Do you need support in assessing your risk of contamination by nitrosamine?
CVO-EUROPE’s knowledge of the strong regulatory constraints of the Life Sciences Industries enables us to better understand the new requirements that are gradually being imposed on manufacturers.
Context
There is a risk of contamination by nitrosamines of drugs products, including OTC and generics:
- It concerns the chemically synthesized APIs,
- but also all raw materials, excipients, dyes, reagents, solvents and catalysts used in the manufacturing process…
Batch recalls have already occurred in France, USA, Switzerland etc…
Health authorities of different countries require all Marketing Authorization Holders (MAH) review their drug products on the possible presence of nitrosamines.
EMA asked this by September 26, 2019, for the active substance scope, with a first deadline by March 26, 2020.
SwissMedic asked this by November 15, 2019, for the chemically synthesized API’s scope, with a deadline by May 15, 2020.
However, due to the COVID-19 pandemia, industries face a big challenge to collect all the required data and meeting the deadline. As a result, the EMA informed of a new deadline for the submission of the risk evaluations to March 2021 the 31st for chemical medicines, and to July 2021 the 1st for biological medicines (step 1). As before, if a risk is identified in step 1, the MAH should submit the appropriate response template to the regulatory authorities and proceed to step 2, as soon as possible.
For Steps 2 and 3, as required, the MAH should complete confirmatory testing and submit their variation applications to the relevant regulatory authorities by 26th September 2022 for chemical medicines, and 1st July 2023 for biological medicines.
Moreover, the EDQM has announced the extension of the deadline for completion of risk for CEP-Holders until July, 31 2020.
Finally, the FDA has published its Nitrosamines guidance on September the 1st of 2020. The risk analysis must be completed before March 1st 2021, and the submission of changes must be done within the 3 years after the publication of the guidance, that is to say before September 1st 2023.
In accordance with the instructions from the various European authorities in the context of theCOVID-19 pandemia, CVO-EUROPE has implemented specific measures such as remote working and videoconferencing to ensure the continuity of our services, while prioritizing the health and safety of our employees, our customers, and our partners.
Our experts are ready to help you to carry out the risk assessment remotely.
Nitrosamines Remediation plan & Nitrosamines CVO-EUROPE offer
CVO-EUROPE can provide support, expertise and resources for any of the following activities (non-limitative list):
Step 1a- Risk Evaluation Preparation
+ Define product prioritization Method using ICHQ9 (Quality Risk Management), ICH M7 and Risk-Mapp Master Matrix ISPE
+ Apply methods for prioritization of products in order to define the sequence they are to be evaluated
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- To be considered: maximum daily dose, duration of treatment, route of administration, dosage and special groups of patients such as pregnant women and children
+ Define Questionnaire for risk evaluation, define template to support Risk analysis and mitigation
Step 1b – Risk Evaluation Execution (by 03/31/2021 for chemical medicines ; by 07/01/2021 for biological medicines)
+ Ensure Internal risk Evaluation, preparation, execution, rapport, e.g FMEA… with the prioritization order
+ Distribute the questionnaire form to external manufacturers with the prioritization order, follow execution of the questionnaire form, collect the data from the questionnaire
+ Review the risk evaluation data (questionnaire, Risk analysis), challenge the data, manage question/answers, propose an action plan, make the decision,
+ Communicate the decision to customers, Health Authorities, archive the data
Step 2 – Confirmatory Testing
+ Require the confirmatory testing to the manufacturer, with the prioritization order
+ Define sample size: number of batches to be sampled for confirmatory testing; define specification limits
+ Ensure Nitrosamines Testing of samples: to be executed using appropriately validated and sensitive methods
+ If necessary, transfer the samples in an appropriate QC lab, or transfer the MoA to the manufacturer lab and validate it
+ Collect the data, review the data, challenge the data, propose an action plan, make the decision, communicate the decision to the customers and Health Authorities (including batch recall if applicable)
Step 3 – Change to the Market Authorization (by 09/26/2022 for chemical medicines ; by 07/01/2023 for biological medicines)
+ Change the product specifications to be considered for batch release
+ Transfer the MoA, validate the MoA
+ Change the manufacturing process to minimize nitrosamine formation or contamination or cross-contamination; the principles described in ICH M7 guideline in relation to toxicology assessment, control strategy and changes to the manufacturing processes for active substances should be applied.
+ Validate the modified process
+ Change the manufacturers contracts
+ Change the market authorization and submit the variation to customers and Health Authorities