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industry focus.

To realise the full benefits of regenerative medicine technology will require substantial manufacturing capability involving large scale processing of biological material. To minimise the transition time between laboratory and clinic there is a need for biologists to be exposed to engineering concepts and ways of thinking. The current tools of the trade for biologists working in regenerative medicine include culture flasks, micro-pipettes and centrifuges. The development cycle to commercialisation will require the use of bench-top bioreactors (1-2L), pilot-scale bioreactors (100-1000L), industrial scale operations, product recovery (downstream processing) and packaging. Some of the considerations in each of these steps are outlined in Table 1.

Biological characteristics of cells impose constraints on bioprocessing parameters, for example, the maximum operating temperature. It is equally true that engineering considerations impact on biology in production scale operations; it would be disheartening, for instance, to optimise manipulation of a cell to express a particular gene if the cells in culture produced a broth that was incapable of adequate mixing or supply of nutrients in large scale vessels.

In practice combining the skills of engineers with those of biologists can be very difficult. Biologists generally have

strong experimental technique and are good at testing qualitative models. On the other hand, as calculations are important in equipment design and process analysis, quantitative methods play a central role in engineering. To scale up (or scale out) regenerative medicine to meet global demand will require a strong focus on engineering principles, and a significant and accelerated narrowing of the gap between the biological and engineering industries. Some of the potential engineering solutions that would make regenerative medicine a global reality are summarised in Table 2.

The UK Government, via its Technology Strategy Board funding arm, has recognised that the UK can take a lead in this systems based approach, investing in regenerative medicine programmes not only in developing therapeutics, but also in tools and technologies and high value manufacturing. Production of therapeutics from cell lineages remains in its infancy, and there are numerous challenges to overcome to transition from laboratory to clinic in a reproducible, scaleable and economically viable way. Similar to the bioprocessing industry over 20 years ago, the introduction of engineering thought processes to biological challenges can result in advancement of the techniques and equipment available to give the UK a lead in translating laboratory discoveries to production therapies.

Table 1: Steps in development of a bioprocess for commercial manufacture of a cell-based regenerative medicine product PROCESS STEP Bench top bioreactors

CONSIDERATIONS Monitoring pH, nutrient supply, mechanical forces Pilot scale bioreactor Industrial scale operation Product recovery and packaging

Loss or variance of performance, aeration and mixing, reactor design and impact – e.g. heterogeneous cell cultures, loss of productivity, revision of economic projections

Auxiliary service facilities (air supply design and sterilisation, supply lines), medium preparation and sterilisation, process control network, containment and safety

Purification, characterisation, QA, automation

Table 2: Engineering and single-use technologies in regenerative medicine production PROCESS

Sterile fluid transfer Cell cultivation Cell washing and concentration Cell Identification Cell release


T-flask/ multi-layer flasks

Stirred tank or rocking bioreactor/ roller bottles

Centrifuge Fluorescence activated cell sorting 14 day sterility check

SYSTEMS SOLUTION Peristaltic pump

Automation without variability Rapid prototyping/3D printing

Continuous centrifuge Disposable cell washconcentration system

Robust production platform to eliminate cell sorting at scale

Rapid sterility assay References

1 Mason C, Dunnill P. A brief definition of regenerative medicine. Regen Med, 2008; 3:1-5.

2 The Guardian, 18 Oct. 2007

3 Werner, Ruffin and West, Regenerative Medicines; a paradigm shift in healthcare. Spring 2011

4 Office for National Statistics (in Taking Stock of Regenerative Medicine, BIS July 2011)


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