# Production of ATMPs: What are the specificities for quality aspects ?

Aurélie Mahalatchimy, Éloïse Gennet, Michael Morrison, Véronique Andrieu,
Julie Veran, Florence Sabatier

► To cite this version:

Aurélie Mahalatchimy, Éloïse Gennet, Michael Morrison, Véronique Andrieu, Julie Veran, et al. Production of ATMPs: What are the specificities for quality aspects?. European Society for Gene & Cell Therapy Congress 2022, Oct 2022, Edinburgh, United Kingdom. MARY ANN LIEBERT, INC140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801, 33 (23-24), pp.A196-A197, 2022. halshs-03901462

HAL Id: halshs-03901462

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Submitted on 15 Dec 2022

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# Production of ATMPs:
## What are the specificities for quality aspects?

Aurélie Mahalatchimy<fnref n="1" />, Eloïse Gennet², Michael Morrison³, Véronique Andrieu⁴, Julie Véran⁵, Florence Sabatier⁶

## INTRODUCTION

Advanced Therapy Medicinal Products (ATMPs) is a European classification of medicinal products based on genes, cells and tissues that have been specifically regulated in the European Union (EU) from 2007. Their manufacturing (i.e. their production) raises specific challenges for ensuring quality and complying with regulatory requirements in order to obtain manufacturing and marketing authorizations. Hence, on top of its **guideline on the manufacturing of Biological active substances and Medicinal Products for Human Use** (26 June 2018, 25 pages revised to consider the new ATMP guidelines), the European Commission also issued **Good Manufacturing Practice specific to Advanced Therapy Medicinal Products** (22 November 2017, very detailed text of 90 pages).

Our hypothesis is that the biological nature that commonly characterizes ATMPs and biologicals may give rise to significant similarities in the manufacturing aspects as addressed by the respective guidelines. Through a comparative textual analysis of the GMP guidelines for biological medicinal products and ATMPs, this poster will highlight the key areas of similarities and differences. This analysis reveals why we have two different texts and whether they are based on substantial differences regarding production between ATMPs and other types of biological medicinal products.

## SPECIFICITIES OF BIOLOGICALS VERSUS ATMPs

<table><thead><tr><th></th><th>ATMPS</th><th>BIOLOGICALS</th></tr></thead><tbody><tr><td>Specific risks</td><td colspan="2">as presented in the scopes and general principles of each text</td></tr><tr><td>Specificities for manufacturing</td><td colspan="2">Specificity of the scope and general principles of each text</td></tr><tr><td>Stages to be considered</td><td>from raw material to final production</td><td>from raw material to active substance</td></tr><tr><td>Appropriate measures of quality control</td><td>Complexity of products & processes, limited batch series, variability of starting materials (especially in autologous setting) > Flexibility and "Risk-based approach"</td><td>Procurement and quality of starting materials of animal origin, mitigation of a higher risk of low purity and microbiological contamination, and of greater variability of biological analytical techniques > "risk quality management principles"</td></tr><tr><td>Especially control of contamination risk</td><td>Section dedicated to aseptic measures covering the entire process management. Rationale: Usual lack of terminal sterilization of the product requiring preventive strategies to limit the introduction of contaminants.</td><td>Provisions addressing the use of animal sources in the manufacturing process and associated contamination risk. Rationale: A large proportion of biologicals or active substances are issued from living or post-mortem animal sources versus ATMPs mostly designed based on human materials.</td></tr></tbody></table>

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## COMMON TOPICS

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## DISCUSSION & CONCLUSION

Explicitly stated that the text on biologicals does not apply to ATMPs which are covered by specific guidelines, but the two texts share common aspects related to the biological nature of the product: **Relevance of having two distinct and exclusive texts?**

Some ATMPs specific requirements may be relevant to other biologicals

e.g., the validation of biological methods used for quality control and testing.

**Variable levels of similarities and differences**

As ATMPs are a specific category of biologicals, e.g., the "risk-based approach" for ATMPs seems matched to the "risk quality management principles" for biologicals, but the former is more prospective with the idea to anticipate and control current poorly known risks.

Some specific Biologicals requirements may be relevant to ATMPs

e.g., Raw materials of animal origin are poorly addressed in the ATMPs guidelines although ATMPs could also in the future be designed based on xenogeneic cells and are prone to necessitate the use of raw materials of animal origin (such as cell culture or extraction reagents etc.).

Unclear rationale for some style/form differences

Very different vocabulary used in the two texts while they have been adopted with a 7 months interval only, and often refer to the same ideas.

The two texts could benefit from being formulated in a more similar manner to facilitate full understanding and implementation by stakeholders, especially manufacturers.

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<footnote n="1">¹Permanent Researcher in law at the French National Centre for Scientific Research (CNRS, CR), Law Faculty, UMR 7318 DICE CERIC, CNRS, Aix Marseille University, Toulon University, Aix-en-Provence, France; ²Post-doctoral Researcher in Law, Law Faculty, UMR 7318 International, Comparative and European laws (DICE) CERIC, CNRS, Aix- Marseille University, Toulon University, Aix-en-Provence, France; ³Senior Research Fellow in Social Sciences, Centre for Health Law and Emerging Technologies (HeLEX), University of Oxford, United Kingdom; ⁴Senior lecturer in Industrial Pharmacy and Pharmaceutical Regulation, Faculty of Pharmacy, Aix-Marseille University, Research Unit Microbes Evolution Phylogeny and Infection (MEPHI) Aix-Marseille University, IRD, France; ⁵Responsible of Cell therapy/Advanced Therapy Medicinal Products' production at Marseille Public Hospital (AP-HM), Biotherapies Clinical Investigation Center, France; ⁶Professor of Hematology and Biotherapy, Pharmaceutical Sciences Faculty, C2VN INSERM INRAe 1263 AIX Marseille University, Director of the cell therapy research centre at Marseille Public Hospital (AP-HM), France. Acknowledgements: This work has been supported by ANR-funded I-BioLex project (ANR-20-CE26-0007-01, coord. A. Mahalatchimy). M. Morrison is funded by the Leverhulme Trust through grant no RPG-2017-330.</footnote>
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