The requirement for QP oversight has been extended to material for use in clinical trials since the introduction of EU Directive 2001/20/EC. Annex 16 clearly states that the principles of the guidance also apply to Investigational Medicinal Products (IMP) for human use, subject to any difference in the legal provisions and more specific guidance published by the European Commission. Where the guidance refers to the Marketing Authorisation for a licensed product, the Clinical Trial Authorisation (CTA) would apply for an IMP
In a presentation by the HPRA earlier this year, deficiencies found in relation to QP related responsibilities were discussed (https://pharmacy.tcd.ie/assets/pdf/QP2017-ciara-turley-HPRA.pdf). These observations give a good insight into the focus of the inspectorate on the QP responsibilities for certification of IMPS and common pitfalls.
In relation to IMPs specifically, the following deficiencies around the certification of IMPs were highlighted as examples.
- there were no technical agreements in place with the Sponsors
- the recertification QP statement for Product X (lot 1234) had been modified from the initial certification statement to remove reference to the Product Specification File and separately, the Product Specification File reference number.
- there was no packaging record for the packaging activity of bulk tablets (PP) into the shipped container (HDPE) that occurred at the site.
- there was no stability data to support the re-certification of Product X (lot 1234) and application of a retest date of Nov 2016 (two and a half years after manufacture). The retest date was based upon testing of the bulk product (stored in PP containers) in May 2016 and addition of an additional 6months from the testing date. The container closure system used in the clinical trial was different (HDPE).
- there was no defined procedure for the recertification of IMPs based upon appropriate and relevant stability data.
In addition, the presentation highlighted common deficiencies in section 1.7 of annex 16. Section 1.7 states that “In addition, the QP has responsibility for ensuring points 1.7.1 to 1.7.21 are secured. These tasks may be delegated to appropriately trained personnel or third parties. It is recognised that the QP will need to rely on the pharmaceutical quality system and the QP should have on-going assurance that this reliance is well founded.” The MHRA blog (https://mhrainspectorate.blog.gov.uk/2017/08/14/annex-16-qp-certification-and-batch-release-frequently-asked-questions-part-2/) addresses the topical question in relation to section 1.7 : ‘Do all the 21 points detailed in Annex 16 section 1.7 apply to IMPs?’
The response given is:
‘The majority of the points apply to both licensed products and IMPs, though there are some exceptions:
For section 1.7.6 (the source and specification of starting/packaging materials) these will need to comply with whatever details have been submitted in the CTA application. In cases where the source and/or specification are not detailed in the CTA, the materials should still be sourced in accordance with the company’s supplier management systems.
Section 1.7.7 refers to the GMP and GDP requirements for the Active Pharmaceutical Ingredient. Note that API GDP does not currently apply to IMPs, however, due diligence should be applied as part of the IMP manufacturer’s quality risk management process. The GMP requirements for IMP APIs can be found in Section 19 of EU GMP Part II.
Similarly, section 1.7.8 (API import registration) and 1.7.9 (GMP for excipients) are not currently applicable to IMPs.
Regarding points 1.7.7 and 1.7.8, it is important to note that where an API or excipient is manufactured and supplied as sterile, then the requirements of EU GMP Annex 1 will apply with respect to processing and sterility assurance. This is also noted in EU GMP Annex 13 paragraphs 17 and 18.
Process validation (1.7.12) requirements for IMPs are described in EU GMP Annex 13. As mentioned above, the requirements for sterile IMPs are the same as for sterile licensed products.
Section 1.7.13 refers to the finished product specification in the Marketing Authorisation. For IMPs, this is the finished product specification in the CTA. Given that IMP processes and specifications may continue to develop, it is essential to ensure that the product is tested and released against the current version of the specification.
As IMPs are not marketed products, the requirements in 1.7.14 relating to post marketing regulatory commitments are not applicable. However, the requirement that ongoing stability data should continue to support QP certification is equally applicable to IMPs and licensed products.
Finally, section 1.7.21 regarding safety features does not apply to IMPs.
It should also be noted that section 1.9 (PLPI supply) does not apply to IMPs.’
Other questions addressed in this article are
- How do the requirements for sampling and testing of imports, detailed in section 1.5 of Annex 16, apply to IMPs?
- What are the legal duties of the IMP QP?
- Do the supporting audit reports of contract manufacturing/packaging/testing sites need to be provided to the QP?
- Do all the 21 points detailed in Annex 16 section 1.7 apply to IMPs?
- In relation to supply chain maps, will the expectations for IMPs be any different to those for licensed medicines?
- Are the document retention times described in Annex 16 section 1.10.1 the same for IMPs as for licensed products?
- How does Annex 16 section 3 (handling of unexpected deviations) apply to IMPs?
- Is it OK to ship IMPs to the clinical site under quarantine?
The manufacturing of Investigational Medicinal Products (IMPs) or Clinical Trial Material (CTM) is more complex than the manufacturing of marketed products. The same is applicable for the role of the Qualified Person (QP). Awareness of inspectorate focus and expectations is a valuable resource.