On 13 December 2019, the European Medicines Agency (“EMA”) published a Questions and Answers document (“Q&A”) providing guidance on the conduct of comparability exercise for advanced therapy medicinal products (“ATMPs”). The Q&A addresses various regulatory questions that arise in situations in which companies developing or marketing ATMPs introduce changes to the manufacturing process and need to generate related comparability data.
EMA’s experience suggests that changes to the manufacturing of ATMPs are “frequent” and even more so in the development of the medicinal product. These changes need, however, to be introduced in accordance with the Good Manufacturing Practices (“GMP”). Moreover, the changes may require a variation of the marketing authorisation for authorised ATMPs or substantial amendments to the clinical trial protocol for ATMPs used in clinical trials.
In addition, the changes to the manufacturing of the ATMP must be supported by the data generated in a comparability exercise. This exercise should focus on the characteristics of the ATMP prior and after the introduction of the manufacturing change. This is valid for both investigational ATMPs and authorised ATMPs.
The position of the EMA is that changes to the manufacturing of the ATMP should not undermine or impact adversely the quality, efficacy or safety of the medicinal product or the related risk-benefit balance. The objective of the comparability exercise is to facilitate the assessment and demonstration of this.
The Q&A provides answers to general regulatory questions, as well as specific guidance for cell-based ATMPs and vector-based gene therapy medicinal products. The position of the EMA is that the comparability exercise for cell-based ATMPs cannot be based solely on the characterisation of the phenotypic markers related to purity confirming a heterogeneity profile. The comparability assessment for this type of ATMPs should, therefore, cover the dynamic nature of the product and the mechanisms relating to the product’s metabolism, differentiation stage, structural organisation and interactions.
Interplay with ICH Q5E
The ICH Q5E guidance issued by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (“ICH”) addresses the comparability of biotechnology and biological medicinal products. This guidance does not, however, apply to ATMPs due to the inherent variability of the starting materials for cell/tissue-based products, as well as the complex biological features and manufacturing processes of the ATMPs in general.
The general principles of ICH Q5E do, however, apply to the conduct of the comparability exercise for ATMPs:
- stepwise conduct of the comparability exercise;
- focus on the manufacturing process steps that are most appropriate top detect change;
- use of suitable and sufficiently sensitive analytical methods;
- generation of data enabling to reach a conclusion on the comparability.
EMA clarifies that the ICH Q5E guidance is particularly relevant for vector-based gene therapies as they are more closely related to biotechnology medicinal products in terms of manufacturing process.
Other key elements of the Q&A
The Q&A highlights a number of additional key considerations for the conduct of the comparability exercise:
- requirement to conduct a comparability exercise for any changes to the manufacturing process of the ATMP occurring at any stage of the development, including introduction of new manufacturing site;
- use of the risk-based approach in the determination of the amount of comparability data that needs to be generated:
- high risk changes or changes to the manufacturing of authorised ATMPs or ATMPs in pivotal clinical trials require the generation of more comparability data;
- only critical changes to the manufacturing of the starting material with impact on the manufacturing of the finished product require the conduct of a comparability exercise.
- requirement to compare both the manufactured products and the manufacturing processes themselves;
- use of appropriate analytical tools for the comparability exercise;
- preferred approach for the comparability exercise:
- side by side testing vs comparison of post-change data with pre-change historical data.
- potential use of healthy donors’ materials;
- need for stability studies and acceptability of statistical approaches;
- determination of the number of batches to be used in the comparability study.
As a general rule, the EMA discourages companies to introduce changes to the manufacturing process or the final ATMP during the conduct of clinical pivotal clinical trials. This is due to the complexity of the comparability exercise in such situations and the potential impact on the validity of the clinical data. If the changes are unavoidable, companies are advised to seek the EMA’s scientific advice.