Guidance

Clinical trials for medicines: Diagnostic Radiopharmaceutical Investigation Medicinal Products and Good Manufacturing Practice requirements

Published 28 April 2026

This guidance clarifies the basis of the requirements defined in the “Clinical trials for medicines: Good Manufacturing Practice and Radiopharmaceutical Investigational Medicinal Products Guidance” (“GMP and RP guidance”) document, published via the clinical trials hub webpage.

Summary

The measures defined in the GMP and RP guidance will enable wider patient access to Diagnostic Radiopharmaceutical Investigation Medicinal Products, through legislation and guidance which allows the manufacture of these products at sites holding an MS (Specials Manufacturing) licence (or MIA licence). This removes the restraint to utilise sites that hold an MIA(IMP) licence whilst aligning with the outcome of the UK consultation that required manufacturing under an approved manufacturing licence.

The safety and quality of the product is continued to be assured via the proportionate involvement of the Qualified Person, the person legally responsible for ensuring that the product has been manufactured and checked in compliance with the requirements of the Clinical Trials legislation, which includes GMP, the product specification, the Clinical Trial application and supporting records submitted to the MHRA.

Legislative Comparison between EU Reg 536/2014 and UK Reg SI 2004/1031, as amended by SI 2025/538

This table includes a comparison of all aspects of these documents as to the specifics for Radiopharmaceuticals:

Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use	Medicines for Human Use (Clinical Trials) Regulations SI 2004/1031 (as amended by SI 2025/538)
Acting in accordance with the ordinary legislative procedure, Whereas: (56) The requirement to hold an authorisation for manufacture or import of investigational medicinal products should not apply to the preparation of investigational radiopharmaceuticals from radionuclide generators, kits or radionuclide precursors
Article 61 Authorisation of manufacturing and import 1. The manufacturing and import of investigational medicinal products in the Union shall be subject to the holding of an authorisation. 5.Paragraph 1 shall not apply to any of the following processes: (b) preparation of radiopharmaceuticals used as diagnostic investigational medicinal products where this process is carried out in hospitals, health centres or clinics taking part in the same clinical trial in the same Member State;	Reg. 36. - Requirement for authorisation to manufacture or import investigational medicinal products Reg. 37A. - Exemption for radiopharmaceuticals used for diagnostic purposes (1) The restriction imposed by regulation 36(1) does not apply to the manufacture or assembly of a radiopharmaceutical used for diagnostic purposes where the conditions in paragraph (2) are satisfied. (2) The conditions referred to in paragraph (1) are that— - the manufacture or assembly is carried out by the holder of a manufacturer’s licence, as defined in regulation 8(1) of the 2012 Regulations, which does not relate to the manufacture of investigational medicinal products; and - the radiopharmaceutical is exclusively for use in a hospital or health centre which is— - (i) a trial location for the clinical trial in which the product is to be used, or (ii) taking part in the clinical trial.
Article 66 Labelling and Article 68 Radiopharmaceuticals used as investigational medicinal products or as auxiliary medicinal products for a medical diagnosis Articles 66 and 67 shall not apply to radiopharmaceuticals used as diagnostic investigational medicinal products or as diagnostic auxiliary medicinal products.	Reg. 46. - Labelling of investigational medicinal products (3) Paragraph (4) applies to an investigational medicinal product which is— (b) a radiopharmaceutical used for diagnostic purposes. 4) Where paragraph (3) applies, the investigational medicinal product must be labelled with at least the following information {where this then lists text to include}

Manufacturing Licences

UK and European legislation both confirm that Manufacturing sites that produce Radiopharmaceutical IMPs will not need to hold a licence or authorisation for IMPs. The outcome of the UK 2022 consultation (Q33) determined that some form of licence was still required, to ensure applicable GMP oversight.

Hence whilst the UK legislation does not allow no licence at all, this allows the manufacturing of Diagnostic Radiopharmaceutical (RP) IMPs to be carried out at sites holding any licence issued by the MHRA. This includes the MS (Specials Manufacturing) and MIA licences. The consultation also determined the scope to be restricted to Diagnostic and not Therapeutic radiopharmaceuticals.

Labelling of Radiopharmaceutical IMPs

Both EU and UK legislation make allowances for radiopharmaceutical labelling. The EU calls for ‘Appropriate’ labelling, whereas the UK SI has some specifics, which are a small subset of those for routine IMPs. Separate guidance has been issued for labelling of all IMPs, including specifics for Radiopharmaceuticals.

Qualified Person and Batch release

This is covered by different sections of both legislations, and there are no specifics called out for radiopharmaceuticals.

Radiopharmaceutical definitions

Within UK legislation these are detailed via the Human Medicines Regulations 2012 SI 2012/1916 (regulation 8(1)

• Radionuclide generator: Any system incorporating a fixed parent radionuclide from which is produced a daughter radionuclide which is to be removed by elution or by any other method and used in a radiopharmaceutical.
• Kits: Any preparation to be reconstituted or combined with radionuclides in the final radiopharmaceutical, usually prior to its administration.
• Radionuclide precursor: Any other radionuclide produced for the radio-labelling of another substance prior to administration, other than a radionuclide that is incorporated in or produced from a generator or is included in a radiopharmaceutical.

Assessment of Legislation and the outcome of the UK consultation for the Clinical Trials) Regulations

Overall, the amendments to the UK SI 2004/1031 (as amended by SI 2025/538) mirrors the legal basis of the EU regulation 536/2014 with respect to radiopharmaceutical IMPs.

The UK 2022 consultation on the reform of the Clinical Trials Legislation did not address any aspects of QP batch release requirements, nor is this mentioned in the EU Regulation. The legislative details also did not differentiate Positron Emission Tomography (PET) radiopharmaceuticals products from or above any other Radiopharmaceuticals.

The 2022 consultation received input from significant numbers of respondents. Q33 was: Do you agree that it is appropriate for radio pharmaceuticals used in a trial to be able to be exempted from the need to hold a Manufacturers Authorisation for IMPs?

Submitted responses to the consultation

These were varied, as evidenced by the example below mentioning licences and Qualified Persons. None were specific for PET.

This is appropriate in some circumstances, for example: those radiopharmaceuticals manufactured using a radionuclide generator to radiolabel a freeze-dried cold kit. However, some other diagnostic radiopharmaceuticals, for examples: those produced by a cyclotron should require an MIA(IMP) and QP certification due to the complexity of the process and expertise required for product characterisation and the many steps included in the GMP lifecycle of these products.

Yes, in some circumstances. This would be welcomed for manufacture of some diagnostic radiopharmaceuticals, although there are instances where we believe MIA(IMP) and QP certification would still be required. For example, an exemption would be of benefit and appropriate to those radiopharmaceuticals manufactured using a Radionuclide generator to radiolabel a freeze dried cold kit. For other radiopharmaceuticals, largely those produced via a cyclotron, we believe there is a higher risk due to the complexity of the manufacturing process, number of critical controls, extensive validation, and degree of product characterisation required. It is our opinion that it is not appropriate for an MIA(IMP) exemption for radiopharmaceutical manufacture of this type for use in a clinical trial.

The UK Radiopharmacy group support the idea that radiopharmaceuticals used in a trial are exempted from the need to hold a Manufacturers Authorisation for IMPs. The group are concerned about the lack of Qualified Persons (QPs) with expertise in radiopharmaceuticals to release radiopharmaceuticals for use in clinical trials. Although we welcome the proposal to remove the need for an MIA(IMP) and hence the need for QPs for release of diagnostic radiopharmaceuticals, we are concerned that this could have a knock-on effect of further reducing the pool of potential QPs for therapeutic radiopharmaceuticals…..

We feel that, rather than requiring a QP, it would be better to identify appropriate personnel within a radiopharmacy unit who are trained and competent to certify clinical trials material for both diagnostic and therapeutic radiopharmaceuticals, whether this be in a unit holding a “Specials” manufacturing licence (MS) or a unit working under Section 10 Exemption e.g. a “clinical trials authorised person”. The identification of such a person could form part of the clinical trials application….

It is unclear whether, under the proposal, a radiopharmaceutical would still be an IMP under clinical trials legislation and so require associated documentation e.g. IMPD, or whether it would be treated as routine radiopharmaceutical manufacture…..

CCRA considers this to be acceptable provided that the hospital, health centre or clinic holds a Specials licence and works to an appropriate level of GMP. There must also be an appropriate level of regulatory oversight to ensure the standards used in the manufacture are equal to those at MIA(IMP) sites (with the exception of QP requirement) so that commercial providers are not at a commercial disadvantage.

The British Nuclear Medicine Society supports the idea that radiopharmaceuticals used in a trial are exempted from the need to hold a Manufacturers Authorisation for IMPs. The Society are concerned about the lack of Qualified Persons (QPs) with expertise in radiopharmaceuticals to release radiopharmaceuticals for use in clinical trials. Although we welcome the proposal to remove the need for an MIA(IMP) and hence the need for QPs for release of diagnostic radiopharmaceuticals, we are concerned that this could have a knock-on effect of further reducing the pool of potential QPs for therapeutic radiopharmaceuticals….

As such there was feedback offering different perspectives and these were taken into consideration during the finalisation of the UK legislation and during the drafting of the supporting guidance.

Note: anonymity of responders has been preserved for individuals, with only details of representative organisations retained where these were stated within the comments section of the submitted response.

An outline of Radiopharmaceutical manufacturing processes and oversight

Radiopharmaceutical sites typically fall into one of two categories within the MHRA inspectorate oversight. The following is a simplified explanation of the differences:

Radiopharmacy sites

Operating radiolabelling of ‘cold’ kit products using the eluate (output) from an authorised generator (a Radionuclide generator). The generator is manufactured in compliance with a Marketing Authorisation and supplied to Radiopharmacy sites in the UK.

• The sterile eluate of the generator is aseptically added to a ‘cold’ (non-radiative) kit to form a new chemical entity, via simple addition and dilution steps that are typically manually processed.  Currently the ‘cold’ kit is typically a commercially licenced sterile product at most MS licenced sites.
• All activities fall under Good Manufacturing Practice (GMP) requirements.

PET sites

These involve the output from a cyclotron accelerator, which generates a highly radioactive, typically short shelf-life starting material. The output from the Cyclotron is considered a starting material and not a precursor. There is no defined substance to which the output of the cyclotron system is added to, and there are no authorised manufacturer’s instructions for use of this output.

• The cyclotron output progresses through a chemical synthesis process, followed by purification typically via ion-exchange chromatography. After this, the final product is diluted and sterilised, typically by passing through a 0.22-micron filter. This is filled into individual units, typically via a small-scale automation process.
• The Cyclotron and output are not covered by GMP, whilst the steps of synthesis, purification and subsequent process steps are covered by GMP

Note: A typical precursor may be for example a Lutetium-177 for radiolabelling - i.e. a vial of radioactive substance that must not be administered to patient without being radiolabelled to a chemical yet are available as standalone products. This could be handled on a Radiopharmacy site where this is utilised within the process in place of the sterile eluate from a generator, with appropriate radiation protection.

The Qualified Person (QP) oversight and release of Diagnostic RP IMP manufactured at MS or MIA licenced sites

A QP must certify that each batch of IMP has been manufactured and checked in compliance with the requirements of EU GMP, the product specification file and the Clinical Trial Authorisation (CTA).

Due to the manufacturing process differences outlined above, the UK GMP and RP guidance, which was generated in response to the update to the UK Clinical Trials legislation, differentiated the controls for these two approaches.

Radiopharmacy Processes

The cold kit is not manufactured at the Radiopharmacy site and can be manufactured and Qualified Person certified at a site holding an MIA(IMP) licence. (Alternatively, the kit may be a licenced product certified by a QP on an MIA licenced site where this is being used in a different way within the trial to that defined within the marketing authorisation.)

This QP certified product can be provided to an MS or MIA licenced site for radiolabelling via the manual addition of the generator eluate, with no further Qualified Person oversight of the final radiolabelled IMP.

• MS licenced sites approved for Radiopharmaceutical activities within the UK do not hold appropriate licences or expertise in the manufacture of the sterile cold kits and these would need to be manufactured at an alternative facility.
• This approach means that QP certification would not be per radiolabelled batch yet would be in place for the entire batch size of the sterile cold kit in advance of radiolabelling.
• This approach has been applied pragmatically to a number of trials already on-going in the UK, prior to the implementation of the updated Clinical Trials legislation. This has been viewed positively by Sponsors who requested this level of support in advance of the legislation.

PET processes

There is no ‘IMP product or intermediate’ provided to the PET site, the IMP is fully manufactured at the PET site.  Due to the low numbers of PET sites holding MIA(IMP) licences, the UK CT regulations (SI 2004/1031) and the GMP and RP guidance document supports the manufacturing to be carried out at MS or MIA licenced facilities authorised for such products. 

However, due to the complexity and need to ensure oversight and compliance with the Clinical Trial Authorisation (CTA) and associated dossiers and files, the involvement of a Qualified Person to carry out batch release was retained as per all IMPs.

• The GMP and RP guidance document indicates that this can be via the MS or MIA licenced site acting as a Contract Manufacturing site to an MIA(IMP) licence holder, where the QP has oversight of the activities at the MS or MIA site and can then perform QP certification.
• Note: QP certification is allowed to be physically remote from the site of manufacture, such as the MS site, but must be prior to administration (see additional details below).

Regulatory requirements and exemptions

Regulation 37 of SI 2004/1031 provides an exemption for hospitals and health centres when carrying out assembly only activities for IMPs.

• Sites are not required to hold an MIA(IMP) licence, and activities are carried out by a doctor, pharmacist, registered pharmacy technician in Great Britain, or person acting under the supervision of a pharmacist.
• This only applies to assembly activities and does not apply to manufacturing activities.
• The material supplied to the hospital or health centre is expected to be a certified product up to the point prior to assembly and in alignment with the Clinical trial Authorisation (CTA) and associated documentation.

This is supported by the MHRA, with details within the Good Clinical Practice (GCP) guide {section 6.2} on exemptions from the need for an MIA(IMP) licence and subsequent Qualified Person certification; where the assembled IMP is to be used in a clinical trial within that hospital or health centre, or another hospital or health centre named as an investigator site within that same trial. 

Regulation 37A provides an exemption for diagnostic radiopharmaceutical manufacture or assembly.

• This disapplies Regulation 36 which is the requirement for an MIA(IMP) licence and hence allows this to be carried out at any MHRA licenced manufacturing facility.

Product Release requirements

Shelf-life considerations with respect to routine Product release:

Medicinal products including Radiopharmaceutical products and Advanced Therapy Medicinal Products (ATMPs) can have short shelf-life requirements, with RP being treated equally alongside ATMPs.

• The exception for investigational radiopharmaceutical products is the allowance of manufacture of diagnostic RP IMPs at a site that holds either an MS, MIA(IMP) or MIA licence via Regulation 37A.  Investigational ATMPs are not exempt and may only be manufactured at sites with an MIA(IMP) licence.
• Both RP and ATMPs require QP certification prior to administration (initial certification), where the final certification can only be completed post administration due to the timeline for completion of all testing (so called two stage certification).
• For radiopharmaceuticals this is confirmed within EU GMP Annex 3 on the Manufacture of Radiopharmaceuticals.
  • Exemptions from the two stage certification has been allowed for Diagnostic RP IMPs manufactured via Radiopharmacy Processes at an MS (or MIA) licenced site as explained in the primary guidance.

Release of Unlicenced Medicines (Specials)

Routine MS licenced site processes for product release of unlicenced medicines (Specials) are carried out by releasing officers under the remit of the individual named as the ‘Quality Control’ person on the MS licence. 

• Release is carried out in conjunction with a review of the production process and against an order from an authorised prescriber. For radiopharmaceutical Specials, this order is typically a high-level request for a specific radiolabelled product by name only, without any instructions or specification beyond a requested dose.
• Any deviations in the manufacturing process, or from the specification or order requirement, may still be accepted if the originating authorised prescriber accepts the deviations.
• There is no quality system or process within an MS licenced facility to ensure that a manufactured product would meet the requirements of a CTA or IMP Product Specification File as required by SI 2004/1031.

Radiolabelled diagnostic Investigational Medicinal Products

These products remain an IMP and would need to be manufactured in line with an approved CTA. The purpose of an investigational medicine (IMP) being used within a clinical trial is not the same as those manufactured under an MS licence to treat a patient, in that it is governed by ICH guidelines, in particular E6 (GCP) and E8.

So in addition to appropriate safety considerations in administrating the IMP to a trial participant, for example a healthy volunteer or patient, the primary purpose of a clinical trial is the collection of data with sufficient integrity in a robustly controlled setting so that the outcome  can be used to fulfil a research aim or objective, and by extension support future full commercial development and marketing authorisation applications to bring novel medicines to market and provide new therapeutic options for patients. 

The existing framework for MS licenced facilities oversight provides an assessment of compliance of general Good Manufacturing Practice and Radiation requirements, which is why manufacturing is supported, but does not address the validity, management or governance of clinical trials because not all aspects of the required IMP quality systems are in place or required at MS licenced facilities.

Deviations that may be acceptable for an unlicenced medicine (Special) under the responsibility of the prescriber may affect the integrity of the data and results for clinical trials and as such would not be appropriate for an IMP.