According to an Article 46(f) of Directive 2001/83/EC as amended for medicinal products for human use, the holder of a manufacturing authorization shall at least be obliged: “to comply with the principles and guidelines of good manufacturing practice for medicinal products and to use as starting materials only active substances, which have been manufactured in accordance with the detailed guidelines on good manufacturing practice for starting materials”.
To provide guidance on how GMP compliance of active substances manufacturers should be established, “Guidance on the occasions when it is appropriate for competent Authorities to conduct inspections at the premises of manufacturers of active substances used as starting materials”, have been published.
According to this document: „When an application for a marketing authorisation, or variation to change or add a new active substance manufacturer, is submitted, the applicant will be required to include a declaration from the Qualified Person of the manufacturing authorisation holder that the active substance(s) concerned is/are manufactured in accordance with the detailed guidelines on good manufacturing practice for starting materials.”
And in addition, this document states that: “It is expected that the holder of the manufacturing authorisation will base such a declaration on carrying out, or having carried out on his behalf, an audit of the manufacturers/distributors of the active substances concerned.”
It is worth to add here, that the QP declaration is also required to be submitted with applications for renewals and batch certification.
Current Chapter 5: Production of the EU GMP Guide under section 5.25 states: “The purchase of starting materials is an important operation which should involve staff who have a particular and thorough knowledge of the suppliers.”, and under section 5.26 states: “Starting materials should only be purchased from approved suppliers …”.
It should be noted, that revised version of Chapter 5: Production of the EU GMP Guide is already published. Deadline for coming into operation is 1 March 2015. Changes include inter alia addition of a new section, on the qualification of suppliers in order to reflect the legal obligation of manufacturing authorisation holders to ensure that active substances are produced in accordance with GMP; the changes include supply chain traceability. “… Audits should be carried out at the manufacturers and distributors of active substances to confirm that they comply with the relevant good manufacturing practice and good distribution practice requirements. The holder of the manufacturing authorisation shall verify such compliance either by himself or through an entity acting on his behalf under a contract. …”
It should also be noted that in case of a third party audit all arrangements between Contract Giver and Contract Acceptor should be in line with Chapter 7: Outsourced Activities of the EU GMP Guide.
Aforementioned document, “Guidance on the occasions when it is appropriate for competent Authorities to conduct inspections at the premises of manufacturers of active substances used as starting materials”, indicates also that Inspectors, during inspection of medicinal product manufacturers, are authorized to examine the audit programmes used by manufacturing authorisation holders for conducting regular audits of active substances manufacturers and review of audit reports. “… Examination, by inspectors, of the audit programmes used by authorisation holders for conducting regular audits (every 2 – 3 years), including review of audit reports, is one of the primary means by which Competent Authorities will determine if manufacturing authorisation holders are in compliance with the above article. …” [an Article 46(f) of Directive 2001/83/EC as amended];
The same position is presented under EMA/ Human regulatory/ Inspections/ GMP/GDP compliance/ Q&A: GMP: “Inspectors may need to see audit reports during inspections as part of the assessment of the manufacturing-authorisation holder’s systems for confirming GMP compliance of active substance manufacturers or suppliers. Inspectors will expect to see the full details of these reports upon request, including responses received from the audited site, indication of closure of deficiencies raised or commitments made.”