Guidance

Common issues: Pharmaceutical

Updated 6 November 2023

An IMPD, together with other supporting documentation such as labelling, manufacturer’s authorisations and a QP declaration on GMP equivalence to EU GMP, should accompany each 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 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. Guidelines on the content requirements of the dossier can be found on the EudraLex website.

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. 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, a full drug substance section of the IMPD should be provided, 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. Copies of spectra should be provided.

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 frequently either missing from the dossier entirely, are deemed to be inadequate or insufficient interpretation of the data has been provided. In each of these circumstances, a GNA point will be raised and the applicant asked to provide additional data or further interpretation.

2. 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, a tabulated summary of the results should be provided. It should be noted that there is no requirement for the inclusion of a full validation report and this should not be provided. CTA applications should be supported by summaries of data rather than full reports.

3. 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. Batch analysis data for each company listed in the IMPD as a proposed site of manufacture for drug substance and for drug product should be provided. 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, batch analysis data will be required for each site of clinical manufacture and, for early phase trials that are often characterised by a limited number of batches, results for relevant non-clinical batches should also be provided. Further details can be found 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, requesting the provision of these data.

4. 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 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, limits for impurities should be justified based on safety and toxicity data. This section of the IMPD should also be used to justify the absence of control over certain characteristics of the substance or product that might otherwise be expected.

It is important that justifications for the specifications are provided so as to ensure that the trial 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.

5. Retest Period

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, a re-test period based on the available stability data should be included in the IMPD. Extrapolation may be used in the setting of the re-test period.

Where the drug substance continues to meet its approved specification and where the proposed re-test period is matched by acceptable real time stability data, no substantial amendment will be required to extend the re-test period. These provisions also apply to setting the shelf life for a biological and biotechnological drug substance (see section S.7 of the Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials).

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. Where stability data are absent or considered insufficient, a GNA point will be raised asking for these to be provided. Where no retest period/shelf life has been clearly and unambiguously proposed, a GNA point will be raised asking the applicant to propose and justify this.

Applicants should note that it is a shelf life that applies to biologically- and biotechnologically-derived drug substances rather than a retest period. Applicants should further note that retest periods should not be applied to drug products; a shelf life should be used.

6. Shelf Life

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 that a shelf life based on available stability data be set. Extrapolation may be used. The guideline also states that where an acceptable shelf life extension plan is included in the IMPD, no substantial amendment will be required to extend the shelf life of the drug product.

An acceptable shelf life extension plan should comprise:

• the specification against which the product is tested
• the criteria used to extrapolate data
• an analysis of trends
• the proposed extension based on available real time data and acceptable accelerated data – this should not exceed four times the available real-time data to a maximum of 12 months or 12 months plus the available real-time data. The same principles can be applied to biological and biotechnological products where an acceptable shelf life extension plan should comprise:
• the specification against which the product is tested
• the proposed extension based on available real time data

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, a GNA point will be raised asking for these to be provided. Where no shelf life has been clearly and unambiguously proposed, a GNA point will be raised asking the applicant to propose and justify this.

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 applicant to provide clarification or amend the proposal.

7. TSE/BSE certification

Sponsors are required to 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, the applicant will be asked to provide further information; this will be raised as a GNA point. 8. 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)). 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) should be provided. Similarly, copies of the MIA(IMP)s should be provided 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, copies of the relevant manufacturer’s authorisation(s) and QP declaration (if applicable) should be provided 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. Any alternative sites that will not be used for the proposed trial should be removed from the dossier. If a copy of the MIA(IMP) has not been provided for a site listed in the IMP dossier, a GNA point will be raised and the applicant required to submit a copy of the document. It should be noted that a full copy of the MIA(IMP) should be provided; 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, a copy of the MIA (IMP) should be provided.

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, this should be made clear in the CTA application.

8. 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. A QP declaration should be provided 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, a QP declaration should be provided 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 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; any alternative sites that will not be used for the proposed trial should be removed 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 the document to be revised and re-submitted.

9. Labelling

Samples of labelling text should be included 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, a GNA point will be raised asking the applicant to provide clarification or amend the trial labelling.