International Cooperation in Pharmaceuticals - Key documents
Commission adopts updated EU-US agreement on mutual recognition of inspections of medicine manufacturers
The European Commission and the United States Food and Drug Administration formally agreed to update Appendix 5 [Pharmaceutical Annex] of the 1998 Agreement to permit both the US and the EU to recognise each other’s good manufacturing practice inspections for pharmaceuticals.
The scope of the agreement covers the vast majority of human medicinal products as included in the list below:
- Marketed finished medicinal products for human use in various pharmaceutical dosage forms such as tablets, capsules, ointments, and injectables,
- Medical gases
- Radiopharmaceuticals or radioactive biological products
- Herbal (botanical) products
- Homeopathic products
- Marketed biological products (therapeutic biotechnology-derived biological products and allergenic products)
- Active pharmaceutical ingredients or bulk drug substance;
A number of products are proposed for inclusion at a future date, specifically medicinal products for veterinary use, no later than July 2019. Vaccines and plasma derived medicinal products are proposed to be considered for inclusion no later than July 2022. Human blood, human plasma, human tissues and organs and veterinary immunologicals are excluded from the scope of the agreement.
The revised annex has entered into force with the signature by both the EU and US. The entry into application of certain articles is however deferred to later dates.
The European Commission, the Member States and the European Medicines Agency are working to apply the MRA as early as November.
Recognition of inspections between the EU and the US will apply as early as 1 November 2017, pending the assessment by the FDA of eight Member States.
Recognition of batch testing will apply once all 28 Member States have been recognised by the FDA.
For More Information
- Links to the full text of the political agreement: English version - French version - German version
- Link to the news release
At the Transatlantic Economic Council (TEC) on 13 May 2008 the work of the European Commission, European Medicines Agency and US Food and Drug Administration on medicines regulation was noted as an example of close and productive collaboration of benefit to citizens.
The TEC noted especially the further strengthening of transatlantic cooperation on medicines regulation. Highlighting this further strengthening of regulatory cooperation was the announcement that a first set of projects on medicinal products had been agreed following the administrative simplification workshop held in Brussels in November 2007.
More specifically, the following priority projects were agreed:
- The Commission/EMA and the FDA will pilot joint inspections of companies manufacturing pharmaceuticals in the US and the EU and of companies manufacturing active pharmaceutical ingredients in third countries.
- The Commission/EMA and the FDA will pilot the exchange of inspection schedules, results and information on inspected manufacturing sites in order to attain more GMP inspection coverage collectively and identify more effectively manufacturing sites producing active pharmaceutical ingredients in third countries.
- The Commission/EMA and the FDA will step up collaboration to determine to what extent dedicated production facilities are necessary for certain pharmaceuticals taking into account a risk-based approach. Subsequently, it is expected that revised EU guidelines will be published for public consultation in the first quarter of 2009. The FDA is also in the process of clarifying this issue by proposing amendments to existing regulations and draft guidance that are currently being issued.
- The EMA and the FDA have recently announced successes in their transatlantic work on biomarker development and validation for various product development purposes. Both parties will continue to work on this initiative with further biomarker development and validation.
These results will provide important benefits for industry and patients. It is of particular note that collaboration on inspections should result in more effective use of resources and a higher safety level for products from third countries.
Work is continuing to identify other items of intensified regulatory collaboration for mutual benefit and this will include further action points from the administrative simplification workshop held in Brussels in November 2007.
Finally, the EMA and FDA agreed recently on an implementation work plan for veterinary medicinal products regulation and also agreed on a process for offering parallel scientific advice to veterinary medicinal products manufacturers that wish to receive such advice simultaneously from the FDA and EMA.
Update of "Contact Details for GMP Annexes".
Currently, MRAs are operational with Australia, Canada, New Zealand and Switzerland for the GMP sector with regard to human and veterinary medicinal products and with Japan with regard to GMP for human medicinal products. A MRA with the USA was concluded, but did not enter the operational phase. After enlargement Canada is in the process of evaluating the new Member States for equivalency.
With the accession of 10 new Member States it was deemed necessary to update the contact details as listed in the different GMP Annexes of the MRAs. The attached contact details will be submitted to the Joint Committees under the different MRAs. The list includes the competent authorities for the GMP sector as nominated by the different Member States. It should be noted that some competent authorities further delegate technical and operational aspects to subordinate authorities. Detailed information on this is available through the respective Joint Sectoral Committees of the MRA partners. For the EU it is published on the EMA website.
This note is aimed at describing, in general terms, the application of Good Manufacturing Practice (GMP) Sectoral Annexes under Mutual Recognition Agreements (MRAs) between EC and third countries (US, Canada, Australia, New Zealand, Japan, Switzerland) to the new Member States.
On 28 April 2004, the European Communities and Japan exchanged diplomatic notes confirming the completion of preparatory work under the Mutual Recognition Agreement's Sectoral Annex on Good Manufacturing Practice (GMP) for Medicinal Products. Following this exchange of diplomatic notes, the Sectoral Annex on GMP became operational on 29 May 2004. Under the Sectoral Annex on GMP for Medicinal Products, certificates issued for confirmed manufacturing facilities in compliance with the GMP requirements of one of the Parties and in accordance with the provisions of the MRA are accepted in the EC and Japan without additional testing. Therefore, both parties expected that the MRA to facilitate trade between the Parties by reducing costs for companies. For the moment the Sectoral Annex covers a limited number of human medicinal products. The Parties will review the scope for its possible expansion in the future.
MRA EU-Switzerland, chapter 15 on medicinal products GMP and batch certification - Revised "explanatory notes".
The Agreement between the European Community and the Swiss Confederation on mutual recognition in relation to conformity assessment entered into force on 1st June 2002. Chapter 15 of this agreement concerns medicinal products GMP inspection and batch certification and allows for mutual recognition of the results of GMP inspections performed in the EU and Switzerland. Since 1 June 2002, imports of medicinal products into the EU from Switzerland are no longer required to be re-inspected at import provided they are imported in accordance with the provisions of chapter 15. The legal references of the "explanatory notes" on the operation of this chapter were revised by the European Commission and the Swiss authorities in October 2002.
New documents agreed by the Joint Committee were published in the Official Journal as follows:
- Decision No 1/2003 (2003/128/EC) in OJ L 56, 01.03.2003, pp. 1-213
- Corrigendum to Decision No 1/2003 (2003/128/EC) in OJ L 66, 11.03.2003, p. 51
- Decision No 2/2003 (2003/154/EC) in OJ L 68, 12.03.2003, pp. 1-39 (including chapter 15)
All language versions are available on EUR-Lex.
The current versions of the Internationally Harmonised Requirements for Batch Certification and the EU Certificate of GMP Compliance of a manufacturer are available on the EMA website.
The operational phase of the EU-Canada Mutual Recognition Agreement entered into force on 1 February 2003.
The Sectoral Annex on Good Manufacturing Practice started its operational phase on 1 February 2003. The Joint Sectoral Group met on 17 January 2003 and agreed that the transitional activities should end. The Joint Committee was informed and recorded at its 6th meeting on 13 March 2003 that this sector is now operational. The list of products covered under the Annex includes human and veterinary medicinal products. Veterinary immunological products are not included. The Annex is not in operation for pre-approval inspections and stable medicinal products derived from human blood or human plasma. The agreement is based on the exchange of certificates of GMP compliance for manufacturers and batch certificates. The contents of these certificates are agreed and available on the EMA website. The two-way alert system is in operation.
The Agreement between the European Community and the Swiss Confederation on mutual recognition in relation to conformity assessment entered into force on 1 June 2002. Chapter 15 of this agreement concerns medicinal products GMP inspection and batch certification and allows for the mutual recognition of the results of GMP inspections performed in the EU and Switzerland. Since 1 June 2002, imports of medicinal products into the EU from Switzerland are no longer required to be re-inspected at import provided they are imported in accordance with the provisions of chapter 15. The legal references of the "explanatory notes" on the operation of this chapter were revised by the European Commission and the Swiss authorities in October 2002.
Models for the Internationally Harmonised Requirements for Batch Certification [PDF format - Word format] and an EU Certificate [PDF format - Word format] of GMP Compliance by manufacturers are also provided.
Following the successful completion of the transitional arrangements for veterinary medicinal products foreseen in part IV the Mutual Recognition Agreement (MRA) between EU and Australia, the operational phase began for veterinary medicinal products on 1 July 2001. This extended the already successful recognition of the results of GMP inspections carried out in the respective territories for medicinal products for human use to cover also the recognition of inspections of veterinary medicinal products. Procedures to facilitate the operation of the agreement affecting both types of products were also agreed. These include agreement on a system for the exchange of information on product defects (rapid alert) and standard formats for certificates of GMP compliance and batch certificates. A copy of the report prepared for the joint committee set up under this agreement is provided.
Prolongation of the transitional period in the Canadian/EC MRA on GMP.
The terms of the sectoral annex on Good Manufacturing Practice (GMP) of the agreement on mutual recognition between the European Community and Canada foresaw a transitional period which was expected to last 18 months during which time the equivalence of the GMP systems of the EC and Canada would be evaluated. In May 2000, a provisional date for completion was set as 15 July 2000. Although the majority of this work was already completed, there were still some outstanding issues that needed to be clarified. It was therefore proposed that the transition period be prolonged. The operational period would therefore not begin on 15 July as previously anticipated.
The Agreement on Mutual Recognition between the European Community and the United States of America was signed by Margaret Beckett (United Kingdom Secretary of State for Trade and Industry) and Commissioner Sir Leon Brittan for the Community and by Charlene Barshefsky (United States Trade Representative). It consists of a framework agreement and sectoral annexes on Telecommunication Equipment, Electromagnetic Compatibility (EMC), Electrical Safety, Recreational Craft, Pharmaceutical Good Manufacturing Practices (GMPs) and Medical Devices. The agreement entered into force on the first day of the second month following the date on which the letters confirming the completion of their respective procedures for the entry into force had been exchanged. For the pharmaceutical sector this meant that the three-year transitional period would start on 1 August 1998.
Representatives of the United States Food and Drug Administration (FDA), the European Commission DG III and the European Agency for the Evaluation of Medicinal Products (EMA) met in London on 1-2 April 1998 to exchange initial views on the implementation of the Sectoral Annex for Pharmaceutical Good Manufacturing Practice of the US-EC Mutual Recognition Agreement. The scope of the meeting was to develop a better understanding of each others' regulatory systems and the responsibilities of the organisations to be involved in the implementation of the Sectoral Annex. The discussions included GMP inspections and mechanisms for the exchange of information. The participants agreed to maintain informal contacts until the agreement becomes effective and to exchange information in preparation for the first meeting of the Joint Sectoral Committee in the United States in September 1998.