The Silver Anniversary of Clinical Protein Production from Recombinant CHO Cell Culture

Title: The Silver Anniversary of Clinical Protein Production from Recombinant CHO Cell Culture

Speaker: Matthew Croughan

Affiliation: Amgen Bioprocessing Center
Keck Graduate Institute (KGI), Claremont, CA

Host: Manuel Carrondo

 Abstract:

In 1983, Genentech initiated the first human clinical trial of a therapeutic protein made in recombinant CHO cell culture. At the time, many viewed recombinant cell culture as a production method of last resort, certainly not one suitable to make a high-dose therapeutic. With low peak cell densities and low specific productivities in medium containing expensive animal-derived components, final product concentrations at harvest were low, typically below 1 mg/L.  Furthermore, there were regulatory risks, as the safety of products from continuous aneuploid cell lines (like CHO) had yet to be established.
Twenty five years later, recombinant CHO cell culture has emerged as one of the dominant methods for production of recombinant proteins, especially high-dose therapeutic antibodies. The story behind this emergence should be viewed as one of the great case studies in new technology development.
In this presentation, data from 25 years of clinical production is analyzed to derive the CHO cell culture equivalent of 'Moore's Law' for semiconductors. Cell culture engineers are pitted against semiconductor and agricultural engineers.  Progress rates for firms new to the field are distinguished from the rates for experienced firms.  For batch and fed-batch CHO cell cultures used for clinical production, titers at harvest for experienced firms have doubled every 3.4 years.  Progress rates are compared against the historical benchmarks for penicillin and used to estimate a future maximum titer of 20 g/L.
Over twenty five years, numerous challenges were faced and successfully overcome.  A timeline of these achievements will be discussed, starting with batch culture in roller bottles, moving through suspension adaptation, medium enrichment, aseptic operations, scale up, and removal of CHO DNA and retrovirus, to high density bioreactor design, viral barriers and inactivation, automation, plant design, and development platforms.  The cost benefits of past and future process development achievements are estimated.  Future market opportunities and cell culture challenges will be discussed.

CV:

Matt Croughan
George B. and Joy Rathmann Professor
Director of the Amgen Bioprocessing Center
Keck Graduate Institute (KGI), Claremont, CA

At KGI, Professor Croughan teaches courses on biotechnology development and manufacturing for students earning a Masters in Bioscience (MBS), a unique professional science degree for those who want a career in leadership at the interface of business, engineering, and biology.   As part of this, he teaches advanced courses in bioprocessing to students in a new Bioprocessing focus track, and also serves as faculty advisor on collaborative projects with industry (Team Masters Projects).  His laboratory classes and research range from monoclonal antibody production and purification, to fermented beverages, to biodiesel production from algae. 

Prior to joining KGI, Dr. Croughan spent 8 years consulting with over 35 firms on biopharmaceutical process development and manufacturing issues.  He still consults with eight firms part-time.

Prior to consulting, Dr. Croughan worked at Genentech for ten years.  He led the development of the first licensed, high-density, fed-batch cell culture process, a breakthrough platform technology now used by Genentech and throughout the industry for production of high-dose therapeutic antibodies and other proteins.  He has a B.S. from U.C. Berkeley and a Ph.D from M.I.T., both in chemical engineering.