Decentralized Manufacturing of Advanced Therapy Medicinal Products

Centralised manufacturing can present some disadvantages and challenges compared to decentralised ATMP manufacturing. Conventional pharmacological manufacturing is a highly centralised process, and involves complicated supply chain logistics and cryopreservation. While this is a time-tested and economically sustainable process for traditional pharmacological drugs, it can be difficult to scale up to advanced therapy drugs, especially when it comes to autologous cell therapies.

Centralised cell therapy manufacturing can be time-consuming due to several factors. First, the process of isolating and expanding cells can take a significant amount of time. In addition, ensuring that patients have access to the therapy can be a time-consuming challenge, especially for those who are far from centralised manufacturing facilities. The logistics involved in transporting the therapy to these patients can mean significant obstacles and delays.

Decentralisation changes the manufacture of cell therapy to a more distributed process, bringing it closer to patients as it improves access and convenience. Doctors with access to a local cell and gene therapy laboratory can work with local staff to create prior approval, schedule collection, create the treatment, release it, and administer the treatment as quickly as possible. Rate-limiting factors are reduced as patient material is available locally, thus reducing logistical and transport challenges.

Decentralised manufacturing is the preferred model for autologous cellular products. It is applicable to both pharmaceutical approaches and to smaller biotech companies and specialised hospitals that are producing ATMPs. Each centre must be able to deliver equivalent ATMPs, regardless of location or operators, hence, the emergence of integrated and automated management systems that allow the apheresis product to pass through the multiple stages of manufacturing within a disposable single-use kit that does not open directly to the environment. The extraction of samples and the addition of reagents or media are carried out by means of sterile tube welders or aseptic access ports, thus maintaining what is known as a functionally closed system, reducing the variation caused by operators. Automated devices have become the preferred method for decentralised CAR T manufacturing. Some of these devices are CliniMACS Prodigy© or Lonza Cocoon©.

As indicated in Part IV of the NCF, the certification and release of ATMP batches manufactured under a decentralised system is especially important as manufacturing in multiple locations increases the risk of product variability.

In particular, the batch certification and release process should ensure that each batch released at any of the sites has been manufactured and verified in accordance with the requirements for commercialization/clinical trial authorisation and other relevant regulatory requirements, including compliance with the NCF. With this in mind, the following aspects should be considered:

A central facility must be identified, which must be established in the EU. The central facility is responsible for supervising the decentralised sites. The central facility must assume, at least, the two following tasks: ensure that those who participate in the certification and batch release process are adequately qualified and trained for their tasks, and perform audits to confirm that the certification and batch release process is being followed as described in the standard operating procedure (SOP).

A contract or technical agreement must be established between the central facility and the decentralised locations. This agreement must establish the responsibilities of each of the parties, including the responsibility of the qualified person (QP).

The qualified person (QP) has the ultimate responsibility for certifying that a batch of ATMPs meets the quality requirements and can be released. The QP of the central facility can trust the data from the decentralised locations, but only as long as it has been provided by qualified and trained personnel.

For all the above reasons, the decentralised manufacture of advanced therapy medicinal products, specifically cell therapies, represents a step towards a more inclusive healthcare system, where advanced treatments are not a privilege, but a right accessible to all.

Bibliography

1. Regulation (EC) No. 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No. 726/2004.
2. Part IV of the Guidelines on specific good manufacturing practice for advanced therapy medicinal products.
3. D 4.1 Roadmap of WP4. Roadmap of the needs and strategy of the implementation of new Advanced Therapies de Restore Horizon
4. Shah, M., Krull, A., Odonnell, L., de Lima, M. J., & Bezerra, E. (2023). Promises and challenges of a decentralized CAR T-cell manufacturing model. Frontiers in transplantation, 2, 1238535.
5. Decentralized manufacturing of cell and gene therapies: Overcoming challenges and identifying opportunities Harrison, Richard P. et al. Cytotherapy, Volume 19, Issue 10, 1140 – 1151

6. Beyond Urban Centers: Expanding CAR-T Therapy with Decentralized Manufacturing. Boston Labs – Inspired Clinical Logistics.