It goes without saying that a principle objective of both the MHRA and of pharmaceutical companies is to protect and improve the health of patients. Good Vigilance Practice (GVP) Module I states that a key quality objective of a pharmacovigilance system is:
'Promoting the safe and effective use of medicinal products, in particular through providing timely information about the safety of medicinal products to patients, healthcare professionals and the public' GVP I.B.4.
When new information about the benefits and risks of a medicine become available it is often appropriate to make changes to the safety information for the product, including the patient information leaflet, so that healthcare professionals and patients are able to use the medicine correctly on the basis of full and comprehensive information.
There is often a complex chain of events leading to the provision of this information to patients. Multiple functions within a company play a role in keeping product safety information “up to date with current scientific knowledge” as required by the Human Medicines Regulations 2012, regulation 76.
Starting in the Good Pharmacovigilance Practice (GPvP) realm, triggers for updates may be identified by pharmacovigilance staff and the corresponding variations submitted by regulatory affairs staff, who will also receive notification of variation approval. At this stage Good Manufacturing Practice (GMP) processes come into play with arrangements for printing the updated leaflets and incorporating these into the supply chain.
The expectations of the MHRA can be found on our website where we have published guidance on packaging, labelling and patient information leaflets.
Here we have said that unless otherwise stated, updates to patient information leaflets should be introduced within 3 to 6 months of approval*.
But what does this timeline actually mean? And how should marketing authorisation (MA) holders and their suppliers ensure they remain in compliance?
MA holders have a responsibility to ensure that their products are manufactured and packaged in accordance with the current MA. In the case of a revision to the leaflet this means there should be a robust system that tracks variation submission and approval dates, and the appropriate post-approval implementation date. By the end of the implementation period, the qualified person (QP) should only be certifying batches containing the revised leaflet. Batches containing the superseded leaflet should not be certified by the QP as they are no longer in compliance with the terms of the MA.
Where the MA holder relies on other companies in the supply chain for manufacturing, packaging, importation and/or batch certification activities, it is essential that this control is retained. This will require clear communication between organisations and consideration of supply chains, lead times and production schedules to ensure that the QP is able to certify all batches with the older artwork within the permitted implementation period.
For example, many products are manufactured and packaged in a third country, then transported by sea to the UK. Introduction of the new leaflet at the manufacturing site will need to be planned and scheduled to account for the lengthy sea journey and for completion of EU import testing, so that QP certification can still occur within the 3 to 6-month post-approval timeline.
The certifying QP also requires visibility of licence variations and approvals, so that they are fully aware of the current approved packaging, and the deadlines for introduction of updates to patient information leaflets.
During recent inspections we’ve seen process gaps that can lead to non-compliance and so we’ve compiled our three top tips to help ensure that updated safety information is implemented on time, keeping patients and healthcare professionals well informed.
- Check that the end to end process facilitates the timely implementation of updates and that there is seamless transition from written procedures covering GPvP, regulatory affairs and GMP processes.
- Define what is meant by ‘implementation’ of an updated leaflet and make sure this is in advance of regulatory deadlines to prevent the need for batches being re-worked should there be any unexpected delays
- Ensure the QP has access to up to date information on the correct leaflet version that should be used at batch certification.
*If a safety variation is submitted as a Type IAIN variation because wording has been pre-agreed by the national competent authority or for example provided by the PRAC following a signal review, you do not have to wait for approval[1] and updates to patient information leaflets should be introduced within 3 to 6 months of the submission of this variation.
[1] Official Journal of the European Union, 2013/C 223/01, 2.1.1. ‘Submission of Type IA notifications’
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3 comments
Comment by Neyshny posted on
Nice-https://mhrainspectorate.blog.gov.uk/2019/12/17/passing-the-baton-from-gpvp-to-gmp-three-top-tips-for-protecting-patients-and-staying-compliant/
Comment by Malgorzata posted on
Do I need to submit leaflet variation for safety update if the medicine has not been placed on the UK market for a long time but the licence is active?
Comment by Sara Berry posted on
There is a legal requirement stated in regulation 76 of the UK Human Medicines Regulations 2012, that “The holder of a UK marketing authorisation for a medicinal product must ensure the product information relating to the product is kept up to date with current scientific knowledge”. In practice for non-marketed products, the MAH should be maintaining the product information as requested by regulatory authorities (including submitting any variations specifically requested by the MHRA), and through establishing adequate change control mechanisms that ensure that any triggers to update product information, such as through signal detection or the monitoring of reference product information, are implemented well in advance of the product being placed on the market. At the time of launch to the market, the product information must be up-to-date.