BIOCHEMICAL AND ENVIRONMENTAL ENGINEERING GROUP: bioproducts

We are developing techniques that will make it cheaper and faster to produce biological therapeutic products, such as those required for cancer treatments, stem cell therapy and Chinese medicine

The challengeThe production of next generation biological therapeutic products, such as monoclonal antibodies to treat cancer or autoimmune diseases, is a complex and costly process. The products are known collectively as biologicals or bioproducts.

To make them, biological cells are first manipulated so that they can synthesise the required bioproduct. Next, large amounts of bioproduct are produced by growing up these cells in industrial fermenters. However, to be used therapeutically (eg so that an antibody is safe for injection), the bioproduct has to be recovered from the cells and purified to exacting regulatory standards.

Drawbacks of current methodsThe pharmaceutical industry currently uses conventional multi- step processes, which often have as many as ten different stages. While the cost of making biological therapeutics is already high due to development costs (eg to meet regulations on patient safety) the multi-step purification process adds significantly to the cost of the production process due to its difficulty and complexity.

Our work in tackling thisWe are improving the separation techniques and aim to at least halve the number of steps of the purification process. This will considerably reduce production costs, as well product development time. We are interested in many different aspects of separation processes in biotechnology; one exciting method we have developed is highly selective expanded bed adsorption (EBA).

a). Costly packed bed technology. In this process expensive centrifugation or microfiltration is required to remove solids (brown) from the liquid containing the bioproduct before it is fed through the bed of beads. The solids, which originate from the cells in which the bioproduct has been synthesized, would otherwise block the flow of liquid through the bed (as shown).

MethodologyCurrent practice for the purification of the bioproducts often uses packed bed liquid chromatography. Liquid feedstock containing the bioproduct is fed through a packed bed of beads that adsorb the bioproduct. However the feedstock has to be first freed of any solids originating from the cells in which it has been synthesized, as these solids would block the flow of liquid. This is done using costly centrifugation or microfiltration. The conventional alternative is to use a fluidised bed which allows solids to flow past the beads. The downside here is that the adsorbent beads are extensively mixed around in the bed, which greatly impairs the separation performance.

We have found far better separation can be achieved if the beads are in an expanded, rather than fluidised, configuration: the beads are arranged similarly to the packed bed but with greater spaces between them. They are not mixed around as in the fluidised bed, and there is no requirement for the centrifugation or microfiltration pretreatment needed for the packed bed operation. We also use highly selective ‘affinity’ ligands attached to the beads, that further improve the efficiency of separating the bioproduct, and reduces the overall number of steps needed to achieve the required purity. This ‘expanded bed adsorption’ technique is far more efficient, resulting in much better separation.

Potential applications 1. For cancer or autoimmune disease treatments

Purification of therapeutic proteins and enzymes2. For stem cell therapy and other regenerative procedures Separation of different types of mammalian cells 3. For use in Chinese medicine

Isolation of active pharmaceutical ingredients from plant material

Our techniques and skills• Affinity, ion-exchange, hydrophobic and mixed mode

chromatography• Packed bed, expanded bed, fluidized bed and countercurrent bed

operation• Novel adsorbent matrices and affinity ligands• Adsorption and chromatographic modelling and optimization

What is new about our work? We are the among the first to have developed the EBA technique and have demonstrated its effectiveness via our extensive publications in scientific literature.

Current industrial partnershipsNone. We are keen to form partnerships with companies interesting in adopting our techniques and strategies. Our techniques may be particularly relevant to the production of generic versions of existing biologicals.

Professor Howard Chase, University of Cambridge, Department of Chemical Engineering and Biotechnology, Pembroke Street, Cambridge, CB2 3RA Tel: 0044 1223 334781 Email: hac1000@cam.ac.uk Web: http://www.ceb.cam.ac.uk/directory/howard-chase

The team

BIOCHEMICAL AND ENVIRONMENTAL ENGINEERING continued

b). Poor adsorbing fluidised bed technology. The alternative conventional fluidised bed allows flow of such solids past the adsorbent beads. However, separation performance is impaired as a result of the extensive mixing of the adsorbent beads in the bed.

Prod

uced

by

Crea

tive

War

ehou

se, C

ambr

idge

c). Solution: the expanded bed. Far better separation can be achieved if the beads are arranged similarly to the packed bed but with greater spaces between them. They are not mixed around as in the fluidised bed, and there is no requirement for the centrifugation or microfiltration needed for the packed bed treatment.