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Nitrosamines – Update from the CEP procedure

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16 December 2020
Strasbourg, France

In June 2018, a manufacturer detected N-nitrosodimethylamine (NDMA) in valsartan active substance batches. This led to multiple regulatory actions addressing the presence of NDMA and other nitrosamine impurities, initially in valsartan but later extended to many other active substances. As 2020 draws to an end, the European Directorate for the Quality of Medicines & HealthCare (EDQM) wishes to provide a summary of the current situation with regard to nitrosamine impurities in substances covered by certifications of suitability to the European Pharmacopoeia monographs (CEPs).

After receiving the initial notification about the presence of NDMA in batches of valsartan, the EDQM began to review the CEP granted for the active substance in question, together with all other valsartan CEPs. On 5 July 2018, the European Commission (EC) launched a review of valsartan-containing medicinal products in accordance with Article 31 of Directive 2001/83/EC, which was to be carried out by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA).

The EDQM immediately contacted all holders of CEPs for valsartan and asked them to provide the requisite information on their substance. The information and data received were assessed and, where necessary, action was taken on CEPs leading, in some cases, to their suspension. It was then realised that all sartans containing a tetrazole ring in their structure could also be affected. Five of these substances are the subject of Ph. Eur. monographs and have been granted CEPs. In September 2018, in addition to the review already underway for valsartan, the EC referral was expanded to medicines containing sartans with a tetrazole ring, which affected the CEPs for candesartan cilexetil, irbesartan, losartan potassium and olmesartan medoxomil. The EDQM contacted the CEP holders for all these substances and asked them to investigate the issue.

The EDQM continued to assess the responses to the requests, which concerned not just NDMA but also N-nitrosodiethylamine (NDEA) and other nitrosamine impurities. The EDQM applied the interim limits agreed with the EMA during the initial assessments, adjusting and continuing to apply the limits published by the latter if and when these changed after July 2018. During this period, the EDQM carried out all the necessary actions regarding CEPs for sartans, including suspending and, if the holder implemented appropriate corrective measures, then reinstating CEPs.

In February 2019, the CHMP article (31) referral report was published (“Sartan medicines: companies to review manufacturing processes to avoid presence of nitrosamine impurities”) and in April of that same year this was rendered binding in the EU and EEA member states. This document included temporary limits to be applied for NDMA and NDEA, resulting in revision of the monographs for the five sartans with an implementation date of January 2020. The revised monographs would cover the transition period of two years until the final limits foreseen in the opinion could be implemented. Further revision of the monographs was therefore also scheduled to ensure that the Ph. Eur. texts consistently reflected the regulatory decisions contained in the report.

In September 2019, the EMA initiated a review under EU Article 5(3) of Regulation (EC) No. 726/2004 for human medicinal products containing active substances manufactured by chemical synthesis; in June 2020, the scope of the review was extended to include all chemical and biological human medicines. The EDQM issued a similar call for review to CEP holders in October 2019 and takes this opportunity to remind any CEP holders, including those which came into the scope in June 2020, to fulfil their responsibilities in this regard if they have not already done so (Announcement to all CEP holders for synthesised APIs regarding presence of nitrosamines). The assessment of the data provided is ongoing, with priority being given to high-risk substances.

The EDQM relies on the principles laid down in the CHMP Opinion for the Article 5(3) referral and the acceptable intakes published by the EMA for NDMA, NDEA and other nitrosamines to support its assessment of the control strategies proposed by manufacturers of active substances covered by CEPs and to ensure the appropriate limits are being applied whenever necessary.

Specific reviews of CEPs for several other active substances, notably ranitidine hydrochloride, metformin and rifampicin, have also been launched after nitrosamine impurities were detected in medicinal products containing them.

  • All CEPs for ranitidine hydrochloride are currently suspended, as the EDQM was informed about the presence of low levels of NDMA in medicinal products containing this active substance. Remedial action is ongoing and the CEPs will only be restored once it is complete.
  • The EDQM has reviewed the CEPs for metformin active substance and it has been concluded that the presence of nitrosamines is not related to the active substance but to the medicinal product: no action has therefore been taken with regard to CEPs for metformin.
  • The presence of nitrosamine impurities in rifampicin is still under investigation and if necessary, appropriate action will be taken.

Controls for nitrosamine impurities have also been introduced in certain CEPs for pioglitazone hydrochloride, rizatriptan benzoate, prednisolone, clarithromycin and tigecycline. This step was taken after review and assessment of the different synthesis routes used for these substances and the data provided by the CEP holders.

Today, all of the currently valid CEPs for the five sartans containing a tetrazole structure comply with the requirements of the current monographs (i.e. a mandatory test is included for nitrosamines, irrespective of whether these impurities have actually been found in any batches). The EDQM has applied the limits in the monographs for NDEA and NDMA and the limits published by the EMA for nitrosamines other than NDEA and NDMA. The initially foreseen further revision of the monographs was put on hold pending a decision at the European level on the appropriate action to be taken. This decision was published in November 2020 on the EMA website (Nitrosamines: EMA aligns recommendations for sartans with those for other medicines) and has an impact on the sartan monographs. These monographs were discussed at the European Pharmacopoeia Commission session in November 2020 and they will be revised to align them with the decision. The sartan CEPs will therefore have to undergo further revision once the monographs themselves have been updated.

It is also important to highlight that, irrespective of the substance, all new or renewed CEPs granted since the beginning of 2019 have included a risk assessment for the presence of nitrosamines. The limits are based on the acceptable intakes for NDMA, NDEA and other nitrosamines published by the EMA. If no limit is described for nitrosamines in these CEPs, this means that either the risk was considered to be nil or, if a risk was identified, that appropriate controls have been introduced into the manufacturing process to ensure that these impurities are not present in the active substance and that data to demonstrate this absence has been provided to the EDQM.

The EDQM continues to ensure that this assessment is performed for any revisions to a CEP manufacturing process in which the synthetic route or sourcing strategy has been modified. In addition, if there are changes to the regulatory decisions and/or Ph. Eur. monographs, these are taken into account during the assessments carried out for the CEPs.

Over the past few years, the EDQM has also played an active role in inspection programs for active substance manufacturers, including re-inspections of some production sites involved in the manufacture of sartan active substances to confirm that the appropriate measures regarding manufacturing and GMP have been implemented.

In addition, the EDQM has co-operated continuously with regulatory authorities at national, international and EU level on this issue and will continue to do so to ensure a co-ordinated, harmonised approach to decision-making and the implementation of decisions. Moreover, the EDQM will also put into practice the recommendations issued as part of the sartans lessons learnt exercise (“Lessons learnt from presence of N-nitrosamine impurities in sartan medicines”).

The EDQM has also set up a dedicated web page to publish, on a regular basis, action taken: https://go.edqm.eu/Nitrosamines.

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