September / October 2018

Regulatory Update: ISPE Presents Industry Initiatives at EMA Interested Parties Meeting

Nuala F. Calnan, PhD
Regulatory Update: ISPE Presents Industry Initiatives at EMA Interested Parties Meeting - Europe

Notes from the recent meeting of the European GMP/GDP Inspectors Working Group (IWG)

ISPE, along with 11 other industry associations, were pleased to participate in the most recent interested parties meeting of the European GMP/GDP Inspectors Working Group (IWG) held at the European Medicines Agency (EMA) on 6 December 2017. The meeting was chaired by Brendan Cuddy, Head of Manufacturing and Quality Compliance at EMA; preparations and contributions were expertly coordinated by Esther Martínez on behalf of the GMP/GDP IWG secretariat. 


The EMA provided an overview of work undertaken by the IWG in 2017 as well as key topics in the 2018 work plan. The presentation also covered the status of each mutual recognition agreement (MRA), with particular emphasis on the US, as its provisions for recognition of inspections had just entered into force on 1 November 2017.

Following EMA’s update, the IWG provided their feedback on the questions raised by the interested parties:

MRAs: It was clarified that veterinary immunologicals are not regulated by FDA and therefore, currently out of the scope of the EU–US MRA.

Non-harmonized GMP inspection procedures: The IWG indicated that this concern is not unique to the veterinary sector and that various working groups are scheduled to review harmonization.

EU GMP Guide Annex 4: The IWG noted that both Annexes 4 and 5 would benefit from updates, given their age, but noted that it would be more appropriate to review them once the proposed new veterinary legislation is finalized. Nevertheless, industry input toward a future revision of both Annex 4 and 5 is welcome either through EMA or via the national competent authorities.

Importation: The European Commission’s current view is that fiscal transactions should be considered as importation, even if the goods remain in the EU. The IWG acknowledged that harmonization is needed on this matter; therefore, the draft Annex 21 (new guidance for importers of medicinal products) will be developed accordingly. Presentation to the IWG is expected in the first half of 2018. The European Federation of Pharmaceutical Industries and Associations (EFPIA) questioned the need for recertification, retesting upon importation, and compliance with the delegated regulation on safety features for products that are fiscally imported (i.e., not physically leaving the EU). The IWG noted those concerns, indicating that they would apply as much flexibility as possible to address these challenges, within the framework of the EU Commission’s guidance. 


The next major item for discussion was the impact of Brexit, including an update on the risk minimization measures and actions being undertaken by industry to assure continuity of supply to the EU market. EMA provided an overview of the steps taken by the agency in preparation for UK withdrawal from the European Union, which included a number of stakeholder interactions as well as the publication of updated Q&As and procedural guidance.

EFPIA, on behalf of the interested parties, delivered a presentation outlining measures being taken by industry to address the supply chain changes that will ensue when the UK leaves the EU. This illustrates the extent and complexity of the work required, which will most likely continue beyond the end of March 2019. The interested parties requested that the IWG facilitate the implementation/transition period wherever possible.

The European Industrial Pharmacists Group supported EFPIA and raised questions about additional challenges posed by the timelines for implementing the delegated regulation on safety features, which would come into application on 9 February 2019, the same quarter as the UK withdrawal from the EU, which is scheduled for 29 March 2019.

EMA indicated that a sub-working group made up of inspectors (including representatives from UK) and EMA colleagues had been formed to gather Brexit-related questions from industry to try to address them. They also indicated that results from the January 2018 EMA survey requesting information from industry on planned variations affecting batch release and batch control testing sites would be posted on the EMA’s “News and Events” website page (“EMA Identifies Gaps in Industry Preparedness for Brexit”). In direct response to a question from the IWG if industry had developed different Brexit-related scenarios, it was confirmed that industry is currently preparing for a “hard Brexit” coming into effect on 29 March 2019. 


The first industry association presentation was delivered by Karoline Bechtold-Peters on behalf of European Trade Association representing Biopharmaceutical Companies—the European Biopharmaceutical Enterprises—a new member to the Interested Parties meeting. The presentation, “A Risk-Based Approach to ID Sampling of Biologic products,” reviewed the challenges of performing 100% inspection of biological drug substances. This necessitates a thaw and integrity breach of the bulk drug substance container to take a sample. The presentation outlined links with Annex 8 to the EU GMP guide, PIC/S guide to GMP, and the WHO Annex 4 in presenting a potential risk-based approach. the IWG indicated that risks are case-specific, however, and should be handled on a case-by-case basis with the local competent authority. At this point in time, they concluded, a revision of Annex 8 does not seem warranted.

ISPE made two presentations. The first on Pharma 4.0, presented by John Berridge, outlined some novel technologies under the umbrella of Pharma 4.0 manufacturing strategies that were receiving industry consideration. It was delivered to brief inspectors on what they may encounter on the shop floor in the coming years. One question raised by the IWG was the likely need for revision of GMPs to accommodate 4.0 technologies. The interested parties answered that it was not an expectation at this time, as the technologies will likely make it easier to comply with current regulatory requirements rather than require any specific changes to GMPs or existing guidance.

ISPE’s second presentation covered the subject cultural excellence. Nuala Calnan, PhD, outlined the ISPE Cultural Excellence Report (April 2017) and the practical resources it provides to help industry organizations develop and foster healthy quality cultures. The PDA Quality Culture team’s complimentary work on assessment and training related to quality culture was highlighted, as was recent University of St. Gallen/FDA research results confirming the impact of cultural excellence on overall pharmaceutical quality system effectiveness. Acknowledging that the GMPs do not currently contain specific requirements on organizational culture, Dr. Calnan noted that a planned update to the Eudralex Volume 4, Chapter 1 introduction offered an opportunity to include some positive reinforcement for companies to consider. She also encouraged the IWG to promote a focus on culture and behavior to enhance patient protection. Finally, as inspectors play an influential role in encouraging adoption within industry, she asked the IWG to commend organizations that are making efforts in this area.

The meeting closed with valuable discussion between industry associations across the range of topics highlighted during the meeting.