By: Phil Crooker, VP - Technical, Regulatory & Access, Parexel
On June 23, 2020 the European Medicines Agency (EMA) released a report on lessons learned from the presence of N-nitrosamine impurities in angiotensin II receptor blocker drugs. You can find a copy of the press release here - https://www.ema.europa.eu/en/news/european-regulators-make-recommendations-drawing-lessons-learnt-presence-nitrosamines-sartan - and a copy of the report here - https://www.ema.europa.eu/en/documents/report/lessons-learnt-presence-n-nitrosamine-impurities-sartan-medicines_en.pdf.
The summary of the report makes some important points that offer insight into the EMA’s current thinking and signaling that the report is intended to address more than just the identification and control of N-nitrosamine impurities.
- The presence of N-nitrosamine impurities and the review of these cases in the European Union (EU) raised several important issues (emphasis added).
- The report has the recommendations from regulators but the EMA noted that industry is encouraged to conduct its own after-action exercises and consider what other actions manufacturers should take (emphasis added).
- Marketing authorization holders (MAH) – who it was noted usually outsource API manufacturing – may not have had sufficient oversight of the manufacturing processes (emphasis added).
- Amendments and clarifications to guidelines would help manufactures and regulators better assess the potential for impurities (emphasis added).
- The recommendations in the report are intended to reduce the potential of N-nitrosamine and other impurities in human medicines (presumably both investigational and marketed drugs) (emphasis added).
Since the overview of the report laid the foundation for the recommendations to apply more broadly than just the identification and control of N-nitrosamine impurities, there are significant implications for manufacturers who are operating in a global environment. Over the past several decades there has been increased reliance on global harmonization for GMP rules and regulatory dossiers. If manufacturers are facing a new impetus from EMA for more information to be provided in regulatory submissions and enhanced CGMP rules, then those are likely to be considerations in other major global markets such as the United States, Canada, Japan and Australia. Manufacturers would prefer to minimize regulatory fragmentation and increased operational complexity and meeting the most comprehensive set of regulatory requirements to enable multiple market access becomes a significant issue.
Let’s have a look at some of the more significant recommendations from the report and their potential implications for industry.
- The EMA should clarify the responsibilities of MAHs, finished product manufacturers, API manufacturers, ASMF holders and API CEP holders throughout the lifecycle of medicinal products, including responsibilities for quality, safety and efficacy. Industry can expect EMA to create or update guidance in this area, and that may include using the existing Reflection Paper on Good Manufacturing Practice and Marketing Authorization Holders published by the EMA on January 14, 2020. You can find a copy here https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-good-manufacturing-practice-marketing-authorisation-holders_en.pdf).
- The EMA reinforced that MAHs must take full responsibility for the quality of their products – including active pharmaceutical ingredients (API). EMA will expect improved mechanisms for CEP and ASMF holders and MAHs to improve exchange of information about impurity formation during API manufacturing, the manufacturing process and control of materials.
- Oversight of the entire supply chain needs to be strengthened and part of that effort will be a renewed focus on thorough development studies and process and product knowledge. This can be a focal area for both inspection and regulatory application review.
- Quality agreements need to be strengthened between MAHs and API manufacturers and EMA will require MAHs to conduct more effective audits of API and intermediate manufacturers. EMA could choose to revise the existing CGMP rules governing contractual relationships and draft a guideline like the existing FDA guidance Contract Manufacturing Arrangements for Drugs: Quality Agreements. A copy of that guidance can be found here - https://www.fda.gov/media/86193/download.
- The EMA will require MAHs to include data on impurities and formation from the API manufacturer in their regulatory submissions irrespective of how the API documentation is submitted (using either an ASMF or CEP). This will likely raise issues about how to ensure data are reliably consistent between the regulatory submission and ASMF or CEP, distinctions between open and closed portions of an ASMF, integrity of proprietary and trade secret information, and the burden of what could be construed as dual reporting and ensuring that the policy goals of the ASMF system remain intact.
- The EMA will ensure that MAHS as well as manufacturing and importation authorization holders are subject to effective, proportionate and dissuasive penalties if product quality is not appropriately ensured. If currently available penalties are not considered adequate, then its foreseeable that EMA could seek the authority to impose new or more penalties related to inadequate oversight of the entire supply chain.
- MAHs could be required to submit a justification for the proposed manufacturing processes and mitigation measures as part of regulatory submissions. This could be in addition to information currently submitted in 3.2.S.2.6 and it opens the door to whether and what extent a regulatory agency will determine whether process development is adequately justified and de-risked. This is an area where ICH Q11 could consider other revisions to ICH Q11.
- There will be additional clarifications for the CGMP expectations for technology transfers and supplier qualifications. Industry can expect that the EMA will prepare new guidance or update existing guidance.
- Similarly, there will be clarified CGMP expectations for qualification and validation of facilities, equipment, utilities and processes for API manufacturing. This information would be in addition to the current content of ICH Q7A, and there could be new regional guidance or an effort to revise ICH Q7A.
- The EMA will increase its reliance on exchanging information, coordinating and sharing workload for assessments and CGMP inspections, expert advice and regulatory decisions. COVID-19 has accelerated the reliance on the Mutual Recognition Agreement (MRA) and this will only increase its importance and its more frequent use. This also reinforces the need for industry to have a reliable understanding of the regulatory threshold that will be used by multiple regulatory agencies for enforcement purposes.
- EMA intends to develop or acquire a data tool for mutagenicity assessments for use by assessors at national competent authorities and EMA. If different health authorities have chosen different tools for the assessment of the same product or application(s), then there is a risk that disparate regulatory decisions could be reached. And there may need to be more than one tool chosen to align with the recommendations in ICH M7(R2) to use two complementary QSAR prediction methodologies.
- Training will be provided to assessors to ensure that future guidelines on controlling impurities, particularly N-nitrosamine impurities, are taken into consideration when assessing pending marketing or variation applications for older products. Industry will need to be prepared that any recommendations in new guidelines or revisions to existing guidelines will apply retrospectively for the very broad purposes of controlling impurities. Except for three situations for marketed products in ICH M7(R2), using such a broad-based retrospective approach has not been the norm and potentially raises both legal and policy issues.
- A risk-based model will be developed for triggering pre-approval inspections (PAI) of API manufacturers. Although the current MRA does not include PAI, they are not precluded from being brought into the scope of the MRA. Divergent criteria, criteria that are applied differently or interpreted differently could increase the regulatory burden on industry for managing PAI for multiple markets or result in health authorities performing multiple or duplicative PAI to mitigate regional differences despite the implementation of the MRA.
- EMA will prepare a new guidance for GMP inspectors to verify during inspections of API manufacturers the measures taken to reduce the risk of the presence of unexpected impurities. Although this does not indicate that the information will be expected to be placed into regulatory submissions – although arguably it could since MAHs will be required to include data on impurities and formation from the API manufacturer in their regulatory submissions irrespective of how the API documentation is submitted – it does appear that this information is even more comprehensive than the recent directive to have MAHs prepare and submit risk evaluations of their manufacturing processes to identify and, if found, to mitigate risk of presence of nitrosamine impurities. You can find further information from EMA on the request to evaluate the risk of the presence of nitrosamine impurities in human medicinal products containing chemically synthesized active pharmaceutical ingredients here - https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-information-nitrosamines-marketing-authorisation-holders_en.pdf.
Implementing only these recommendations would be a significant regulatory burden on industry that could have ripple effects in multiple major markets. The pharmaceutical industry in Europe was given a chance to review the report and offer comments and those can be found here - https://www.ema.europa.eu/en/documents/comments/overview-comments-received-recommendations-report-lessons-learnt-presence-n-nitrosamine-impurities_en.pdf. It could take many years to implement some of these recommendations, much less most of them, if they involve new or revised guidance and legislation or directives. However, EMA and national competent authorities can also implement many of these recommendations as part of inherent discretion on a case-by-case basis. This is a roadmap for what could be a very complex and integrated expansion of regulatory oversight of the supply chain and industry would be well served to be aware of the issues and have contingency plans in place to anticipate and pre-empt these issues before they become regulatory pressure points.