Earlier this year I posted the first part of 'Around the world in 80 ways' focussing on API supply chains. Here as promised is part 2.
The supply chain for Active Pharmaceutical Ingredients (APIs) has been increasing in complexity for a number of years with the potential for a number of players to be involved, with multiple possible routes around the world available (significantly more than 80!).
Where complex supply chains are in place along with a limited understanding of the overall picture, the risk of falsified APIs entering the supply chain unnoticed is significantly increased.
A number of controls have been implemented within Europe to minimise the risk of falsification and this second and final post in the series highlights a number of these and provides background on what is required of the various parties involved.
This second post concentrates on the Finished Drug Product Manufacturer utilising the API.
Finished Drug Product Manufacturer Requirements
Supply Chain Traceability
I only have to re-state who manufactures the API in my PQR and as we’ve always used the same company that’s easy.
No, that’s not the requirement.
Finished Drug Product manufacturers are required to carry out Product Quality Reviews periodically and EU Guideline Chapter 1 1.10 i) now requires ‘review of supply chain traceability of active substances’. This is often misinterpreted by companies as simply being a requirement to state the manufacturer and supplier of the API, but actually the requirement is to fully map all the parties involved in the supply chain and periodically re-assess this for accuracy. Chapter 5 5.29 provides more detail on this and makes it clear that the Active Substance supply chain traceability starts at the ‘active substance starting materials’ i.e. the Registered Starting Materials for the API manufacturing process.
Registration of Suppliers
Our APIs are manufactured to GMP, we’ve gone through vendor assurance and I know the route of supply, so that’s our due diligence complete.
No, that is insufficient.
Finished Drug Product manufactures have to check that your API Manufacturers, Importers and Distributors are appropriately registered for all the activities they perform. You can confirm on the EudraGMDP website in the API Registrations tab, if a company is registered and what they are actually registered to do (Manufacturer, Distributor or Importer). For example, if re-packaging, re-labelling or dividing up of active substances occurs then these are classed as manufacturing activities and the registration should also need to identify the site as a Manufacturer.
As with all other types of registrations, they can lapse, be revoked or be subject to restrictions, so there is also a requirement to check the status of the registrations periodically.
If you identify a company in a supply chain that is not registered or is not registered for all the appropriate activities undertaken then inform the MHRA of the details and subsequently take appropriate corrective actions.
Audits of API Suppliers
We audit the API manufacturer, so that’s us covered.
No, that’s only part of the requirement.
EU Guideline Chapter 5 5.29 makes it clear that the as well as carrying out an audit at the manufacturer of the API, there is a requirement for the Manufacturing Authorisation Holder to also audit the distributors of active substances.
Confirmation at Inspection
When Finished Dose Form sites are inspected by the MHRA, it will be typical for the inspector to establish that there is a system in place to confirm the appropriate registrations of API Manufacturers, Distributors and Importers are in place and there is a periodic review. The compliance with the procedures would be expected to be able to be demonstrated.
QP Responsibilities
The updated Annex 16 point 1.7.2 now makes QP knowledge of the active substance supply chain a clear requirement; ‘the entire supply chain…. is documented and available for the QP’. Point 1.7.3 also requires that all the relevant audit reports are available to the QP and as outlined above, this includes the audit reports of the active substance distributors.
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