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Sean Milmo is a freelance writer based in Essex, UK.
EU and US regulators are striving to work together on improving GMP inspection efficiencies and avoiding duplication of efforts.
The European network of medicines regulatory agencies, co-ordinated by the European Medicines Agency (EMA), announced in March 2015 its strategy until 2020 (1), with one of the priorities being its contribution to greater worldwide collaboration on inspections of pharmaceutical production sites. A key part of the network’s agenda in achieving this objective would be to reach an agreement with FDA on co-operation on inspections of drug manufacturing sites to assess compliance with good manufacturing practice (GMP).
The European Union and FDA have been striving unsuccessfully for nearly 20 years to reach a long-term deal on GMP inspections that would avoid duplication and help to reduce the overall costs of monitoring the growing number of Asian plants producing finished drugs and APIs for the European and US markets. An EU–FDA deal would be considered a major breakthrough in the struggle to achieve international collaboration in GMP inspections. FDA and the EU, through its network of national licensing authorities headed by EMA, are by far the most active in conducting GMP inspections, not only in their own territories, but throughout the world.
Another view, however, is that bilateral agreements, even as big as the one between the EU and FDA, are no longer the main driving force behind the global advancement of GMP inspection standards. Instead, a much greater influence is now being exerted by two Geneva-based international bodies-the International Conference on Harmonization (ICH), which draws up worldwide standards on GMP, and the Pharmaceutical Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S), which has been developing standards for inspections to ascertain GMP compliance. Soon, the newly founded International Coalition of Medicines Regulatory Authorities (ICMRA), which is headquartered in Canada, will become a third international body involved in the setting of global GMP standards.
Efforts to create uniform, worldwide standards on GMP inspections have increasingly been driven by multilateral agreements thrashed out within a few key international organizations. Nonetheless, the lengthy endeavours by the EU and US to reach a long-term bilateral deal on GMP inspections has been helping to clarify key issues that need to be resolved during negotiations on agreements aimed at making more efficient use of the stretched resources of regulatory agencies.
Mutual recognition agreement
EMA and FDA are hoping that by early 2016, a final framework for a mutual reliance agreement on inspections and its implementation will have been completed. This deal on a final framework will have been around 20 years after EU and US authorities started discussing plans for a mutual recognition agreement (MRA) that would embrace pharmaceuticals and several other sectors.
In 1998, an US–EU MRA was reached covering pharmaceuticals, medical devices, and four other sectors, including telecoms equipment and electrical appliances (2). The procedure was that after the drawing up of individual MRAs for each sector, there would be a transition period to see if they worked so that they could become permanent arrangements. The mutual recognition was not of standards but of inspection, testing, and certification requirements relating, in the case of pharmaceuticals, to GMP in production plants. It quickly became clear early in the three-year transition for the pharmaceuticals MRA that it would be impractical and politically unsustainable. In fact, it had been virtually abandoned before the transition period ended in 2001.
The main problem was the differences in regulatory structures. While FDA is a long-established single central authority with GMP inspections responsibilities, the EU, at the time, had medicines authorities in 21 member states with the task of carrying out inspections. EMA, the EU’s central medicines agency founded only in 1995, had not yet fully taken over its current role in ensuring uniform GMP standards and inspection processes.
The EU had successful MRAs on GMP inspections with a number of countries-one of first being with Health Canada, the Canadian pharmaceuticals licensing authority, which was finalized in 1998 (3). Nonetheless, after the collapse of the pharmaceuticals MRA with the US, the European Commission decided that, in future, MRAs would be negotiated “only in cases where there is a clear equivalence of respective rules and a real prospect of making them operate almost automatically” (4).
After a lull of a few years, EMA and FDA continued their efforts to find common ground on inspections. They were helped by the development of much closer ties between the two organizations as a result of joint activities in a number of areas, such as orphan and pediatric medicines, scientific advice, quality-by-design (QbD) assessments, and pharmacovigilance.
Instead, after six years of joint pilot inspection programs covering both finished products and APIs, an alternative to MRAs had begun to emerge in the form of a mutual reliance deal. EMA, EU member states, and FDA decided in 2014 to start to work on a mutual reliance initiative (MRI) (5).
“In general, MRAs on GMP allow EU authorities to rely on GMP inspections performed by other regulators, the waiving of batch testing of products on entry into the EU, and information sharing on inspection-related information and quality defects,” explains an EMA spokesperson. “In the context of the MRI, the term ‘mutual reliance’ means that the EU, member state authorities, and FDA would rely upon each other’s data and information from GMP inspections to the extent possible,” she continues. “Because of the differing legal systems and other factors, from time to time, the US and EU might take different actions on an application, facility, or products, based on the same inspectional findings.”
The main emphasis has shifted to information sharing to enable inspection resources to be focused on high-risk inspection sites. One idea to come out of the pilot joint inspection programs was for a master file of manufacturing sites for inspection, including those in third countries. From this master file, EMA created its central EudraGMDP database (6) providing information on GMP and good-distribution-practice (GDP) certificates. A major objective of the database is to help the co-ordination of inspections in third countries among national medicines authorities and to facilitate the sharing of information on the outcomes of inspections.
Data integrity and quality metrics
Now that organizations such as PIC/S are encouraging more information sharing among inspectorates across the world, the EU–US mutual reliance deal might focus on specific areas of GMP inspections that are raising new concerns. One of these areas is the matter of data integrity, which has been growing in importance because of the massive rise in the technological capacity to gather large quantities of data. However, this increase has not been commensurate with measures by companies to ensure the generation of accurate data or to improve their ability to process data efficiently.
After a recent inspection of the Czech API manufacturer VUAB Pharma, FDA heavily criticized the company for failing to “prevent unauthorized access or change to data and to provide controls preventing data omissions” (7). The United Kingdom Medicines and Healthcare products Regulatory Authority (MHRA) has this year updated its guidance on data integrity (8), which it says has become a “hot topic” after a number of data failures led to withdrawals of drug supplies across multiple markets (9).
Another issue is how much the MRI will take into account moves by FDA to use quality metrics as an indicator of quality management efficiencies so that it can plan risk-based inspections more effectively. The agency recently published guidance on quality metrics (10) to gauge how well quality systems on medicinal products and API sites are being maintained.
Because, at least in EU–US trade relations, the idea of MRAs in the pharmaceuticals sector is being replaced by that of mutual reliance, medicine and API producers will be watching closely the extent to which their inspection fees are being reduced, particularly in the US in the context of the Generic Drug User Fee Amendments (GDUFA).
The European Fine Chemicals Group (EFCG), representing mainly API but also generic-drug manufacturers and which has been pressing for a EU–US MRA in pharmaceuticals, criticized in 2014 the mutual reliance concept, saying it was only a “half-way house” to a mutual recognition agreement (11).
“The difference may be just for legal reasons,” says Guy Villax, chief executive of the Portuguese pharmaceutical company Hovione FarmaCiencia SA and an EFCG board member. “At the end of the day, what is important is how much a mutual reliance deal will bring down inspection costs so that the inspection fees can be reduced, particularly for GDUFA purposes.”
Costs will also be an important consideration for EU and US regulators. The more successful the MRI is in the raising inspections efficiencies, the more they can concentrate on improving GMP levels in the most worrying sites and also start investigating sites that have never been inspected before.
1. HMA & EMA, “EU Medicines Agencies Network Strategy to 2020,” Consultation Draft EMA/MB/151414/2015 (London, March 2015).
2. European Commission, COM (1998) 180 Final, An Agreement on Mutual Recognition in relation to Conformity Assessments between the European Community and the United States of America (Brussels, March 1998).
3. European Community and Canada, CE/CA/en 3, Agreement on Mutual Recognition between European Community and Canada (Brussels, October 1998).
4. European Commission, “Priorities for bilateral/regional trade-related activities in the field of MRAs for industrial products and related technical dialogue,” SEC (2004) 1072 (Brussels, August 2004).
5. Howard Sklamberg, “Ensuring Pharmaceutical Quality Through International Engagement,” FDA Voice, May 2014.
6. EudraGMP, accessed Aug. 13, 2015.
7. FDA Warning Letter, accessed Aug. 13, 2015.
8. MHRA, Data Integrity, Definitions and Guidance for Industry (London, March 2015).
9. MHRA Blog, Good Manufacturing Practice (GMP) data integrity: a new look at an old topic, part 1, accessed Aug. 13, 2015.
10. FDA, Request for Quality Metrics-Guidance for Industry Draft (Washington, July 2015).
11. G.M. Baccalini, “Global Business Developments,” presentation at EFCG press conference, CPhI, Paris, October 2014.
About the Author
Sean Milmo is a freelance writer based in Essex, UK, firstname.lastname@example.org.
Article DetailsPharmaceutical Technology
Vol. 39, No. 9
Citation: When referring to this article, please cite it as S. Milmo, "Collaborating on GMP Inspections," Pharmaceutical Technology, 39 (9) 18–19 (2015).