Since September 26, 2019, all EU Marketing Authorization Holders (MAH) of medicines for human use are facing what might feel for many, as a new requirement: review their drug products on the possible presence of nitrosamines.
The European Medicines Agency (EMA) has sent a notice, to marketing authorization holders to review their human medicinal drug products containing chemically synthesized APIs on the potential risk of containing nitrosamines impurities.
MAHs are now facing a clear requirement with strict deadlines; fulfilling the three-step approach as outlined below:
Step 1: Risk Evaluation
MAHs should perform risk evaluation of their medicinal products containing chemically synthesized APIs. MAHs should prioritize products in order to establish the sequence in which their products are to be evaluated. The risk evaluation of all products should be concluded, at the latest, within 6 months of the publication of the EMA notification. MAHs should inform the concerned Competent Authorities when the risk evaluation is concluded. If a risk of the presence of nitrosamines is identified as a result of the evaluation, the MAH should proceed to Step 2.
Step 2: Confirmatory Testing
In the event that a risk of the presence of nitrosamines is identified as a result of the risk evaluation, confirmatory testing should be carried out using appropriately validated and sensitive methods in accordance with the prioritization deriving from the risk evaluation conducted in Step 1. Products identified as high priority should be tested as soon as possible. Confirmatory testing of all medicinal products identified to be at risk of the presence of nitrosamines and submission of required changes in the manufacturing authorizations should be concluded at the latest within 3 years of the publication of the EMA notification or at an earlier time if otherwise justified.
MAHs should inform the Competent Authorities immediately if tests confirm the presence of a nitrosamine impurity irrespective of the amount detected.
Step 3: Changes to the Marketing Authorization
MAHs should apply for a variation in a timely manner to introduce any required changes, such as an amendment of the manufacturing process or changes to product specifications.
At all steps, timelines should be shortened, and authorities immediately informed if findings indicate an immediate risk to public health.
If for many pharmaceutical companies the three-step requirement does not present particular technical challenges, for all those situations where the portfolio of human medicinal products with chemically synthesized APIs is large, the exercise can feel like an insurmountable mountain to climb.
EMA appeals to the MAH responsibilities as rationale for the strict implementation deadlines, explicitly reminding the MAH’s that control of impurities already falls under the scope of their responsibilities as per current Directive 2001/83/EC (see Paragraph ‘Responsibilities of MAHs’ in the “Information on nitrosamines for marketing authorization holders EMA/189634/2019”).
Therefore, regardless of the impact for companies, EMA has issued a clear statement, with specific deadlines, which are not likely going to be extended, given the adopted standpoint that control of nitrosamines (as well as all impurities in general) already falls under MAH responsibilities and is therefore not a new requirement.
The key for success in this regulated, yet complex, environment is employing a results-driven program from day one, making use of a chemistry-based strategy, which will enable you to streamline the required effort for both Risk Assessment as well as Analytical Method development and validation.
A multidisciplinary approach involving Formulation experts, Quality Assurance, Quality Control and Regulatory Affairs, is essential to fulfilling this requirement from EMA and ensure control of nitrosamines presence in medicinal products for human use.
Other major regulatory bodies (e.g. FDA, Health Canada) are also taking a position on this issue; positions that should be taken into account whilst making decisions for all the human medicinal products in a company’s portfolio worldwide.
Although FDA and Health Canada seem to be in alignment with the EMA on the relevance of the issue, EMA is so far the only agency that has issued the most detailed guidance.
FDA has issued a separate statement for companies, while Health Canada has not issued any statement nor guidance but as a precaution has requested to stop distributing all ranitidine drugs while gathering and sharing information with other regulators, including the U.S. Food and Drug Administration and the European Medicines Agency, and with Canadian companies to better understand the issue.
As the nitrosamine control issue does not formally fall into the category of new requirements, it still can prove to become a significant effort for all those pharmaceutical companies with a large portfolio of products with chemically synthesized APIs; needing therefore close monitoring as to prevent product shortages.
For more information, please visit our page on the EMA Advice on Nitrosamines.