Revision 2 of ICH Q5A Guideline on viral safety evaluation of biotechnology products derived from cell lines of human or animal origin comes into effect
Virus contamination is a major concern for the manufacture of biotechnology products. While products derived from cell lines of human or animal origin have not so far been involved in the transmission of infectious viruses to humans, given that these cell lines are susceptible to viral contamination, a potential risk exists. ICH Q5A Guideline on viral safety evaluation of biotechnology products derived from cell lines of human or animal origin is the pivotal guidance document covering the testing and viral safety evaluation of these products, as well as the data expected in the dossier for marketing authorisation.
Sources of Viral Contamination
ICH Q5A categorises the sources of viral contamination as endogenous to the master cell bank (MCB) or adventitious. Endogenous viruses are maintained from one cell generation to the next. Most eukaryotic cell lines, particularly those derived from rodents, contain endogenous retroviruses, which may give rise to retroviral-like particles (RVLPs). Rodent RVLPs are not pathogenic to humans but could theoretically cause immunogenicity in a patient. Therefore, the presence of RVLPs must be identified at the cell bank stage, and an estimate of their numbers in the final product must be calculated.
Adventitious viruses are those unintentionally introduced during the process; these viruses may be introduced to the MCB through use of cells from an infected animal, use of a virus to establish the cell line, use of contaminated biological reagents or raw materials, or as contamination during the cell handling and cell banking processes.
ICH Q5A Pillars to Virus Reduction
ICH Q5A outlines three complimentary pillars to virus reduction in biomanufacturing. The first pillar concerns prevention of viruses entering the process by selecting and testing cell substrates and other raw materials for the absence of viruses; the second pillar covers testing of in-process materials at unprocessed bulk harvest stage to confirm absence of viruses or enumeration of virus particles if present; and the third pillar concerns process clearance capability, which involves the virus safety risk assessment and virus clearance studies to validate the capability of the process for viral clearance.
Manufacturers are expected to implement at least two, but usually three, effective virus reduction steps in their downstream process. Virus reduction is achieved by complimentary steps dedicated to virus removal or inactivation. Virus removal steps include virus separation by chromatography (e.g. anion-exchange) and virus retentive filtration. Chemical steps such as high/low pH treatment and solvent/detergent treatment contribute to virus inactivation.
ICH Q5A Revision to R2
ICH Q5A (R1) was introduced in 1999. In recent years the ICH recognised that a revision was necessary to reflect current scientific knowledge relating to test methods and process controls and the growth in new biotechnology product types. The main revisions to the guideline include:
Addition of emerging product types, such as genetically engineered viral vectors and viral-vector-derived products;
Addition of newer technologies for virus assay testing such as polymerase chain reaction (PCR) and next generation sequencing (NGS);
Virus clearance validation and risk mitigation strategies for advanced manufacturing such as continuous manufacturing;
On a risk-assessed basis, the possibility to use a platform or modular approach based on prior knowledge to reduce the overall virus clearance validation package required.
Timeline
ICH Q5A (R2) was adopted by the US FSA in January 2024, and by the European Medicines Agency on 14 June 2024.
