API Focused MHRA Inspections at Dosage Form Manufacturers

The MHRA published a document entiteled “API focused MHRA Inspections at dosage form manufacturers". In this document the MHRA underlines the responsibilty of final dosage form manufacturers to assure that all APIs used for the manufacture of the medicinal products are manufactured according to GMP as defined in Part 2 of the EC GMP Guide (ICH Q7).

In the document the MHRA defines that “Manufacturing Authorisation holders must have a supplier evaluation and approval programme covering APIs (this must be in place irrespective of whether a QP declaration has been required, i.e. it applies to all existing drug products as well as new applications). This program must accumulate a body of evidence which enables the GMP compliance status of each API supplier to be determined. The programme must also include periodic re-evaluation of each supplier’s status.

A number of key pieces of evidence are typically required by MHRA (taken from the document):

Supplier approval and control

  • Approved manufacturers and supplier listings must be in place.
  • Procurement systems must only allow purchase and receipt of APIs that are approved or undergoing controlled assessment (through change control).
  • The entire supply chain for a supplied API must be defined and approved by the Manufacturing Authorisation holder. This must include all steps from input of the starting material to the API process through intermediate stages of manufacture and any subsequent Agents, Brokers, Traders, Distributors, Repackers and Relabellers i.e. all steps within the scope of the EC GMP Guide part II.


  • It is expected that in order to approve an API source an audit(s) will have been conducted by or on behalf of the Manufacturing Authorisation holder.
  • All steps in the supply chain of the active substances in use by a Manufacturing Authorisation holder will have been audited, including those in third countries, by or on behalf of the Manufacturing Authorisation holder.
  • Audits of API sites must be conducted against the requirements of the EC GMP Guide part II (ICHQ7a) by auditors with suitable knowledge and experience in API manufacture.


  • Qualified auditors must have demonstrable evidence that they:
      - Have been trained in the techniques of auditing
      - Have sufficient training or experience in API manufacture to support a capability to audit effectively in the environment. This is particularl important as API plants and GMP issues are very different to a dose form facility.
      - Have specific knowledge and experience of the requirements of the EC GMP Guide part II.

Deviation Management/Inspection findings

  • Any deficiencies identified through the audit(s) must be risk assessed, classified and appropriate action taken.
  • Any deficiencies identified must be managed to conclusion via an effective Corrective and Preventive Action (CAPA) management system.


  • The audit report should be available for inspection by MHRA at the Manufacturing Authorisation holder site.
  • A Technical Agreement (Supply/Quality Agreement) must be in place with the API manufacturer/supplier(s).
  • Contents of the Technical Agreement (TA) should be compliant with Chapter 7 of the EC GMP Guide.
  • An incoming goods inspection program must be in place.

With regard to the 3rd party Auditors the MHRA defines among others that the scope of the audit must be clearly defined with the auditor and must include appropriate/defined elements of the supply chain. Also a Technical Agreement should be in place between the auditor and the contract giver complying with Chapter 7 of the EC GMP Guide and auditors must have no vested interests in the outcome. If the Audits needs to be initiated by the Manufacturing Authoristation holder (also defined by EMEA) those Audit reports initiated not by the Marketing Authoristation holder but by the API manufacturer or the Trader are unlikely to be accepted by MHRA.

The MHRA emphasizes in the document that a number of actions will be taken against the Manufacturing Authoristation holder if they do not comply with the requiements, among other actions the suspension or removal of a Marketing Authorisation. Examples for critical findings are:

  • Findings of actual or potential threat to patient safety from the drug product containing a particular API.
  • No supplier evaluation / audit of API supplier and no receipt testing conducted (API at most receipted on C of A with no supporting information)
  • Continued failure to demonstrate adequate compliance with the EU regulations on use of GMP compliant APIs.

Source: MHRA Guidance


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