What are the GMP Requirements for Investigational Medicinal Products (IMPs)?

One of the most important steps in the development process of a medicinal product is clinical trials. In this context, the manufacture, testing, release and supply of flawless investigational medicinal products (IMPs) are of great importance. Aborted or unusable studies lead to significant additional development costs and delays in the market launch of the product.

Compliance with GMP (Good Manufacturing Practice) in the manufacture, packaging and labelling of investigational medicinal products (IMPs or Investigational New Drugs - INDs) is therefore crucial for ensuring the quality of a medicinal product intended for use in humans within the context of clinical trials.

GCP - ICH E6 Guideline

The ICH E6 Good Clinical Practice (GCP) Guideline stipulates that IMPs intended for use in a clinical trial must be manufactured in accordance with applicable GMP standards and handled in accordance with the product specifications and the protocol. Procedures should be in place for the handling, shipment, storage, dispensing, return and destruction (or alternatively disposal) of the IMP. The sponsor should ensure that the IMP (including the comparator and placebo) is sufficiently characterised in accordance with the stage of development of the IMP, is manufactured in accordance with applicable GMP guidelines, and is coded and labelled in a manner that protects blinding. Furthermore, the labelling should comply with applicable legal requirements. The IMP should be packaged in such a way as to prevent contamination and unacceptable changes during transport and storage. The sponsor should also specify acceptable storage temperatures, storage conditions (e.g. protection from light) and the shelf life of the investigational medicinal product, suitable reconstitution fluids and procedures, as well as devices for product administration. Furthermore, the sponsor should inform all parties involved (e.g. monitors, investigators, pharmacists) of these specifications.

GMP for IMPs - Annex 13 EU GMP Guidelines

Regulation (EU) No. 536/2014 (Clinical Trials Regulation, CTR) established a uniform framework within the EU for the conduct of clinical trials in humans. The CTR also brought into force the "Detailed Commission Guideline on Good Manufacturing Practice for Investigational Medicinal Products" (GMP for IMPs). This has been incorporated into the existing Annex 13 of the EU GMP Guidelines. The labelling requirements for investigational medicinal products are now no longer contained in Annex 13 but in Annex VI of the CTR.

The manufacture of investigational medicinal products is often more complex than that of products already on the market, due to the lack of established routine procedures, the variety of study designs and the resulting packaging designs, as well as the frequent need for randomisation and blinding.

A Product Specification File (PSF) must therefore be available, containing all the information necessary to draw up the precise written instructions for processing, packaging, quality control, batch release and shipment of a clinical trial product, or referring to documents in which this information can be found.

A manufacturing authorisation is also required for IMPs (manufacture and import of investigational medicinal products). The manufacturing authorisation must cover the relevant activities and dosage forms (including IMP manufacture, filling, packaging, labelling/presentation (including randomisation/blinding)). In practice, however (at least in Germany), it is often the case that a standard manufacturing authorisation can also cover IMP manufacture if both authorised medicinal products and IMPs are manufactured at the site. Simple reconstitution (e.g. at the trial site prior to administration to the patient) does not require a manufacturing authorisation if it is carried out under the conditions set out in Annex 13. However, reconstitution is only exempt from authorisation if it does not constitute a change to the product beyond the intended extent and is carried out in accordance with the trial protocol/instructions

Active Substances for Clinical Trials 19 (EU GMP Guidelines Part II, Chapter 19)

The GMP requirements for active substances are set out in Chapter 19 (Active Substances for Use in Clinical Trials) of the EU GMP Guidelines Part II (Basic Requirements for Active Substances used as Starting Materials). Appropriate GMP principles should be applied during the production of active substances for clinical trial purposes. However, these remain subject to fundamental GMP principles (e.g. traceability, documentation, quality assurance). The manufacturing and testing procedures should, however, be flexible to allow for changes as knowledge of the process increases and the clinical trial progresses from pre-clinical to clinical phases. Once drug development reaches the stage where the active substance is produced for use in medicinal products for clinical trials, manufacturers should ensure that the active substance is manufactured in suitable facilities using appropriate manufacturing and testing procedures to ensure the quality of the active substance.

Further information, for example on validation requirements in early phases, can be found in the two EMA documents 'Requirements for the chemical and pharmaceutical quality documentation concerning IMPs' and 'Requirements for quality documentation concerning biological IMPs' in EudraLex Volume 10, as well as in Annex 7 of the WHO 'Good Manufacturing Practices for Investigational Products'.

Specific FDA Requirements for the Manufacture and Testing of Investigational Drugs

The regulatory GMP requirements for the manufacture of INDs are set out in 21 CFR Part 210/211 and Part 312 (Investigational New Drug Application).

The specific features for investigational medicinal products (compared to the EU) include:

• Responsibility for release lies with the 'Quality Control Unit'
• According to 21 CFR 312.6, an expiry date is not generally specified as a standard labelling requirement for IND products.
• The manufacture of IMPs for Phase I does not need to comply with the GMP requirements under CFR 211. The FDA Guidance for Industry: CGMP for Phase 1 Investigational Drugs provides guidance on FDA-compliant investigational product manufacturing in Phase 1.
• Child-resistant packaging is required from clinical phases 2-4 onwards for solid oral dosage forms.
• Where a colouring agent is subject to certification under US law, only a colouring agent that has been certified accordingly may be used.
• Specific import/export rules for IND medicinal products are set out in 21 CFR 312.110.

The EU-US MRA on the Mutual Recognition of GMP Inspections does currently not cover clinical trial medicinal products.

Packaging, Labelling and Blinding (EU)

Particular challenges in the manufacture of IMPs, compared to commercial products, often lie in packaging, randomisation, coding, blinding and complete traceability.

Annex VI of the CTR sets out the labelling requirements for investigational medicinal products. For products not yet authorised, stability and shelf-life studies are often not yet complete, and new information regarding the expiry date of the IMP emerges during the course of the development phase. This means that IMPs already shipped and personalised for patients must subsequently be labelled with the new expiry date. The applicable regulations require new labelling on both the inner and outer packaging, meaning that in the event of a change, the packs must also be opened in order to update the information on the inner packaging. Frequent updates to the expiry date on the primary packaging of unauthorised medicinal products used in clinical trials may, in certain cases, pose potential risks to the quality and safety of these products (e.g. due to the need to open the packaging, which requires breaking tamper-evident seals and dismantling multi-layer kits; or through prolonged exposure to light or higher temperatures in the case of medicinal products that are sensitive in this regard). Therefore, in certain cases, given the nature and extent of the risk, it is appropriate and proportionate to omit the expiry date from the primary packaging if a risk assessment justifies this, the information is available elsewhere and patient safety remains assured. To implement this option within the CTR legal framework, the European Commission has published an amendment to the CTR via Delegated Regulation 2022/2239.

Further information, for example on the criteria for relabelling during an ongoing clinical trial to extend the expiry date, can be found in the two EMA documents "Requirements for the chemical and pharmaceutical quality documentation concerning IMPs" and "Requirements for quality documentation concerning biological IMPs" in EudraLex Volume 10.

Two-stage IMP Release Procedure (EU)

According to the Template for IMP Batch Release, the first step is the certification of each batch by the Qualified Person (QP) of the manufacturer, packager or importer in accordance with the CTR, to ensure that the provisions of the CTR and those set out in Article 12 (Responsibilities of the QP) of Delegated Regulation (EU) 1569/2017 have been complied with and documented (including compliance with GMP). The second step is the regulatory authorisation for the use of the IMP in a clinical trial by the sponsor (i.e. verification of the completion of batch certification by the QP (GMP) and of the authorisations required for the clinical trial (GCP) prior to delivery of the IMP to the clinical trial site). Both steps should be documented and recorded in the Clinical Trial Master File (TMF). The investigational medicinal products should remain under the sponsor's control until the release process is complete.

Storage and Transport of IMPs

It should be ensured that the shipment of investigational medicinal products takes place under conditions that minimise risks that could compromise the quality and integrity of the product. This includes the security of the product (e.g. against tampering, manipulation or theft), ensuring that applicable GDP principles are observed, e.g. regarding documentation, transport (including the selection of containers and packaging, qualification and/or validation activities, monitoring of transport conditions) and outsourced activities. Particular challenges often arise from very low storage and transport temperatures. The USP Chapter <1079.1> Storage and Transportation of Investigational Drug Products contains, amongst other things, information on risk assessment and traceability (Track & Trace).

Further information can be found in the 'Guideline on the responsibilities of the sponsor with regard to handling and shipping of investigational medicinal products for human use in accordance with Good Clinical Practice and Good Manufacturing Practice'.

Useful Links

• The Clinical Trials Regulation from a QP's Perspective - GMP Journal, Issue 41
• Compassionate Use and other Managed Access Concepts - GMP Journal, Issue 32
• EudraLex Volume 4 (EU GMP)
• EudraLex Volume 10 (EU Clinical Trials Guidelines)
• CLINICAL TRIALS REGULATION (EU) NO 536/2014 - QUESTIONS & ANSWERS
• TRS 1044 - Annex 7: WHO good manufacturing practices for investigational products