Hi all,
EMA just issued a new version of EMA/409815/2020. The new content is as follow (based on the historical index):
Updates to Q&As 8, 9, 10, 14 and 15 to clarify the expectations for
risk assessments, confirmatory testing and dossier requirements for
products where nitrosamine impurities can be controlled according to
ICH Q3A/B limits. Update to Q&A 10 to update Ames test acceptability
section. Update to Q&A 16 to clarify the responsibilities of MAHs and
API manufacturers when reference is made to ASMFs and CEPs.
Editorial correction of Q&A 4.
Adopted_Nitrosamines EMEA-H-A5(3)-1490 - QA Art. 5(3) - version 21 (europa.eu)
Apologies for not detailing which specific updates. Hopefully, someone could identify all differences (compared to Rev.20.). Of most relevance by my personal opinion I can say is the Q&A 16. It is a joint effort between API manuf and MAH to address the topic and the Q&A now further enfatize that.
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thanks a lot Diego for your information and i agree with you that the update in Question 16 is the most important of all.
below are the updates which we have identified:
Q8 (How should confirmatory tests be conducted by MAHs and manufacturers)?
For products where nitrosamine impurities can be controlled according to ICH Q3A/B principles, see Q&A 10, confirmatory testing is generally not needed if the risk can be sufficiently mitigated based on scientific considerations that demonstrate that the relevant ICH Q3A/B thresholds will not be exceeded. In such cases, the justification should be documented in the risk assessment in the MAH’s pharmaceutical quality system. For products with only advanced cancer indications as defined within the scope of ICH S9, and where the above principle has been applied to mitigate the potential risk of nitrosamine impurities, the approach should be revised should the indication ever move beyond the relevant ICH S9 setting. In these instances, confirmatory testing would generally be required considering the resultant lower applicable limits when ICH Q3A/B ceases to apply.
Q9 (What are the requirements of the analytical method(s)?):
For products where nitrosamine impurities can be controlled according to principles of ICH Q3A/B, see Q&A 10, where tested the LoQ for the analytical procedure should be at or below the applicable reporting threshold for the respective drug substance and/or drug product.
Q10 (Which limits apply for nitrosamines in medicinal products?):
All Ames assays initiated after August 2023 must comply with the requirements of the EAT protocol (Appendix 3)
Q14 (What is the approach for new and ongoing marketing authorisation applications (MAA)?)
For products where nitrosamine impurities can be controlled according to ICH Q3A/B principles, see Q&A 10, confirmatory testing is generally not needed if the risk can be sufficiently mitigated based on scientific considerations that demonstrate that the relevant ICH Q3A/B thresholds will not be exceeded. In such cases, the justification should be documented in the risk assessment in the MAH’s pharmaceutical quality system. For products with only advanced cancer indications as defined within the scope of ICH S9, and where the above principle has been applied to mitigate the potential risk of nitrosamine impurities, the approach should be revised should the indication ever move beyond the relevant ICH S9 setting. In these instances, confirmatory testing would generally be required considering the resultant lower applicable limits when ICH Q3A/B ceases to apply.
Q15 (When should a test for nitrosamines be included in the MA dossier?)
Where nitrosamine impurities can be controlled according to ICH Q3A/B principles and the risk can be sufficiently mitigated based on scientific considerations that demonstrate that the relevant ICH Q3A/B thresholds will not be exceeded, then a specification limit in the dossier is not expected.
Q16 (What are the responsibilities of MAHs for APIs with CEPs or ASMFs?)
Directive 2001/83/EC.
APIs documented in CEPs and ASMFs may be used in different finished products, potentially with different formulations, manufacturing processes and indications. To mitigate levels of nitrosamines impurities , a given finished product may need a particular quality of API with additional tests or tighter limits compared to the Ph. Eur. monograph of that substance, e.g. tighter limits for amine impurities that may be converted to nitrosamines during formulation and storage of the finished product. It is the responsibility of the MAH to work with its API suppliers to ensure that API of acceptable quality is used for a given finished product amongst any other measure that may be implemented to reduce nitrosamine impurities. Additional parameters and appropriate limits should therefore be included in the finished product manufacturer’s active substance specification as required.
best regards
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