Advancing Biologics Development Programs with Legacy Cell Lines: Advantages and Limitations of Genetic Testing for Addressing Clonality Concerns Prior to Availability of Late Stage Process and Product Consistency Data.

The bioprocessing industry uses recombinant mammalian cell lines to generate therapeutic biologic drugs. To ensure consistent product quality of the therapeutic proteins it is imperative to have a controlled production process. Regulatory agencies and the biotechnology industry consider cell line ″clonal origin″ an important aspect of maintaining process control. Demonstration of clonal origin of the cell substrate, or production cell line, has received considerable attention in the past few years and the industry has improved methods and devised standards to increase the probability and/or assurance of clonal-derivation 1-4. However, older production cell lines developed before the implementation of these methods, herein referred to as ″legacy cell lines″, may not meet current regulatory expectations for demonstration of clonal-derivation. In this article, the members of the IQ Consortium ″Working Group on Clonality″ present our position that the demonstration of process consistency and product comparability of critical quality attributes (CQAs) throughout the development life cycle should be sufficient to approve a license application without additional genetic analysis to support clonal origin, even for legacy cell lines that may not meet current day clonal-derivation standards. With this commentary we discuss advantages and limitations of genetic testing methods to support clonal-derivation of legacy cell lines and wish to promote a mutual understanding with the regulatory authorities regarding their optional use during early drug development, subsequent to IND application and prior to demonstration of product and process consistency at BLA submission.