Lessons learnt from presence of N-nitrosamine impurities in sartan medicines 23 June 2020 EMA/526934/2019 Lessons learnt from presence of N-nitrosamine impurities in sartan medicines Overview and recommendations Overview In mid-2018, the European medicines regulatory network1 became aware of the presence of N- nitrosamines in sartan2 active pharmaceutical ingredients (APIs) and instituted regulatory actions across the EU, including recalls of some medicines from pharmacies and measures to prohibit the use of APIs from certain manufacturers. A subsequent review of sartans by the European Medicines Agency (EMA) found that the risk from the N-nitrosamine impurities (which are classified as probable human carcinogens) was low.3 In the vast majority of sartan medicines, N-nitrosamines were either not found or were present at very low levels. Given the greater risk to patients from stopping their treatments, regulators advised patients not to stop their sartan treatments without speaking with their healthcare professional. As for the source of the impurities, EMA’s review concluded that the use of the solvent dimethylformamide together with sodium nitrite in the presence of an acid led to the formation of N- nitrosamines during the manufacture of sartan APIs. There was also a potential for contamination from other sources, including solvents, reagents and manufacturing equipment already contaminated with N-nitrosamines. Taking these root causes into account, the review set out new requirements for marketing authorisation holders (MAHs) of sartan medicines, including the requirement to test their products for N-nitrosamines and make necessary changes to their API manufacturing processes.4 The sartans case and the subsequent review of sartans in the EU raised a number of important issues. First, it had become clear that the potential for N-nitrosamine formation had not been recognised during the development or evaluation of sartan medicines. Second, although the risk to patients was considered low, some API batches contained levels of impurities that necessitated regulatory actions, such as recalls. Third, the incident caused significant concern among patients and the general public with possible implications on adherence to treatments. In May 2019, the network embarked on a lessons learnt exercise to consider ways to prevent unexpected impurities such as N-nitrosamines from being present in human medicines and to better manage such cases should they occur in the future. Drawing on the experience from the sartans incident, the lessons learnt group made recommendations covering prevention, incident management, market surveillance, communication and international cooperation. 1 The network comprises the European Commission, the European Medicines Agency, national competent authorities in the European Economic Area and the European Directorate for the Quality of Medicines & HealthCare. 2 Also known as angiotensin II receptor blockers. 3 The review was carried out under Article 31 of Directive 2001/83/EC. 4 See more details of the outcome of the review on EMA’s website. 1 The recommendations from this exercise are those of regulators in the European regulatory network. Other stakeholders, such as the pharmaceutical industry, are encouraged to conduct their own exercises and consider what additional actions they should take. Preventing N-nitrosamines from being present in medicines The European network has several guidelines aimed at controlling impurities in APIs and finished products, many developed in conjunction with international partners under the auspices of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). In addition, the European Pharmacopeia sets out standards for the quality of medicines and their ingredients which are legally binding within the EU. These guidelines provide detailed information on how companies should assess the risks of impurities being present in their products, how they should report such risks to authorities and measures they should take to mitigate them. One such guideline, ICH M7 (R1), which complements others such as ICH Q3A, ICH Q3B, ICH Q3C and ICH Q3D, provides information on N-nitrosamines which are considered part of a ‘cohort of concern’ because of their mutagenic potency. Despite available guidance, the potential for N-nitrosamine impurities in sartans was not recognised during the development, manufacture and evaluation of medicines subsequently found to contain them. In addition, MAHs, who usually outsource API manufacturing, may not have had sufficient oversight of the manufacturing processes. The lessons learnt group evaluated relevant guidelines and determined that certain amendments and clarifications would help both companies and regulators better assess the potential for impurities such as N-nitrosamines. In addition, the group proposed further training for regulatory assessors in the network to improve the chances of identifying potential impurities during the evaluation of marketing authorisation applications and certificates of suitability (CEPs). Responding to the presence of unexpected impurities The network reacted swiftly once the presence of N-nitrosamines became known, taking immediate measures to protect patients and the quality of medicines in the EU. These measures included coordinating recalls of medicines across the EU, prohibiting the use of affected APIs in EU medicines (via CEP suspensions or issuance of certificates of non-compliance with good manufacturing practice (GMP)), testing of medicines on the market, inspecting manufacturing sites and conducting an EU-wide review of sartans medicines. The scale of the actions taken by regulators and the speed with which they were carried out demonstrated the network’s ability to coordinate activities of its constituent parts effectively and take a leading role in the global response to major incidents. The Rapid Alert Network (RAN) and the Incident Review Network (IRN) served as important forums in this regard, allowing the network to take timely decisions to protect the quality of EU medicines. The experience gained from the sartans case affords the network the opportunity to assess and improve the efficiency of its regulatory responses to such incidents. To this end, the lessons learnt group identified areas for improvement. These include the development and use of improved technology to obtain information and track activities within the network and the review of guidelines and procedures for sampling and testing of products on the market. With respect to sampling and testing, additional resources for official medicines control laboratories are required to enable the network to deal with unexpected impurities potentially affecting several medicines. 2 Communicating with patients and healthcare professionals The presence of N-nitrosamines in sartans led to significant public interest. In the early stages, a major challenge faced by communication teams within the network was the dearth of information about the potential risk to patients and medicines that could be affected. Patients across EU (and the wider world) were understandably concerned about the safety of their medicines, and healthcare professionals needed adequate information to be able to advise them. The network reacted by communicating once recalls of medicines began. Using lines-to-take, the network delivered consistent messages to the public and media and developed more reassuring messages as additional information on the risk to patients became available. Among the important messages delivered by the network were that the risk to patients was very low, that most sartans tested had no detectable N-nitrosamines or had very low levels, and that patients should not stop taking their medicines without speaking to a healthcare professional. The lessons learnt group concluded that public communication from regulators could be improved by including in their communication materials more specific details such as batch numbers (e.g., following recalls) and available alternatives. Other ways to improve the impact of public communication include working more closely within the network, using more tools such as social media, and taking extra measures to reach target audiences. Cooperating with international partners When the presence of N-nitrosamines in a sartan API came to light in late June 2018, it was clear that the findings would have far reaching and immediate global implications. The concerned APIs were used in medicinal products distributed in many regions and countries in the world, a situation that necessitated widespread recalls and coordinated regulatory actions. In response, the European regulatory network enhanced its cooperation with international partners using both new and established tools. An ad hoc ‘Angiotensin II Receptor Blockers (ARB) International Strategic Group’ led by Health Canada was created to coordinate activities of the various authorities and to ensure that they were aware of each other’s actions. The strategic group comprised Health Canada, the European Medicines Agency, US Food and Drug Administration, Japan’s Ministry of Health, Labour and Welfare/Pharmaceuticals and Medical Devices Agency, Australia’s Therapeutic Goods Administration, Singapore’s Health Science Authority, and Swissmedic. Areas of cooperation included the assessment of risks, testing methods and inspections, and public communication. The setting up of this strategic group was instrumental in coordinating international