What is an IMP? Understanding Investigational Medicinal Products

GMP and GCP Inspectors collaborate with MHRA Clinical Trials, offering support to address stakeholder queries regarding the manufacturing, importing, labeling, licensing, and handling of Investigational Medicinal Products (IMPs). This guide provides answers to frequently asked questions about IMPs.

Manufacture vs. Reconstitution

A common question revolves around differentiating between manufacturing and reconstitution. EU GMP Annex 13 in Eudralex Volume 4 provides clarification:

Annex 13, 2010:

“Manufacturing authorisation and reconstitution

Both the total and partial manufacture of investigational medicinal products, as well as the various processes of dividing up, packaging or presentation, is subject to the authorisation referred to in Article 13(1) Directive 2001/20/EC, cf. Article 9(1) Directive 2005/28/EC. This authorisation, however, shall not be required for reconstitution under the conditions set out in Article 9(2) Directive 2005/28/EC. For the purpose of this provision, reconstitution shall be understood as a simple process of:

• dissolving or dispersing the investigational medicinal product for administration of the product to a trial subject,
• or, diluting or mixing the investigational medicinal product(s) with some other substance(s) used as a vehicle for the purposes of administering it,

Reconstitution is not mixing several ingredients, including the active substance, together to produce the investigational medicinal product.

An investigational medicinal product must exist before a process can be defined as reconstitution.

The process of reconstitution has to be undertaken as soon as practicable before administration.”

The clinical trial application/IMP dossier and clinical trial protocol, or related documents, should define this process and be readily available at the site.

Detailed Commission guidelines on good manufacturing practice for investigational medicinal products for human use (“Updated Annex 13”):

“The reconstitution is understood as the simple process of dissolving or dispersing the investigational medicinal product for administration of the product to a trial subject, or diluting or mixing the investigation medicinal product with some other substance(s) used as a vehicle for the purpose of administering it to a trial subject.

Reconstitution is not mixing several ingredients, including the active substance, together to produce the investigational medicinal product. An investigational medicinal product must exist before a process can be defined as reconstitution.

The process of reconstitution has to be undertaken as close in time as possible to administration and has to be defined in the clinical trial application dossier and document available at the clinical trial site.”

Essentially, a ‘simple process’ involves dissolving or dispersing the IMP in a diluent right before administration, or diluting it with a vehicle like water for injection, saline, or glucose (potentially in an IV bag). These activities are typically classified as reconstitution. Conversely, activities like measuring or weighing multiple materials, combining them in a specific sequence with a set mixing time, incorporating in-process tests to verify details like concentration or pH, sterile filtration into another container, and integrity testing of filters before making a release decision are all regarded as manufacturing. These must be performed at a facility with an MIA(IMP) and certified by a Qualified Person before being released to the Sponsor for use in a clinical trial. Each scenario is considered on a case-by-case basis – if in doubt, consult the clinical trials helpline.

‘As soon as practicable before administration’ ideally means at the bedside. However, performing these activities in the clinic’s pharmacy, perhaps in a clean area like a laminar air flow cabinet, may be acceptable. Preparing IMP for later storage does not qualify as reconstitution.

Frequently Asked Questions on IMPs

This section addresses common queries related to manufacturing, licensing, testing, and importing IMPs.

Manufacture / Reconstitution

1. My investigational medicinal product (IMP) unit is engaged in reconstituting sterile injections and then giving them to the clinical trial subjects. What licence, if any, do I need?

   Simple reconstitution or dilution (including serial dilution) of an IMP, including a sterile injection for administration purposes, is not considered manufacturing. Therefore, a Manufacturer’s Authorisation for Investigational Medicinal Products (MIA(IMP)) is not required. Labeling after reconstitution with an identifier to ensure the dose goes to the correct subject is also permissible without an MIA(IMP).

   1a. The reconstitution we are carrying out involves the addition of another material as well as the diluent. Does this still fall outside the definition of manufacture?

   The addition of another material may fall within the scope of manufacture, but depends on the nature and reasons for the additions. Weighing out, adding other materials, or combining IMPs is not considered administration and would require authorization under a MIA(IMP). This situation should be discussed with a MHRA Clinical Trials pharmaceutical assessor pre-submission.

Licensing and Testing

2. I know that small quantities of medicinal products can be manufactured and labelled by my local hospital with no licence at all as long as it is done by a pharmacist. Why is a hospital required to hold an MIA(IMP) authorisation to conduct a similar activity for IMPs?

   The Human Medicines Regulations 2012 apply to therapeutic doses. While exemptions exist for manufacturing licenses for certain medicinal products, such as the ‘Section 10’ exemption, no such exemption exists for IMPs. Manufacturing even one dose of an IMP for immediate use requires an MIA(IMP) authorization and Qualified Person (QP) certification.

   2a. Does this mean that all such manufactured IMPs need to be analytically tested before they can be certified, even if the quantity is very small?

   Yes. Analytical requirements should be agreed upon with MHRA Clinical Trials via the clinical trial application (CTA). If an activity defined as manufacture takes place, the resulting IMPs should be tested to confirm that the specification submitted in the CTA is met. Exceptions may exist for certain types of products, such as ATIMPs or radiolabelled IMPs where testing may not be performed before release due to a very short shelf life. The rationale should be documented and agreed upon by MHRA Clinical Trials in advance.

   2b. Does the release testing for my IMP need to be carried out in a GMP-certified laboratory?

   The analysis should be performed in a GMP-compliant laboratory. Testing in support of certification and release is part of manufacturing and therefore compliance with GMP is expected. For an IMP, the certifying QP may rely on the results of analysis from a non-EU laboratory and not repeat testing on import to the EU/UK, however they must 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. This is described in the sections relating to release of batches within EU GMP Annex 13.

3. Please clarify reference sample requirements for IMPs

   Paragraph 8 in Part 2, Schedule 7 of the Medicines for Human Use (Clinical Trials) Regulation 2004 (as amended) [SI 2004 1031] requires the manufacturing authorisation holder to keep samples of each batch of formulated products readily available for examination. There should be enough finished packs for testing in duplicate. As IMPs are often small packing runs from one bulk batch, EU GMP Annex 19 accepts a justification for retaining the required sample quantity of the bulk batch and separate samples of packaging components used on each packing run. The sample of the bulk batch should be in the final primary pack in order to be representative of the materials supplied for use on a clinical trial. The requirements are also detailed in EU GMP Annex 13.

   Samples of IMPs used in UK clinical trials should be stored within the UK, EEA or an MRA country unless suitably justified and defined in a technical agreement between the sponsor, importer and third country manufacturer (cost of the IMP itself would not be considered an acceptable justification to not hold appropriate samples).

4. We have a contract to supply the local hospital with ‘Specials’ and IMPs. We are even located within a hospital site. We need to employ a QP at great expense just to certify the IMPs. We have never needed one for the specials. Why?

   ‘Specials’ are unlicensed medicines manufactured under a manufacturer’s specials licence (MS) for a special clinical need and are under the responsibility of the prescribing doctor. QP certification of products manufactured under an MS is not required. IMPs are governed by different legislation (The Medicines for Human Use (Clinical Trials) Regulation 2004 (as amended) [SI 2004 1031]). An IMP requires a clinical trial authorization application including a description of the IMP and QP certification for each batch.

5. I work in a clinical trials unit situated in my local hospital. We have an MIA(IMP) and carry out assembly of IMPs for immediate use within the unit. However, the hospital production unit itself assembles IMPs and doesn’t have a MIA(IMP). Is this permissible?

   Regulation 37 of The Medicines for Human Use (Clinical Trials) Regulation 2004 (as amended) [SI 2004 1031] contains a specific exemption. A hospital or health center does not need a MIA(IMP) authorization to assemble an IMP when the ‘assembly’ is carried out by a doctor or pharmacist, or under the supervision of a pharmacist. ‘Assembly’ is related to packaging and labelling only and not to the preparation of medicines from their ingredients. The product must be used exclusively in that hospital or health center or any other that is a trial site for the same clinical trial. This exemption does not apply to other organizations within a hospital or to companies contracted to supply hospitals or health centers.

6. We perform over encapsulation of tablets in order to blind them. Capsules are containers so this counts as packaging doesn’t it?

   No. Capsules are specifically excluded from the definition of a container in the Clinical Trials Regulations SI 2004 1031. An MIA(IMP) with ‘capsule manufacture’ listed as authorized would be necessary in this case.

7. We are a firm of respected pharmaceutical consultants some of whom are QPs. We do a lot of contract regulatory and auditing work for companies involved in clinical trials and the manufacture of IMPs. Can we have a MIA(IMP) so that we can perform IMP certification for our clients?

   No. An organization cannot act as a contract batch certification site only. The sponsors of a clinical trial may wish to keep the final QP certification step of IMP manufacture in house as they carry ultimate responsibility for the trial. Any contract organization must be involved with some manufacturing or importation of an IMP if they wish to carry out batch certification.

8. We wish to enter the business of storing and distributing IMPs. What licences do we need if any?

   The legislation does not require any MHRA license to store and distribute IMPs. However, you need to be named within the appropriate annex of your client’s MIA(IMP) as a site of storage and distribution.

9. We prepare radio-imaging pharmaceuticals from licenced kits and Technetium generators for use in clinical trials. Do we need an MIA(IMP)?

   The preparation of such radiopharmaceuticals using Technetium generators is considered manufacturing and so an MIA(IMP) is required if they are to be used as IMPs. According to Clinical Trial Regulations an investigational medicinal product (including a licenced medicinal product) is:

   (a) used or assembled (formulated or packaged) in a way different from the form of the product authorised under the authorisation

   (b) used for an indication not included in the summary of product characteristics under the authorization for that product

   (c) used to gain further information about the form of that product as authorised under the authorization (Article 2).

   However, it may be that the radiopharmaceutical used in a clinical trial may not be an IMP. There are classes of products used in clinical trials which are ‘not IMPs’ (NIMPs) and details of the definitions can be found in Eudralex Volume 10 on Clinical Trials. NIMPs include challenge agents, rescue medication, agents used to assess end points and others. Clinical trial legislation does not apply to these as long as a), b) and c) don’t apply.

   Further information relating to NIMPs is included in Q18 and Q25.

10. We manufacture tablets used for IMPs and some of these contain penicillins or other beta-lactams. Does the MHRA need to know about such manufacture?

    Yes. The MHRA needs to know about such manufacture which brings with it special GMP considerations. Include the relevant information in the application form describing such manufacture.

11. We manufacture IMPs purely for export to countries outside the EEA. Do we need an MIA(IMP)?

    Yes. An MIA(IMP) license is required for the manufacture of an IMP regardless of whether the IMP is for use in the UK, an EEA Member State or a non-EEA Member State (Third Country).

12. What is the regulatory situation with respect to veterinary clinical trials and IMPs?

    The Veterinary Medicines Directorate is responsible for such regulatory issues and contact details are available on the following link: https://www.gov.uk/government/organisations/veterinary-medicines-directorate.

13. What happens if there is an adverse event during a clinical trial and the possibility of a recall or product defect of IMPs?

    Inform the Defective Medicines Report Centre (DMRC) at the MHRA and MHRA Clinical Trials. The Clinical Trial Regulations make provision for notification of adverse events and notification of suspected unexpected serious adverse reactions. Further guidance for handling investigations into possible product defects and product recall actions is detailed in Chapter 8 of the EU GMP Guide (Eudralex Vol 4).

Import

14. What sites should appear on the QP declarations relating to IMP manufacture in third countries which accompany CT applications?

    All sites involved in manufacturing steps starting with the conversion of the API into the dosage form and including primary and secondary packing and also any contract laboratories involved with release or stability testing. A guidance template for the information that should be included on the QP Declaration is provided in Eudralex Vol 10 Chapter III.

    Note: Import of finished IMPs that have been QP certified in an EEA country into Great Britain requires an oversight process under the supervision of a UK MIA(IMP) holder (see Q15b), however this does not require a UK QP Declaration.

15. We need to import some IMPs from a manufacturing site in the USA. The site has had an inspection by an EU Competent Authority a few months ago. Does this mean that I don’t need to go out there to do another audit myself before I sign 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 an MHRA inspection.

    15a. We also intend to use some IMPs that were manufactured at a site in Switzerland. Do we need to include a QP import declaration with the CTA submission? This will have been certified by a Swiss Responsible Person (RP) so does this also require certification by an EU QP?

    Although there is a Mutual Recognition Agreement (MRA) with Switzerland, it remains a third country therefore the IMP would need to be imported by an MIA(IMP) holder. A QP Declaration of EU GMP compliance would need to be included as part of the CTA for each site outside the EU and the IMP would need to be certified by a QP upon import prior to release for use in the clinical trial.

    15b. We intend to use some IMPs for our trial in Great Britain that were manufactured at a site in the EU/EEA. Do we need to include a QP import declaration with the CTA submission? This will have been certified by an EEA QP so does this also require certification by a UK QP?

    Since the UK’s exit from the EU, and from January 2022, import of finished IMPs into Great Britain from EEA countries requires oversight by a UK MIA(IMP) holder. Additional certification by a UK QP is not required, however the UK MIA(IMP) holder responsible for the import oversight process needs to be listed in the UK CTA along with the site of final certification in the EEA.

    Further details on the requirements for this process can be found at the following link: https://www.gov.uk/government/publications/importing-investigational-medicinal-products-into-great-britain-from-approved-countries.

16. We import an IMP for a clinical trial which has just been halted for ethical reasons. We need to continue to supply the IMP as a therapy to patients who were on the trial. What is the regulatory situation here?

    Once a trial has stopped, the product ceases to be an IMP and becomes a medicinal product. Material already existing physically as an IMP in the UK can be retrospectively notified to the MHRA Import Notification System (INS) as an importation of unlicensed medicines according to MHRA Guidance Note 14. This regularises the stock as an unlicensed medicine and the packs can be supplied as such, should MHRA not object to it.

17. Are QP statements required for APIs used in IMPs?

    There is no requirement for APIs used in IMPs to comply with EU GMP Part II in full, but there remains a responsibility for IMP manufacturers to assure themselves that the API is of an appropriate quality. The EMA has also published a Q&A concerning the GMP status of APIs used in IMPs.

18. What is the regulatory situation for the importation of NIMPs into the UK?

    As NIMPs are not IMPs, the general requirements relating to medicinal products come into force, in particular the need for a Marketing Authorisation under the Human Medicines Regulations 2012. Further information on the importation of unlicensed medicines is available on the MHRA website: Supply of unlicensed medicinal products.

Stability / Shelf Life

19. We have got some more stability information on our IMP and wish to extend the shelf life. What do we do?

    MHRA Clinical Trials needs to be informed via a variation to the CTA. The Product Specification File (PSF) needs to undergo a controlled change and IMPs already manufactured will need to be relabeled.

20. Some of our stock has already gone out. Do we need to bring it back to the site with the MIA(IMP) to be relabelled with the new shelf life?

    No. It is permissible for the relabeling to be done at the clinical site. The certifying QP should be aware of this and be involved in setting up the required GMP systems. EU GMP Annex 13 deals specifically with this issue.

    20. a. We have the stability data and necessary regulatory approval to extend the shelf life of our product and fully intend to include this new date for the next campaign of product. We have some remaining stock from a batch of IMP that we would like to continue to use in the ongoing trial however it is frozen material and therefore difficult to perform the relabelling activities. Can we continue to use the product past the labelled expiry date as long as we have the relevant information available to clinic staff?

    This approach is usually not acceptable, except where provision of IMP is critical to the ongoing care of trial participants and has been agreed by MHRA Clinical Trials in advance of implementation.

21. If an IMP has a shelf life extension after QP certification and is consequently relabelled with a revised expiry date, is a further QP certification required?

    A new certification after relabelling is required for stock which has not been shipped to an investigator site. For product held at the trial site, QP certification is not required if the relabelling activity is carried out by, or under the supervision of a pharmacist, or other healthcare professional, with appropriate documented evidence in accordance with EU GMP Annex 13.

QPs and Packaging / Labelling Activities

22. Do the MHRA issue certificates of eligibility for transitional IMP QPs?

    Confirmation that a transitional IMP QPs has been assessed as being suitable and eligible to act as a QP at a given site can be verified by referring to list of authorised personnel within the appropriate UK MIA(IMP) licence.

23. Annex 13 of the Orange Guide allows for some packaging and labelling to take place after QP certification, for example expiry updating at a trial site under the supervision of the clinical trial pharmacist. Under what circumstances is this permissible and what are the GMP expectations?

    This ‘post certification labeling’ can be used for application of an identifier, expiry date labeling, investigator name, or protocol number.

    GMP expectations for ‘post certification labeling’ are:

    • finished IMP doses, certified by a QP, should exist prior to the labeling
    • the activity should be planned and described in the CT protocol
    • relative responsibilities should be described in a technical agreement where appropriate
    • the process should be described in an SOP
    • personnel doing the labeling should be appropriately trained and retrained at intervals
    • labels should be stored securely
    • the activity should be carried out in a partitioned area
    • a line clearance at the start and end of the activity should be carried out and label reconciliation performed to 100%
    • the activity should be recorded in a batch record
    • the certifying QP should be aware of the post certification process

24. What is the MHRA view on medication pooling?

    Medication pooling is the production of IMPs which may be used in a number of clinical trials and which are left in a “generic” state until after QP certification. This is acceptable provided that the QP certification is against all of the possible clinical trials which may use the IMP.

25. What is the expectation for QPs in relation to non-investigational medicinal products?

    Non investigational medicinal products (NIMPs) are not IMPs and so the legislative requirements do not apply to such products. There is an expectation for the Sponsor to ensure that NIMPs are of the necessary quality for human use.

26. Provided it is considered that the safety, quality and efficacy of a batch of IMP have not been compromised, does a QP have any discretion to certify that batch as suitable for release even if it does not meet the specification in the Clinical Trials Authorisation?

    As for licensed products, there is no such discretion available to a certifying QP.