In June 2020, the EMA finalised a review under Article 5(3) of EU Regulation (EC) No 726/2004 to provide guidance to Marketing Authorisation Holders (MAHs) on how to avoid the presence of nitrosamines in human medicinal products. As part of the outcome of this review, the European medicines regulatory network agreed new deadlines to implement the Article 5(3) opinion. However, the EDQM has decided not to change the deadline for CEP holders, which remains therefore 31 July 2020.
Moreover, from 1 October 2020, applicants and CEP holders should systematically include a risk assessment regarding the potential formation of nitrosamines in any new CEP application, sister file or renewal application, as well as in any revision where a risk of nitrosamine formation may be introduced (i.e. changes to the manufacturing process, change of suppliers of starting materials or intermediates, etc.).
Read the latest update on nitrosamines risk assessment for CEP holders (16 December 2020).
In 2018, certain types of nitrosamines (N‑nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA)) were detected in a number of active substances used in the treatment of hypertension and in related medicines. Nitrosamines are known as possible carcinogens for humans: only very low amounts are acceptable according to current regulatory requirements (ICH M7 “cohort of concern”). Their detection requires highly sensitive analytical methods. As clarified by the European Medicines Agency (EMA), their presence in active substances may be linked to several factors, e.g. from processing conditions to accidental introduction due to cross-contamination (from processes running in parallel on the same production lines) or recovery procedures for solvents, or also from degradation of the substances.
In line with its mandate to promote and protect public health in Europe by ensuring access to good quality medicines and healthcare, the EDQM has been working actively at various levels to address the presence of nitrosamines in active substances and medicines by:
- contacting all CEP holders concerned to obtain the relevant information;
- undertaking a major re-assessment of relevant CEP dossiers, and taking the necessary action (e.g. revisions of CEPs, suspension of CEPs when the detected nitrosamine content is above the commonly agreed temporary limits in the EU);
- extending the exercise, which started with sartans with a tetrazole ring, to ranitidine HCl and subsequently to all synthesised APIs;
- conducting GMP inspections of manufacturing sites for the APIs concerned;
- revising relevant European Pharmacopoeia (Ph. Eur.) monographs to add limits for N-nitrosamine impurities, an important part of ensuring the continuity of the supply of medicines for the benefit of patients in Europe;
- elaborating a general chapter providing analytical procedures to control the relevant N-nitrosamine impurities;
- working with its network of Official Medicines Control Laboratories (OMCLs) to co-ordinate sampling and testing and to ensure that analytical test procedures for determination of nitrosamines are developed and made available to stakeholders.;
- regularly updating all stakeholders concerned, from national authorities to manufacturers, on the state of the works and on initiatives taken.
The EDQM has been co-operating continuously with regulatory authorities at national, international and EU level and has regularly published updates on its website.
Further to the legally binding European Commission decision of 2 April 2019 on nitrosamine impurities in medicines containing the five active substances initially concerned (valsartan, candesartan, irbesartan, losartan and olmesartan), the Ph. Eur. Commission decided to revise the corresponding monographs (Valsartan, Losartan potassium, Irbesartan, Candesartan cilexetil and Olmesartan medoxomil). The revised monographs, which were published in the 10th Edition of the Ph. Eur. in June 2019 and became effective on 1 January 2020, now include the interim limits for these impurities (NDMA and NDEA) described in the Annex to the European Commission decision.
These interim limits are applicable for a two-year transition period, during which batches containing NDMA or NDEA above the interim limits, or both nitrosamines at whatever quantifiable level, will not be allowed on the market. After the transitional period (i.e. as of 1 April 2021), levels of NDMA or NDEA in active substances should be “not quantifiable” (< 0.03 ppm). The 5 sartan monographs will subsequently be revised a second time for publication in Ph. Eur. Suppl. 10.4 (implementation date: 1 April 2021).
Along with this approach, the Ph. Eur. Commission also proposed to revise general monograph 2034 Substances for pharmaceutical use, to include clear requirements in the Ph. Eur. for manufacturers to address the risk of contamination of substances for pharmaceutical use by nitrosamine impurities. This revision proposal was published in Pharmeuropa 32.1 for public enquiry.
In parallel, a general chapter on analytical methods for detection of nitrosamines has been published in Pharmeuropa 32.2 for public consultation from April to June 2020 (see news of 07/04/2020, below).
As soon as the EDQM was warned of the presence of NDMA in a specific source of valsartan, the data from the other dossiers for the same substance were reviewed and updates were requested from the CEP holders in order to address the potential presence of nitrosamines. As a result, some CEPs were revised to include limits for nitrosamines controlled by validated methods.
When levels of NDMA were found to be above the acceptable limit of 0.300 ppm (this temporary limit was elaborated by the EMA’s SWP taking into account the permitted daily exposure [PDE] for NDMA and the maximum daily dose of valsartan) in a source of valsartan in 2018, the CEP concerned was immediately suspended.
The EDQM also conducted a complete review of the manufacturing information submitted in all CEP applications for the substance concerned and for all other structurally related active substances. In addition, all new applications or renewals of CEPs – or any revisions where the synthetic route or sourcing has been modified – for all APIs have been systematically assessed.
For active substances which contained nitrosamines above the limits temporarily defined in the EU, the respective CEPs were suspended. A number of these CEPs were restored as soon as the companies implemented corrective actions which were assessed as satisfactory by the EDQM.
The EDQM has continued to assess data received from all other manufacturers concerned as a way of ensuring that appropriate controls are in place. This has also been confirmed by re-inspections of manufacturing sites, confirming that appropriate GMP actions have been put in place.
In September 2019, the EDQM was informed about the presence of low levels of NDMA in ranitidine HCl and the CEPs for ranitidine HCl were suspended until more information on the mechanisms triggering the formation of NDMA in this substance becomes available.
In October 2019, the EDQM contacted all CEP holders and requested that they extend investigations to other APIs.
In December 2019, the EDQM was informed about the presence of traces of NDMA in metformin HCl and contacted all holders of metformin CEPs and requested them to address this issue. At this stage there is no indication that metformin HCl drug substance is affected.
The EDQM also worked on co-ordinating the development of testing procedures that would ensure adequate control of impurities, as well as a risk-based sampling and testing programme focusing on the most pressing issues. These allowed all members of the European Network of OMCLs with the necessary equipment on hand to ensure efficient and targeted controls on medicinal products containing sartans. This was a crucial step in providing strong and efficient technical support to regulatory authorities.
In spite of the challenges related to testing nitrosamines, notably the need to develop highly sensitive detection methods, the broad coverage of N-nitrosamines and the need to test different types of APIs, the OMCL Network has developed analytical methods for the determination of NDMA following three general principles, as well as specific methods for determining NDEA. An additional method released by a German OMCL (CVUA Karlsruhe) was the first to simultaneously determine the presence of both NDMA and NDEA in sartan tablets. A specific method for NMBA (N-nitroso-N-methyl-4-aminobutyric acid derived from the use of N-methylpyrrolidone) was also developed by the Bavarian OMCL and published on the EDQM website. Over time, the published methods have been further refined to make them suitable for a broader spectrum of molecules and/or to cover additional nitrosamines. An overview of publicly available methods developed by the OMCL Network and by partner organisations can be found under Ad-hoc projects of the OMCL Network.
Under the co-ordination of the EDQM, the OMCL Network has developed:
- a common format for communicating sampling plans and testing results among participating laboratories;
- a risk-oriented sampling plan in discussion with the EMA, the NCA, inspectorates and CMDh representatives which is continually amended.
The purpose of testing activities has been to confirm levels of contamination in the products concerned, to perform market surveillance of similar products and of products theoretically of low concern, and to analyse samples derived from GMP inspections.
The analytical methods of the OMCL Network/EDQM are also used:
- for testing APIs other than sartans, coming from “suspected” production sites;
- as a starting point for developing methods for the future Ph. Eur. work on general methods.
Furthermore, test methods for additional N-nitrosamines, such as NDIPA (N-nitroso-diisopropylamine), NEIPA (N-nitroso-ethyl-isopropylamine), NDBA (N-nitrosodibutylamine), NMBA (N-nitroso-N-methyl-4-aminobutyric acid derived from the use of N-methylpyrrolidone) have been developed by the OMCLs.
List of methods made available by the OMCL Network of the EDQM: Ad-hoc projects of the OMCL Network
16/12/2020 - Nitrosamines – Update from the CEP procedure
18/01/2019 – Update on the review of CEP applications for sartans
19/11/2018 – Update on the review of CEP applications for sartans