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Industry must never become complacent about the safety of drug products and should seek to continually perform surveillance even if the drug is well-established.
Editor’s Note: This article was published in Pharmaceutical Technology Europe’s May 2020 print issue.
In 2018, regulatory authorities were alerted of nitrosamine impurities in valsartan that had originated from an API manufacturer based in China (1). “Within Europe, the issue is generally considered to be centred around a report of a non-good manufacturing practice (GMP) compliance (2), which was submitted by the competent authority of Italy in September 2018,” explains Diego Martinez, senior manager CMC at PharmaLex.
This report pertained to an inspection of Zhejiang Huahai Pharmaceutical (a Chinese manufacturer of a valsartan API), which led to dozens of recalls of various sartans medicines, Martinez continues. Furthermore, the US Food and Drug Administration (FDA), after completing its own inspection, issued an import alert on Zhejiang Huahai Pharmaceutical (3) and then, a few months later, a warning letter (4), iterating the deviations from current GMP for APIs. Other ingredients manufacturers have also been issued warning letters by FDA, including Aurobindo Pharma, Hetero Labs, Lantech Pharmaceuticals, Torrent Pharmaceuticals, and Mylan (5).
“The change that resulted in the formation of the potential carcinogen, N-nitrosodimethylamine (NDMA), was introduced into the manufacturing process of the valsartan API in approximately 2012 or earlier, but was not uncovered by regulators until more than five years later,” says Martinez. “Since its discovery, recalls have been conducted by a variety of firms that purchased the contaminated API from either the same or a limited number of API manufacturers.”
In September 2019, the same potential carcinogen (NDMA) was identified by FDA in Zantac and other generic versions of the drug (ranitidine) (6). “The contaminants have also been found in low levels in batches of pioglitazone produced by Hetero Labs (7), indicating the potential for the carcinogens to affect products other than sartans and ranitidine medicines,” adds Martinez.
The European Medicines Agency (EMA) has been actively investigating the origin and prevalence of nitrosamine contaminants in human medicine, reveals Martinez. “Both EMA and FDA have established limits for nitrosamines in the affected medicines,” he says.
In a recent publication from EMA on the topic, requirements on manufacturing authorization holders (MAHs) have been imposed (1). These requirements include an evaluation of all finished pharmaceutical products (FPPs) that contain chemically-synthesized APIs by MAHs to assess any potential presence of nitrosamines. “EMA has requested that MAHs complete the review before 1 October 2020,” asserts Martinez.
“Revisions are being made to the European Pharmacopoeia to the drug substances monographs for the sartan series to include testing for nitrosamines,” Martinez continues. “In addition, the general monograph for APIs (General monograph 2034) is under revision and will also include appropriate tests.”
Similarly, FDA is actively working to identify and recall medicines that have nitrosamine levels above interim acceptable limits and regularly updates its published list of angiotensin II receptor blocker (ARB) products with respect to nitrosamine content (5). “However, both EMA and FDA have emphasized that the risks associated with an abrupt discontinuation of ARB products, such as stroke, far outweigh the low risk associated with continuing to take medications with nitrosamine impurities,” Martinez adds.
“As a result of investigations into the presence of nitrosamines, it is apparent that a complete consideration of potential nitrosamine contamination in an FPP must be broader than whether sources of amines and nitrites are concurrently used in the preparation of the API,” says Martinez. “Manufacturers of all FPPs should be assessing their products for any circumstances that might inadvertently lead to nitrosamine content and taking steps to mitigate these risks.”
Manufacturers must also make all relevant information, required for an appropriate risk assessment, available to MAHs, Martinez explains. “For those products that have active substance master files (ASMFs) and certification of suitability to the monographs of the European Pharmacopoeia (CEPs), MAHs remain responsible for ensuring that robust risk evaluations have been appropriately performed prior to taking responsibility for the quality of the API and medicinal product,” he adds.
These robust evaluations, either performed by the MAH or API manufacturer (including ASMF or CEP holders), must be performed in accordance with Article 46 of Directive 2001/83/EC, Martinez stresses. “MAHs should apply for a variation in a timely manner to introduce any required changes,” he notes. “The variation should contain information on amendments to the marketing authorization-i.e., module 3 (3.2.S and 3.2.P), the active substance master files (ASMF), or certificates of suitability (CEP)-that are necessary to amend the method of manufacture or control of the active substance and/or finished product.”
Health authorities have issued general recommendations that MAHs of all FPPs evaluate whether or not nitrosamines are present in products that contain chemically synthesized APIs. “Although nitrosamines are not expected to form during the manufacture of the vast majority of medicines, the possibility of cross contamination or unintentional introduction of amines and nitrites has prompted the request for companies to undertake this precautionary review,” Martinez confirms. “MAHs together with API and finished product manufacturers are required to perform risk evaluations using quality risk management principles, as outlined in [the] ICH [International Council for Harmonization] Q9 guideline. The principles described in [the] ICH M7 guideline in relation to toxicology assessment, control strategy, and changes to the manufacturing processes for active substances should be applied.”
In any products that are likely to include nitrosamines, it is recommended that MAHs perform confirmatory testing on the API, the FPP, or both, Martinez iterates. However, as the low levels at which nitrosamine impurities occur can prove problematic in testing, several test methods have been published for assistance in this area.
“FDA has recommended the use of a liquid chromatography–high-resolution mass spectrometry (LC–HRMS) method when testing ARB drug products as a result of the lower temperature conditions of the method (8)-higher temperature conditions of some test methods may cause the sample to generate NDMA,” says Martinez. “Similarly, the Official Medicines Control Laboratories (OMCLs) Network of the Council of Europe has also published several methods (9), which may be used when testing for nitrosamines in various drug substances.”
“In my opinion, the nitrosamine impurities issue could be useful as a ‘lesson learned’ that following procedures is important,” Martinez says. “It is beneficial to view the issue as a way of enhancing the value of risk assessment tools, particularly from a regulatory standpoint. These tools have been frequently used in quality processes as they employ scientific data to direct the best course of action and now they should be implemented in regulatory procedures more regularly too.”
European authorities are conducting an exercise to establish what lessons can be learned from the identification of nitrosamines in sartans. At the time of writing, this ‘lesson learnt’ group is in the process of finalizing its recommendations on how the presence of impurities can be prevented and better managed in the future (10).
“Several conclusions can be drawn from the experiences with sartans,” summarizes Martinez. “We need continuous and continuing safety surveillance of drugs-even very old drugs and those presumed to be quite safe. The safety profile of a drug is never fully known. We cannot become complacent. A high level of suspicion must be maintained particularly with odd and unexpected safety signals and serious adverse events. Late appearing safety issues can be totally unexpected.”
1. EMA, “Information on Nitrosamines for Marketing Authorization Holders,” ema.europa.eu, 19 Sep. 2019.
2. EMA, “EU Inspection Finds Zhejiang Huahai Site Non-Compliant for Manufacture of Valsartan: EMA and National Authorities Considering Impact on Other Active Substances Produced at the Site,” ema.europa.eu, Press Release, 28 Sep. 2018.
3. FDA, “Import Alert 66-40,” fda.gov, 28 Sep. 2018.
4. FDA, “Warning Letter: Zhejiang Huahai Pharmaceutical,” fda.gov, 29 Nov. 2018.
5. FDA, “FDA Updates and Press Announcements on Angiotensin II Receptor Blocker (ARB) Recalls (Valsartan, Losartan, and Irbesartan),” fda.gov [Accessed 21 April 2020].
6. FDA, “Statement Alerting Patients and Health Care Professionals of NDMA Found in Samples of Ranitidine,” fda.gov, Press Release, 13 Sep. 2019.
7. EMA, “Update on Nitrosamine Impurities: EMA Continues to Work to Prevent Impurities in Medicines,” ema.europa.eu, Press Release, 26 April 2019.
8. FDA, “Liquid Chromatography–High-Resolution Mass Spectrometry (LC–HRMS) Method for the Determination of Six Nitrosamine Impurities in ARB Drugs,” fda.gov, 21 May 2019.
9. Council of Europe, “Ad-Hoc Projects of the OMCL Network,” edqm.eu [Accessed 21 April 2020].
10. EMA, “Update on Nitrosamines in EU Medicines,” ema.europa.eu, Press Release, 3 March 2020.
Pharmaceutical Technology Europe
Vol. 32, No. 5
When referring to this article, please cite it as F. Thomas, “Complying Confidently? Learning Lessons from Nitrosamine Impurities,” Pharmaceutical Technology Europe 32 (5) 2020.