You have a clinical trial approved in the EU and a product made outside it. Before the investigational medicinal product (IMP) is released for use in the trial, a Qualified Person (QP) in the EU must certify each batch, as Article 62(1) of the Clinical Trials Regulation requires. This post explains QP release for clinical trials from the sponsor’s side: what the QP checks, what you still have to release yourself, and what to have ready before the batch ships.

Key takeaways

• QP release of an IMP has two steps: the QP certifies each batch, then the sponsor gives its own regulatory release before the IMP is supplied to the site.
• An IMP made outside the EU has to be imported by an EU authorisation holder whose MIA covers it, and the clinical trial application needs a QP certification for the third-country site.
• The QP assesses each batch against the Product Specification File, so gaps in that file and open deviations can hold up certification.

What is QP release in clinical trials?

QP release in clinical trials is the QP’s certification that each batch of IMP complies with the good manufacturing practice (GMP) requirements of Article 63. The QP must ensure this for every batch manufactured in or imported into the EU, and must certify it (Article 62(1)). The IMP cannot be released until the QP has certified the batch (C(2017) 8179, section 8). For the service itself, see our page on QP release for IMPs.

The rule applies to every batch, not only the first one. Article 2(2)(24) of the Regulation defines manufacturing to include dividing up, packaging and labelling, so relabelling a batch is a manufacturing operation as well. HPRA says the same about labelling and relabelling of authorised products used as IMPs (AUT-G0170, section 9.1).

Manufacture or import of IMPs in the EU needs a manufacturing and import authorisation (MIA) (Article 61(1)), and the holder must have at least one QP at its disposal (Article 61(2)). In practice, a sponsor based outside the EU needs an EU authorisation holder with a QP to certify its batches. In Ireland the sponsor, or its legal representative, must also be established in the European Economic Area (HPRA AUT-G0170, section 3.7).

Certification by the QP and release by the sponsor: the two steps

Getting an IMP to a trial site in the EU is a two-step process. It is easy to treat it as one.

1. QP certification. The QP certifies that the batch meets the GMP requirements of Article 63 of the Regulation and Article 12 of Delegated Regulation 2017/1569. The Product Specification File is the basis for the QP’s assessment of the batch.
2. Regulatory release by the sponsor. The sponsor then verifies that the QP’s certification is complete and that the necessary authorisations are in place for the clinical trial, before the IMP is supplied to the site. The IMP stays under the sponsor’s control until this release process is complete. The sponsor can delegate the task to the manufacturer, with the arrangements set out in a written agreement. Both steps are described in the EMA guideline on the responsibilities of the sponsor with regard to handling and shipping of IMPs (EMA/INS/GMP/258937/2022, in effect from 1 January 2023).

Decide who in your organisation, or at your CRO, gives the regulatory release before the first batch is certified. Otherwise a certified batch can wait in a warehouse because nobody has authority to send it.

The legal basis now: Regulation 536/2014, Delegated Regulation 2017/1569 and the GMP guideline for IMPs

Some guidance on IMP release refers to Directive 2001/20/EC and to Annex 13 of the EU GMP Guide. The Regulation repealed the Directive from the date it applied (Article 96(1)), and the Commission guideline on GMP for IMPs is now listed in the Annex 13 position in EudraLex Volume 4.

Links to Regulation 536/2014 and Delegated Regulation 2017/1569 in this post go to the text as originally adopted, hosted on legislation.gov.uk. It is EU law, not UK law, and the pages do not show later amendments.

• Regulation (EU) No 536/2014, the Clinical Trials Regulation, sets the requirements for the authorisation, the QP and certification in Articles 61 to 63. It has applied since 31 January 2022, according to the EMA.
• Commission Delegated Regulation (EU) 2017/1569 sets the principles of GMP for IMPs (text).
• The Commission guideline on GMP for IMPs (C(2017) 8179) gives the detailed expectations, including the Product Specification File (section 2.1) and release of batches (section 8). Read the guideline.

Trials started under the Directive were allowed to continue under it for three years from the Regulation’s date of application (Article 98(1)). From 31 January 2025, trials approved under the Directive that are still running have to comply with the Regulation, the EMA states. If your quality agreements, SOPs or supplier contracts still quote the Directive or Annex 13, update them before you ask an EU QP to certify against them.

What the QP checks: Product Specification File, IMPD, batch records, test results and deviations

The QP certifies against a defined set of documents. If one is missing or out of date, the QP has less to base the assessment on. Before the batch ships, expect the QP to ask for the following, based on sections 2.1 and 8 of C(2017) 8179. The guideline says the QP’s assessment “may include as appropriate” such items, so the exact set depends on the product and the stage of development.

• The Product Specification File (PSF). This is the reference file that pulls together the specifications, manufacturing and packaging instructions, test methods and labelling for the IMP. The guideline says it is continually updated as development proceeds, and that the applicable sections should be available at the start of manufacture of the first batch.
• The clinical trial authorisation and its amendments, the protocol and the randomisation codes, as appropriate. Section 2.1 lists them as part of the PSF. If you hold an Investigational Medicinal Product Dossier (IMPD), keep it consistent with the PSF.
• Executed batch records for manufacture and packaging, including the blinding and labelling steps. The guideline says these records should include all deviations and planned changes.
• Certificates of analysis and the test results behind them, with the analytical methods used.
• Deviations and changes, with any additional checks and tests that followed.
• Shipping and storage records that show the source and conditions of storage and shipment.
• Technical agreements that set out who does what between the sponsor, the manufacturer, the testing laboratory and the EU authorisation holder. Section 2.1 lists relevant technical agreements as part of the PSF.

These documents come from several parties across the IMP supply chain. For QP release, agree in writing who sends what to the QP, and when.

IMPs made outside the EU: importation, the MIA and the QP declaration for IMP sites

Where IMP manufacturing takes place outside the EU, the product has to be imported by an EU authorisation holder before it can be certified. The importer must ensure the product was made to quality standards at least equivalent to EU GMP, and that the third-country manufacturer is authorised to make it in its own country. (Delegated Regulation 2017/1569, Article 3(2)).

This has two practical consequences for a non-EU sponsor.

You need an EU importer with an MIA whose scope covers IMPs. Check the scope of any importer’s MIA before you rely on it. In Ireland, IMPs from a third country must be imported by a site holding an MIA that includes third-country importation, and each imported batch must be certified by the QP before release (HPRA AUT-G0170, section 9). HPRA also requires batch-release sites to list the manufacturing sites in the supply chain as contract manufacturers on their MIA. For importation, see our page on EU pharmaceutical importation and MIA licence, which names clinical sponsors among the clients it serves. Our QP release for IMPs service covers QP certification and release of IMPs. It does not cover import licensing, storage or distribution.

The clinical trial application needs a QP certification for the IMP site. The sponsor submits a certification by an EU QP that manufacture meets GMP at least equivalent to EU GMP when the IMP is not authorised, has no marketing authorisation in an ICH country and is not made in the EU, unless mutual recognition agreement (MRA) arrangements provide otherwise (Annex I, section F, paragraph 33). Do not assume an MRA covers you. According to the EMA’s MRA page, IMPs are excluded from the Japan and Israel agreements and are not yet included in the US agreement. Where no MRA applies, the QP determines equivalence through knowledge of the manufacturer’s quality system, which is normally acquired through audit (C(2017) 8179, section 8). Plan the audit early, because the certification is needed before the trial application is submitted.

Release of the IMP must not occur until the QP has certified the batch (C(2017) 8179, section 8). We describe the steps between arrival and certification for commercial products in what happens after a product arrives in Ireland.

Blinding, comparators, labelling and other IMP-specific points

IMPs raise questions that commercial batch release does not.

• Blinding. The guideline asks for systems that keep the blind while allowing blinded products to be identified when necessary (section 6.4). In practice, keep the randomisation and coding records under controlled access, and agree with the QP what they can see. That is practice, not a quoted rule.
• Comparators. The guideline defines a comparator as an IMP used as a reference, including a placebo. For a product bought on the EU market under a marketing authorisation, the QP’s certification can be limited to confirming it matches the trial authorisation and covering the blinding, trial-specific packaging and labelling done by the manufacturer (section 8). If a comparator is repackaged, the guideline asks for a justified retest date and a reference sample taken at a representative point (section 6.3). A comparator imported directly from a third country follows the third-country route above.
• Authorised medicines used without change. Different rules can apply: for example, no GMP documents are required in the application for an authorised, unmodified IMP. Confirm the position for your product early (Annex I, section F, paragraph 32).
• Labelling. IMP labels must meet the labelling requirements of the Clinical Trials Regulation. Article 66 and Annex VI list the particulars for unauthorised IMPs, including the main contact, the batch or code number, a trial reference code, the words “for clinical trial use only” or similar, storage conditions and the expiry or re-test date. Article 67 and section C of Annex VI cover authorised IMPs. Article 69 leaves the label language to the member state. In Ireland the label text must be in English, and other languages may be added (HPRA AUT-G0170, section 3.6).
• Work at trial sites. Relabelling or repackaging carried out in hospitals, health centres or clinics by authorised pharmacists or other permitted persons can fall outside the need for a manufacturing authorisation. It applies only for sites in the same trial in the same member state, and in Ireland these processes are registered with HPRA (Article 61(5); HPRA AUT-G0170, section 9.2). Reconstitution before use is not treated as manufacture. It is done as close as possible to administration and described in the clinical trial application (C(2017) 8179, scope section).

QP release for clinical trials: when to release clinical batches and what causes delays

The QP assesses each batch against the Product Specification File and the supporting records, so gaps in the file can hold up QP release of IMP batches. These are gaps that can hold up certification or release. The list is practical advice, not drawn from a regulatory source:

• a PSF that does not match the latest protocol amendment or IMPD version;
• deviations still open when the batch is ready to ship;
• certificates of analysis or batch records sent in pieces, from different parties;
• no current GMP evidence for the third-country site;
• labels not yet approved for every member state in the trial;
• no named person ready to give the sponsor’s regulatory release.

Work back from the date of the first site activation. Leave time for the QP’s review, for answering questions, and for the sponsor’s release. For the factors that drive release time in general, see how long batch release takes.

Moving from clinical supply to commercial release

When the product approaches a marketing authorisation, the release basis changes. Annex 16 of the EU GMP Guide applies to medicinal products holding a marketing authorisation, and its principles also apply to IMPs, subject to any difference in the legal provisions and more specific guidance. Under Annex 16, the QP must ensure the batch complies with GMP and the marketing authorisation, and certification can only be performed by a QP of the manufacturer or importer described in that authorisation (sections 1.1 and 1.3 of Annex 16). The documents the QP needs change with the release basis.

Start this transition well before approval. Check whether your EU importer and QP can cover both clinical and commercial supply, and plan for the period when both run at once. Our post on QP certification under Annex 16 for commercial products covers what the commercial side involves.

How Inglasia can help

Inglasia Ireland provides QP certification and release of IMPs for clinical sponsors supplying trials in the EU. Our QPs certify batches before they go to trial sites. Regulatory release to the site is a separate sponsor step, which the sponsor can delegate.

For QP certification and release of IMPs, see our QP release for IMPs page. Importation is a separate service, described on our EU pharmaceutical importation and MIA licence page. You can also contact us.