Cell therapy-processing economics: small-scale microfactories as a stepping stone toward large-scale macrofactories

Aim: Manufacturing methods for cell-based therapies differ markedly from those established for noncellular pharmaceuticals and biologics. Attempts to ‘shoehorn’ these into existing frameworks have yielded poor outcomes. Some excellent clinical results have been realized, yet emergence of a ‘blockbuster’ cell-based therapy has so far proved elusive. Materials & methods: The pressure to provide these innovative therapies, even at a smaller scale, remains. In this process, economics research paper, we utilize cell expansion research data combined with operational cost modeling in a case study to demonstrate the alternative ways in which a novel mesenchymal stem cell-based therapy could be provided at small scale. Results & Conclusions: This research outlines the feasibility of cell microfactories but highlighted that there is a strong pressure to automate processes and split the quality control cost-burden over larger production batches. The study explores one potential paradigm of cell-based therapy provisioning as a potential exemplar on which to base manufacturing strategy

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

Putting a price tag on novel autologous cellular therapies

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.2016.05.005Cell therapies, especially autologous therapies, pose significant challenges to researchers who wish to move from small, probably academic, methods of manufacture to full commercial scale. There is a dearth of reliable information about the costs of operation, and this makes it difficult to predict with confidence the investment needed to translate the innovations to the clinic, other than as small-scale, clinician-led prescriptions. Here, we provide an example of the results of a cost model that takes into account the fixed and variable costs of manufacture of one such therapy. We also highlight the different factors that influence the product final pricing strategy. Our findings illustrate the need for cooperative and collective action by the research community in pre-competitive research to generate the operational models that are much needed to increase confidence in process development for these advanced products

Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

Background Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762. Findings Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. Interpretation Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function. Funding UK Stroke Association and NIHR Health Technology Assessment Programme

A new business model for cell-based therapeutics

Cell-based therapeutics have attracted large amounts of investment as they may offer effective treatments for a wide variety of health problems. In spite of extensive research relatively few examples of successful businesses exist. The products have several features that are challenging to manage when manufacturing at full scale. This feature is an obstacle to commercialisation that is often overlooked during research. For some cell-based therapeutics this may not be a problem. Traditional, centralised business models can be used with confidence for low volume production to treat high value indications, such as life-threatening disorders: the margins justify the expense. By contrast, when the products are required in large numbers and applied at high cell doses for less dramatic conditions the traditional model of business will be difficult to manage and to fund at full scale. An example is the cell-based repair of osteoarthritic damage to joints such as the knee. Overall business value for this target is high because the market is large and is growing. Effective therapy requires large cell doses and commands a modest value per dose. When using a traditional business model (requiring centralised manufacture and a long-distance, low temperature supply chain) very large sums of money must be put at risk during development in order to build adequate capacity. New ways of manufacturing and supplying such products are needed. A new model of business is developed in this thesis. The model requires lower initial capital investment and the business can be grown incrementally in line with demand rather than putting all the investment at risk at once. Data from published work and from laboratory experiments are used to derive the direct costs of manufacture. Structured Analysis and Design Technique and Activity Based Cost analysis are used to build a quantitative model of a centralised business. The model is compared with suitable alternatives based upon the extended enterprise model. The points of sensitivity in the cost model for the extended enterprise are identified and the model is refined to provide a less capital-intensive route for business development. The results and methods are of general applicability to similar products

A new business model for cell-based therapeutics

Cell-based therapeutics have attracted large amounts of investment as they may offer effective treatments for a wide variety of health problems. In spite of extensive research relatively few examples of successful businesses exist. The products have several features that are challenging to manage when manufacturing at full scale. This feature is an obstacle to commercialisation that is often overlooked during research. For some cell-based therapeutics this may not be a problem. Traditional, centralised business models can be used with confidence for low volume production to treat high value indications, such as life-threatening disorders: the margins justify the expense. By contrast, when the products are required in large numbers and applied at high cell doses for less dramatic conditions the traditional model of business will be difficult to manage and to fund at full scale. An example is the cell-based repair of osteoarthritic damage to joints such as the knee. Overall business value for this target is high because the market is large and is growing. Effective therapy requires large cell doses and commands a modest value per dose. When using a traditional business model (requiring centralised manufacture and a long-distance, low temperature supply chain) very large sums of money must be put at risk during development in order to build adequate capacity. New ways of manufacturing and supplying such products are needed. A new model of business is developed in this thesis. The model requires lower initial capital investment and the business can be grown incrementally in line with demand rather than putting all the investment at risk at once. Data from published work and from laboratory experiments are used to derive the direct costs of manufacture. Structured Analysis and Design Technique and Activity Based Cost analysis are used to build a quantitative model of a centralised business. The model is compared with suitable alternatives based upon the extended enterprise model. The points of sensitivity in the cost model for the extended enterprise are identified and the model is refined to provide a less capital-intensive route for business development. The results and methods are of general applicability to similar products

3D bioprinting in a 2D regulatory landscape: gaps, uncertainties, and problems

In this paper we assess both the ex ante and the ex post dimensions of the regulatory landscape of 3D bioprinting governance. While the former is mainly concerned with the market approval and safety of 3D bioprinting, the latter is concerned with the matter of liability once bioprinting has been licensed or authorised for use. In this 2D landscape, we highlight three sets of choices: whether regulation should focus on the process, the product or both; whether to rely on existing regimes or create a new bespoke and distinct regulatory framework; and whether to employ top down, bottom up, or co-regulation. We identify a series of interpretative uncertainties as well as gaps in the current legal regimes. We consider an initial provisional ‘process-based’ approach and a co-regulation model for bioprinting governance. We anticipate that the study of the regulatory landscape will offer key insights in relation to other types of biofabrication

A 3D bioprinting exemplar of the consequences of the regulatory requirements on customized processes

Computer-aided 3D printing approaches to the industrial production of customized 3D functional living constructs for restoration of tissue and organ function face significant regulatory challenges. Using the manufacture of a customized, 3D-bioprinted nasal implant as a well-informed but hypothetical exemplar, we examine how these products might be regulated. Existing EU and USA regulatory frameworks do not account for the differences between 3D printing and conventional manufacturing methods or the ability to create individual customized products using mechanized rather than craft approaches. Already subject to extensive regulatory control, issues related to control of the computer-aided design to manufacture process and the associated software system chain present additional scientific and regulatory challenges for manufacturers of these complex 3D-bioprinted advanced combination products

Pullulan: a new cytoadhesive for cell-mediated cartilage repair

Introduction: Local delivery of mesenchymal stem cells (MSCs) to the acutely injured or osteoarthritic joint retards cartilage destruction. However, in the absence of assistive materials the efficiency of engraftment of MSCs to either intact or fibrillated cartilage is low and localization is further reduced by natural movement of the joint surfaces. It is hypothesised that enhanced engraftment of the delivered MSCs at the cartilage surface will increase their reparative effect and that the application of a bioadhesive to the degraded cartilage surface will provide improved cell retention. Pullulan is a structurally flexible, non-immunogenic exopolysaccharide with wet-stick adhesive properties and has previously been used for drug delivery via the wet surfaces of the buccal cavity. In this study, the adhesive character of pullulan was exploited to enhance MSC retention on the damaged cartilage surface. Methods: MSCs labeled with PKH26 were applied to pullulan-coated osteoarthritic cartilage explants to measure cell retention. Cytocompatability was assessed by measuring the effects of prolonged exposure to the bioadhesive on MSC viability and proliferation. The surface phenotype of the cells was assessed by flow cytometry and their multipotent nature by measuring osteogenic, adipogenic and chrondrogenic differentiation. Experiments were also carried out to determine expression of the C-type lectin Dectin-2 receptor. Results: MSCs maintained a stable phenotype following exposure to pullulan in terms of metabolic activity, proliferation, differentiation and surface antigen expression. An increase in osteogenic activity and Dectin-2 receptor expression was seen in MSCs treated with pullulan. Markedly enhanced retention of MSCs was observed in explant culture of osteoarthritic cartilage. Conclusions: Pullulan is a biocompatible and effective cytoadhesive material for tissue engraftment of MSCs. Prolonged exposure to pullulan has no negative impact on the phenotype, viability and differentiation potential of the cells. Pullulan dramatically improves the retention of MSCs at the fibrillated surface of osteoarthritic articular cartilage. Pullulan causes an upregulation in expression of the Dectin-2 C-type lectin transmembrane complex