A Statistical Approach to Determining Criticality of Residual Host Cell DNA

Abstract

We propose a method for determining the criticality of residual host cell DNA, which is characterized through two attributes, namely the size and amount of residual DNA in biopharmaceutical product. By applying a mechanistic modeling approach to the problem, we establish the linkage between residual DNA and product safety measured in terms of immunogenicity, oncogenicity, and infectivity. Such a link makes it possible to establish acceptable ranges of residual DNA size and amount. Application of the method is illustrated through two real-life examples related to a vaccine manufactured in Madin Darby Canine Kidney cell line and a monoclonal antibody using Chinese hamster ovary (CHO) cell line as host cells.

Key words:

• Critical quality attribute
• Infectivity
• Oncogenicity
• Quality by design
• Residual host cell DNA
• Risk assessment

ACKNOWLEDGMENTS

We thank Dr. Jason Zhang for his technical support in producing the graphs in the manuscript and Mr. Tim Schofield and Dr. Laura Richman for their helpful comments that greatly helped improve the manuscript.