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The “expansion” stage of CAR-T cell drug product production and logistics
The “expansion” stage of CAR-T cell drug product production and logistics. Due to the increasing number of patients, this phase is parallel to clinical trials. The production process must be adapted to the number of patients, and the process must be “expanded” (ie, replicated to increase or scale up).
Process validation must prove that the process is robust and ready for commercial production. All relevant validation and verification activities must be completed before the final process verification can be carried out.
Horizontal expansion is defined as horizontal expansion (compared to larger bioreactors, autologous CAR-T are more small bioreactors). In biotechnology, this is discussed to reduce risk and is a flexible process verification method that has better cost control than traditional scale-up procedures.
For autologous CAR-T cell technology, only one way to scale out is possible, and it is reasonable to expand the scale of treatment for allogeneic.
Although autologous CAR-T does not have to adjust the horizontally expanded manufacturing process, because a batch is still a patient of autologous products, manufacturing more batches will bring other challenges, such as cost or logistics barriers.
Mount et al. believe that there are mainly these challenges:
- (1) ignoring scalability issues,
- (2) automation,
- (3) raw material supply,
- (4) intermediate and product stability,
- (5) clean room,
- (6) process Control and general process robustness/failure rate.
These challenges have a direct impact on costs.
In the development process, management of the cost of large-scale sales of goods should be considered as early as possible, because this may conflict with the price acceptable to the payer. One way to solve this problem is to go back and calculate from the price acceptable to the payer to determine the cost of production.
Important factors affecting cost are raw materials, consumables, staff and management expenses, facility and capital depreciation, and process design and strategy. It is important to understand the relationship between them. For example, a large number of key production activities should be carried out outside the manufacturing clean room.
In addition, logistics, sales and marketing costs and profits will also affect bonuses [Figure 2].
Jenkins and Farid analyzed seven different processes of allogeneic CAR-T cell therapy to understand the economic driving factors in the production process. Compare the cost of each product with the target selling price. Facts have proved that for cell expansion, the use of tissue culture plastic culture vessels (such as T-flasks and multi-layer containers) proved to be much more expensive than rocking motion bioreactors or gas-permeable containers. It was found that the cost of gene delivery (viral transduction efficiency, electroporation efficiency) per batch and the capacity of downstream processing equipment (in terms of cell number) are key process economic drivers. In addition, the analysis of the multi-parameter decision shows that a process consisting of a rocking motion bioreactor, a rotating filter membrane, and an independent MACS platform is the preferred process design to obtain a target price of commodity cost per dose that is significantly lower than 15%.
Not only is the cost of goods an economic burden in the process of horizontal expansion, but also an investment in new manufacturing facilities. A sad example is the rise and fall of Dendreon, which had a market value of more than $1 billion in 2000 and is one of the most valuable companies in the field. In the early 2010s, more than US$500 million was spent on building a new manufacturing plant, which was eventually buried and filed for bankruptcy in 2014 (Dodson & Levine, 2015).
As the number of patients increases, a network must be established with clinical sites. It is necessary to ensure compliance with patient cell collection and product management regulations. From the perspective of GMP, cell collection at the clinical site can be regarded as the first step in manufacturing and therefore must be qualified. It is important to involve transfusion doctors and hematologists and persuade them, because the success of treatment also depends on their expertise. In addition, the manufacturing process also needs to have enough qualified personnel, who need to receive theoretical and practical training on procedures. Depending on the complexity of the training plan, this may take several months.
To a certain extent, this field can benefit from the well-established international cell therapy association. JACIE and FACT have established a voluntary monitoring and certification system for hematopoietic stem cell transplantation projects. Manufacturers of CAR-T products can use the existing certification of clinical sites to reduce their site visits. In particular, the new ATMP EU guide 7.26 allows, if the organization is authorized and supervised in accordance with the 2004/23/EC directive, it does not necessarily require the ATMP manufacturer to conduct additional audits.
In addition, JACIE/FACT cooperated to develop a set of quality practice standards, which were published in the International Standards for Immune Effector Cell Therapy, including CAR-T product regulations. Here, clinical and quality infrastructure are designated to promote the safe management of immune effector cells, and to standardize the follow-up monitoring and reporting of patient results to achieve continuous process improvement. In particular, guidance on the management of related toxicities is essential for any center that manages T-cell therapy (see also chapter 3.7 on pharmacovigilance).
As the number of patients increases, logistics and product supply chains are getting more and more attention. So far, no specific guidelines have been issued except for some tips on the distribution, storage and reception of batteries in the JACIE/FACT standard. Patients related to product traceability are critical, because using the wrong product can have fatal consequences. It is necessary to encode all relevant information of hospitals and manufacturers with universal identifiers to avoid possible mismatches between products and patients (Hartmann et al., 2017). Since the product is processed by multiple teams in a complex network (clinical site collection, transportation, manufacturing, transportation, infusion), it is necessary to ensure and verify the identity chain and the chain of custody at all steps (Maus & Nikiforow, 2017). The European Single Code (SEC) supports the maintenance of the identity chain, which has been introduced by Directive (EU) 2015/565 and applies to all human cells and tissues. However, there is (currently) no universal standard in the international scope, which will pose a challenge to products distributed globally.
In addition, there is a need to clarify appropriate communication channels between logistics networks to be able to quickly upgrade care, deal with substandard products produced due to the high variability of incoming materials, and manage potentially serious toxicity. The management of a globally distributed team combined with scheduling that limits manufacturing capacity (slot allocation) is complicated, especially in the case of unforeseen events (patient conditions, transportation delays, etc.). Online platforms are becoming more and more important to track the status of products in real time and to disseminate information or promote actions among all parties. Of course, our vision is to seamlessly integrate this type of software with other different existing electronic management systems, such as electronic batch recording manufacturing systems, laboratory information management systems, quality management systems, patient management systems, express service systems or Clinical outcome evaluation system. The more responsibilities that are transferred to such electronic systems, the higher the risk of malfunction or hacking. Therefore, extensive verification activities are required as a computerized system in accordance with GMP Annex 11 and GAMP5.
As the last step of development, process verification is the key to prove that the production is consistent within the predetermined specifications and meets the quality attributes. Especially due to the variability of the starting materials in CAR-T technology, it is necessary to establish a robust production process. Process validation should be carried out on a commercial scale, that is, after expansion/expansion. In traditional scale-up, the pilot batch size must correspond to at least 1/10 of the commercial production scale batch (EMA/CHMP/CVMP/QWP/749073/2016). Since this does not apply to (autologous) personalized medicines, three consecutive batches are usually considered acceptable to prove effectiveness.
Quality risk management in accordance with ICH Q9 represents the basis of verification activities to prove, improve and provide greater assurance to deal with potential risks. If multiple production facilities are established, a good concept must be put forward to show effective production and comparability between sites. Finally, the process verification data must be provided for MA submission in Chapter 3.2.P.3.5 of the CTD. Ongoing plans (re-validation, product life cycle, product quality review) should collect and evaluate product and process data related to product quality to prove that the maintenance of the process during the regular commercial production process is under control.
All in all, the key factors for the successful horizontal expansion of CAR-T technology are:
1) Optimize the manufacturing process through automation and cost management,
2) Establish a clinical network,
3) Availability of qualified personnel,
4) Maintain the identity chain and the chain of custody throughout the supply chain,
5) Coordinate logistics and communication through real-time tracking and feedback, and finally
6) Shift to a decentralized manufacturing model.
The relevant regulations of the European Union are listed below:
We can also use the above regulations as a reference, specifically, the main GMP guidelines (GMP appendix-cell therapy products) and regulations related to process validation.
(source:internet, reference only)