This guidance has been updated to include sections on the following:
- lifecycle management
- CAPA implementation
Lifecycle management
MAHs are reminded of their responsibilities to ensure the quality, safety and efficacy of their medicines and are expected to continue to review and re-visit the outcome of the risk evaluation and risk assessment as and when new information becomes available.
This includes:
- Changes to known root causes which may also affect the product in question, including when a new Acceptable Intake (AI) limit is published for the product in question.
- Changes in the product lifecycle that may require a revision of the risk evaluation and may change the outcome of the risk evaluation (e.g. changes to formulations, processes or supply chains).
Appropriate timelines for reviewing the previous risk evaluation and for conducting confirmatory testing (if needed), should be followed depending on the risk identified.
Any changes to the risk classification must be handled in the product life cycle by submission of an appropriate procedure supported by a cover letter and all supporting data.
- The risk evaluation should be maintained throughout the lifecycle of the product.
- It should be provided as part of the updated CTD documentation whenever required for a variation submission.
- This would include, but is not limited to:
- changes to the active substance source or manufacturing process,
- changes to the finished product manufacturing process,
- composition or packaging.
MAH compliance with these obligations for nitrosamines will be subject to market surveillance through regular controls by competent authorities including during inspections.
CAPA Implementation
In case levels of N-nitrosamines are detected exceeding the AI, MAHs are expected to establish and implement corrective and preventive actions (CAPAs) without any delays in order to ensure patients safety and product quality.
- The implementation of CAPAs and submission of step 3 responses should be done at the earliest opportunity, but within 3 years from the establishment and publication of the AI.
- If companies become aware that they will not be able to bring their product into compliance within this 3-year period, they should inform MHRA with detailed justification and timelines for completion of CAPAs.
Source: MHRA