Guidance

Common issues: Pharmaceutical

Updated 12 January 2026

An investigational medicinal product dossier (IMPD), together with other supporting documentation such as labelling, manufacturer’s authorisations and a Qualified Person (QP) declaration on Good Manufacturing Practice (GMP) equivalence to European Union (EU) GMP, should accompany each Clinical Trial Authorisation (CTA) application. On a case by case basis, this may be a full dossier or a simplified dossier. Information on when a simplified dossier can be used is available in guidance from the European Commission.

Current relevant guidance (such as CT-1) remains applicable as the best source of material for understanding the requirements of the CTA submission package (whilst considering the UK as a standalone regulator).

The Quality section of the IMPD should include information and data describing the manufacture, characterisation, testing, control and stability of the drug substance (active ingredient) and drug product.

Separate guidelines are available for products containing chemically-defined active ingredients and for those containing biologically- or biotechnologically-derived active ingredients. However, despite the availability of these guidelines, a number of common deficiencies relating to the Quality section of the dossier have been identified.

Reference to an Active Substance Master File (ASMF) is not permitted for a CTA application, except where the ASMF has been previously assessed and authorised, in relation to a MAA, by an EU member state competent authority.

Note that if the active substance used is already authorised in a drug product within the EU/EEA or in one of the ICH-regions, reference can be made to the valid marketing authorisation, instead of submitting the ASMF. You should give the name of the drug product, marketing authorisation number or its equivalent, marketing authorisation holder and the country that granted the marketing authorisation should be given. If these conditions do not apply, you should provide a full drug substance section of the IMPD, in accordance with the guidelines.

1. Characterisation data

The IMPD must include data elucidating the structure and other physicochemical and/or biological characteristics of the drug substance, in accordance with the relevant guidelines.

Section 2.2.1.S.3.1 of the Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials requires the structure of chemically-defined substances to be established with suitable methodology and relevant data to be provided. You should provide copies of spectra.

Section S.3 of the Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials describes the characterisation data required for biological products. This guideline further requires that if the manufacturing process of a biological has changed during development, comparability data will be required to ensure that the changes have not had an adverse impact on clinical characteristics of the product (see section S.2.6 of the guideline).

Characterisation data are often either missing from the dossier entirely, or we consider them to be inadequate or that insufficient interpretation of the data has been provided. In each of these circumstances, we will raise a deficiency point and the applicant will be asked to provide additional data or further interpretation.

2. Impurities

Sections 2.2.1.S.3.2 and 2.2.1.P.5.5 of the IMPD should provide information about potential impurities of the drug substance and drug product, respectively. A common deficiency found in CTA submissions is where insufficient information is provided about impurities.

For a drug substance, where a pharmacopoeial monograph cannot be referenced, information about impurities (including process-related impurities, product-related impurities, residual solvents etc) is required.

For a drug product, information about any additional impurities and degradation products is required.

Information is also required about any mutagenic impurities that could be present in the drug product, in line with the scope and requirements of ICH M7. This includes ‘cohort of concern’ impurities, such as those containing N-nitroso- structures (nitrosamines), which could be present or form in drug substances and drug products.

As a minimum, a summary of a nitrosamine risk assessment should be included in the IMPD, which should have considered the key areas of risk for both the drug substance (such as its route of synthesis, starting materials, solvents, reagents, catalysts, impurities, intermediates, packaging etc) and drug product (such as its manufacturing process, impurities, intermediates, excipients, packaging etc).

This is required at all phases of clinical development, although it is recognised that the depth of such assessments may be limited during early development. In cases where a risk of presence/formation of a nitrosamine impurity is identified, the risk assessment should be submitted in full for assessment, and additionally include information about the potential risk to trial participants, the risk mitigation steps taken and any control limits introduced.

3. Sterilisation and bioburden control

Sterility is a critical quality attribute for all sterile drug substances, drug products and containers. Sterility cannot be assured by testing alone, and needs to be assured by the use of a suitably designed, validated and controlled manufacturing process.

Sterility is achieved by controlling several factors such as the bioburden, the sterilisation procedure, the integrity of the container closure system, and in the case of aseptic processing, the use of satisfactory aseptic technique.

For highly sensitive products, where terminal sterilisation of the finished product is not possible, use of sterile filtration and/or aseptic processing under validated and controlled conditions can be accepted.

Where sterile filtration is used for this purpose, the integrity of the sterilising filter should as a minimum be verified by online testing immediately after use. Nominal pore sizes of 0.22µm or less are acceptable without further justification.

Bioburden testing should be performed on the bulk solution immediately before final sterile filtration.

In most situations, a limit of NMT 10CFU/100ml (or equivalent for smaller batch sizes) would be acceptable for bioburden testing. Alternative bioburden control regimes must be robustly justified.

4. Batch analysis data

Sections 2.2.1.S.4.4 and 2.2.1.P.5.4 of the Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials require the provision of representative batch analysis data in order to demonstrate that each manufacturer can produce batches at the proposed scale, according to the method described in the IMPD, and to the agreed specifications.

You should provide batch analysis data for each company listed in the IMPD as a proposed site of manufacture for drug substance and for drug product. In this context, a company is regarded as a legal entity.

It may be possible to provide data for batches that have been produced at a different scale or using a modified method. In such circumstances, the IMP dossier should include a justification that these batches are representative of the clinical trial material.

In the same way, a substantial amendment supported by batch analysis data will have to be submitted and approved prior to the inclusion of manufacturing sites which represent a new company (legal entity).

For biological and biotechnological products, you must provide batch analysis data for each site of clinical manufacture. For early phase trials that are often characterised by a limited number of batches, you should provide results for relevant non-clinical batches.

Further details are available in sections S.4.4 and P.5.4 of the Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials.

Failure to include batch analysis data for all manufacturing sites listed in the IMPD will result in a GNA point being raised, asking you to provide these data.

5. Drug substance retest period or shelf life

For chemical drug substances, section 2.2.1.S.7 of the Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials requires the provision of stability data summarised in a tabular format.

To ensure that the drug substance complies with its specification at the time of manufacture of the drug product, you should include a re-test period based on the available stability data in the IMPD. Extrapolation may be used in the setting of the re-test period.

For biologically and biotechnologically derived (biological) drug substances, the general principles for chemical drug substances apply. However, the Sponsor should note that it is a shelf life that applies to biological drug substances rather than a retest period. Section S.7 of the Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials provides further information. 

The retest period or shelf life can be extended without a substantial amendment if you provide:

• a stability protocol
• a retest period or shelf life extension plan
• a statement that in case of any significant negative trend the Sponsor will inform the competent authority 

The stability protocol should cover the maximum planned retest period or shelf life. In situations where a retest period or shelf life extension plan has been proposed but is insufficiently detailed or is unacceptable, we will raise a GNA point requiring the sponsor to provide clarification or amend the proposal.

The common deficiencies relating to stability of the drug substance are the absence of stability data and/or the absence of a proposed retest period or shelf life. Where stability data are absent or considered insufficient, we will raise a GNA point asking you to provide these. Where no retest period or shelf life has been clearly and unambiguously proposed, we will raise a GNA point asking the Sponsor to propose and justify one.

While there is no requirement to include a retest period or shelf life extension plan in the IMPD, we encourage the Sponsor to submit one, wherever possible, to negate the requirement to submit a substantial amendment.

6. Drug product shelf life

For drug products containing chemical drug substances, Section 2.2.1.P.8 of the Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials requires the provision of stability data summarised in a tabular format. A shelf life based on the stability profile of the drug substance and available stability data should be included in the IMPD.

For drug products containing a biological drug substance, the general principles above apply. Section P.8 of the Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials provides further information.

The Sponsor should further note that they should not apply retest periods to drug products. They should use a shelf life.

The shelf life can be extended without a substantial amendment. You should provide:

• a stability protocol
• a shelf life extension plan
• a statement that in case of any significant negative trend, the Sponsor will inform the competent authority 

The stability protocol should cover the maximum planned shelf life. In situations where a shelf life extension plan has been proposed but is insufficiently detailed or is unacceptable, a GNA point will be raised requiring the Sponsor to provide clarification or amend the proposal.

As for the drug substance, the common deficiencies relating to stability of the drug product are the absence of stability data and/or the absence of a proposed shelf life.

Where stability data are absent or considered insufficient, we will raise a GNA point asking you to provide these.

Where no retest period or shelf life has been clearly and unambiguously proposed, we will raise a GNA point asking the Sponsor to propose and justify one.

While there is no requirement to include a shelf life extension plan in the IMPD, we encourage the Sponsor to submit one, wherever possible, to negate the requirement to submit a substantial amendment.

7. Method validation data

Sections 2.2.1.S.4.3 and 2.2.1.P.5.3 of the Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials and section S.4.3 of the Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials require that a tabulated summary of the results of the validation of analytical methods used in the control of the drug substance and drug product is included in the IMPD for phase II and III trials.

These data are required in order that the applicant demonstrates that the analytical methods are suitable for their intended purpose and that confidence can be held in the batch release and stability data.

For phase I trials, it is sufficient to confirm the suitability of the analytical methods used and provide the acceptance limits and parameters for performing validation of the analytical methods in tabulated form.

However, if analytical validation has already been carried out, you should provide a tabulated summary of the results. Note that there is no requirement for the inclusion of a full validation report. You should not provide this. You should support CTA applications with summaries of data rather than full reports.

8. Justification of specifications

Sections 2.2.1.S.4.5 of the [Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials](https://www.ema.europa.eu/en/requirements-chemical-pharmaceutical-quality-documentation-concerning-investigational-medicinal-products-clinical-trials-scientific-guideline and sections S.4.5 and P.5.6 of the Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials require the Sponsor to provide a brief justification for the specifications, acceptance criteria and methods used to control the quality and safety of the drug substance and drug product. In particular, you should justify limits for impurities based on safety and toxicity data.

You should also use this section of the IMPD  to justify the absence of control over certain characteristics of the substance or product that might otherwise be expected.

You must provide justifications for the specifications so as to ensure that the Sponsor has considered all potential quality attributes of the active ingredient and formulation that may impact on the safety and/or efficacy of the drug product.

The absence of this information will result in a GNA point requiring the applicant to provide a justification for all proposed specification limits and/or to justify the absence of control over certain characteristics.

9. QP declaration

A QP must provide a declaration regarding the equivalence to EU GMP for IMPs, including active and placebo comparators manufactured in third countries that are not on the approved country list.

The QP declaration is usually signed by a QP named on the manufacturer’s authorisation of the importer but may be signed by a QP at the batch release site if this is different.

In such cases, a copy of the manufacturer’s authorisation for the batch release site is also required.

You should provide a QP declaration for any third-country sites involved in the manufacture, which includes assembly (packaging and/or labelling) of unauthorised drug products and/or comparator products (including placebos).

Similarly, you should provide a QP declaration for authorised drug products and/or comparator products if the third-country sites are not already included in the marketing authorisation. The QP declaration should be trial and product specific and presented in line with the QP declaration template.

A common deficiency relating to the QP declaration is the absence of some third-country sites listed in the IMP dossier from the declaration.

As noted above, the IMPD should list only sites involved in the manufacture of the IMP for the trial for which it has been submitted.

You should remove any alternative sites that will not be used for the proposed trial from the dossier. In addition, QP declarations are frequently submitted that are non-specific in terms of either the trial or product or both.

Where there are deficiencies in the QP declaration, a GNA point will be raised requiring you to revise and resubmit the document.

10. TSE/BSE certification

Sponsors must provide information relating to the avoidance and control of transmissible spongiform encephalopathy (TSE) agents within the CTA application. This can be provided as an appendix to the IMPD or as a separate document.

This information can include, for example, certification and control of the production process, as appropriate for the material, process and agent. Documentation should be provided for all relevant materials, including reagents used during manufacture as well as active ingredients and/or excipients included in the drug product.

The Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products, EMEA/410/01 in its current version is to be applied.

Where no information has been provided or the documentation is considered insufficient to address the TSE/BSE concern, we will ask the applicant to provide further information. This will be raised as a GNA point.

11. Manufacturer’s authorisation

The manufacture, which includes assembly (packaging and/or labelling), of an IMP can only be undertaken by the holder of an authorisation for the manufacture of IMPs (often referred to as an MIA(IMP)).

You should provide copies of the MIA(IMP)s for all UK and EU sites involved in the manufacture (including packaging and/or labelling) and/or importation and/or batch certification of unauthorised drug products and/or comparator products (including placebos).

Similarly, you should provide copies of the MIA(IMP)s for authorised drug products and/or comparator products if the EU sites are not already included in the marketing authorisation.

For a cross-referral to the IMPD of a previously approved CTA application, you should provide copies of the relevant manufacturer’s authorisation(s) and QP declaration (if applicable) since these are study specific.

Provision of these documents provides evidence that the sites involved in the manufacture of the IMP are suitable to carry out such activities. 

CTA applications are frequently deficient in terms of the provision of copies of the MIA(IMP) for all sites involved. The IMPD should list only sites involved in the manufacture of the IMP for the trial for which it has been submitted and a copy of the MIA(IMP) for each site provided. You should remove any alternative sites that will not be used for the proposed trial from the dossier.

If a copy of the MIA(IMP) has not been provided for a site listed in the IMP dossier, we will raise a GNA point and the applicant must submit a copy of the document.

Note that you should provide a full copy of the MIA(IMP). The abbreviated version available on EudraGMP is generally not acceptable.

It should be noted that if a Certificate of GMP compliance of a manufacturer is not accepted. You should provide a copy of the MIA (IMP).

Further information is available on Importing Investigational Medicinal Products (IMP) into Great Britain from countries on an approved country for import list.

Applicants may also wish to note that where assembly is carried out in a hospital or health centre by a doctor, a pharmacist or a person acting under the supervision of a pharmacist and the IMP is assembled exclusively for use in that hospital or health centre, or any other hospital or health centre which is a trial site for the clinical trial in which the product is to be used, the site does not require a manufacturer’s authorisation. If this scenario applies, you should make this clear in the CTA application.

12. Labelling

You should include samples of labelling text in the CTA application for all IMPs, including active and placebo comparators. The labelling text should comply with the requirements defined in Annex 13 of the EU guideline to Good Manufacturing Practice.

Any deviations from Annex 13 should be justified. Where a Sponsor wishes to claim an exemption from the need for specific trial labelling under the provisions of Regulation 46 of SI 2004 No 1031, a statement to this effect has to be included in the application.

The most frequent deficiency relating to product labelling is the absence of a justification either for deviations from Annex 13 requirements or for the use of standard dispensing labels in place of specific trial labelling.

Under both circumstances, we will raise a GNA point asking the applicant to provide clarification or amend the trial labelling.