This work quantifies the highest risk activities and interdependencies in cell therapy new produc... more This work quantifies the highest risk activities and interdependencies in cell therapy new product development (NPD). A simulation model based upon an activates based and information driven  approach of the Design Structure Matrix (DSM), using Latin Hypercube sampling methods with discrete event simulation evaluated the interdependencies between critical development tasks. Input data was collected from quarterly financial reports of cell therapy developers and developmental milestones as reported in company press releases and publications. . Successfully planning and managing development processes is problematic in an emerging industry lacking precedents and standardised technology platforms.  Methods of understanding and reducing developmental uncertainty and risk are needed to aid resourcing decisions. A particular requirement is to understand the impact of process and clinical development, in this highly regulated sector. Results from the model quantify the probabilit...
Cell-based therapies have the potential to make a large contribution toward currently unmet patie... more Cell-based therapies have the potential to make a large contribution toward currently unmet patient need and thus effective manufacture of these products is essential. Many challenges must be overcome before this can become a reality and a better definition of the manufacturing requirements for cell-based products must be obtained. The aim of this study is to inform industry and academia of current cell-based therapy clinical development and to identify gaps in their manufacturing requirements. A total of 1342 active cell-based therapy clinical trials have been identified and characterized based on cell type, target indication and trial phase. Multiple technologies have been assessed for the manufacture of these cell types in order to facilitate product translation and future process development.
Supplementary Information Files for 'Distributed automated manufacturing of pluripotent stem ... more Supplementary Information Files for 'Distributed automated manufacturing of pluripotent stem cell products'<br>Abstract:Establishing how to effectively manufacture cell therapies is an industry-level problem. Decentralised manufacturing is of increasing importance, and its challenges are recognised by healthcare regulators with deviations and comparability issues receiving specific attention from them. This paper is the first to report the deviations and other risks encountered when implementing the expansion of human pluripotent stem cells (hPSCs) in an automated three international site–decentralised manufacturing setting. An experimental demonstrator project expanded a human embryonal carcinoma cell line (2102Ep) at three development sites in France, Germany and the UK using the CompacT SelecT (Sartorius Stedim, Royston, UK) automated cell culture platform. Anticipated variations between sites spanned material input, features of the process itself and production sys...
Human stem cells have the potential to transform medicine. However, hurdles remain to ensure that... more Human stem cells have the potential to transform medicine. However, hurdles remain to ensure that manufacturing processes produce safe and effective products. A thorough understanding of the biological processes occurring during manufacture is fundamental to assuring these qualities and thus, their acceptability to regulators and clinicians. Leaders in both human pluripotent and somatic stem cells, were brought together with experts in clinical translation, biomanufacturing and regulation, to discuss key issues in assuring appropriate manufacturing conditions for delivery of effective and safe products from these cell types. This report summarizes the key issues discussed and records consensus reached by delegates and emphasizes the need for accurate language and nomenclature in the scientific discourse around stem cells.
This paper summarizes the proceedings of a workshop held at Trinity Hall, Cambridge to discuss co... more This paper summarizes the proceedings of a workshop held at Trinity Hall, Cambridge to discuss comparability and includes additional information and references to related information added subsequently to the workshop. Comparability is the need to demonstrate equivalence of product after a process change; a recent publication states that this 'may be difficult for cell-based medicinal products'. Therefore a well-managed change process is required which needs access to good science and regulatory advice and developers are encouraged to seek help early. The workshop shared current thinking and best practice and allowed the definition of key research questions. The intent of this report is to summarize the key issues and the consensus reached on each of these by the expert delegates.
Academic centers, hospitals and small companies, as typical development settings for UK regenerat... more Academic centers, hospitals and small companies, as typical development settings for UK regenerative medicine assets, are significant contributors to the development of autologous cell-based therapies. Often lacking the appropriate funding, quality assurance heritage or specialist regulatory expertise, qualifying aseptic cell processing facilities for GMP compliance is a significant challenge. The qualification of a new Cell Therapy Manufacturing Facility with automated processing capability, the first of its kind in a UK academic setting, provides a unique demonstrator for the qualification of small-scale, automated facilities for GMP-compliant manufacture of autologous cell-based products in these settings. This paper shares our experiences in qualifying the Cell Therapy Manufacturing Facility, focusing on our approach to streamlining the qualification effort, the challenges, project delays and inefficiencies we encountered, and the subsequent lessons learned.
Journal of tissue engineering and regenerative medicine, 2016
Manufacture of red blood cells (RBCs) from progenitors has been proposed as a method to reduce re... more Manufacture of red blood cells (RBCs) from progenitors has been proposed as a method to reduce reliance on donors. Such a process would need to be extremely efficient for economic viability given a relatively low value product and high 2E12 cell dose. Therefore, the aim of these studies was to define the productivity of an industry standard stirred-tank bioreactor and determine engineering limitations of commercial RBC production. Cord blood derived CD34+ cells were cultured under erythroid differentiation conditions in a stirred micro-bioreactor (ambr™). Enucleated cells of 80% purity could be created under optimal physical conditions: pH 7.5, 50% oxygen, without gas-sparging (which damaged cells) and with mechanical agitation (which directly increased enucleation). O2 consumption was low (~5x10(-8) µg/cell.hr) theoretically enabling erythroblast densities in excess of 5x10(8) /ml in commercial bioreactors and sub-10 L/unit production volumes. The bioreactor process achieved a 24% ...
This work quantifies the highest risk activities and interdependencies in cell therapy new produc... more This work quantifies the highest risk activities and interdependencies in cell therapy new product development (NPD). A simulation model based upon an activates based and information driven  approach of the Design Structure Matrix (DSM), using Latin Hypercube sampling methods with discrete event simulation evaluated the interdependencies between critical development tasks. Input data was collected from quarterly financial reports of cell therapy developers and developmental milestones as reported in company press releases and publications. . Successfully planning and managing development processes is problematic in an emerging industry lacking precedents and standardised technology platforms.  Methods of understanding and reducing developmental uncertainty and risk are needed to aid resourcing decisions. A particular requirement is to understand the impact of process and clinical development, in this highly regulated sector. Results from the model quantify the probabilit...
Cell-based therapies have the potential to make a large contribution toward currently unmet patie... more Cell-based therapies have the potential to make a large contribution toward currently unmet patient need and thus effective manufacture of these products is essential. Many challenges must be overcome before this can become a reality and a better definition of the manufacturing requirements for cell-based products must be obtained. The aim of this study is to inform industry and academia of current cell-based therapy clinical development and to identify gaps in their manufacturing requirements. A total of 1342 active cell-based therapy clinical trials have been identified and characterized based on cell type, target indication and trial phase. Multiple technologies have been assessed for the manufacture of these cell types in order to facilitate product translation and future process development.
Supplementary Information Files for 'Distributed automated manufacturing of pluripotent stem ... more Supplementary Information Files for 'Distributed automated manufacturing of pluripotent stem cell products'<br>Abstract:Establishing how to effectively manufacture cell therapies is an industry-level problem. Decentralised manufacturing is of increasing importance, and its challenges are recognised by healthcare regulators with deviations and comparability issues receiving specific attention from them. This paper is the first to report the deviations and other risks encountered when implementing the expansion of human pluripotent stem cells (hPSCs) in an automated three international site–decentralised manufacturing setting. An experimental demonstrator project expanded a human embryonal carcinoma cell line (2102Ep) at three development sites in France, Germany and the UK using the CompacT SelecT (Sartorius Stedim, Royston, UK) automated cell culture platform. Anticipated variations between sites spanned material input, features of the process itself and production sys...
Human stem cells have the potential to transform medicine. However, hurdles remain to ensure that... more Human stem cells have the potential to transform medicine. However, hurdles remain to ensure that manufacturing processes produce safe and effective products. A thorough understanding of the biological processes occurring during manufacture is fundamental to assuring these qualities and thus, their acceptability to regulators and clinicians. Leaders in both human pluripotent and somatic stem cells, were brought together with experts in clinical translation, biomanufacturing and regulation, to discuss key issues in assuring appropriate manufacturing conditions for delivery of effective and safe products from these cell types. This report summarizes the key issues discussed and records consensus reached by delegates and emphasizes the need for accurate language and nomenclature in the scientific discourse around stem cells.
This paper summarizes the proceedings of a workshop held at Trinity Hall, Cambridge to discuss co... more This paper summarizes the proceedings of a workshop held at Trinity Hall, Cambridge to discuss comparability and includes additional information and references to related information added subsequently to the workshop. Comparability is the need to demonstrate equivalence of product after a process change; a recent publication states that this 'may be difficult for cell-based medicinal products'. Therefore a well-managed change process is required which needs access to good science and regulatory advice and developers are encouraged to seek help early. The workshop shared current thinking and best practice and allowed the definition of key research questions. The intent of this report is to summarize the key issues and the consensus reached on each of these by the expert delegates.
Academic centers, hospitals and small companies, as typical development settings for UK regenerat... more Academic centers, hospitals and small companies, as typical development settings for UK regenerative medicine assets, are significant contributors to the development of autologous cell-based therapies. Often lacking the appropriate funding, quality assurance heritage or specialist regulatory expertise, qualifying aseptic cell processing facilities for GMP compliance is a significant challenge. The qualification of a new Cell Therapy Manufacturing Facility with automated processing capability, the first of its kind in a UK academic setting, provides a unique demonstrator for the qualification of small-scale, automated facilities for GMP-compliant manufacture of autologous cell-based products in these settings. This paper shares our experiences in qualifying the Cell Therapy Manufacturing Facility, focusing on our approach to streamlining the qualification effort, the challenges, project delays and inefficiencies we encountered, and the subsequent lessons learned.
Journal of tissue engineering and regenerative medicine, 2016
Manufacture of red blood cells (RBCs) from progenitors has been proposed as a method to reduce re... more Manufacture of red blood cells (RBCs) from progenitors has been proposed as a method to reduce reliance on donors. Such a process would need to be extremely efficient for economic viability given a relatively low value product and high 2E12 cell dose. Therefore, the aim of these studies was to define the productivity of an industry standard stirred-tank bioreactor and determine engineering limitations of commercial RBC production. Cord blood derived CD34+ cells were cultured under erythroid differentiation conditions in a stirred micro-bioreactor (ambr™). Enucleated cells of 80% purity could be created under optimal physical conditions: pH 7.5, 50% oxygen, without gas-sparging (which damaged cells) and with mechanical agitation (which directly increased enucleation). O2 consumption was low (~5x10(-8) µg/cell.hr) theoretically enabling erythroblast densities in excess of 5x10(8) /ml in commercial bioreactors and sub-10 L/unit production volumes. The bioreactor process achieved a 24% ...
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Papers by Mark McCall