Investigational Medicinal Products: EU and QP Expectations

Investigational Medicinal Products: EU and QP Expectations

Investigational Medicinal Products: EU and QP expectations

The manufacturing of Investigational Medicinal Products (IMPs) can be considered more complex than the manufacturing of marketed products. The same can be said of the role of the Qualified Person (QP). At MIAS Pharma we are frequently approached by manufacturers outside the EU who want to run clinical trials in the EU. These clients have a lot of questions about EU expectations for QP declarations and certification of IMP material. Here are some FAQs on the topic:

1. What are the legal duties of the IMP QP?
The QP responsible for final certification of a finished IMP must ensure compliance with any specific expectations for GMP as per the CTA and IMPD registered details (as applicable). This includes confirmation that the correct version of the documents within the submission are available to the QP where any substantial amendments have been submitted.
It is important to note that on occasion there are ‘conditions of approval’ included on the letter of authorisation for the clinical trial which do not require a specific response to the Competent Authority as long as these are met. The QP should have visibility of these conditions and ensure that they have been met, as applicable, prior to certification.

2. What sites should appear on the QP declarations relating to IMP manufacture in third countries which accompany clinical trial applications?
All sites involved in manufacturing steps starting with the conversion of the API into the dosage form and including primary and secondary packing. Any contract laboratories involved with release or stability testing should also be included on the QP declaration.

3. Do supporting audit reports of contract manufacturing/packaging/testing sites need to be provided to the QP?
Annex 16 states that all audit reports should be available to the QP. All the relevant supporting information (including the proposed audit responses from the audited site) should be readily available to the QP.

4. An IMP is being imported from a manufacturing site in the US. The site has had an inspection by an EU Competent Authority a few months ago. Does this mean that the QP doesn’t need to go there to do another audit personally before signing the QP Declaration of GMP compliance?
No. The starting point for a QP declaration of EU GMP should be an audit conducted by or on behalf of the importing company. Any departure from this should be justified and documented and will be subject to scrutiny during regulatory inspection. It may be possible to use the fact of a regulatory inspection by an EU Competent Authority as part of this justification, but these are general inspections which may not address the specific technical or GMP issues associated with a specific product. A regulatory inspection cannot be used unconditionally to remove the need for a product-specific audit. The audit does not need to be done by the QP, however the QP needs to be satisfied that it has been done correctly by an appropriately trained individual, as the QP will be taking final responsibility.

5. How do the requirements for sampling and testing of imported medicinal products (detailed in section 1.5 of Annex 16) apply to IMPs?
Testing is required as per the CTA specifications, but the importer may rely on the results of analysis from a non-EU laboratory and does not need to repeat the testing on import to the EEA. However, they should assure themselves that the laboratory is compliant with EU GMP as part of the process of supply chain assurance and issuance of the QP Declaration for import. If the QC laboratory in the third country is not compliant with EU GMP then the IMP would require import testing, as per Annex 16 section 1.5.

6. In relation to supply chain maps, will the expectations for IMPs be different to those for licensed medicines?
The IMP QP should exercise due diligence in understanding the risks to the product and patient as part of their certification for release of each IMP batch for use in a trial. The supply chain for manufacture, testing and packaging of the IMP would be included in the IMPD as part of the CTA. Where this includes any sites located outside the EU/EEA, these would require the issuance of a QP Declaration of compliance with the equivalent of EU GMP. The supply chain is a living document which should be maintained to reflect current supply chains.

7. Is it acceptable to ship IMPs to the clinical site under quarantine?
The release process for IMPs differs from that for authorised medicinal products in that there is a requirement for both the QP certification and release by the Sponsor following fulfilment of the requirements of Article 9 of Directive 2001/20/EC. This is often referred to as the ‘two-step release process’ or the ‘technical and regulatory green lights’.
At least step one (QP certification) of the two-step process should be performed before shipping of any IMP to any site that does not hold an appropriate authorisation (paragraph 4.1 of EU GMP Annex 16). Whilst there is no specific requirement preventing IMP being shipped to clinical sites prior to step two of the process, there would need to be appropriate, robust controls in place to prevent supply to the clinical trial investigator for administration to trial participants before the licensing authority has approved the clinical trial and a favourable opinion has also been received by an ethics committee.

If you would like to discuss your specific requirements relating to EU QP declarations and batch certification of IMP material and how MIAS Pharma can support you in preparing for your EU clinical trials, get in touch with us at +353 (1) 846 3605 or