Recombinant protein therapeutics, or biologics, are an important class of pharmaceuticals for which Chinese Hamster Ovary (CHO) cells are the most commonly used expression system. Assessment of clonality remains a key factor in the development of any new stable cell lines for novel biopharmaceuticals or biosimilars.
In recent years proof of clonality has become a focus for the FDA and other regulatory authorities. Many companies have received comments back on this topic during the IND review process of their biological products. Clonality is thought to minimize the heterogeneity of cell banks and thus allow for consistent manufacture a product.
Regulatory Requirements
This is the primary concern for drug developers and is governed by the FDA/EMA and other regulatory bodies. Documentation of clonality is encouraged as part of IND process and is mandatory by the time of BLA (Biological Licence Application).
"It is expected that clonal cell lines are developed as referenced by ICH Q5D and EMA/CHMP"
Rachel Novak, US FDA, Jan 2017
Recent developments such as single cell sorting and high-throughput imaging allow for the acquisition of evidence supporting clonality. Rederiving a clonal cell line by additional limited dilutions is time-consuming, costly and, crucially, may affect production and growth rates of cell lines. This is especially undesired when time lines for submission are short. Creative Bioarray provides the genetic characterization of (CHO) producer cell lines by FISH, which offers information on transgene integrity and integration sites.
Creative Bioarray's Clonality Analysis Service (FISH) has the following Features:
- Detection of each individual integration site
- Analyze 100-200 cells per sample
- Rapid 4 week turnaround time, including addition reporting
- High accuracy and sensitively
- Competitive pricing
References
- Frye, Christopher, et al. "Industry view on the relative importance of "clonality" of biopharmaceutical-producing cell lines." Biologicals 44.2 (2016): 117-122.
- Wurm, Florian M., and Maria João Wurm. "Cloning of CHO cells, productivity and genetic stability—a discussion." Processes 5.2 (2017): 20.
- ICH Q5D Derivation and characterisation of cell substrates used for production of biotechnological/biological products (CPMP/ICH/294/95)
- Welch, J. (2017). Tilting at clones: A regulatory perspective on the importance of "Clonality" of mammalian cell banks. CDER/OPQ/OBP/DBRRIV April 24, 2017.
- Paul Wu, et al. "Tools and methods for providing assurance of clonality for legacy cell lines" in "Cell Culture Engineering XVI", A. Robinson, PhD, Tulane University R. Venkat, PhD, MedImmune E. Schaefer, ScD, J&J Janssen Eds, ECI Symposium Series, (2018).
