How to transition from lab to commercial-scale ATMP Manufacturing
This is the first article of our series, “The ATMP Manufacturer’s Guide to Commercialisation and cGMP Compliance”.
The shift from R&D to the regulated cGMP facility is often a difficult gap to bridge, which can lead to delays and the halting of projects and puts tremendous pressure on developers. After all, any delay automatically means a delayed treatment for the patient, which may then be too late.
To overcome this gap and ensure a seamless transition, it is necessary to work cGMP compliant from the beginning. However, it is essential to consider among others these six important factors.
- Get the protocols cGMP-ready
- Prepare the protocols for commercial volumes
- Ensure sterility
- Clearly define the equipment selection strategy
- Think automation
- Build the right team
1. Get the protocols cGMP-ready.
In research, it is necessary to carefully consider the individual process steps - the laboratory protocols. They are independent, operator-controlled actions that, when adapted to a strictly regulated environment, become manufacturing protocols, and should be considered as a unified manufacturing platform. This platform guarantees a standardised methodology that ensures the quality, safety, purity, and reproducibility of your final product at any scale.
The goal is to establish a robust cGMP-compliant platform that achieves a high degree of standardisation and automation. For this purpose, it is necessary to characterise and evaluate whether the four main pillars of quality, purity, safety, and reproducibility are guaranteed.
This strategy allows you to identify the critical parameters, evaluate them and make the necessary improvements. This process should be repeated until the platform is stable, GMP-ready, and scalable. Again, timing plays an important role - the sooner this strategy is implemented, the sooner a controlled, commercial environment can be created.
2. Prepare the protocols for commercial volumes
Besides preparing the protocols, the manufacturing strategy should also be optimised to achieve greater throughput.
Higher throughput implies an increase in the number of batches produced or an increase in the volume of a batch, depending on the product type. Both strategies represent considerable complexity in terms of facility design and selection of the required equipment. Here, it is advisable to bring experts on board who are familiar with the complexity of scalable manufacturing of ATMPS. With the help of instruments such as data-driven tools or process simulations, they can identify and eliminate inefficiencies and bottlenecks and define optimised commercial manufacturing.
It is not realistic for many ATMP manufacturers, especially those with several product types in development, to stick to a single manufacturing strategy for a given product type. The size and scope of their commercial pipeline probably will vary over time, based on drivers such as regulatory approval, patient demand, and even supplier-related constraints. To accommodate these changes for any product at a commercial scale, you need a manufacturing facility based on production platforms.
This flexibility requires greater investment in smart facilities that enable modular process platforms. The benefits seem to outweigh the costs, as more and more manufacturers are moving to multi-modular platforms.
3. Ensure sterility
The unique nature of cell and gene therapies requires that the safety and sterility of the final products can only be guaranteed if the equipment and processes are designed to meet the stringent requirements of a complete aseptic manufacturing process, which requires the highest cGMP standards of all.
One of the most important measures for commercial and aseptic manufacturing is to establish a contamination control strategy (CCS). Again, many manufacturers prefer to work with experts who are familiar with the stringent requirements of contamination control and who review the facility design, equipment, and process, as well as the individual raw materials for sterility. In the best-case scenario, all contamination and cross-contamination risks can be identified and evaluated, to develop solutions for risk reduction.
The goal is to create a closed process in an aseptic production facility to protect the environment as well as your process from the risks of manual intervention.
The more you are able to protect your process from both the environment and the risks of manual intervention, the more control you have over the quality of your final product. A closed process is also favourable from a facility perspective; a closed process eliminates the need for high background classifications, changing areas, airlocks, and other costly or space-consuming facility details.
However, in actuality, many of the technologies involved in achieving full closure of the cell and gene therapy manufacturing process are still emerging. By the time this technology matures, the industry will likely need to embrace the concept of managing process-related risks through contained and automated technologies, rather than through environmental controls. Between now and then, you will likely encounter the challenge of incorporating certain open and manual stages into your aseptic process.
4. Clearly define the equipment selection strategy
Often the only question when selecting equipment is stainless steel, single-use, or hybrid technology. However, two interrelated factors should be considered to ensure efficiency, reliability, and quality in the facility: the equipment and its impact on the facility.
When considering the appropriate equipment for a commercial ATMP fabrication, the factors of availability, cleanability, scalability, and vendor experience should be considered and evaluated.
In terms of the manufacturing facility, it is important to ensure that the equipment is suitable for the design of the facility and aligns with the business plan. Additionally, modularity should be considered to prepare for future growth and to be able to operate flexibly.
5. Think automation
In the second article of the ATMP series, we will go into more detail about system automation, which is an important factor in the Pharma 4.0 movement. However, it should be pointed out in advance that it is necessary to document the automation process to verify compliance with cGMP guidelines and to set up the IT infrastructure needed to gather, analyse, and utilise large amounts of process data generated by automated systems. Follow these principles and you start moving towards faster, safer, and more reliable cell and gene therapy manufacturing, enhanced by intelligent automation.
6. Build the right team
The last, but just as important, factor for a seamless transition from lab to commercial manufacturing is the assembly of a harmonised project team - a team of experts from different disciplines and departments, such as the following:
- Procurement
- Process engineering
- Project management
- Strategic facility planning
- Equipment design
- Architecture, Engineering, and Construction (AEC).
- Research and development (R&D)
- Manufacturing Science and Technology (MS&T).
- Analytical Science and Technology (AS&T).
- Quality Control (QC)
- Quality Assurance (QA)
- Manufacturing and production
Setting the course today for future commercial manufacturing
As the above factors already indicate, it is crucial to think about cGMP compliance in research and development at an early stage so that a standardised and robust production platform can be established. Adopting an early strategy lays the foundation for cost-effective, sustainable, but most importantly, efficient cGMP manufacturing of ATMPs that ultimately benefits the patients and provides them with the medication they so urgently need.
About the authors
Michela Castellani-Kleinschroth is a process specialist at CRB Group. She holds a doctorate in Biochemistry from Goethe University, Frankfurt, Germany. Castellani-Kleinschroth has extensive experience leading tech transfers within intercultural, cross-functional teams to achieve realisation of clinical trials suites and GMP compliant production. She is a local expert for Tech Transfer from process development to cGMP manufacturing and is well networked within the Phacilitate. Castellani-Kleinschroth is also an active member of ISPE, ESCGT, and the CGT Circle. She participates in the ISPE “Women in Pharma” Chapter to support women in the pharma industry.
David Estapé is senior fellow, biopharmaceutical process, at CRB Group, and is a recognised biotechnology thought leader. Throughout his career, he has led or supported design and provided GMP consulting services for clients within the biotech, vaccine, and blood plasma pharmaceutical industries. With a strong interest in new technologies and regulatory trends, Estapé participates heavily in organisations like BioPhorum and the International Society for Pharmaceutical Engineering.
Tabea Martins is project manager at CRB Group and is a recognised thought leader in front-end design studies. She has held different positions as project and process technology manager single use EQP and ATMP over 15 years in the life sciences industry. Martins is also an active member of the Pharma ISPE D/A/CH chapter. She graduated from the University of Applied Sciences, Esslingen with a degree in Biotechnology Engineering and a Master Professional of Technical Management CII.
