With more and more cell therapies entering the market, Dr Maitry Ganatra, global market development director at Thermo Fisher Scientific guides readers on how to comply with regulatory standards to ensure quality and safety, and ultimately make it to commercialisation.
Market
In recent years, sophisticated cell therapies have emerged to treat a broad range of cardiovascular, neurological and autoimmune diseases, among others. The complexity and variability of these therapies present unique challenges for the transition from the research phase to commercialisation. Thorough consideration of current good manufacturing practice (cGMP) requirements and regulatory compliance early in the process, even during the research stage, can help alleviate the challenges involved in scaling up. Additionally, applying quality by design (QbD) principles to the production process can ensure high quality and safety of new therapeutics, making commercialisation easier.
Fundamental considerations when transitioning from research to commercialisation of cell therapies
Commercialisation of cell and gene therapies, whether allogeneic or autologous, can be challenging. In allogeneic cell therapy, where a single cell type is mass produced for treating multiple patients, the challenge is that of scaling up a thousand-fold from the research phase, while still maintaining the necessary physiological conditions. When processes get scaled up, laboratory instruments, such as centrifuges and CO2 incubators used during the research phase, may not be compatible with the requirements of the cGMP environment. Typically, when equipment designed for research purposes are used in a cGMP compliant facility without consideration of validation and documentation requirements, this can pose a huge issue during commercialisation.
Scaling up could introduce inconsistencies across multiple factors, including incubator temperature, composition of reagents, such as media or growth factors, as well as cell culture parameters, such as incubation time. Even the slightest change in production conditions upon moving from research level to the multi-liter scale can have an impact on how the cells behave, ultimately affecting the quality and safety of the therapy. In adapting research workflows to meet commercial cGMP requirements, cell therapy manufacturers often realise too late that processes that work well at the research stage are incompatible with the cGMP environment. Furthermore, they often underestimate how involved the regulatory compliance process can be; each piece of equipment needs to be validated to ensure it meets the highest standards and relevant documentation should be produced.
In autologous cell therapy, where each batch of cells is produced for only one patient, modified and re-introduced into the same patient, the challenge is that of scaling out and producing multiple batches corresponding to multiple patients, while maintaining due diligence throughout the process-heavy workflow.
Scaling out in autologous cell therapy demands more space and a large number of instruments, each being compliant with regulatory standards. The challenges here involve managing the complexity of working with multiple sets of equipment, having sufficient space for all these systems and keeping track of which instrument is used for a specific therapy. When processing multiple batches in autologous cell therapy, every patient sample needs to be tracked as it goes from the hospital to the manufacturing site and back to the patient, thereby adding logistical burden to the process. On the whole, scaling out relies on having the operational capacity to accommodate all the equipment as well as the materials, manpower and time involved in the process.
Recognising these challenges, many technology vendors offer advice and guidance around cGMP compatible instrumentation, including centrifuges, biological safety cabinets, cold storage equipment and CO2 incubators. A standard laboratory CO2 incubator, for example, cannot be moved to a cGMP environment without temperature mapping or testing for installation, operational and performance qualifications (IQ, OQ and PQ). To this effect, some vendors even offer customisable solutions to help meet cGMP requirements.
Applying quality by design principles to cell therapy manufacturing
Increased testing does not necessarily improve the quality of the final product. A more robust solution is to build quality into entire production workflows. The US Food and Drug Administration (FDA) encourages implementation of the Quality by Design (QbD) principles into the production, manufacturing and regulation processes.
In adopting the QbD principles, every step of the process, starting from raw materials to the operating plant, clean room, and water and materials used, all should adhere to high-quality standards. Every piece of equipment used in the manufacturing process needs to meet quality requirements, such as being certified by the International Organisation for Standardisation.
Recognising the challenges posed when transitioning from research to commercialisation of cell and gene therapies, many instrument vendors apply the QbD principles and undertake all of the necessary performance testing to deliver equipment that meet the requirements of cGMP compliant facilities. Some of the steps involved in performance testing include temperature testing, ramp up/ramp down testing, sterilisation, and electrical checks. By inspecting the overall safety and configuration of the instrumentation, the required factory end-of-line testing is completed.
Vendors also provide the relevant documentation required in adhering with the cGMP standards, for example, issuing the certificate of conformance and providing instrument calibration documentation, equipment drawing and critical component specifications. To ensure that each piece of equipment is installed per vendor specifications, meets the quality requirements, and offers consistent and reproducible results, IQ, OQ and PQ validation protocols are performed, followed by issuing the respective documentation.
In addition to testing for compliance and offering documentation, some vendors provide user and maintenance training to ensure best practices are upheld in the day-to-day workflow.
Planning ahead for successful cell therapy commercialisation
As pharmaceutical manufacturers transition cell therapies from the research to the commercialisation phase, they start acknowledging the complexity that comes from scaling up and expanding workflows, while staying compliant with the regulatory requirements. Carefully planning cell therapy production processes beforehand, understanding the needs of cGMP compliance and collaborating with knowledgeable technology vendors who offer solutions adhering to QbD principles, can set cell therapy manufacturers up for successful commercialisation.