European Pharmacopoeia Activities on Control of Nitrosamines and other DNA-Reactive Impurities

Abstract

The European Pharmacopoeia (Ph. Eur.) is the official pharmacopoeia in Europe which is mandatory in 39 member states of the pharmacopoeia convention including the European Union.1European Pharmacopoeia, https://www.edqm.eu/en/membership-observership.Google Scholar Beyond this region Ph. Eur. is a quality standard which is used in more than 100 countries worldwide. There are several legal texts, such as the Council of Europe's convention on the elaboration of a European Pharmacopoeia and the European Union Directives 2001/82/EC and 2001/83/EC, as amended, which make the Ph. Eur. mandatory. Requirements for control of impurities, organic or inorganic, solvents, elemental impurities or DNA-reactive impurities may be described in general and/or individual monographs and in general chapters and texts which become mandatory when they are referred to in a monograph.2General Notices. European Pharmacopoeia. 10th ed. 2022:6344Google Scholar General monographs which are typically used to describe, amongst other characteristics, requirements for the control of impurities are the general monographs “Substances for pharmaceutical use, 2034”3General monograph 2034 Substances for pharmaceutical use. European Pharmacopoeia. 10th ed. 2021:4817–4819.Google Scholar and “Pharmaceutical preparations, 2619”.4General monograph 2619 Pharmaceutical preparations. European Pharmacopoeia. 10th ed. 2019:880–882.Google Scholar General monograph 2034, for example, indicates under “Related substances” that “Unless otherwise prescribed or justified and authorised, organic impurities in active substances are to be reported, identified wherever possible, and qualified as indicated… ”. The indication refers to requirements for reporting, identification and qualification thresholds for impurities as provided by ICH Q3A. Exempted from these requirements are DNA-reactive impurities for which it is stated that “Specific thresholds may be applied for impurities known to be unusually potent or to produce toxic or unexpected pharmacological effects”. This statement makes clear that stricter requirements are to be applied for genotoxic impurities. Furthermore, the general monograph 2034 states that for DNA-reactive impurities the requirements of ICH M7 must be complied with for active substances used in medicinal products for human use, thus rendering ICH M7 legally binding in the member states of the European Pharmacopoeia convention. In addition to the requirements described in general monographs, the European Pharmacopoeia describes controls of DNA-reactive impurities in individual monographs where the principles of ICH M7 are followed. ICH M7 offers different strategic options in case of presence of DNA-reactive impurities, such as control of nitrosamines on the API level or alternatively appropriate control strategies as control on intermediate level, by in-process controls or "fate and purge" process knowledge. Tests are only described if there is a structural alert and, additionally, mutagenicity testing lead to a positive result, a structural alert alone is considered insufficient. There are two possibilities to include a test or a control strategy:-either to describe a statement in the production section or-to include a specific test in the test section of a monograph. The statements in the production section constitute mandatory requirements for manufacturers which cannot necessarily be verified by an independent analyst. For this reason, production sections may contain information on control strategies or even specific tests for genotoxic impurities in cases where either no suitable, selective, or sensitive test is known, or the test would require too sophisticated equipment. Furthermore, in some cases knowledge about the manufacturing process which is property of the manufacturer or marketing application holder and not available to public is required. Moreover, controls of intermediates occurring in the manufacturing process may be described. In that case the marketing authorisation holder (MAH) must ensure compliance of the production with defined requirements. For several years already there are a few monographs in the European Pharmacopoeia having statements on genotoxic impurities in the production statement, e. g. clopamide5Monograph 1747 Clopamide. European Pharmacopoeia. 10th ed. 2017:2265–2266.Google Scholar or in the test section, e. g. gliclazide.6Monograph 1524 Gliclazide. European Pharmacopoeia. 10th ed. 2021:5826–5827.Google Scholar The production statement in the monograph for clopamide requires from the manufacturer to evaluate the potential for formation of cis-2,6-dimethyl-1-nitrosopiperidine and to ensure its absence in the final product. It must be borne in mind that complete absence cannot be guaranteed. Accordingly, absence must be controlled to respective limits for nitrosamines. In recent years the problem of genotoxic impurities in pharmaceuticals became more prominent with the so-called “sartan case”. Sartans belong to the group of antihypertensive angiotensin-II-receptor antagonists. In June 2018 the European authorities and EDQM were informed that Valsartan, manufactured by a Chinese company, namely Zhejiang Huahai Pharmaceutical, was contaminated with NDMA (N-Nitrosodimethylamine). NDMA is known as possible carcinogen for humans and is well known from the food area and can be present, e. g. in smoked meat, BBQ etc. Nitrosamines are part of the so-called “cohort of concern” in the ICH M7 Guideline7ICH guideline M7(R1) on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk, European Medicines Agency (EMA), 25 August 2015 EMA/CHMP/ICH/83812/2013 Committee for Human Medicinal ProductsGoogle Scholar and their control requires sensitive analytical procedures as the amount to be controlled is usually at ppm or even ppb-level. The unit ppm and ppb as used in the manuscript refer to the mass of the respective nitrosamine to the mass of the API or drug product. Following a recall of valsartan, a so-called EU Art. 31 Referral was executed, and the outcome was an opinion expressed by the Committee for Medicinal Products for Human use (CHMP) which was endorsed by the EU Commission and published on 2nd April 2019. Therein it was expressed that for all N-Nitrosamines, the Marketing Authorisation Holder (MAH) had to ensure a control strategy was in place for sartan API batches used in their drug products. As a consequence, the five monographs on sartans, containing a tetrazole moiety, were revised in the European Pharmacopoeia by introducing interim limits for NDMA and NDEA (N-Nitrosodiethylamine) in the test section of the monograph. The specifications followed the ones given in the CHMP opinion, e. g. 0.300 ppm for NDMA and 0.082 ppm of NDEA in Valsartan.8Monograph 2423 Valsartan. European Pharmacopoeia. 10th ed. 2020:4167–4168.Google Scholar The transition period should last for two years, i. e. until 2nd April 2021. The individual monographs that were revised accordingly were: Valsartan, Irbesartan, Losartan potassium, Candesartan cilexetil and Olmesartan medoxomil.8Monograph 2423 Valsartan. European Pharmacopoeia. 10th ed. 2020:4167–4168.Google Scholar,9Monograph 2465 Irbesartan. European Pharmacopoeia. 10th ed. 2020:2990–2991.Google Scholar,10Monograph 2232 Losartan potassium. European Pharmacopoeia. 10th ed. 2020:3117–3118.Google Scholar,11Monograph 2573 Candesartan cilexetil. European Pharmacopoeia. 10th ed. 2020:2070–2072.Google Scholar,12Monograph 2600 Olmesartan medoxomil. European Pharmacopoeia. 10th ed. 2020:3415–3416.Google Scholar In addition, a production section was introduced in these monographs in which manufacturers were requested to ensure that their manufacturing process did not generate NDMA and NDEA, and to develop appropriate control strategies. Later, it has been found that the synthesis of the tetrazole moiety within the sartan did not represent the only source of nitrosamine formation in sartans, but nitrosamines could also be formed by interaction with excipients and/or packaging materials, like lidding foils containing nitrocellulose. Therefore, another CHMP opinion was published on the 9th July 2020 which provided recommendations regarding the detection, management and prevention of presence of nitrosamines in medicinal products for human use.13CHMP opinion: EMA finalises opinion on presence of nitrosamines in medicines, 9 July 2020 EMA/341963/2020Google Scholar In this opinion which was aligned with sartan medicinal products by publication of a press release in November 2020, the focus was now put on medicinal products instead of APIs, which means that drug products have been included as outlined below for the specific example of metformin drug products. The CHMP opinion also contains a link to the EMA nitrosamine homepage “Nitrosamine Impurities”,17EMA – “Nitrosamine Impurities”, https://www.ema.europa.eu/en/human-regulatory/post-authorisation/referral-procedures/nitrosamine-impurities).Google Scholar which provides useful information and is continuously updated. EMA also provides specific information in Q&A documents such as EMA/409815/2020 Rev. 1218EMA – “Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products” (October 2022),https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-questions-answers-marketing-authorisation-holders/applicants-chmp-opinion-article-53-regulation-ec-no-726/2004-referral-nitrosamine-impurities-human-medicinal-products_en.pdfGoogle Scholar. For this reason and to be aligned with the regulatory decisions it was necessary to revise the five sartan monographs again. As the focus was now on medicinal products, the test sections with the interim limits for NDMA and NDEA for the APIs were omitted and the production sections were revised and now gave clear instructions to manufacturers to perform a risk assessment and, if a risk had been identified, the manufacturing process should be modified, and a control strategy implemented. Furthermore, a reference to the new general chapter 2.5.42 N-Nitrosamines in active substances14General chapter 2.5.42 N-Nitrosamine in active substances. European Pharmacopoeia. 10th ed. 2021:5979–5982.Google Scholar was introduced. This chapter was introduced into Ph. Eur. to provide information about ultra-sensitive and selective analytical methods for detection and quantification of N-Nitrosamines in APIs as described below. In order to avoid a “regulatory gap”, the five sartan monographs have exceptionally been adopted by the Ph. Eur. Commission by correspondence and were put into force on 1st of April 2021 by the so-called rapid implementation procedure. Using this strategy, a full alignment between regulatory decisions and recommendations and the legally binding pharmacopoeial monographs could be obtained. In parallel to the revisions of the five monographs on sartans containing a tetrazole ring, the new general chapter 2.5.42 was elaborated by the relevant Ph. Eur. working party. This new, non-mandatory general chapter is in force since 1st of January 2021 and provides help to users. It describes three analytical procedures, validated for the five sartan APIs. These are the following:-GC-MS (validated as limit test)-LC-MS/MS (validated as limit test)-GC-MS/MS (validated as quantitative test). These procedures may also be used for other APIs or for medicinal products but then need validation for the specific substance or product. As in recent years other occurrences of N-nitrosamines in medicinal products have been observed (e. g. rifampicin, metformin HCl, ranitidine and others), the CHMP opinion of July 2020 concerned medicinal products for human use in general and no longer only sartan APIs. Examples such as metformin drug products showed that drug product manufacturing, for example the interaction between APIs and nitrosating impurities in excipients, can also lead to the formation of nitrosamines. In order to be aligned with current regulatory practice, the Ph. Eur. Commission decided to revise the production section of the general monographs “Substances for pharmaceutical use, 2034” and “Pharmaceutical preparations 2619” so that manufacturers are obliged to perform risk assessments and to establish control strategies for those substances and products for human use which are in scope of these general monographs. First drafts of both general monographs were published for enquiry in Pharmeuropa15Pharmeuropa 33.2, p 204–208 (April 2021).Google Scholar,16Pharmeuropa 33.2, p 170–174 (April 2021).Google Scholar and have finally been adopted at the 174th session of the European Pharmacopoeia Commission in November 2022 with a slightly modified wording. Following the well-known sartan cases, several regulatory decisions have been taken on the European level and world-wide. The EDQM (European Directorate for the Quality of Medicines) followed the different recommendations and decisions, and several texts of the European Pharmacopoeia were revised and elaborated to take account of the developments and further revisions will follow. Apart from the ongoing discussions about the revision of the above-mentioned general monographs, further discussions will be held on the fate of production and test sections of individual monographs describing controls, limits, or analytical procedures for N-nitrosamine impurities. After a future implementation of the revised general monographs, theoretically specific controls described in individual monographs may no longer be necessary as there will be general, mandatory requirements for nitrosamine control expressed in the two general monographs.