Annex 16 of the EU guideline for Good Manufacturing Practice (GMP) provides guidance on the certification by a Qualified Person (QP) and batch release in the EU. The document not only applies to human or veterinary medicines which hold a Marketing Authorisation or are manufactured for export, but also to Investigational Medicinal Products (IMPs) for use in human clinical trials, although focus is very much on the former two product types. For this reason, the MHRA has gathered a list of exceptions or specific requirements relating to IMPs in a ’Part 2’ FAQ article which succeeds ‘Part 1’ published by Trevor Watson earlier this year.
The key finding are summarised hereafter:
- Requirements for sampling and testing of imports (section 1.5): If testing has been performed in a non-EU country by an EU GMP-compliant laboratory, the importer may rely on the results of analysis and are not required to repeat testing. This exemption should be detailed in the QP declaration issued for import. It is important to note that Mutual Recognition Agreement of GMP with the EU, not always include the manufacture of IMPs. Further information are available on the EMA website.
- Legal duties of the IMP QP: Since the QP is responsible for ensuring GMP compliance of the IMP as per the Clinical Trial Application (CTA) and IMP Dossier (IMPD) information, Sponsors must provide the QP with any relevant substantial amendments. This also includes any conditions of approval listed in the agency approval letter.
- Access to audit reports (section 1.7.3): Where several QPs are responsible for certification of the manufacturing process (e.g. different QPs for bulk manufacture and packaging sites), the QPs should only have access to the relevant audit reports. The final certifying QP can rely on certification by other QPs and therefore access to those same audit reports are not necessary
- Source and specification of starting and packaging material (section 1.7.6) need to comply with information submitted in the CTA, or the company’s supplier management systems if no details were submitted.
- GMP and GDP (Good Distribution Practice): requirements for Active Pharmaceutical Ingredients (APIs), API import registration and GMP for excipients (Section 1.7.7, 1.7.8 and 1.7.9) are not applicable to IMPs. Requirements can be found in EU GMP part II, Annex 1 and Annex 13.
- Process validation for IMPs (Section 1.7.12 of Annex 16) is described further in EU GMP annex 13.
- Post marketing commitments (section 1.7.14 of Annex 16) and safety features (section 1.7.21) do not apply to IMPs, however ongoing stability data should support the IMP’s QP certification.
- Supply chain map (section 1.7.2): This information is included in the IMPD and must be kept up-to-date. Where authorised test and comparator products are used, they should be sourced from an authorised supplier (Wholesale Distribution Authorisation and GDP certificates should be documented). A QP Declaration of Compliance is requested for sites outside the EU.
- Document retention time (section 1.10.1): Currently the document retention time is 5 years after the end of the trial, according to EU GMP chapter 4. With the implementation of the Clinical Trial Regulation 536/2014, retention time will be increased to 25 years.
- Deviations and updates to IMPDs: The EMA clinical trials guideline provides information on how to manage the CTA, post-approval.
- Release process: IMPs are released through a two-step process: Technical release (QP declaration) and regulatory release (Competent Authority approval and Ethics Committee favourable opinion). It is permissible to ship the IMP to the trial site before step two of the process but robust controls must be in place to prevent supply to the trial investigator.
The full FAQ article can be accessed on the MHRA Inspectorate blog here.