https://mhrainspectorate.blog.gov.uk/2017/02/27/around-the-world-in-80-ways-part-2-of-2/

Around the world in 80 ways (part 2 of 2)

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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12 comments

  1. Farooq Ali

    Excellent, I have something to say, what about vendor monopoly or exclusive supplier, the business requires his item or facility to be approved can we negotiate the terms ?
    The traditional medicine sector where science has just entered , even QC methods are newborn babies, the vendors are mostly farmers and know little about GACP what is your thinking on that.

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    • Mark Birse

      Thank you for your questions.

      With regards to vendor monopoly or exclusive supply, the drug product manufacturer must ensure that the appropriate elements of Part I of the EU Guide is applied to the active materials that are being sourced. If the supplier does not meet these expectations, then efforts should be made to find a different supplier that does meet these. Alternatively there should be communications with the company to ensure that the necessary requirements will be achieved.

      The GMP classification of the herbal material is dependent upon the use made of it by the Manufacturing Authorisation Holder and thus the herbal product manufacturers should ensure that the relevant steps are carried out in accordance with the marketing authorisation/registration. EU GMP Part II Guide, Annex 7 ‘Manufacture of Herbal Medicinal Products’ identifies the specific requirements for circumstances under which compliance with GACP, Part I, and Part II of the GMP guide would be required. There are specific sections in Annex 7 dealing with ‘Specifications for Starting Materials’ and on ‘Quality Control’ that clearly identify the approach to testing.

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  2. Naveen Kumar V

    Hi,
    Is it mandate to perform vendor audits for the excipients manufacturers for the excipients to be used in medicinal products for human use. If so any reference document available stating the same.

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  3. John Cooper

    Scenario; An API is produced in the EU, exported to a Third country for storage and then imported into the EU for use in drug product manufacture. The Supply chain has been fully mapped. Stability testing has been conducted through shelf life (storage and distribution). The storage site in the Third country has been audited by the QP making the API declaration. Is it acceptable to release the imported API on the basis of the original CofA issued by the authorised EU manufacturing site?

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    • Mark Birse

      The requirement to carry out identify testing of starting materials upon receipt at a site is identified in Volume 4, Part I, Chapter 5 5.33, 5.35 and Annex 8 2. The considerations for full or partial testing of starting materials is outlined in Chapter 5 5.35 and the position adopted should be based upon a number of factors which are considered in Chapter 5 5.27, 5.28 and 5.29.

      In the scenario presented, it should be noted that all the sites receiving the starting material from the Third country should be registered as an importer of APIs and also appropriate registrations should be in place for any players in the supply chain. The materials would also be required to be handled in line with the ‘Principles of Good Distribution Practice of active substances for medicinal products for human use’ guidance.

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  4. Ian Humphrey

    Many API's used by UK based manufacturers are covered by a CEP. The EDQM assessment covers all aspects of GMP including the discussed requirement for route of supply information and auditing and verification of starting material suppliers.
    The access to a current CEP therefore means that the EDQM have assessed the information that the MHRA is requesting from license holders.
    Does the MHRA advice cover API's covered by a CEP and has this been discussed with the EDQM in order to avoid unnecessary duplication of activities?

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    • Mark Birse

      EU GMP Guideline Annex 16 1.7.2 identifies the requirement for supply chain traceability and states ‘The entire supply chain of the active substance and medicinal product up to the stage of certification is documented and available for the QP’. This is therefore not an MHRA specific request or expectation, but rather a European GMP requirement. It should also be noted that the CEP process is a dossier review, to understand whether the proposed API manufacturing process and analytical controls are sufficient to ensure that the material would comply with the specification in the Ph. Eur. monograph. It is not an assessment of compliance with GMP, and it should not be mistaken for one.

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  5. sandeep

    "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"
    Does this mean, the Drug product manufacturer shall have visibility of API manufacturer's starting material suppliers ?

    Link to this comment Reply
    • Mark Birse

      As stated in Chapter 5 5.29, “Supply chain traceability should be established and the associated risks, from active substance starting materials to the finished medicinal product, should be formally assessed and periodically verified.” It would therefore be expected that the source of the registered starting material suppliers would be known and the route of supply of these materials to the API manufacturer was included in the supply chain mapping and evaluation.

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  6. Cecilia Cseke

    Hello,
    I was wondering, on what level the supply traceablilty of the active substance should be handled in a PQR, if there are more than one API suppliers involved. Apart from what was delineated in the article, should there also be a batch-level list, indicating which API supplier was used for which specific batch during the review period? Or is the mapping on the molecule-level sufficient for the PQR itself, whilst ensuring, that batch-level information is available in case of an issue, specific only to one of the API suppliers used in the manufacturing of the product?

    Link to this comment Reply
    • Mark Birse

      EU GMP Guideline Annex 16 1.7.2 identifies that ‘The entire supply chain of the active substance and medicinal product up to the stage of certification is documented and available for the QP’. Chapter 1 1.10 i) requires that a ‘review of starting materials including packaging materials used in the product, especially those from new sources and in particular the review of supply chain traceability of active substances.’ It would therefore be considered appropriate that the PQR delineated the various routes available.

      The company quality system should be then able to readily identify the routes applicable to a given material if needed. If there were any issues identified in the materials supplied, it may be appropriate to trend the results obtained against the various sources and routes utilised, to determine if there was a causal link.

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