EMA on International Cooperation, Harmonization, and Reliance in GMP
Opening the 2023 ISPE Europe Annual Conference on 8 May, Peter Twomey, Head of Inspections for the European Medicines Agency (EMA), offered a keynote address titled International Cooperation, Harmonization, and Reliance in GMP.
Twomey previously filled the role of GCP/Pharmacovigilance Inspection Manager with Ireland’s Health Products Regulatory Authority (HPRA) and Pharmacovigilance Inspector with the United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA), as well as other positions in the industry. He is now responsible for leading the office which supervises the compliance with GxP for medicines throughout their lifecycle at a European level, and contributes to marketing surveillance, the handling of quality defects and recalls, as well as harmonization and policy development for inspections. These activities are undertaken in close collaboration with national regulators throughout Europe and regulators in third countries. He assured attendees that an area of focus is always both “looking at regulations” and making sure they are fit-for-purpose as well as looking for ways to increase international regulatory harmonization and striving to maintain adequate inspection capacity.
He began his keynote address by identifying EMA’s strategic Good Manufacturing Practice (GMP) priorities with an emphasis on how inspection challenges raised by the COVID-19 pandemic were met by using alternative and novel ways to carry out inspections during the pandemic. He also noted that the adaptations developed to the challenges presented by the COVID-19 pandemic had to be consistent with EMA’s strategic priorities, which he identified as including modernizing GMP and facilitating innovation; focusing on international collaboration for harmonizing guidelines and standards; supporting inspection capacity; and focusing on inspection reliance and new approaches - such as those developed during the pandemic including verifying compliance remotely.
He explained how inspection cooperation had been established through Mutual Recognition Agreements (MRAs), agreements that allow EU authorities and their counterparts in other parts of the world to rely on each other’s GMP inspection system, share information on both inspections and quality defects, and waive batch testing (requirements) of products upon importing them into their respective territories.
The first of EMA’s MRAs were forged with Australia and New Zealand, starting in 1999; however, the EMA has over the years established MRAs with seven territories, adding the U.S., Canada, Japan, Switzerland, and Israel.
“Considerable efficiencies came with introducing MRAs,” he said, citing the importance of the EMA’s work with the U.S. Food and Drug Administration (FDA). “By relying on inspections carried out by (MRA partners), this resulted in less duplication of work,” he said. For example, for product and inspection types included under the MRA with the US, this resulted in a reduction of inspections conducted by EU authorities in the USA by 70%, as inspections conducted by the FDA could be relied on. Twomey noted that opportunities to further reduce the duplication of inspections were available, including expanding the recognition of inspections carried out by MRA partners to manufacturing sites outside of their respective territories. Developing the MRAs took many years of painstaking work but it was worth it, “a win-win.”
He pointed out that the most recently developed MRAs were established between the EMA and the FDA and include inspections for veterinary products, vaccines, and plasma-derived products.
Twomey, who is the chair of the Expert Working Group drafting revision 3 of the ICH GCP E6, addressed the ongoing effort at harmonizing guidelines and standards and cited the recent changes with ICH Q9 with regard to quality risk management and Annex 1, which focused on sterile products manufacturing which becomes operational in August 2023. He also discussed Annex 11 regarding computerized systems as well as Annexes 4 and 5 regarding veterinary medicinal products that are currently on-going revisions.
Returning to finding new ways of working in response to the challenges to inspections raised by the COVID-19 pandemic, Twomey noted various mechanisms the EMA are utilizing to ensure optimal compliance supervision.
Focusing on the use of remote and distant methods of compliance oversight, Twomey told attendees that between 2020 and 2022, 59 EMA coordinated inspections of manufacturing sites producing centrally authorized products (CAP) were conducted remotely via distant assessment. A further 443 distant assessments were conducted by EU national medicine regulators relating to nationally authorized products. Twomey added. “This was a pragmatic approach that helped address COVID-19 travel restrictions.”
Twomey also described an ongoing pilot project, titled the GMDP IWG Inspection Reliance Pilot, being carried it by the GMP/GDP Inspectors Working Group. The pilot, aimed at evaluating the impact of reliance on PIC/s authorities for GMP verification, began in October 2022 and will be completed in December 2023.
Twomey explained that when re-inspections of active pharmaceutical ingredient (API) and finished product sites are carried out in territories of PIC/s authorities, authorities who are members of the GMDP IWG may conduct a desk-based review of the inspection report and responses, and additional information if needed. Based on this assessment, the validity of a GMP certificate may be extended.
According to Twomey, “reliance” means taking into account assessments performed by another regulatory authority or any other authoritative information when reaching a regulatory decision. In the pilot, inspections will be carried out with one authority inspecting on-site, and the other authority(ies) joining remotely, with a focus on chemistry, manufacturing, and control (CMC).
In the future, said Twomey, the International Coalition of Medicines Regulatory Authorities (ICMRA) will also conduct a pilot project focused on collaborative assessments and hybrid inspections. The pilot will involve at least two regions, target three collaborative assessments, and carry out three hybrid inspections. Currently, there are six regulators participating in this pilot.
“The objectives will include the development of a common framework for collaborative assessment and inspections and the identification of best practices and standards,” said Twomey.
Twomey also noted how third countries are increasingly relying on EMA coordinated inspection information when developing their own inspection programs, telling attendees that during the period 2020 through 2022, 12 EMA inspection reports were sent to third country authorities.
In conclusion, he reiterated that cooperation, harmonization, and reliance are key parts of the EMA’s GMP strategy.
“There have been many successes to date, including harmonization of standards on inspections through MRAs along with reduced duplication of effort and more efficient use of resources,” he said. “In addition, the pandemic catalyzed the use of reliance and distance assessments, which have gone on to form part of the PIC/s and ICMRA pilot projects.”
Twomey also took two questions from attendees. He was asked if, given the success of inspections conducted remotely during the pandemic, to what degree remotely carried out inspections might become the “new normal” in future inspections?
He responded that he expected that on-site inspections will continue to be the norm, but there will likely always be a place for remote elements of inspections and the potential for distant assessments. He suggested that remotely carried out inspections have the potential to reduce the burden on industry. “The use of distant and remotely conducted inspections will always be a useful tool to keep in our back pockets,” he concluded.
Twomey was also asked how joint inspections might be carried out in the future and what kind of communication tools will be used to assure cooperation and reliance. He suggested if such inspections involve remote elements, then communication platforms agreed with inspectors should be used, such as Microsoft Teams® or Zoom® which were often used successfully during the pandemic. He further suggested that appropriate resources should be available on-site to help host the inspection and use of different communication platforms.