ATMPs are very different to other modalities, often requiring heightened segregation with some unique challenges. The industry is not always clear in how to interpret the regulations with the European Medicines Agency (EMA) and Pharmaceutical Inspection Co-operation Scheme (PIC/S) taking a slightly different approach. For example, these organizations have differing stances on whether Annex 1 applies to ATMPs and how industry needs to design and operate ATMP facilities based on ICH Q5A and current industry trends (cGMPs).
Traditional manufacturing processes are for synthetically derived compounds (small molecules), or proteins or peptides expressed by cellular systems (large molecules). ATMPs are based on genes, cells, or tissues delivered to patients for therapeutic benefits and are often referred to as " personalized medicines." For example, cell therapy products involve manipulating whole living cells that are introduced into the patient to treat a disease or injury.
There are two types of cell therapies:
- Autologous therapies, e.g. CAR-T, are derived from a single patient and returned to the same patient after in vitro manipulation.
- Allogeneic products are derived from multiple donors and the final cell therapy can be used to treat many patients.
It is not possible to sterile filter cell therapies due to the size of the cells. From a facility design perspective, cell therapies that undergo any gene modifications are broadly considered to be cell therapies (even though they may be marketed as gene therapies).
The US Food and Drug Administration (US FDA) has issued guidance on cell and gene therapy facilities, but has yet to issue specific regulations. For example, the “FDA Perspective on Commercial Facility Design for Cell and Gene Therapy Products” by Lily Koo, PhD, with the US FDA, is excellent with some very useful case studies.
The European Union (EU) has issued regulations specifically for cell and gene therapies in the form of EudraLex Volume 4, Part IV ”Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products (November 2017).” The regulations were formerly part of EudraLex Volume 4, Annex 2, Manufacture of Biological active substances and Medicinal Products for Human Use. As a general rule, where no explicit ATMP regulations exist, other applicable regulations can be utilized.
The International Council for Harmonisation (ICH) and PIC/S have been instrumental in harmonizing GMPs and regulations. PIC/S has over 50 signed-up members states. However, PIC/S has started to diverge from the ATMP regulations in Europe and is not aligned in the same way it as is with Annex 1. These differences were explored in more detail to understand what is new or different when compared to the EMA regulations.
PIC/S has started to diverge from the ATMP regulations in Europe with respect to Annex 1 and how it is to be applied.
There is more clarity in PIC/S Annex 2A regarding the types of ATMPs that are included (illustrated in Table 1 and Figures 1 to 3 of Annex 2A). The same information does reside in a question-and-answer publication by the EMA (EMA/246400/2021, dated 24 February 2021), but is not referenced in EudraLex Part IV and therefore not so easily located. PIC/S Annex 2A is also more aligned with Annex 1 by referencing ”Quality Risk Management” and a “Contamination Control Strategy.”
The difference between good manufacturing practices (GMPs) and good tissue practices (GTPs) for starting materials is explained in several guideline documents. GMP guidelines apply to the manufacturing of pharmaceuticals, ensuring products are consistently produced and controlled according to quality standards, while GTP guidelines are specifically for the handling, processing, and storage of human cells, tissues, and tissue-based products.
ICH Q5A is focused on the viral safety of biotechnology products. The latest version (R2) of ICH Q5A, adopted on 1 November 2023, is beginning to impact ATMP facilities by encouraging manufacturers to perform viral clearance steps when it is possible to do so. For processes like lentiviral vector (LVV) where viral clearance may not be a viable option, a risk-based approach is recommended.
The latest version (R2) of ICH Q5A, adopted on November 1, 2023, is beginning to impact ATMP facilities by encouraging manufacturers to perform viral clearance steps when it is possible to do so.
An approach for accommodating multiple ATMP modalities being adopted by the industry is featured in a paper published in ISPE’s Pharmaceutical Engineering® magazine in November 2022, “Accommodating Multiple Modalities in the Same Facility.” The paper, authored by Tom Bannon and Alf Penfold, explains a structured approach that takes into consideration the regulations whilst applying Quality Risk Management to the different modalities and corresponding facility features.
The United Kingdom’s Medicines and Healthcare products Regulatory Agency's (MHRA) development of a regulatory framework for drugs and medical products manufactured at or near the point of care is explained. This framework aims to guide the manufacture of personalized medicines, such as cell and gene therapies, in portable units, and became law in July 2025.
In summary, there is quite a lot of information on ATMPs in relation to the available guidance and regulations. For example, the differences between EudraLex Part 4 and PIC/S Annex 2A, a regulatory-driven process and methodology for accommodating multiple ATMP modalities, the demarcation between GTP and GMP, the impact of ICH Q5A on viral vector facilities, and the introduction of Point of Care Manufacturing regulations for personalized medicines.
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