Care) website. Following the end of the commenting phase in mid-August, the final guideline is now available to view. You can access the new guideline "Content of the dossier for sterile substances (PA/ PH/CEP (23) 54)" in the "Certification Policy Documents & Guidelines" section of the EDQM website under "Content of a dossier".
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Supplement 11.7 to the European Pharmacopoeia
The Supplement 11.7 to the European Pharmacopoeia (Ph.Eur.) is now available. All CEP holders (Certificate of Suitability of Monographs of the European Pharmacopoeia - holders) are required to adapt their specifications and thus the respective CEPs to the new monographs by April 1, 2025.
All substances that are subject to the implementation of the amended or updated monographs are listed in a table. In addition to the names of the substances, the classifications (Case A or Case B) are also listed.
The list of categorized substances and further information on Supplement 11.7 to the European Pharmacopoeia (Ph.Eur.) can be found on the EDQM website.
U.K./ Brexit
MHRA: New rules for manufacturers and wholesalers after Brexit
The UK Medicines and Healthcare Products Regulatory Agency (MHRA) has published a new guidance for manufacturers and wholesalers of medicinal products to implement the Windsor Framework rules for medicinal products for human use. The rules have been in force since January 1, 2025.
The guideline addresses the requirements for labeling, packaging and import of medicinal products for human use, including the use of "UK Only" labels and the non-application of the EU Falsified Medicines Directive (FMD). Specific guidance is provided for Qualified Persons (QPs) and Responsible Persons for Import (RPis). Further details can be found on the MHRA website.
MHRA explains the Windsor Framework in a new document
The MHRA has published an 'Explainer for Industry' on the key changes introduced by the Windsor Framework for the supply of medicines in Northern Ireland. The document is intended as both an educational tool and a guide to ensure that stakeholders are prepared for the regulatory change under the Windsor Framework. This 'Explainer' is now intended to provide a detailed overview of the regulatory changes introduced by the Windsor Framework in relation to the supply of medicinal products for human use in Northern Ireland.
Switzerland
Technical interpretation on shipment under quarantine published
Swissmedic has published a new document in English on the subject of "Shipment under Quarantine". It clarifies some situations in which a shipment under quarantine of active substances, intermediates or medicinal products would be acceptable for inspectors. The nine-page PDF document with the document number I-SMI. TI.26e, valid since 14.02.2024, is publicly available for download on the authority's website.
The core of the document is the fourth chapter (Interpretation). It outlines various situations that could, in principle, lead to the decision to consider quarantine shipping (e.g. limited storage capacity, long transportation times). It is also emphasized that quarantine shipping is generally not in line with GMP requirements and should therefore not be the standard practice, and that appropriate safety measures must be implemented in any case.
Changes for the Responsible Person
Technical Interpretation 17 "Responsible Person: requirements" has been updated with some of the requirements applying in retrospect. Therefore, if one of the clarifications has led to the requirements of the previous version no longer being fulfilled, an immediate modification is required.
Example: Chapter 5.5 requires the Responsible Person (RP, or Fachtechnisch verantwortliche Person, FvP) to have a good knowledge of the local language. Companies whose already approved RPs do not meet these requirements are given a period of 12 months starting from the publication date of the updated technical interpretation to make the necessary adjustments by either appointing a new RP with the required language skills or ensuring that the current RP acquires the required language skills within this period.
The changes are summarized in chapter 9 of the document.
Introduction of a dedicated GMDP database
Similar to the EudraGMDP database of the EMA (European Medicines Agency), the Swiss Medicines Agency Swissmedic has put a SwissGMDP database into operation, in which the GMP and GDP certificates of every company in Switzerland that has a valid Swissmedic manufacturing authorization are listed. These SwissGMDP certificates contain all approved activities, which means that, in contrast to the EudraGMDP, the GDP activities and Swiss-specific GMP activities of Swiss companies are also listed in the certificates. The GMP/GDP status of a company can be viewed very easily by all companies, authorities and persons on this SwissGMDP.
Furthermore, the SwissGMDP enables a query of all license holders with a valid manufacturing authorization including their locations and authorized activities and will replace the previous table of license holders.
Further information on the use of the SwissGMDP database can be found in the guidance document.
Updated guideline on the conduct of inspections
Swissmedic has updated the Guideline I-SMI.RL.01 "Conduct of inspections of establishments manufacturing or distributing medicinal products or collecting blood". Version 4.0 was released on October 21, 2024 and thus entered into force.
The PDF file is available for download on the Inspectorate website.
Outlook
EMA plans for the next three years
The European Medicines Agency EMA has published a new version of the 3-year work plan for the Inspectors Working Group 2 for the period January 2024 to December 2026. The plan is prepared by the GMDP Inspectors Working Group (GMDP IWG). It also includes some updated timeframes for the revision of GMP requirements. Here is an overview:
| Document | Scheduled Changes | Time Frame |
| GMP Guide: Chapter 4 (Documentation) | To provide the European Commission with a final text for the amended chapter in order to assure data integrity in the context of GMP. This would be in parallel with similar consideration of Annex 11 (Computerised Systems). To work with GCP IWG, GLP IWG and PhV IWG on this topic. | Q1 2026 |
| GMP Guide: Annex 11 (Computerised Systems) | To provide the European Commission with a final text for the amended annex in order to assure data integrity in the context of GMP. This would be in parallel with similar consideration of Chapter 4 (Documentation). To work with GCP IWG, GLP IWG and PhV IWG on this topic. | Q1 2026 |
| Guidelines on GMP specific to ATMPS | Review the Guidelines in collaboration with CAT and the European Commission following the publication of a new regulation on standards of quality and safety for substances of human origin intended for human application and need to update legal references and definitions. | Q4 2024 |
| GMP Guide: Annex 3 Manufacture of Radiopharmaceuticals | To provide the European Commission with a final text for an amended Annex 3 following a review and update of the Annex to reflect current state of the art. | Q4 2026 |
| GMP Guide: Annex 4 (Manufacture of Veterinary Medicinal Products Other Than Immunological Veterinary Medicinal Products) | To review comments received from concept paper stakeholder consultation and draft an updated text. | Q4 2024 |
| GMP Guide: Annex 5 (Manufacture of Immunological Veterinary Medicinal Products | To review comments received from concept paper stakeholder consultation and draft an updated text. | Q4 2024 |
| GMP Guide: Annex 6 Manufacture of Medicinal Gases | To provide the European Commission with a final text for an amended Annex 6 following a review and update of the Annex to reflect current state of the art. | Q4 2026 |
| GMP Guide: Annex 15 Qualification and Validation | To provide the European Commission with a final text for an amended Annex 15 in the context of new technology in facilities, products and processes and following up on LLE recommendations, and extend the scope to APIs. | Q4 2026 |
| GMP Guide: Annex 16 Certification by a Qualified Person and Batch Release | To provide the European Commission with a final text for an amended Annex 16 following up on LLE recommendation | Q4 2025 |
| GMP Guide: GMP for Novel Veterinary Medicinal Products | To provide the European Commission with a final text. | Q4 2025 |
| GMP Guide: GMP for Autogenous Veterinary Vaccines | To provide the European Commission with a final text | Q4 2025 |
| GMP and Marketing Authorisation Holders | To revise the paper in line with recommendations from the Nitrosamines LLE, to strengthen guidance for MAHs in terms of having adequate quality agreement with manufactures. | Q4 2025 |
| ICH Q12: Lifecycle Management | To support the EU members of the Expert Working Group (EWG) in developing the training materials on the guideline with particular emphasis on GMP inspection and Pharmaceutical Quality System aspects, in liaison with PIC/S initiative. | Q4 2025 |
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.
Noten:
1 https://www.edqm.eu/en/-/how-to-identify-the-manufacturing-sites-linked-to-cep-application-revised-document-
2 https://www.ema.europa.eu/en/documents/other/work-plan-good-manufacturing-practice-good-distribution-practice-inspectors-working-group-2024-2026_en.pdf
