title: The integrated simulation and assessment of the impacts of process change in biotherapeutic antibody production.
abstract: Growing commercial pressures in the pharmaceutical industry are establishing a need for robust computer simulations of whole bioprocesses to allow rapid prediction of the effects of changes made to manufacturing operations. This paper presents an integrated process simulation that models the cGMP manufacture of the FDA-approved biotherapeutic CroFab, an IgG fragment used to treat rattlesnake envenomation (Protherics U.K. Limited, Blaenwaun, Ffostrasol, Llandysul, Wales, U.K.). Initially, the product is isolated from ovine serum by precipitation and centrifugation, before enzymatic digestion of the IgG to produce FAB and FC fragments. These are purified by ion exchange and affinity chromatography to remove the FC and non-specific FAB fragments from the final venom-specific FAB product. The model was constructed in a discrete event simulation environment and used to determine the potential impact of a series of changes to the process, such as increasing the step efficiencies or volumes of chromatographic matrices, upon product yields and process times. The study indicated that the overall FAB yield was particularly sensitive to changes in the digestive and affinity chromatographic step efficiencies, which have a predicted 30% greater impact on process FAB yield than do the precipitation or centrifugation stages. The study showed that increasing the volume of affinity matrix has a negligible impact upon total process time. Although results such as these would require experimental verification within the physical constraints of the process and the facility, the model predictions are still useful in allowing rapid "what-if" scenario analysis of the likely impacts of process changes within such an integrated production process.
authors.affiliation: The Advanced Centre for Biochemical Engineering, University College London, Torrington Place, London WC1E 7JE, United Kingdom.
authors.forename: Sunil
authors.initials: S
authors.lastname: Chhatre
authors.forename: Carl
authors.initials: C
authors.lastname: Jones
authors.forename: Richard
authors.initials: R
authors.lastname: Francis
authors.forename: Kieran
authors.initials: K
authors.lastname: O'Donovan
authors.forename: Nigel
authors.initials: N
authors.lastname: Titchener-Hooker
authors.forename: Anthony
authors.initials: A
authors.lastname: Newcombe
authors.forename: Eli
authors.initials: E
authors.lastname: Keshavarz-Moore
mesh_terms: D000997:Antivenins / Q000737:chemistry* / Q000276:immunology / Q000627:therapeutic use*; D005591:Chemical Fractionation / Q000379:methods*; D003198:Computer Simulation; D004339:Drug Compounding / Q000379:methods*; D015195:Drug Design; D007140:Immunoglobulin Fab Fragments; D007128:Immunoglobulin Fragments / Q000737:chemistry* / Q000276:immunology / Q000627:therapeutic use*; D008956:Models, Chemical; D018511:Systems Integration
chemical_list: D000997:Antivenins; C431183:Crotalidae Polyvalent immune Fab; D007140:Immunoglobulin Fab Fragments; D007128:Immunoglobulin Fragments