IMPD: EMA provides further Clarification for Quality of IMPs

The European Medicines Agency EMA has published a set of new Questions and Answers regarding the quality of Investigational Medicinal Products (IMPs).

The respective Question and Answer page is developed and maintained by the joint CHMP/CVMP Quality Working Party (QWP), and addresses a number of questions that have been brought to the attention of QWP by Marketing Authorisation Holders (MAHs) and/or EEA Competent Authorities, on matters related to quality of medicinal products. It provides the EEA harmonised position on issues that can be subject to different interpretation or require clarification, typically arising from discussions or correspondence during assessment procedures.

The structure of the chemical and pharmaceutical data to be submitted in the Investigational Medicinal Product Dossier (IMPD) is described in the "Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments and declaration of the end of the trial". However the document provides no guidance on the required detail of information. Guidance on standard information which should normally be presented in the quality part of an IMPD is provided in the Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation concerning Investigational Medicinal
Products in Clinical Trials (CHMP/QWP/185401/2004). The new set of questions mainly refers to the latter one.

Here is an overview on the new Q&As:

Q: On which basis should specifications for related impurities be set?

A: Safety considerations should be taken into account. The limits should be supported by the impurity profiles of batches of active substance used in non-clinical and clinical studies. Results between batches should be consistent (or the clinical batches should show better purity results than non-clinical and previous clinical batches). Compliance with ICH requirements is not required, if proper justification is provided.

Where specifications are set for potential genotoxic impurities, the guidance given in EMEA/CHMP/SWP/431994/2007

Q: How should industry notify amendments?

A: The table in the Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation Concerning IMPs in Clinical Trials (CHMP/QWP/185401/2004) gives examples of what should be notified as substantial amendments and of changes where a notification will not be necessary. The list is not exhaustive, and the Sponsor should decide on a case-by-case basis if an amendment is to be classified as substantial or not.

Substantial amendments should be notified using the Notification of Amendment Form. Relevant updated sections of the documentation should be submitted, not the entire Quality Investigational Medicinal Product Dossier (IMPD).
For non substantial amendments documentation should not be proactively submitted, but the relevant internal and study documentation supporting the change should be recorded within the company and if appropriate, at the investigator site.  At the time of an overall IMPD update or submission of a Substantial Amendment the non-substantial changes can be incorporated into the updated documentation. There is no need to use the Notification of Amendment Form for these changes.

Q: Are drug substance and drug product batch data for all proposed manufacturing sites listed required to be submitted in the IMPD?

A: No, tabulated batch results are sufficient. Data for representative batches should be included in the batch analysis table of the IMPD. Results for batches controlled according to previous, (wider) specifications are acceptable if the results comply with the specification for the planned clinical trial. The results should cover the relevant strengths, but the batches do not need to be the same that will be used in the clinical trial.

Wolfgang Schmitt
CONCEPT HEIDELBERG (a service provider entrusted by the ECA Foundation)