Quantification of variation in biological input materials and its effect on manufacture and process control

Currently cellular therapies, such as hematopoietic stem cell transplantation (HSCT), are produced at a small scale on a case-by-case basis, usually in a clinical or near-clinical setting. Meeting the demand for future cellular therapies will require a robust and scalable manufacturing process that is either designed around or controls the variation associated with biological starting materials. Understanding variation requires both a measure of the allowable variation (that does not negatively affect patient outcome) and the achievable variation (with current technology). The prevalence of HSCT makes it an ideal case study to prepare for more complex biological manufacturing with more challenging regulatory classifications

A meta-analysis of biological variation in blood-based therapy as a precursor to bio-manufacturing

Currently cellular therapies, such as hematopoietic stem cell transplantation (HSCT), are produced at a small scale on a case-by-case basis, usually in a clinical or near-clinical setting. Meeting the demand for future cellular therapies will require a robust and scalable manufacturing process that is either designed around or controls the variation associated with biological starting materials. Understanding variation requires both a measure of the allowable variation (that does not negatively affect patient outcome) and the achievable variation (with current technology). The prevalence of HSCT makes it an ideal case study to prepare for more complex biological manufacturing with more challenging regulatory classifications. A systematic meta-analysis of the medical literature surrounding HSCT has been completed of which the key outcomes are the following: (i) the range of transplanted CD34+ cells/kg can be up to six orders of magnitude around the median for allogeneic procedures and four orders of magnitude for autologous procedures, (ii) there is no improvement in variation encountered over a period of 30 years and (iii) as study size increases, the amount of variation encountered also increases. A more detailed, stratified source from a controlled single-site clinical center is required to further define a control strategy for the manufacture of biologics

Quantification of variation in biological input materials and its effect on clinical outcome and manufacture

Using blood and blood-based products as a case study, this project will investigate and seek to manage biological input variation from a processing perspective by relating this to clinical outcome (i.e. patient benefit) and exploring the concerns due to input variation when manufacturing a biological therapeutic at multiple sites. • Hematopoietic stem cell transplants are used to treat blood-based cancer and immunological deficiency • Over 130,000 transplants were carried out in Europe between 1990 and 2000[1] • The living cell is the product, introducing more complexity and sensitivity than found in pharmaceuticals • Humans are the source of the raw material, and we are inherently variable • Variation affects the cost, the safety of the therapeutic and the efficacy of the treatmen

Quantification of biological variation in blood-based therapy – a summary of a meta-analysis to inform manufacturing in the clinic

Background and Objectives Biological raw materials, the basis for cellular therapies such as stem cells, have a significantly greater degree of complexity than their traditional pharmaceutical counterparts. This can be attributed to the inherent variation of its source – human beings. Currently, cell therapies are made in small, ad hoc batches, but larger scale production is a prerequisite to meeting future demand and will require a quality-by-design approach to manufacturing that will be designed around, or be robust to this variation. Quantification of variation will require understanding of the current baseline and stratification of its sources. Materials and Methods Haematopoietic stem cell therapy was chosen as a case study to explore this variation, and a PRISMA-guided (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) systematic meta-analysis was carried out for a number of predetermined cell measurements. Results From this data set, it appears that the extent of variation in therapeutic dose (in terms of transplanted total nucleated cells and CD34+ cells per kilogram) for HSCT is between one and four orders of magnitude of the median. Conclusions This is tolerated under the practice of medicine but would be unmanageable from a biomanufacturing perspective and raises concerns about comparable levels of efficacy and treatment. A number of sources that will contribute towards this variation are also reported, as is the direction of travel for 4 greater clarity of the scale of this challenge

Investigating UK Biobank blood metrics variation to inform cell therapy manufacturing process control [poster]

Investigating UK Biobank blood metrics variation to inform cell therapy manufacturing process control [poster

Comparability: manufacturing, characterization and controls, report of a UK Regenerative Medicine Platform Pluripotent Stem Cell Platform Workshop, Trinity Hall, Cambridge, 14–15 September 2015

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

Establishing the variation of blood metrics within UK Biobank to inform cell therapy manufacturing processes

Aim: Understanding blood component variation as a function of healthy population metrics is necessary to inform biomanufacturing process design. Methods: UK Biobank metrics were examined for variation in white blood cell count as an analog to potential manufacturing starting material input. Results: White Blood Cell count variation of four orders of magnitude (6.65 × 109 cells/liter) was found. Variation increased with age, increased with weight up to 80 kg then decreased. Health state showed a greater absolute number of participants with elevated count. Female range was greater than male. Cell count/distributions were different between centers. Conclusion: This variation and range of process input signals a requirement for new strategies for manufacturing process design and control

A meta-analysis of biological variation in blood-based therapy as a precursor to bio-manufacturing

This paper was accepted for publication in the journal Cytotherapy and the definitive published version is available at http://dx.doi.org/10.1016/j.jcyt.2016.01.011Currently cellular therapies, such as hematopoietic stem cell transplantation (HSCT), are produced at a small scale on a case-by-case basis, usually in a clinical or near-clinical setting. Meeting the demand for future cellular therapies will require a robust and scalable manufacturing process that is either designed around or controls the variation associated with biological starting materials. Understanding variation requires both a measure of the allowable variation (that does not negatively affect patient outcome) and the achievable variation (with current technology). The prevalence of HSCT makes it an ideal case study to prepare for more complex biological manufacturing with more challenging regulatory classifications. A systematic meta-analysis of the medical literature surrounding HSCT has been completed of which the key outcomes are the following: (i) the range of transplanted CD34+ cells/kg can be up to six orders of magnitude around the median for allogeneic procedures and four orders of magnitude for autologous procedures, (ii) there is no improvement in variation encountered over a period of 30 years and (iii) as study size increases, the amount of variation encountered also increases. A more detailed, stratified source from a controlled single-site clinical center is required to further define a control strategy for the manufacture of biologics

Cell microfactories: manufacturing cell-based therapeutics [TCES abstract]

Cell microfactories: manufacturing cell-based therapeutics [TCES abstract

Cell microfactories: manufacturing cell-based therapeutics [FIRM abstract]

Cell microfactories: manufacturing cell-based therapeutics [FIRM abstract