Inspections and compliance
In the European medicines regulatory network, the responsibility for carrying out inspections rests with EU NCAs, but EMA plays an important role. The Agency coordinates the verification of compliance with the principles of good manufacturing practice (GMP), good clinical practice (GCP), good laboratory practice (GLP), good pharmacovigilance practices (GVP) and certain aspects of the supervision of authorised medicinal products in the EU. The main verification tool is inspections. Some are carried out routinely, while others are triggered by request of the CHMP or CVMP in the context of the assessment of marketing authorisation applications and/or matters referred to these committees in accordance with EU legislation.
The inspection programme at the EU level that EMA coordinates to verify compliance with the principles of GMP, GCP and pharmacovigilance includes:
- a risk-based programme of GMP inspections based on the results of inspections of pharmaceutical manufacturing sites by trusted authorities;
- a risk-based programme of routine GCP inspections at sites of clinical research organisations (CROs) most often used in the conduct of bioequivalence trials included in a marketing authorisation application in the mutual-recognition and decentralised procedures (in collaboration with NCAs/ the CMDh);
- a risk-based programme of routine inspections of the pharmacovigilance systems in place for CAPs (in collaboration with NCAs); and
- a two-year programme of routine GCP inspections based on risk factors and a random element, to ensure that a diverse range of applications, trials and sites and geographical locations are covered.
EMA ensures the best use of resources by promoting mutual reliance and work-sharing with other international authorities. For GMP inspections, there are several mutual recognition agreements in place.
Through its inspectors’ working groups, the Agency coordinates the development and setting of standards for GMP, GCP, GLP and GVP. This helps to harmonise standards within the EU and internationally, to strengthen global supply chains and improve access to authorised medicines. The delivery of training and capacity building on inspection-related activities for inspectors and assessors, including non-EU regulators, is one focus area for EMA. The Agency is the primary contact point for notification of suspected quality defects for CAPs and coordinates their investigation, evaluation and follow-up. It also operates a sampling-and-testing programme to supervise the quality of CAPs placed on the market and to check compliance of these products with their authorised specifications.
Inspections
GMP, GCP, GLP and pharmacovigilance inspections requested by the CHMP or CVMP for medicines that are subject to centralised authorisation procedures take place worldwide. However, they represent just a small part of the total number of inspections performed by the EU/EEA inspectors, who also carry out inspections as part of their national programmes.
GMP inspections
The number of GMP inspection requests in 2023 rose to levels comparable to those of 2021.
Seven GMP inspections conducted by EEA authorities led to the issuing of a non-compliance statement. Medicines manufactured at a site with such a non-compliance statement cannot be sold in the EU.
EEA authorities issued one statement of GMP non-compliance relating to CAPs either in connection with the active substance or the finished product, however no recalls were necessary. When inspections lead to findings, companies must implement corrective action plans agreed with the inspecting authorities.
GMP certificates and non-compliance statements issued by EEA authorities
| 2019 | 2020 | 2021 | 2022 | 2023 | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| GMP certificate | GMP non-compliance statement | GMP certificate | GMP non-compliance statement | GMP certificate | GMP non-compliance statement | GMP certificate | GMP non-compliance statement | GMP certificate | GMP non-compliance statement | |
| EEA/EU | 2,235 | 11 | 1,695 | 1 | 1,825 | 5 | 1,730 | 2 | 1,857 | 2 |
| China | 51 | 4 | 11 | 0 | 24 | 0 | 15 | 0 | 44 | |
| India | 105 | 1 | 64 | 0 | 29 | 0 | 81 | 2 | 101 | 4 |
| USA | 127 | 0 | 35 | 0 | 52 | 0 | 118 | 0 | 155 | |
| Rest of the world | 108 | 0 | 38 | 0 | 52 | 0 | 187 | 2 | 231 | 1 |
| Total | 2,626 | 16 | 1,843 | 1 | 1,982 | 5 | 2,131 | 6 | 2,388 | 7 |
Note: This table shows the number of GMP certificates and non-compliance statements issued by EEA authorities as an outcome of GMP inspections conducted between 2019 and 2023. It includes GMP inspections requested by the CHMP or the CVMP.
GCP inspections
The number of GCP inspections is 75, exactly the same as in 2022. These activities are not yet back to the levels recorded before the pandemic.
Pharmacovigilance inspections
EMA, in cooperation with competent authorities in Member States, maintains a risk-based programme for routine pharmacovigilance inspections of marketing authorisation holders of CAPs and ensures its implementation. It also plays a key role in the coordination of pharmacovigilance inspections specifically triggered by the CHMP or CVMP and in inspection follow-up.
In 2023, 14 pharmacovigilance inspections were requested by the CHMP or CVMP. Most EU/EEA pharmacovigilance inspections (over 90 %) are conducted under the national pharmacovigilance inspection programmes, which relate to marketing authorisation holders with product authorisations of all types (including CAPs).
Market surveillance and quality defects
Manufacturers are required to inform authorities of quality defects in manufactured product. This can lead to a recall of batches from the market or prevention of their release by the manufacturer. Where a defect is considered to be a risk to public or animal health, the marketing authorisation holder is requested to withdraw the affected batches of the CAP from the EU market and the supervisory authority issues a rapid alert. The alert is classified from 1 to 3, depending on the expected risk to public or animal health posed by the defective product:
- Class 1 recall: the defect presents a life-threatening or serious risk to health;
- Class 2 recall: the defect may cause mistreatment or harm to the patient or animal, but is not life-threatening or serious; and
- Class 3 recall: the defect is unlikely to cause harm to the patient, and the recall is carried out for other reasons, such as non-compliance with the marketing authorisation or specification.
In 2023, the Agency received 257 suspected quality defect notifications, the highest number recorded in recent years. Of these, 188 cases were confirmed quality defects and led to batch recalls of 9 CAPs.
| Category | 2020 | 2021 | 2022 | 2023 |
|---|---|---|---|---|
| Quality defects confirmed cases | 164 | 185 | 188 | |
| Recalls | 15 | 10 | 11 | 9* |
| Class 1 | 3 | 1 | 2 | 0 |
| Class 2 | 3 | 7 | 5 | 6 |
| Class 3 | 9 | 2 | 4 | 2 |
*1 recall not classified
The main reasons for recall of CAPs in 2023 included:
Manufacturing laboratory control issues include out-of-specification results obtained during quality control testing.
Product contamination and sterility issues include chemical, microbiological or physical contamination of the medicinal product.
Product label issues include issues related to labelling of the medicinal products (e.g., missing or incorrect batch number).
Product packaging issues relate to physical issues (e.g., a mix-up or a damaged container).
Product physical issues relate to incorrect product physical properties (e.g., friability, size/ shape, leakage).
Parallel distribution
EMA checks that the parallel distribution of CAPs from one Member State to another by a company independent of the marketing authorisation holder is compliant with the rules.
Parallel distribution notifications received
| Category | 2019 | 2020 | 2021 | 2022 | 2023 |
|---|---|---|---|---|---|
| Initial notifications | 2,468 | 3,172 | 2,555 | 1,816 | 2,092 |
| Notifications of bulk change | 12 | 10 | 19 | 32 | 21 |
| Annual updates | 4,270 | 11,624 | 4,816 | 5,509 | 5,477 |
| Total | 8,853 | 14,806 | 7,390 | 7,357 | 7,590 |
Certificates
EMA also issues electronic-only certificates to confirm the marketing authorisation status of medicines that have either been authorised, or for which an application for marketing authorisation has been submitted to the Agency.