Editor’s Note:This article was published in Pharmaceutical Technology Europe’s August 2020 print issue.
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Sean Milmo is a freelance writer based in Essex, UK.
EU regulators are requesting more effective action be taken to tackle serious impurities in APIs and finished products.
Editor’s Note:This article was published in Pharmaceutical Technology Europe’s August 2020 print issue.
The discovery of N-nitrosamines in sartan anti-hypertensive drugs two years ago could ultimately have a much wider impact on pharma manufacturers, as well as regulators, than previously expected. Instead of introducing stricter rules on monitoring only the presence of N-nitrosamines in medicines, European Union regulators want manufacturers and national regulators to take more effective action in tackling serious impurities in APIs and finished products.
This decision follows a study of the N-nitrosamines cases by a ‘lessons learnt’ group within the EU’s medicines licensing network, which concluded that the presence of the impurities had much broader implications for marketing authorization holders (MAHs) regarding the lack of control of production processes of not only medicines but their ingredients as well (1).
The N-nitrosamines saga began in mid-2018 when European medicines regulators discovered that Zhejiang Huahai, a Chinese drug manufacturer, was exporting an API containing N-nitrosamines for an angiotensin II receptor blocker or sartan hypertension treatment, called valsartan, to Europe (2). N-nitrosamines are classified as being probable human carcinogens.
Soon after the initial discovery, N-nitrosamines—mainly N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA)—were found in other sartan medicines, or their APIs, on the European market (2). The first response of the EU’s medicines licensing network, which is headed by the European Medicines Agency (EMA) and covers all the national drug agencies in the EU, was to recall some medicines from pharmacies and ban the use of sartan APIs made by some manufacturers (1).
Further investigation by EMA revealed that the risk from N-nitrosamines in sartans, despite their carcinogenic classification, was low (1). In the vast majority of sartans, N-nitrosamines were either not present or present at low levels only.
EMA also concluded that the source of the impurities was the use of the solvent dimethylformamide with sodium nitrite in the presence of an acid, which led to the formation of N-nitrosamines during the manufacture of sartan APIs (1). There was also the potential for the source to be N-nitrosamine-contaminated solvents, reagents, or manufacturing equipment.
As a result, MAHs of sartans were instructed by EMA in January 2019 to test their products specifically for N-nitrosamines and, if necessary, to make changes to the production processes for the APIs of the medicines (2). It then became clear that the presence of N-nitrosamines was not just a problem for sartans and their APIs but other medicines and potentially signalled difficulties with the detection of a wide range of impurities.
In April 2019, the EU medicines licensing network asked MAHs manufacturing the diabetes medicine pioglitazone to check their processes for NDMA after low levels of the impurity were found in batches of the drug made by an Indian producer (3).
EMA then revealed in September 2019 that it was starting a review of over-the-counter versions of ranitidine after tests had found NDMA in the medicine (4). The agency’s human medicines committee (CHMP), in April 2020, recommended the suspension of all ranitidine medicines due to NDMA in the products (5). Although the NDMA levels were generally low, the impurity had been found in several medicines at levels considered unacceptable. There were also unresolved questions about the source of the impurity in ranitidine. However, a final recommendation on the suspension was postponed in June 2020, after a ranitidine MAH asked for a re-examination of the decision (5).
The ‘lessons learnt’ group, which reported in June 2020 after being set up in May 2019 and hearing evidence from a stakeholder’s workshop in Amsterdam in November 2019, concluded that the underlying issue with all the N-nitrosamine cases was inadequate control of impurities (1).
Despite the availability of plenty of guidance from the Geneva-based International Council for Harmonization (ICH) on requirements for human pharmaceuticals and from the European Pharmacopoeia standards on certificates of suitability (CEPs), the potential for N-nitrosamines impurities was not recognized during the development, manufacture, and evaluation of medicines found to contain them, the lessons learntgroup said (1). “MAHs, who usually outsource API manufacturing, may not have sufficient oversight of the manufacturing process,” the group added.
Guidelines needed to be clarified and amended to help MAHs but also regulators to better assess the possible presence of impurities, like N-nitrosamines, the group suggested. The group proposed “further training for regulatory assessors in the network to improve the chances of identifying potential impurities during the evaluation of marketing authorization applications and certificates of suitability.”
The broadening of the range of the group’s recommendations from N-nitrosamines to other impurities has been accepted by EMA and the rest of the network, except they have narrowed the scope to “potentially carcinogenic” substances.
“The network is currently working on the implementation of the recommendations, including timelines for the different recommendations,” an EMA spokesperson told Pharmaceutical Technology Europe.
EMA sees the recommendations as complementing requirements specific to N-nitrosamine impurities, which were announced in July 2020 and stipulated by the agency’s human medicines committee (CHMP) (6).
The requirements followed a request in September 2019 by EMA’s Executive Director Guido Rasi under article 5(3) of the EU regulation 726/2004 for the CHMP to give a scientific opinion on the issue of identification of N-nitrosamine impurities in chemically synthesized APIs as well as in biological products (6).
The opinion would cover all scientific knowledge on N-nitrosamine impurities in APIs and their impact on the safe use of medicines. In drawing up the opinion, the CHMP would work with the coordination group (CMDh) of the medicine regulatory bodies of the EU member states and Iceland, Liechtenstein, and Norway.
According to CHMP’s article 5(3) report, the presence of N-nitrosamines in medicinal products should be at or below limits based on principles set out in the ICH M7 guideline on the assessment and control of DNA reactive mutagenic ‘cohort of concern’ compounds, which include N-nitrosamines, and are derived from a lifetime exposure risk of 1 in 100,000 (6).
The lessons learnt recommendations are extensive in scope, covering not just the prevention of N-nitrosamines and other impurities but also incident management, market surveillance, communication, and international cooperation.
They focus more on the responsibilities, as laid down in guidelines, of MAHs, finished product and API manufacturers, and active substance master file (ASMF) and CEP holders. A guidance review is, for example, proposed to clarify the responsibilities of these groups in respect of quality management systems, personnel, documentation, supplier qualification, contract and technical agreements, and management of quality defects.
Guidance should raise awareness of the importance of adequate knowledge of products and processes in order to “strengthen oversight of the entire supply chain” (1). According to the lessons learnt proposals, for example, guidelines should be updated on the need for improved exchanges of information between ASMF and CEP holders and MAHs on API product and process materials and the creation of impurities during API production. This would help MAHS “take full responsibility for the quality of their products, including APIs” (1).
The need for more effective audits of API and intermediate manufacturers should be emphasized in guidance. The reliability of the qualified personnel declaration system should be improved to enable MAHs to exercise more authority over API and intermediate manufacturing while supply-chain traceability of APIs and finished products should also be upgraded.
The lessons learnt report proposes that ICH guidelines be revised with the M7 guidance giving more details on the control of impurities and possibly being extended retroactively to older products. The report also recommended additions to the EU’s good manufacturing practice (GMP) guidance on the requirement to retain API and excipient samples, including those of product batches to enable batch-specific supply-chain traceability of APIs and finished products. GMP inspectors should also possibly be given guidance on how to verify during inspections what measures API producers have taken to reduce the risk of unexpected impurities.
The lessons learnt group acknowledges that its recommendations should synchronize well with the proposals put forward by CHMP under the article 5(3) procedure as well as other EU N-nitrosamine-related initiatives. However, the group stresses that its proposals come from regulators within the EU’s medicines licensing network. “Other stakeholders, such as the pharma industry, are encouraged to conduct their own exercises to consider what additional actions they should take,” the group specified (1).
1. HMA and EMA, “Lessons Learnt from Presence of N-Nitrosamine Impurities in Sartan Medicines” (Amsterdam, 23 June 2020).
2. EMA, “Angiotensin-II-Receptor Antagonists (Sartans) Containing a Tetrazole Group” (Amsterdam, 1 Feb. 2019).
3. EMA, “Update on Nitrosamine Impurities: EMA Continues Work on the Prevention of Impurities in Medicines,” ema.europa.eu, Press Release, 26 April 2019.
4. EMA, “EMA to Review Ranitidine Medicine Following Detection of NDMA,” ema.europa.eu, Press Release, 13 Sept. 2019.
5. EMA, “Ranitidine-Containing Medicinal Products” (Amsterdam, 30 April 2020, Updated 26 June 2020).
6. EMA and CHMP, “Assessment Report: Procedure Under Article 5(3) of Regulation EC(No) 726/2004; Nitrosamine Impurities in Human Medicinal Products” (Amsterdam, 25 June 2020).
Pharmaceutical Technology Europe
Vol. 32, No. 8
When referring to this article, please cite it as S. Milmo, “Tackling Serious Impurities,” Pharmaceutical Technology Europe 32 (8) 2020.