The final EMA Guidelines (Rev. 2) on the quality requirements for pharmaceutical and biological investigational medicinal products (IMPs) have been released on the EMA website together with an overview of comments received on the draft guidelines published last year. The date of coming into effect was 31 January 2022, which is also the application date of the Regulation (EU) No. 536/2014 on clinical trials (CTR).
According to the agency, it should be clearly differentiated between the requirements for an Investigational Medicinal Product Dossier (IMPD) for a clinical trial (CT) and a marketing authorization dossier. Information to be provided for IMPs should focus on the risk aspects and should consider the nature of the product, the state of development / clinical phase, patient population, nature and severity of the illness as well as type and duration of the CT.
Scope of the guidelines
The guideline provides the documentation requirements on the chemical and pharmaceutical quality of IMPs and Auxiliary Medicinal Products (AxMPs) containing
- chemically defined drug substances (DS),
- synthetic peptides & synthetic oligonucleotides,
- herbal substances & herbal preparations,
- chemically defined radioactive / radio-labelled substances.
Requirements for IMPs and AxMPs to be tested in phase I – IV studies as well as the requirements for comparators and IMPs to be tested in generic bioequivalence studies are included. Guidance on standard information which should usually be presented in the quality part of an IMPD is provided (for certain situations, e.g. where the DS from the specific source to be used for an IMP is already included in a medicinal product authorized within the EU a simplified IMPD will suffice). In addition, examples are provided for changes to IMPs, containing chemically defined or herbal DS, and their classification (e.g., Substantial Modification (SM), Non-substantial Modification (NSM)).
The guideline addresses the specific documentation requirements on the biological, chemical and pharmaceutical quality of IMPs containing biological / biotechnology derived substances and applies to proteins & polypeptides (produced from recombinant or non-recombinant cell-culture expression systems), their derivatives, and products of which they are components (e.g. conjugates). Moreover, the guideline lists examples of modifications which are typically considered as “substantial”. The guideline also applies to AxMPs containing proteins & polypeptides as active substances. The principles may also apply to other product types such as proteins & polypeptides isolated from tissues and body fluids. However, Advanced Therapy Medicinal Products (ATMPs) are out of scope.
GMP for IMPs
In general, all IMPs should be produced in accordance with the principles and the detailed guidelines on Good Manufacturing Practices (GMP) for IMPs (EU GMP Guide, Annex 13).
Overview of Comments
Many of the comments received related to the question “What is a SM / NSM?”. Some of the comments addressed, for example, the following topics:
- “Further clarification regarding the difference between a non-substantial change and a non-substantial modification (NSM) would be appreciated.“
It has been clarified that non-substantial changes relevant to the supervision of the trial are a concept introduced under the CTR (Art. 81.9 non-substantial modifications), which aims to update information in the CTIS (Clinical Trials Information System) without the need for a substantial modification application, when this information is necessary for oversight but does not have a substantial impact on patients’ safety and rights and / or data robustness. “The sponsor shall permanently update in the EU database information on any changes to the clinical trial which are not substantial modifications but are relevant for the supervision of the clinical trial by the Member states concerned”.
- “The change of an importing site that does not perform QP release should be reported as NSM.”
It has been clarified that addition or replacement of an importation site that is not a QP certification site is a NSM.
- The proposal that the “replacement or addition of a testing or packaging site could be considered as non-substantial change” has been rejected (GMP compliance of all packaging and QC testing sites has to be checked). Thus, addition or replacement of manufacturing, packaging, or testing site remains a SM.
- The proposal for adding “Addition of a new size of the existing container closure system” (e.g. additional bottle sizes) to the examples for amendments to the container closure system under “non-substantial” has been rejected (this type of change could be considered as a SM in specific cases).
For further information please see the two EMA guidelines (Rev. 2) on the requirements to the chemical and pharmaceutical quality documentation concerning IMPs and on the requirements for quality documentation concerning biological IMPs.