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Annex 16 QP Certification and Batch Release – Frequently Asked Questions – part 2

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In May 2016 Alan Moon posted ‘Manufacture of Investigational Medicinal Products – Frequently Asked Questions’, and earlier this year Trevor Watson posted the first part of ‘Annex 16 QP Certification and Batch Release – FAQs’. In this follow-up post we concentrate on the application of Annex 16 to Investigational Medicinal Products (IMPs).

accurately measuring ingredients into a petri dishThe guidance in Annex 16 applies to human and veterinary products which hold an MA or are manufactured for export, and much of the wording reflects this. However, 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.

The guidance in Annex 16 also makes reference to the existence of Mutual Recognition Agreements (MRA). It is important to note that the scope of these MRAs does not extend to the manufacture of IMPs in all cases, for example the agreements with Japan and Israel do not include IMPs at all and the agreement with Australia does not include IMPs for Phase I trials. Further information can be found at this page of the EMA website.

It can be considered that the majority of Annex 16 applies to IMPs. Any exceptions to this, or any specific requirements relating to IMPs, are detailed below.

  1. How do the requirements for sampling and testing of imports, detailed in section 1.5 of Annex 16, apply to IMPs?

The requirements can be found in Article 13.3(b) of Directive 2001/20/EC, and in Article 11 of Directive 2003/94/EC. 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.

Conversely, if the QC laboratory in the third country is not compliant with EU GMP then the IMP would require import testing, as per the requirements described in Annex 16 section 1.5.

This was also covered in question 2 of the FAQ blog relating to manufacture of investigational medicinal products.

  1. What are the legal duties of the IMP QP?

The QP responsible for final certification of the 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.

  1. Do the supporting audit reports of contract manufacturing/packaging/testing sites need to be provided to the QP?

Annex 16 section 1.7.3 states that all audit reports should be available to the QP. Where a single QP is responsible for certification of the entire process, then all the relevant supporting information (including the proposed audit responses from the audited site) should be readily available to that QP.

Where the responsibilities are shared between one or more QPs (e.g. separate QPs at the bulk manufacture and packaging sites), then those responsibilities should be clearly defined in a technical agreement. If one QP provides confirmation of compliance with EU GMP and the relevant MA/CTA for partial manufacture (e.g. up to bulk manufacture), then that QP should have access to the relevant parts of the MA/CTA and the relevant audit reports. Where the final certifying QP is then reliant on this confirmation by the first QP, there is no expectation for the final QP to also require access to those same audit reports.

  1. Do all the 21 points detailed in Annex 16 section 1.7 apply to IMPs?

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.

  1. In relation to supply chain maps, will the expectations for IMPs be any different to those for licensed medicines?

The IMP QP should exercise due diligence in understanding the risks to the product and subject / 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.

Where authorised test and comparator products are used in clinical trials, these should be sourced from a supplier suitably authorised to do so and relevant checks on Wholesale Distribution Authorisation and GDP certificate or equivalent should be documented. Where these are sourced from a non-EU country such as an ICH region or MRA-partner, similar appropriate controls should be applied and a QP Declaration would be required. Further information regarding this can be found in section 3 of the EMA “Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials”.

  1. Are the document retention times described in Annex 16 section 1.10.1 the same for IMPs as for licensed products?

Retention times for documentation associated with manufacture of IMPs are described in EU GMP Chapter 4 (paragraph 4.11) which says that the batch documentation must be kept for at least five years after the completion or formal discontinuation of the last clinical trial in which the batch was used. It also goes on to say that other requirements for retention of documentation may be described in legislation in relation to specific types of product. With the pending implementation of the Clinical Trials Regulation 536/2014, the retention period of the Trial Master File (TMF) will be increased to 25 years from the end of the trial. As the QP certificate forms part of the essential documents required in the TMF this will need to be considered as part of manufacturers’ archival processes.

  1. How does Annex 16 section 3 (handling of unexpected deviations) apply to IMPs?

The requirements for handling of unexpected deviations, as described in the previous blog post, apply equally to licensed products and IMPs.

It is noted that when managing Clinical Trial Applications, two options for updating the IMPD details are available; a substantial or non-substantial amendment. The EMA’s “Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials” provides examples of what would constitute a substantial amendment. The sponsor does not have to notify non-substantial amendments to the national competent authority or the Ethics Committee. However, non-substantial amendments should be recorded and contained in the documentation when it is subsequently submitted, for example in the subsequent notification of a substantial amendment. It should also be available on request for inspection at the trial site or the sponsor premises as appropriate.

Changes to the specifications (with the exception of tightening limits) would be considered as requiring a substantial amendment.

If the deviation falls into the non-substantial amendment category, then it would be acceptable to amend the IMPD at the next update. The deviation investigation should include a documented justification of the decision to classify as a non-substantial amendment and there should be a robust system in place to ensure that it is notified appropriately at the next filing.

  1. Is it OK 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 (Article 9 of Directive 2001/20/EC and regulations 12 and 13 of SI 2004/1031 in the UK).

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  1. Comment by Concepcion Rubalcava posted on

  2. Comment by Claudio Lorck posted on

    My comment is actually a question to chapters 1.3 and 1.4 of Annex 16:
    Before relying on the GMP confirmation of a QP for a previous manufacturing step, is it expected that the final QP has accepted the Quality System of the QP of the previous manufacturing step (1.3 ... accepted pharmaceutical quality systems ...)?
    This would mean that additionally to the written agreement between the QPs as requested in 1.4.3, the final QP would have to assess the Quality System of the QP of the previous manufacturing step, e.g. by auditing the Quality System of the "previous" QP. Is my understanding correct?
    Thanks for commenting,

    • Replies to Claudio Lorck>

      Comment by Sara Berry posted on

      Thank you for your query. Where an intermediate QP certification is taken into consideration by the final certifying QP, there is no specific requirement for the final QP to personally audit the other QP’s quality system, however the final QP would be expected to exercise a level of due diligence and understanding of the compliance status of the intermediate site. This may take into consideration aspects such as, but not limited to:
      - the appropriate authorised dosage forms and activities being included on the intermediate site’s Manufacturer’s Authorisation and associated GMP certificate
      - visibility of the relevant audit reports used to approve the intermediate site
      - relevant deviations for each batch
      - general facility and system failures that may not occur at the time of specific batch manufacture but do potentially impact the batch
      - relevant change controls
      - appropriate responsibilities defined in written agreements between the relevant organisations and QPs as applicable.
      Ultimately it is the responsibility of the final certifying QP to satisfy themselves that the information on which they base their certification decision is appropriately supported and justifiable to the Competent Authorities as required.

  3. Comment by Siegfried Schmitt posted on

    I have a question regarding the segregation of duties. Would it be acceptable for a QP to be in the role of the head of the production department? Would this constitute a conflict of interest?

    • Replies to Siegfried Schmitt>

      Comment by Sara Berry posted on

      Thank you for your query. This would be an unusual scenario and would need to be discussed and assessed on a case by case basis therefore we would encourage any organisation considering this arrangement to contact the MHRA via with the specific details so that an accurate response can be provided.