Approaches to Lifecycle Management and Regulatory Readiness in Advanced Therapies
At the 2024 ISPE Annual Meeting & Expo, a session focused on lifecycle management considerations for cell and gene therapy was held. This session invited experts in their field to review quality/regulatory strategies aimed at broadening patient access while fostering affordability in the realm of transformative medical innovations. Challenges and opportunities inherent in the lifecycle management of cell and gene therapy products were discussed, from initial development stages to post-market considerations. Three experts presented an array of topics covering these considerations.
Stephanie Martin, Product Quality Lead with Adaptimmune, discussed the critical aspects of particulate control strategies for advanced therapy medicinal products (ATMP). Her key learnings highlighted the requirements set forth by regulators, directing that the final product be "essentially free of visible particles." This presents a significant challenge for ATMP manufacturers, particularly due to the inherent limitations of single-use systems, which struggle to achieve complete particle-free status. Martin emphasized the importance of implementing a comprehensive particle control lifecycle, which focuses on selecting appropriate materials and process controls aimed at minimizing particulates throughout manufacturing. A fundamental aspect of this strategy is gaining a thorough understanding of the various sources, types, sizes, and quantities of particles that may emerge during the production process. By doing so, manufacturers can bolster their confidence in the visual inspection practices that are essential for detecting visible particles effectively. This proactive approach allows for the timely identification of any issues and facilitates a culture of continuous improvement.
Jon Halling, Managing Director for Quality with Catapult Cell and Gene Therapy, alongside Alf Penfold, Technical Director - GMP/Regulatory Compliance with PM Group, shifted focus towards ATMP regulatory collaboration and organizational readiness. They introduced an innovative model developed by CGT Catapult Stevenage, which is designed to assist organizations with limited good practice (GxP) experience in progressing their clinical assets efficiently and effectively. This model not only reduces compliance and financial risks significantly but also accelerates product progression compared to traditional methods. This pace of development runs parallel to the maturation of compliance and the growth of organizations, enabling them to respond to the rapidly evolving science and technologies driving ATMP development.
A critical point raised was the necessity of facility designs that accommodate various modalities, reinforcing the importance of risk management philosophies in conjunction with the scrutiny from the health authorities. CGT Catapult's collaborative relationship with the Medicines and Healthcare products Regulatory Agency (MHRA) has proven invaluable, providing validation and guidance as their operational model evolves.
Halling and Penfold shared additional insights concerning inspection learnings throughout their experience. They highlighted the significance of maintaining a structured validation lifecycle, as well as challenges related to software qualification, identifying gaps in prior knowledge and awareness that led to a shift in responsibility for computer software validation (CSV) from IT to specialized CSV contractors, ultimately transitioning to the permanent validation team post-knowledge transfer. A similar trend was seen with data integrity, both in paper and electronic formats. This prompted a comprehensive redevelopment of compliance approaches, which included expert training across all operational levels, from executives to operators. Some of the remediation measures proposed were the development of a data integrity master plan, introducing risk-focused processes, and conducting a full retrospective reassessment of existing systems.
Ingrid Markovic, PhD, Senior Science Advisor with the US Food and Drug Administration’s (US FDA) Center for Biologics Evaluation and Research (CBER), addressed lifecycle management considerations for cell and gene therapies. She outlined several active initiatives at CBER, which include advancing manufacturing technologies through research, providing platform technology provisions, and defining the use of accelerated approvals specifically for gene therapies.
Additionally, CBER is exploring the possibility of concurrent submission and product reviews in collaboration with other regulatory authorities, alongside launching a communication pilot aimed at rare diseases. Markovic conveyed that harmonizing manufacturing approaches is an important step in increasing the ease with which processes could be transferred to contract manufacturing organizations.
Furthermore, she highlighted the need for the automation of manufacturing processes, supporting the development of automated or semi-automated fabrication devices within a machine-disposable manufacturing paradigm. She also presented a review of the regulatory tools available for manufacturers, which included comparability protocols (e.g., the post-approval change management protocols), the ICH Q12 guidelines, and drafts for the Advanced Manufacturing Technologies Designation Program and the Platform Technology Designation Program for Drug Development, both of which have been established by the US FDA. This comprehensive examination stressed that advanced manufacturing technologies hold great promise for increasing agility, flexibility, reliability, and cost-effectiveness in the production of complex biological products. The US FDA remains committed to collaborating with sponsors to implement these innovative manufacturing technologies effectively.
In summary, the discussions from this event shed light on several critical areas related to the development and manufacturing of ATMPs. From the necessity of effective particulate control strategies to the collaborative efforts required for regulatory compliance and organizational readiness, the insights provided by industry and regulatory experts underline a collective commitment to advancing the field. By fostering innovative practices, embracing new technologies, and ensuring robust compliance frameworks, stakeholders in the ATMP space aim not only to meet regulatory expectations but also to enhance product quality and patient outcomes. This collaborative and adaptive approach is crucial in navigating the complexities of designing and manufacturing therapies that have the potential to transform patient care.
Disclaimer
This is an informal summary of a presentation on 14 October 2024 at the 2024 ISPE Annual Meeting & Expo in Orlando, Florida, USA. It has not been vetted by any of the agencies or regulators mentioned in this article, nor should it be considered the official positions of any of the agencies mentioned.
