Evaluating downstream processing options at the bioprocess-business interface

Lead Research Organisation: University College London
Department Name: Biochemical Engineering

Abstract

In recent years, therapeutic antibodies produced in recombinant mammalian cells have become the fastest growing part of the new biopharmaceuticals sector. Along with this growth there have been significant increases in titres during the cell culture, such that all companies now face great challenges in handling the resulting materials during downstream processing. This challenge combined with the major time pressures on bioprocess development means that the decisions now rest on a multitude of process and business issues and have become extremely complex. The cost of experimentation to explore all these options is prohibitive and hence modelling tools are vital for different process sequences and operating conditions to be examined inexpensively, thus saving time and reducing costly pilot/scale trials. The proposed programme will link the leadership in antibody production of CAT, the manufacturing expertise of AstraZeneca and the leadership in bioprocess decisional support systems of UCL to tackle some of these intricate process-business decisions. The resulting decision-support algorithms will identify the most cost-effective downstream manufacturing strategies for the future. This will be achieved by developing combinatorial optimisation techniques and integrating them with multi-objective decision analysis and detailed process economic and logistical models to allow for a holistic assessment of the interactions between operational and financial indicators for alternative purification strategies.

Publications

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Allmendinger R (2014) Closed-loop optimization of chromatography column sizing strategies in biopharmaceutical manufacture. in Journal of chemical technology and biotechnology (Oxford, Oxfordshire : 1986)

 
Description Efforts to improve upon the cost-effectiveness of antibody manufacturing have been impeded by a lack of a systematic framework to assess the process-business trade-offs of competing process configurations. The deliverables of this research have highlighted valuable insights into the process economic drivers of antibody processes. The case study results have demonstrated the robustness and limitations of the current process platform while identifying and prioritsing alternative strategies that lead to both an increase in process efficiency and a reduction in costs. This has kept manufacturing off the critical path and significantly shortened the time required to prioritise cost-effective manufacturing strategies to cope with future trends. This knowhow from the models has contributed to focusing experimental resources at MedImmune only onto the most promising manufacturing processes and avoided significant investment into alternative strategies that the models identified as economically uncompetitive. The case studies have also helped to identify strategies that offer cost savings over the current process platform. At up to 25% of sales value, any reduction in the cost of goods (COG) represents a very significant financial return. Our analysis has shown that even a conservative estimate of 5% COG reductions can translate into over £5m annual savings for a commercial facility with annual operating costs of £100m. Our case studies illustrated strategies for achieving over 5% savings in COG.
Exploitation Route This research provides economic benefits to the wider biotech industry by highlighting valuable insights into the process economic drivers of antibody processes and the case study results highlight alternative strategies that lead to both an increase in process efficiency and a reduction in costs. The biotech industry has access to a new methodology, disseminated through publications as well as conferences, that will enhance understanding of their manufacturing systems, act as a test bed for their evaluation and hence significantly shorten the time required to prioritise cost-effective manufacturing strategies to cope with future trends. This can facilitate the growth of UK discovery-based companies to embrace more development capability and lead to the capture of a larger percentage of the total value of drug development. Furthermore, by identifying the most cost-effective strategies early in development, this will have spillover benefits to the NHS and patients by making new therapies available faster for patients. This has social impacts since significant pressures exist to ensure new antibody candidates are not so costly so as to preclude wide use. The NHS and patients will also benefit from a wider variety of drugs with MedImmune's antibody products which are being developed as potential treatments for severe conditions and areas of unmet medical need where treatment has immense social implications on the quality of life and hence getting people back to work. Dissemination of the case study results to the wider community will help identify potential bottlenecks in antibody processes, the scope of development needed and the overall feasibility of various routes. Hence, effective use of the modelling outcomes can lead to more concentrated R&D efforts and more effective use of resources by highlighting critical experiments to perform. Obviating the need for extensive pilot scale trials will improve energy efficiency, lead to waste reduction and lower inputs to production. Furthermore the tool will allow the exploration of routes which are sustainable given projected increases in upstream performance.
Sectors Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description The set of Bioprocess Decisional Tools developed through the research has been used extensively by the consortium to obtain a greater understanding of the impact of critical decisions, constraints and uncertainties on key financial, operational and risk metrics. The advantages, insights and impact gained from the approaches established by the research have also been disseminated to a wider community of industrialists through peer-reviewed publications, book chapters, international keynote presentations and Masters-level MBI® industrial training modules at UCL. The benefits to UK and international biotech companies of using the findings from the Decisional Tools developed span savings in cost and time, improvements in service delivery, creation of jobs, transfer of knowledge and priority shifts in investment decisions. R&D cost and time savings leading to competitive advantage: In UCL's 2008-2011 collaboration with MedImmune, Bioprocess Decisional Tools were created and applied to industrial case studies that identified more cost-effective manufacturing routes for therapeutic antibody production. MedImmune is a leader in the development and manufacture of novel antibody-based therapeutics which themselves represent the fastest-growing segment in the biotech sector. The outcomes of the UCL modelling helped to focus precious process development resources onto the most attractive strategies for further experimental verification, thus saving time and reducing costly experimentation. This conferred an important competitive advantage gained through time savings in an industry where timely market introduction of a novel drug can mean the difference between a blockbuster drug and one that barely makes a profitable return on R and D expenditures. The use of the UCL modelling outcomes] has already led to a reduction of development times for a product in early phase development of the order of 6 months. MedImmune views this time saving as critical as it allows it to stay ahead of the competition and establish its product as the standard of care and achieve greater market share. UCL estimates the value to a biopharmaceutical company arising from sales revenue of a new product starting six months early to be 50-100 million USD. MedImmune believes this estimate is conservative. Informing priority shifts in investment decisions: The collaboration with MedImmune also led the company to prioritise its R&D activities. Thus the models resulting from the research have contributed to focusing experimental resources at MedImmune only onto the most promising manufacturing processes. This led to priority shifts in R&D expenditure from investigating novel non-chromatography based steps (such as precipitation) to optimising existing chromatography steps.As a result of these changes, the company avoided significant investment into alternative strategies that the models identified as economically uncompetitive: 6 months' exploratory experimental work (equivalent to 12 man months) was not wasted but redirected to optimising the existing platform. The improved methods of cost optimisation helped to mitigate potential future losses and avoid the need for significant redevelopment prior to commercialisation and launch of a product. Manufacturing cost savings leading to improved business performance: In addition to R&D savings, Bioprocess Decisional Tools have also been used to optimise the cost of goods (COG) of manufacturing processes, leading to improved business processes. In UCL's collaboration with MedImmune, strategies offering 5-15% savings in COG were identified. UCL estimates the value of a 5% COG reduction as worth £5 million pa at a typical commercial antibody production facility". Jobs created and transfer of knowledge and skilled people: The UCL collaboration with MedImmune led directly to the creation in 2011 of two new employment contracts, each worth £100k, for a subcontract programmer to create a user-friendly version of the process economics tool for in-house use and for the company-based PDRA to extend process economic analyses and perform experimental work on the most promising strategies identified by the tool. The latter has retained support and is now integral to MedImmune's Downstream Processing team. Decisional Tools lectures and interactive workshops have been delivered as part of the Masters-level MBI® training courses at UCL (Effective Biopharmaceutical Development and Manufacture; Mammalian Cell Processes; Facility Design and Economics). Since 2008, we have transferred our specialist knowledge of current approaches to accelerating bioprocess development while cutting costs at 18 such sessions, extending the reach of our non-academic engagement to some 105 senior industrialists from more than 85 leading companies worldwide.
First Year Of Impact 2008
Sector Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic

 
Description BBSRC Grouped
Amount £190,625 (GBP)
Funding ID BB/J003816/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2011 
End 09/2015
 
Description EPSRC
Amount £171,950 (GBP)
Funding ID "IDTC Award (£85,257) with MedImmune support (£86,693)" 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 09/2011 
End 09/2015
 
Description EPSRC
Amount £171,950 (GBP)
Funding ID "IDTC Award (£85,257) with MedImmune support (£86,693)" 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 09/2011 
End 09/2015
 
Description EPSRC
Amount £5,168,034 (GBP)
Funding ID EP/I033270/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 10/2011 
End 10/2016
 
Title DT/F00236X/1: Evaluating downstream processing options at the bioprocess-business interface 
Description Multi-product biopharmaceutical facilities need flexible process configurations that can adapt to products with diverse characteristics and impurity loads so as to avoid bottlenecks and delays, whilst meeting final product specifications and cost targets. In order to aid the design of such facilities, this work presents a meta-heuristic optimisation approach using genetic algorithms where different levels of decision are addressed (facility, product sequence and unit operation) and multiple process and business criteria are used to evaluate each alternative generated. This is applied to a case study on the production of therapeutic monoclonal antibodies (mAbs), with a focus on the optimal purification sequences and chromatography column sizing strategies to cope with different facility configurations of upstream and downstream trains and different product impurity loads. The industrial case study provides novel insights that allow the identification of the most cost-effective purification sequences and column sizing strategies that meet demand and purity targets for each product in the facility. Emphasis is placed also on providing methods to visualise the trade-offs in the set of optimal solutions with similar cost values so as to enhance the decision making process. 
Type Of Material Computer model/algorithm 
Year Produced 2011 
Provided To Others? Yes  
Impact The tool outputs helped identify the most feasible strategies from an integrated process-business perspective which is critical to the realisation of more cost-efficient antibody processes. At the end of the project, use of the modelling results have allowed targets to be set to enable development scientists and engineers to plan more focused laboratory and pilot scale studies. Hence this will contribute to keeping manufacturing off the critical path. The benefit of accelerated development of processes will give potential for earlier market availability of new products. 
 
Description DT/F00236X/1: Evaluating downstream processing options at the bioprocess-business interface / TP/7/BIO/6/I/M0003H 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution UCL acted as lead university organisaiton in this TSB and EPSRC funded project. UCL set out to develop advanced decisional tools to address typical process design challenges in the biotech sector, to test them on industry demonstration projects and to disseminate the work to the community. These goals were made possible through this project collaboration that linked MedImmune's expertise in antibody production with UCL's leadership in bioprocess decisional support systems. The funding facilitated true collaboration with MedImmune. This enabled increased understanding and communication in areas ranging from process development and manufacturing through to clinical trials management. The formulation of industrially-relevant case studies and assumptions helped not only demonstrate the functionality of the toolkit developed but also helped answer key questions of relevance to the sector related to limitations of existing manufacturing platforms and identification of alternative manufacturing strategies that potentially provide cost savings. The funding provided opportunities to disseminate the research at key meetings.
Collaborator Contribution The project changed from a three-partner project (AstraZeneca, CAT (now MedImmune Ltd), UCL) to a two-partner project (MedImmune Ltd, UCL) in January 2009 following AstraZeneca's acquisition of CAT and MedImmune Ltd and their decision that all biotech-related projects would be led by MedImmune Ltd. This did not affect the core objective of the project. However, the proposal was revised to account for change in lead organization. In this project MedImmune Ltd acted as lead organisation on the grant. MedImmune provided access to expertise in both clinical and commercial scale production of antibodies, R&D portfolio management, clinical trials management and regulatory compliance. AstraZeneca provided expert input on supply chain management and regulatory compliance.
Impact Outcomes: 1) Develop advanced multi-objective combinatorial optimisation techniques that allow efficient exploration of the large number of possible permutations of decisions so as to identify the most promising strategies. [Achieved - Genetic algorithms were created to optimise decisions on the facility, process and unit operation levels. Multiple criteria were considered such as COG/g and time.] 2) Create an integrated decision-support tool that links the optimisation model to the process economic models developed at MedImmune. [Achieved - This allowed efficient exploration of the large number of possible permutations of decisions so as to identify the most promising strategies.] 3) Generate appropriate methods of presenting the modelling outputs that illustrate the risk-reward trade-offs and optimal set of solutions. [Achieved - Advanced methods of visualising the trade-offs in the outputs were generated such as bubble plots and discrete contour plots (heat maps).] 4) Formulate industrially-relevant case studies to be addressed with the tool. [Achieved - the case studies were formulated through interviews with MedImmune staff both in the UK and Gaithersburg (USA) sites] 5) Tool application to purification optimisation scenarios. [Achieved - these case studies screened a large database of possible sequence permutations, sizing strategies and facility configurations so as to identify the most cost-effective purification strategies.] 6) Training. [Achieved - A user-friendly tool interface and training package was developed. MedImmune personnel were trained to use the tool.] 7) Dissemination of research outputs to academic and industrial community. [Achieved - these include presentations at key conferences, including the highest profile conference of the discipline in 2010, inclusion in a book chapter and paper submissions to international peer-reviewed journals.] 8) Follow on support - New doctoral collaborations between UCL and MedImmune have been set up to extend the toolkit developed in this project with predictive models and advanced data analysis techniques (2 EPSRC IDTC EngD awards, 1 BRIC award). The systematic methodology created played a key role in the set up and success of the EPSRC Centre for Innovative Manufacturing in Emergent Macromolecular Therapies (2011-2016). Multidisciplinary project linking biochemical and chemical engineers with biochemists, manufacturing scientists and industrial engineers and operational research experts.
Start Year 2007
 
Description DT/F00236X/1: Evaluating downstream processing options at the bioprocess-business interface / TP/7/BIO/6/I/M0003H 
Organisation MedImmune
Country United States 
Sector Private 
PI Contribution UCL acted as lead university organisaiton in this TSB and EPSRC funded project. UCL set out to develop advanced decisional tools to address typical process design challenges in the biotech sector, to test them on industry demonstration projects and to disseminate the work to the community. These goals were made possible through this project collaboration that linked MedImmune's expertise in antibody production with UCL's leadership in bioprocess decisional support systems. The funding facilitated true collaboration with MedImmune. This enabled increased understanding and communication in areas ranging from process development and manufacturing through to clinical trials management. The formulation of industrially-relevant case studies and assumptions helped not only demonstrate the functionality of the toolkit developed but also helped answer key questions of relevance to the sector related to limitations of existing manufacturing platforms and identification of alternative manufacturing strategies that potentially provide cost savings. The funding provided opportunities to disseminate the research at key meetings.
Collaborator Contribution The project changed from a three-partner project (AstraZeneca, CAT (now MedImmune Ltd), UCL) to a two-partner project (MedImmune Ltd, UCL) in January 2009 following AstraZeneca's acquisition of CAT and MedImmune Ltd and their decision that all biotech-related projects would be led by MedImmune Ltd. This did not affect the core objective of the project. However, the proposal was revised to account for change in lead organization. In this project MedImmune Ltd acted as lead organisation on the grant. MedImmune provided access to expertise in both clinical and commercial scale production of antibodies, R&D portfolio management, clinical trials management and regulatory compliance. AstraZeneca provided expert input on supply chain management and regulatory compliance.
Impact Outcomes: 1) Develop advanced multi-objective combinatorial optimisation techniques that allow efficient exploration of the large number of possible permutations of decisions so as to identify the most promising strategies. [Achieved - Genetic algorithms were created to optimise decisions on the facility, process and unit operation levels. Multiple criteria were considered such as COG/g and time.] 2) Create an integrated decision-support tool that links the optimisation model to the process economic models developed at MedImmune. [Achieved - This allowed efficient exploration of the large number of possible permutations of decisions so as to identify the most promising strategies.] 3) Generate appropriate methods of presenting the modelling outputs that illustrate the risk-reward trade-offs and optimal set of solutions. [Achieved - Advanced methods of visualising the trade-offs in the outputs were generated such as bubble plots and discrete contour plots (heat maps).] 4) Formulate industrially-relevant case studies to be addressed with the tool. [Achieved - the case studies were formulated through interviews with MedImmune staff both in the UK and Gaithersburg (USA) sites] 5) Tool application to purification optimisation scenarios. [Achieved - these case studies screened a large database of possible sequence permutations, sizing strategies and facility configurations so as to identify the most cost-effective purification strategies.] 6) Training. [Achieved - A user-friendly tool interface and training package was developed. MedImmune personnel were trained to use the tool.] 7) Dissemination of research outputs to academic and industrial community. [Achieved - these include presentations at key conferences, including the highest profile conference of the discipline in 2010, inclusion in a book chapter and paper submissions to international peer-reviewed journals.] 8) Follow on support - New doctoral collaborations between UCL and MedImmune have been set up to extend the toolkit developed in this project with predictive models and advanced data analysis techniques (2 EPSRC IDTC EngD awards, 1 BRIC award). The systematic methodology created played a key role in the set up and success of the EPSRC Centre for Innovative Manufacturing in Emergent Macromolecular Therapies (2011-2016). Multidisciplinary project linking biochemical and chemical engineers with biochemists, manufacturing scientists and industrial engineers and operational research experts.
Start Year 2007