The European Medicines Agency (EMA) has published two draft guidelines on quality requirements for investigational medicinal products (IMPs). According to the EMA, the documents are to be seen in connection with the Clinical Trials Regulation (EU) No. 536/2014 (CTR). It is expected that the CTR will become applicable in January 2022. Comments regarding the two EMA draft guidelines should be sent to EMA by 31 August 2021.
According to the Agency, clinical trials will often be designed as multi-centre studies, potentially involving different EU Member States. Thus, it is the aim of the two draft guidelines to define EU harmonized documentation requirements. In general, IMPs should be produced in accordance with the GMP guidelines for IMPs (EU GMP Guide, Annex 13). Recently, the WHO published a second draft version of the WHO´s GMP for IMPs. The WHO deadline for comments is 31 August 2021.
Quality documentation for IMPs (small molecules)
The draft guideline contains required information for
APIs (Active Pharmaceutical Ingredient, Drug substance),
Auxiliary Medicinal Products,
Drug Substance - DS
Information on Validation
Process validation and / or evaluation is not applicable for DSs to be used in clinical trials.
Analytical procedure validation: Phase I The suitability of the analytical methods used should be confirmed. The acceptance limits (e.g. for the determination of the impurity content) and the validation parameters (i.e. specificity, linearity, range, accuracy, precision, quantification and detection limit) should be presented in a tabulated form. Phase II and III The suitability of the analytical methods used should be demonstrated. A tabulated summary of the results for the validation parameters should be provided. However, it is not necessary to provide a full validation report. For DSs which comply with a Ph. Eur., USP or JP monograph, reference to the relevant monograph will be sufficient.
Information on Stability
The stability data available at the respective development stage should be summarized in a table. Critical stability parameters (e.g. photosensitivity, hygroscopicity) need to be presented and potential degradation pathways should be described. For DSs covered by a pharmacopoeial monograph, confirmation that the DS will meet specifications at time of use will be acceptable. The retest period should be defined based on the available stability data and should be clearly stated. Otherwise, a statement should be included that the DS is tested immediately before the drug product manufacture.
Investigational medicinal Product - IMP
Information on Validation
Process validation and / or evaluation: Data are not required during the development phases, i.e. clinical phases I to III, except for non-standard sterilization processes not described in the Ph. Eur., USP or JP. In this case, the critical manufacturing steps, the validation of the manufacturing process as well as the applied in process controls should be described.
Analytical procedure validation: The same requirements as for the DS are applied.
Information on the container closure system (CCS)
For dosage forms that have a higher potential for interaction between product and CCS (e.g. parenterals, ophthalmic products, oral solutions), details on, for example, extractables & leachables may be required for phase III studies. For dosage forms where an interaction is unlikely, e.g. solid oral dosage forms, a justification for not providing any information may suffice.
Information on Stability
The shelf-life and storage conditions should be defined based on the stability profile of the DS and the available data on the IMP. Extrapolation may be used, provided that stability studies are conducted in parallel to the clinical studies and throughout its entire duration. Bracketing and matrixing may be acceptable, where justified. Phase I It should be confirmed that an ongoing stability program will be carried out with the relevant batch(es) and that, prior to the start of the clinical trial, at least studies under accelerated and long-term storage conditions will have been initiated. Phase II and III The available stability data should be presented in a tabulated form. An evaluation of the available data and justification of the proposed shelf- life should be provided. Data should include results from studies under accelerated and long-term storage conditions.
Quality documentation for biological IMPs (large molecules)
The requirements outlined in the draft document apply to IMPs containing biological / biotechnology derived substances, such as:
Proteins and polypeptides, their derivatives, and products of which they are components (e.g. conjugates),
Auxiliary Medicinal Products containing proteins and polypeptides as active substances,
Other product types such as proteins and polypeptides isolated from tissues and body fluids.
Advanced Therapy Medicinal Products (ATMPs) are excluded from this guideline.
Process validation Active substance: Data should be collected throughout development, although they are not required to be submitted in the IMPD. IMP: The state of validation of aseptic processing and lyophilization should be briefly described. The validation of sterilizing processes should be of the same standard as for product authorized for marketing. The dossier should particularly include information directly relating to the product safety, i.e. on bioburden and media fill runs.
Analytical procedure validation Phase I and II The suitability of the analytical methods should be confirmed. Acceptance limits (e.g. for the determination of the impurity content) and the validation parameters (i.e. specificity, linearity, range, accuracy, precision, quantification and detection limit) should be presented in a tabulated form. If validation studies have been undertaken for early phase trials, a tabulated summary of the results of analytical method validation studies could be provided for further assurance. Phase III Validation of analytical methods used for release and stability testing should be provided. A tabulated summary of the results of the validation carried out should be submitted (e.g. results or values found for the validation parameters). By the end of phase III full method validation must be completed, including confirmation of robustness. However, it is not necessary to provide a full validation report.
Information requested for stability: - Stability protocol, - Stability results, - Shelf-life determination (including extension of shelf-life beyond the period covered by real-time stability data), - Stability commitment, - Post-approval extension.
The methods used for analyzing the stability-indicating properties should be discussed. A re-test period (as defined in ICH Q1A) is not applicable for the active substance. The relevant stability data should be summarized in a tabular format. By phase III the applicant should have a comprehensive understanding of the stability profile. The same requirements as for the active substance apply to the medicinal product. The presented data should justify the proposed shelf life of the product from its release to its administration. The stability protocol for the IMP should take into account the stability knowledge of the active substance. Bracketing and matrixing may be acceptable, where justified. In-use stability data should be presented for preparations intended for use after reconstitution, dilution, mixing or for multidose forms (not required if the preparation is to be used immediately after opening or reconstitution).