Cell culture media impact on drug product solution stability.
To enable subcutaneous administration of monoclonal antibodies, drug product solutions are often needed at high concentrations. A significant risk associated with high drug product concentrations is an increase in aggregate level over the shelf-life dating period. While much work has been done to understand the impact of drug product formulation on aggregation, there is limited understanding of the link between cell culture process conditions and soluble aggregate growth in drug product. During cell culture process development, soluble aggregates are often measured at harvest using cell-free material purified by Protein A chromatography. In the work reported here, cell culture media components were evaluated with respect to their impact on aggregate levels in high concentration solution drug product during accelerated stability studies. Two components, cysteine and ferric ammonium citrate, were found to impact aggregate growth rates in our current media (version 1) leading to the development of new chemically defined media and concentrated feed formulations. The new version of media and associated concentrated feeds (version 2) were evaluated across four cell lines producing recombinant IgG4 monoclonal antibodies and a bispecific antibody. In all four cell lines, the version 2 media reduced aggregate growth over the course of a 12 week accelerated stability study compared with the version 1 media, although the degree to which aggregate growth decreased was cell line dependent. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:998-1008, 2016.
Bioproduct Research and Development, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
Jennifer L
JL
Purdie
Bioproduct Research and Development, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
Ronald L
RL
Kowle
Bioproduct Research and Development, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
Amie L
AL
Langland
Biotechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285.
Chetan N
CN
Patel
Bioproduct Research and Development, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
Anli
A
Ouyang
Bioproduct Research and Development, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
Donald J
DJ
Olson
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D016466:CHO Cells; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D003412:Cricetulus; D003470:Culture Media / Q000737:chemistry*; D003545:Cysteine / Q000737:chemistry*; D004355:Drug Stability; D005290:Ferric Compounds / Q000737:chemistry*; D000644:Quaternary Ammonium Compounds / Q000737:chemistry*; D012996:Solutions
D000911:Antibodies, Monoclonal; D003470:Culture Media; D005290:Ferric Compounds; D000644:Quaternary Ammonium Compounds; D012996:Solutions; D003545:Cysteine; C013531:ferric ammonium citrate
cell culture; cell culture media; cysteine; drug product stability; iron