With all nitrosamines deadlines passed, EMA updates its guidelines


Nov. 17, 2023

Last week, the EMA updated its guidelines on nitrosamine impurities. Although most requirements remain the same, the agency has added a new – but limited — regulatory reliance option. The update also includes some restructuring as well as changes to two items in the nitrosamines Q&A document.

Quick background on nitrosamines in global medicinal products

  • Nitrosamines are a large and diverse class of chemicals, with more than 300 different structurally distinct species known today. Nitrosamines’ chemical properties are varied in terms of traits like size, shape, and hydrophilicity, with these traits dictated by the atoms or chemical groups that attach to the central nitrogen-containing portion of the amine structure. As is the case with any chemical reaction, certain factors such as temperature and pH level can also influence the likelihood that a chemical reaction will occur, and a nitrosamine will be formed.
  • Health experts recommend avoiding exposure to nitrosamines because many of them have been deemed reasonably likely to be carcinogens. Yet, the body of evidence for carcinogenicity varies by specific molecule. Given the simple structure that constitutes a nitrosamine, the abundance of their chemical precursors in the environment, the frequent occurrence of favorable conditions during which a reaction can occur, and the different “recipes” that can lead to their formation, these compounds are widespread. Humans are regularly exposed to trace amounts of nitrosamines in sources ranging from pesticides, cosmetics, toiletries, and household items to food (e.g., through preservatives), water, and even the air. Since nitrosamine formation is not usually a desired outcome, the prevention of nitrosamine formation is “a multifaceted problem with no single solution.”
  • In recent years, nitrosamines, and most commonly N-nitrosodimethylamine (NDMA), have been found in finished drug products in several classes, including medicines used for diabetes, hypertension, acid reflux, and smoking cessation. [For a thorough discussion of the basics of nitrosamine chemistry, the history of nitrosamine detection, and known health risks, read AgencyIQ’s analysis of recent FDA meetings on nitrosamines here.]
  • In 2018, NDMA was first detected in the active pharmaceutical ingredient (API) for valsartan, a blood pressure drug. The NDMA was a byproduct of new chemicals used in a tweaked manufacturing process, it was later determined. The FDA estimated that the products containing the affected API had likely been on the market for about four years before this discovery. By early 2019, it became apparent that NDMA was not the only nitrosamine forming in API synthesis. As a result, FDA established what it said were “interim limits” for three nitrosamine compounds: NDMA, NDEA and NMBA.
  • In September 2019, the European Medicines Agency (EMA) launched a “ call for review“ for medicinal products containing chemically synthesized APIs to request that sponsors conduct a three-step process to review their manufacturing processes in order to identify and, if necessary, mitigate the risk of presence of nitrosamine impurities and report the outcome back to authorities. This was eventually expanded to include biological products as well. Investigations revealed that nitrosamine impurities were found in pharmaceutical products due to reasons outside API synthesis, through re-use of chemical precursors containing leftover contaminants.
  • EMA’s investigation ended up revealing even more causes of nitrosamine impurities in drugs, discovering, for example, that formation happened during the heat-sealing process of in certain products using blister-packaging. To top it off, it was also discovered that nitrosamines could be produced not just during API synthesis, but also during excipient production. Exposure to high heat during the storage process could also cause nitrosamines to form, according to the investigation.
  • Relatively recently, it was discovered that in certain cases, final drug products themselves are nitrosamine precursors. In contrast to previously known conditions where nitrosamine impurities were the unintended consequences of manufacturing changes or packaging issues, this newly discovered source of nitrosamine impurities is directly linked to the final drug products’ ability to be transformed into entirely new, unique species of nitrosamines (e.g., nitroso-propranolol, nitroso-quinapril, etc.) when exposed to nitrosating agents within the body. These API-derived nitrosamines are referred to as Nitrosamine Drug Substance Related Impurities (NDSRIs) and represent an unprecedented development with manufacturing, quality, and product safety implications.
  • In the last several months, we’ve learned that NDSRIs are much more prevalent than was previously anticipated. In a study of more than 12,000 small molecule drugs, researchers found 40.4% of the APIs analyzed were nitrosamine precursors. This means that entire classes of critical drugs (like ACE inhibitors and beta blockers) containing secondary or tertiary amine moieties in their API molecular structures are technically nitrosamine precursors. Again though, it’s not clear what the actual risk of these molecules is to humans.
  • The EMA tackled the NDSRI issue by issuing updated guidance in July. The updated EMA guidance introduces a new Carcinogenic Potency Categorization Approach (CPCA), which is a cornerstone of the new approach that both EMA and FDA are taking to determine the Acceptable Intake (AI) of a given NDSRI and aid in risk assessment for various APIs. The guidance was accompanied by a stand-alone appendix on acceptable intake limits. The update sees the EMA shifting its position on the use of the Ames bacterial reverse mutation test, as long as enhanced testing conditions are followed. [Read AgencyIQ’s analysis of the new EMA approach here and here as well as the U.S. guidance.]
  • In August 2023, the U.K.’s MHRA adopted the some of EMA’s changes. The U.K. Medicines and Healthcare products Regulatory Agency (MHRA) generally follows E.U. guidelines on nitrosamines risk assessment, detection, and mitigation, and accordingly implemented most of EMA’s updates. According to the last update, MHRA plans to align with international guidelines as far as possible, while communicating directly with marketing authorization holders about any diverging assessments. The guideline notes that the regulator accepts limits based on the International Council for Harmonisation’s (ICH) M7 guideline, as well as E.U. guidelines. The regulator highlighted the historical ties to E.U. review and the importance of consistency in assessments. However, based on its own review, the MHRA may recognize E.U. limits, or conduct a national assessment before determining any market actions. [Read AgencyIQ’s analysis of the new EMA approach here and here.]

Last week, the EMA updated the nitrosamine guideline to allow CPCA categories from other regulators

  • First of all, the EMA notified all marketing authorization holder that the evaluation period deadlines for review have passed, so sponsors should have completed the three steps of review, mitigation, and reporting. The agency exhorted firms to treat notification of nitrosamine impurities to the EMA and national competent authorities as a priority. EMA noted that “authorities in the EU will continue to take all measures to protect patients and ensure that medicines in the EU meet the required quality standards.”
  • This same information is relayed in the updated Question 3 of the early October update to Version 18 of the nitrosamines Q&A. The update emphasizes that marketing authorization holders and manufacturers should collaborate in implementing precautionary measures to mitigate nitrosamine risk throughout the product lifecycle, particularly if changes have been made. The updates response also makes clear that E.U. regulators “will also continue to collaborate with international partners on Nitrosamine to reflect scientific advances.”
  • The application of guideline ICH M7(R2) has been recognized in the latest update to various questions including Question 10. Previous versions referred to the previous version, ICH M7(R1) s.
  • Marketing authorization holders can now also refer to CPCA categories from “ other sources.” EMA explains that marketing authorization holder may refer to CPCA categories from other regulatory authorities if the nitrosamine is not included in Appendix 1, which currently lists acceptable intakes for about 50 nitrosamines. However, the answer notes that “this will need confirmation to allow control of the substance at the level corresponding to that category.” Sponsors should also note that the list of known nitrosamine impurities was updated at the end of September. The updated includes five additional nitrosamines and adds CAS numbers to several others.
  • The updated guideline includes the need to mitigate risks from nitrosamine throughout the lifecycle. The revised question 3 notes that risk from nitrosamines should be mitigated during “the manufacturing and storage of all authorised medicinal products and throughout the lifecycle of the product if any changes are made.” Question 5 notes that the quality of the product needs to be assured throughout the medicine’s lifecycle, and imposes on manufacturers the responsibility to be aware of new information that might indicate a previously unassessed risk in the life cycle of the product. This might come from a manufacturing or other change, or be new information such as newly discovered risk factors or new limits for nitrosamines.
  • Annexes discussing the CPCA approach and Enhanced Ames Test have been removed to separate Appendices. The CPCA approach is now discussed in Appendix 2 and the Enhanced Ames Test in Appendix 3.

What’s next

  • Although no new regulatory actions seem to be in the offing, EMA certainly puts marketing authorization holders on notice of their obligations. The deadlines for all three steps in the nitrosamine evaluation have passed. Although the EMA hasn’t planned any actions to enforce the requirement yet, the agency is clear that the time has passed for marketing authorization holders to have taken appropriate action. Stakeholders should ensure that their nitrosamine impurity assessments, risk mitigation measures, and potential changes to marketing authorizations are submitted.
  • For now, EMA is allowing sponsors to rely on non-EMA sources to categorize of nitrosamines not included in the Appendix 1 (formerly Annex 1). The potential to use CPCA categories published by other regulatory authorities may provide some benefit if EMA is slower than other regulators to update requirements. Generally, the EMA is swift in updating guidelines. However, this may still offer marketing authorization holders to conduct risk mitigation and reporting requirements by relying on values established by another reference regulator that might be faster in updating requirements if needed and justified.
  • Globally, several major regulators have moved swiftly and in relative unison to achieve a harmonized approach to address the problem of nitrosamine impurities in drug substances. The suite of actions expected of sponsors and associated deadlines are generally convergent among EMA, FDA, MHRA, and Health Canada, for example. The relatively recent recognition of the threat of NDSRIs and adoption of new methods for assessment and establishment of Ais, such as the enhanced Ames test and the CPCA approach, have also been accomplished in parallel. Overall, EMA can more readily adopt this permissive approach to reliance on other regulators’ CPCA determinations because of this unified stance, easing at least one aspect of a challenging situation for sponsors.

To contact the author of this item, please email Kirsten Messmer ( kmessmer@agencyiq.com).
To contact the editor of this item, please email Kari Oakes ( koakes@agencyiq.com).

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