Manufacturing automation within the supply chain to ensure patient safety

Lead Research Organisation: Cranfield University
Department Name: Sch of Aerospace, Transport & Manufact

Abstract

The cell therapy industry is offering huge opportunities to transform the way healthcare is delivered. However, the current
amount of manufactured goods is limited and the manufacturing processes require drastic transformation to be able to
respond to the potential demand. This proposal will aim to create a demonstrator that allows flexible manufacturing by
automating the storage and retrieval of sample vials from multiple large capacity Cryogenic storage devices. Adopting this
technology / solution requires the cell therapy sector to develop an integrated supply chain to enhance the number of
manufactured goods. The current project will first stabilise and subsequently grow robust pharmaceutical supply chains.
In order to achieve this, the project will develop and implement novel rapid prototyping and manufacturing capability at
Fisher Bioservices. This design-led approach will reduce risk in the early stages of the development process, thereby
dramatically improving attrition rates and return on investment. The company will be recognised as leading the
transformation of developing cell therapy goods. The benefits are not limited to the company, its clients and supply chain
partners but will be realised across the whole value chain, including patients and wider society.
Cranfield's main role focuses on investigate the improvement options to address the bottlenecks identified. This will look
into developing tools and processes improving the manufacturing and supply chain. In line with the main aim of this WP,
the following objectives are defined:
1. Review suitable simulation approaches (Linear Optimisation, Discrete Event, Agent Based, and System Dynamics). This
will incorporate recent research in Gene Therapy, Aerospace and Defence
Manufacturing (which are relatively low-volume, highly advanced technological manufacturing)
2. Design and develop computerised simulation models to optimise the manufacturing (and supply chain) workflows. This
will involve using commercial off the shelf software packages and bespoke
tools developed for improving decisions in automation.
3. Develop an innovation roadmap to embed the findings from the simulation models which will feed into WP3
(DEVELOPMENT OF A MODULAR INTEGRATED AUTOMATED CRYOGENIC STORAGE
ARCHITECTURE) and WP 4 (NEXT GENERATION FACILITY)
4. Validate the results and findings from simulation modelling with the real system. This can be done by multi-expert
workshops and comparisons with historical data
Cranfield University will be involved across the WPs. Furthermore, WP 2 will be contributing to other WPs as covered
below:
1. Based on the scope of work defined in WP1 (ASSESSMENT OF CURRENT MANUAL SYSTEMS), Cranfield University
will work closely with the Cell Therapy Catapult and others to collaboratively
conduct the review and gain knowledge from WP1
2. WP3 to provide relevant data required to develop simulation models (e.g. type of automation, degree of automation,
cost of automation)
3. WP4 to provide relevant data required to design the proposed production system
4. Specific outputs to WP3 include various Decision making toolsets to identify where and how automation can be applied,
what time and cost savings can be achieved through automation, what is the future supply chain going to look like. Case
reports for industrial validations demonstrating the benefits of automation strategy using simulation modelling.
5. Specific outputs to WP4 include optimised process configurations for FBS manufacturing supply chains
6. From time to time the project partners need to validate the model developed and provide feedback. Validation to happen in 2 stages:
a. To check of the model developed confirms to the real system (to be done by FBS)
b. To check if the results from simulations are consistent with the initial assessment and meets the targets (to be done by
FBS and Cell Therapy Catapult)

Planned Impact

The aim of this industry-led project is to develop and implement novel rapid prototyping and manufacturing capability at
Fisher Bioservices in order to support with drastically increasing the manufacturing scale. Impact and working with
beneficiaries is embedded in the project; not a separate event after completion. That means that throughout the project all
partners are committed and contribute their skills and experience to achieving our common aims and objectives.
Beneficiaries will include all partners who are involved in this project. However, FBS will directly benefit from process
optimisation through simulation modelling in terms of reducing their lead time to manufacture and supply critical products
but also substantially reduce the cost associated with resources, rejections, losses etc. Given the benefits of simulation, the
adoption of simulation-based studies in the biopharmaceutical sector is limited when compared to other manufacturing
sectors. This has created a huge gap in the current market to utilise simulation modelling techniques for designing
biopharmaceutical manufacturing processes (Saraph, Prasad V. "Future of simulation in biotechnology industry."
Simulation Conference, 2004. Proceedings of the 2004 Winter. Vol. 2. IEEE, 2004.). As early adopters of these techniques
to innovate their workflows, FBS can further gain significant competitive advantage and set standards as world leaders in
Cell Therapy manufacturing and supply chain. Additionally, significant value can be added through dissemination of the
knowledge and results from this project. Cranfield University along with other industrial partners will develop a number of
relevant courses and events targeted at university students and industry executives. Furthermore, the results will be
presented in international journals and conferences to maximise the dissemination impact. Cranfield University will also
benefit from the establishment of this relatively new research area allowing future collaboration with other research groups
both within and outside the university.
An effective multi-disciplinary approach is needed for the project to be successful. This requires intensive communication
across disciplines and organisations. Cranfield plans to set up a web-based communication portal to enable effective
engagement of all project partners. Furthermore it is important that we develop a dialogue with stakeholders and
beneficiaries. Findings and outcomes at key stages in the project will be shared using the portal and social networking
media.
Cranfield will ensure that clinicians and patient will be involved with other stakeholders throughout the project. The PI has
already been able to identify and involve NHS partners in the preparation of this proposal. We will apply co-creation and codesigning
simulation and modelling methods to ensure that the rapid prototyping and manufacturing system delivers
products than can be processed by supply chain partners, used by clinicians and will be accepted by patients. Only this
approach will lead to fast adoption and diffusion and will ultimately ensure the commercial success of the approach.
This programme of multi-disciplinary research will provide a model for translating scientific
discoveries into clinical and commercial solutions. Knowledge transfer is an ongoing Impact
affecting each of the phases in the work plan. The project will offer case studies of production systems and supply chains
that are potentially applicable to other areas in the pharmaceutical sector. This will be disseminated through:
1. Developing and maintaining a project web-portal
2. Publishing articles and papers
3. Organising and participating in events such as seminars and conferences
4. Delivering education programmes
5. Developing further applied research activities in pharmaceutical product development

Publications

10 25 50
publication icon
Ahmet Erkoyuncu J (2016) A framework to estimate the cost of No-Fault Found events in International Journal of Production Economics

publication icon
Farsi M (2019) A modular hybrid simulation framework for complex manufacturing system design in Simulation Modelling Practice and Theory

 
Description Flexibility is an essential element for manufacturing systems in a globalised industry environment. For the systems which entail complex operations and processes, achieving flexibility necessitates a comprehensive study of the intricate interactions between different components and aspects of the system. Such interactive behaviour in a complex system can be studied by implementing an integrated framework which assesses the behaviour of the system over time. In this research study, a flexible manufacturing system model and simulation of a cell-based therapy and cryostorage company is presented using combined Discrete Event Simulation (DES) and Agent-Based Modelling (ABM) simulation techniques. Furthermore, the hybrid computational modelling is integrated with 2D/3D process visualisation and dynamic data analysis to create a decision support system using scenario analysis. The developed computational modelling and simulation is verified and validated against the real data from the studied case.

• This research paper has extended our knowledge and understanding about the highly complex and interactive processes and regulations such as cell therapy industry and cellular cryo-storages sectors by a comprehensive literature review, interviewing experts and several site visits and shop floor observation.
• In this study a novel prototyping and manufacturing capability at the studied cellular cryo-storage company has been developed in order to demonstrate and extend the knowledge about flexible manufacturing in such complex systems.
• The developed framework and toolsets support academics, researchers and industrial sectors of this field, to extend their knowledge about the current stage of cellular cryo-storage sectors in the UK and subsequently outline and develop the next generation of this practice.
• In this study an integrated framework has been developed to model and simulate the complex behaviour of a cellular cryo-storage system using combined ABM and DES techniques, 2D/3D simulation visualisation and dynamic data analysis and visualisation.
• Several dynamic data analysis, parameters variation and optimisation have been conducted to address the bottlenecks and with regards to utilisation, inventory capacity and time in- system. The focus is to improve the productivity of the company with respect to an increase in the total number of dispatches.
• The developed computational toolsets enable decision-makers to simulate different scenarios within the current practice in order to identify the corresponding impacts on the process performance. Adopting this technology and decision support tool requires the cell therapy sector to develop an integrated and efficient supply chain to enhance the number of manufactured goods.
• The proposed framework and toolsets support decision-makers regarding enhancing their decisions and improving or modifying the corresponding policies and regulations in cellular cryo-storage sectors.
• The developed framework and the computational modelling and simulation method is applicable in other systems and organisations with complex and interactive behaviour.
Exploitation Route There are numerous statistical analysis, which can be included into the current developed framework and the computational model. For instance, adding the cost details in each phase can deliver a generic cost analysis and management toolset. The generic framework can be utilised for assessing Cost of Goods (CoGs) analysis of the bioprocess components of cell therapy manufacturers. Moreover, the presented computational model is a virtual platform to test several actual and possible disruptions, breakdowns, and other emergency scenarios to enhance decision-making. The computational model can be integrated with several risk assessment techniques to perform Failure Modes and Effects Analysis (FMEA) in a complex system. Concerning the cell-based therapy processes, the combined risk assessment and cost analysis can highlight the behaviour of the system's current state which can be fed into the future state. Finally, the results can provide sufficient information to design and develop more cost effective and flexible manufacturing processes. Focusing on cell-based therapy supply chain, the developed computational model can be completed by integrating the current considered phases with the other phases of the entire supply chain. The complete computational model provides an integrated and comprehensive framework to analyse the behaviour of the whole end-to-end supply chain.
Sectors Aerospace, Defence and Marine,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description Prototype computer simulation model enabled to: - Capture the current bottlenecks in the manufacturing process. - Demonstrate the number of daily and monthly dispatches which are between 8-11 and 150-250 respectively. - The computational model demonstrates the total number of dispatches for the 8-month period from Jan 2016 until the end of August 2016, which is 1558. - The Company is aiming to increase its number of cryo-products dispatches to 600 per day. This is approximately 70 times higher than the current practice. The next generation of manufacturing has been designed to enable this. This includes: o Identifying practical solutions for the company to remove the current bottlenecks (e.g. technological applications, as well as lean type implementation) in the system. The bottlenecks have been captured by the developed computational model and have been verified by the experts in the company. o Identifying next generation new technologies in cell-based cryo-storage practices and applying them in a computational model to predict their impacts on the manufacturing process. o Modifying the factory layout of the procedures and proposing a new floor plan for the studied company with respect to the findings from the previous points. - Finally, the developed computational model will be modified based on the outcomes from this project to estimate the total number of daily dispatches.
First Year Of Impact 2018
Sector Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic

 
Description Training material on simulation for MSc level students
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact A one week training was delivered on simulation, and there after an MSc Group project was applied with 4 students. The students learned extensively about the cell therapy manufacturing context. The students contributed to improving the manufacturing capability in the Fisher Bio Services context.
 
Description Manufacturing
Amount £1,000,000 (GBP)
Funding ID 102787 
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 04/2017 
End 04/2019
 
Title Mixed modelling toolkit for cell therapy manufacturing 
Description A modelling toolkit was developed in a commercial off the shelf software package called Anylogic. The developed model contributes to academia with the new knowledge in mixed modelling approach developed. It contributed to industry by increasing productivity in manufacturing. 
Type Of Material Improvements to research infrastructure 
Year Produced 2017 
Provided To Others? Yes  
Impact The company was demonstrated how the company can make a 10 fold increase in number or pharma solutions, 
 
Title Mixed modelling approach 
Description The model considers the cell therapy manufacturing processes and helps to optimise the number of pharma products for customers. 
Type Of Material Computer model/algorithm 
Year Produced 2017 
Provided To Others? Yes  
Impact The company was shown how to increase the number of products for patients; which will have a major impact on their market reach and will also help with supporting a a larger range of patients. 
 
Description Supply Chain Mapping for ATMP's Manufacturers 
Organisation Cell and Gene Therapy Catapult
Country United Kingdom 
Sector Private 
PI Contribution CGT Catapult Cluster at Stevenage Bioscience Catalyst is established by Innovate UK to motivate the CGT innovation at scale regarding the growth of the cell and gene therapy industry and supporting them to overcome barriers for scaling-up and commercialisation. To tackle part of the challenges regarding developing a large-scale manufacturing system, Cranfield developed a detailed model for the manufacturing support functions concerning the ATMP manufacturing space for the autologous process.
Collaborator Contribution The Cell and Gene Therapy catapult contributed to achieve the following objectives:established through fulfilling the following objectives: 1. Developing a computational model for the support functions of CGT Catapult as a supply chain including ATMP manufacturing for the autologous process, GMP warehousing, CGT Cluster, patient treatment centres and logistics (Just in Time delivery system) (see Figure 1 ). 2. Identifying future bottlenecks and tipping points as the demand increases through the product development cycle, 3. Identifying the optimum model of the scale-up supply chain. 4. Identifying the support infrastructure required from the CGT Catapult to support the above, in term of: a. GMP warehousing (patient sample, bill of material and final product handling), b. QC support (environmental monitoring, raw material, in-process control and final product plus the likely increased demand for speed), c. QA, QP Certification, d. Handling of waste
Impact 1. Journal paper in development (focuses on reporting on advanced modelling and simulation capability), 2. white paper in development to disseminate findings from study to industry, 3. new Innovate UK proposal
Start Year 2017
 
Description Dissemination to project partners 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Industry/Business
Results and Impact This involved getting the project partners (Fisher Bio Services, Cryogatt, and the Cell and Gene therapy catapult) up to date with the developed project outputs.
Year(s) Of Engagement Activity 2017,2018
 
Description Presentation at the annual Cell and Gene Therapy Catapult 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Some of the major project outcomes were presented. This showed up to date simulation methods and results, which were useful for a number of the delegates.
Year(s) Of Engagement Activity 2017