Retrospective Analysis of Autologous Chondrocyte-Based Cytotherapy Production for Clinical Use: GMP Process-Based Manufacturing Optimization in a Swiss University Hospital

Abstract

Cultured autologous human articular chondrocyte (HAC) implantation has been extensively investigated for safe and effective promotion of structural and functional restoration of knee cartilage lesions. HAC-based cytotherapeutic products for clinical use must be manufactured under an appropriate quality assurance system and follow good manufacturing practices (GMP). A prospective clinical trial is ongoing in the Lausanne University Hospital, where the HAC manufacturing processes have been implemented internally. Following laboratory development and in-house GMP transposition of HAC cell therapy manufacturing, a total of 47 patients have been treated to date. The main aim of the present study was to retrospectively analyze the available manufacturing records of the produced HAC-based cytotherapeutic products, outlining the inter-individual variability existing among the 47 patients regarding standardized transplant product preparation. These data were used to ameliorate and to ensure the continued high quality of cytotherapeutic care in view of further clinical investigations, based on the synthetic analyses of existing GMP records. Therefore, a renewed risk analysis-based process definition was performed, with specific focus set on process parameters, controls, targets, and acceptance criteria. Overall, high importance of the interdisciplinary collaboration and of the manufacturing process robustness was underlined, considering the high variability (i.e., quantitative, functional) existing between the treated patients and between the derived primary HAC cell types.

Current Status of PRP Manufacturing Requirements & European Regulatory Frameworks: Practical Tools for the Appropriate Implementation of PRP Therapies in Musculoskeletal Regenerative Medicine

“…In common affections, such as articular lesions/inflammation or tissue scaring, regenerative medicine options may reduce the need for traditional medication administration and may provide a holistic solution in complex pathophysiological situations [ 5 , 6 ]. With highly versatile therapeutic approaches, which have been constantly improving for several decades, regenerative medicine can potentially address all systems and tissues of the human body [ 7 , 8 , 9 , 10 , 11 ].…”

“…Clinical results yielded by the application of cell-based therapies have been evolving rapidly since the 1980s, particularly in burn patient care and in orthopedics [ 2 , 6 , 9 , 12 ]. The use of biological products/cells has demonstrably improved clinical outcomes, such as those reported for PRP administration in burn patients and for cutaneous wound management [ 8 , 13 ].…”

“…Switzerland has adapted this same approach in the Therapeutic Products Act (TPA) and requires similar practices and standards [ 46 , 47 ]. This study secondly shows the importance of PRP-based product preparation (i.e., manufacturing process and controls) standardization, which is a prerequisite for sound clinical evaluation of high-quality therapeutic interventions [ 9 ]. Despite detailed descriptions of the necessary GMP manufacturing infrastructure in the applicable framework documents, few elements pertaining to process design are provided [ 39 , 40 , 41 , 49 ].…”

“…Despite detailed descriptions of the necessary GMP manufacturing infrastructure in the applicable framework documents, few elements pertaining to process design are provided [ 39 , 40 , 41 , 49 ]. Therefore, the choice of the exact manufacturing process and protocol is the responsibility of the manufacturer, which should carefully consider and optimize the workflows, technical specifications, and key parameters of PRP preparation and clinical delivery [ 9 , 15 , 16 , 35 ].…”

Current concepts and perspectives for articular cartilage regeneration

“…In terms of legislation, expanded cells belong to Advanced Therapy Medicinal Products (ATMPs) and must follow specific rules already encoded for conventional drugs and known as Good Manufacturing Practices (GMPs). GMPs entail the standardization and control of medicinal manufacturing, ensuring their safety and reducing contaminations [ 15 ].…”