14/15 December 2022
The guideline "ICH Q 5 A (R1) Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin" has been in force since 1997. The guideline is dedicated to the testing and evaluation of biotechnological products with regard to their viral safety. These are products derived from characterised cell lines of human or animal origin (i.e. mammals, birds, insects). This refers to the data that should be submitted as part of the marketing authorisation application or registration package. The term "virus" in this guidance does not include non-conventional transmissible agents, such as those associated with Bovine Spongiform Encephalopathy (BSE) and scrapie. Issues related to BSE should always be discussed by the applicant directly with the competent authority.
The previous guidance refers to products derived from cell cultures obtained from characterised cell banks. It covers products derived from in vitro cell cultures, such as interferons, monoclonal antibodies and recombinant DNA products, including recombinant subunit vaccines. It also includes products derived from hybridoma cells grown in vivo as ascites, for which special considerations apply. Appropriate additional information on the testing of cells grown in vivo is provided in Appendix 1. Not covered by this guidance are inactivated vaccines and live vaccines containing self-replicating pathogens and genetically engineered live vectors.
In October, the EMA published a revised version, which is open for comments until 10 February 2023. In the new guidance, the following statement can be found in comparison:
"This document covers products produced from in vitro cell culture using recombinant DNA technologies such as interferons, monoclonal antibodies, and recombinant subunit vaccines. It also covers products derived from hybridoma cells grown in vivo as ascites: special considerations apply for these products, and Annex 1 contains additional information on testing cells propagated in vivo. The document also applies to certain genetically-engineered viral vectors and viral vector-derived products, which can undergo virus clearance without a negative impact on the product. These products may include viral vectors produced using transient transfection or from a stable cell line, or by infection using a recombinant virus. It also includes viral vector-derived recombinant proteins, for example, baculovirus-expressed Virus-Like Particles (VLPs), protein subunits and nanoparticle-based vaccines and therapeutics. Furthermore, the scope includes Adeno-Associated Virus (AAV) gene therapy vectors that depend on helper viruses such as baculovirus, herpes simplex virus or adenovirus for their production. Specific guidance on genetically engineered viral vectors and viral vector-derived products is provided in Annex 7. Inactivated viral vaccines and live attenuated viral vaccines containing self-replicating agents are excluded from the scope of this document.."
At this point, we can see the innovations that take into account the development of new technologies. Especially NGS as a replacement for in vivo assays is worth mentioning with regard to the European 3R strategy. But VLP and AAV are now also of global importance, e.g. in vaccines. These developments made a revision urgently necessary.
All biotechnological products derived from cell lines are at risk of viral contamination, which could have serious side effects or clinical consequences for the patient. This can be due to viral contamination of the starting material or contamination during the manufacturing process. Although no such case of transfer from cell lines into biotechnological products has been demonstrated to date, it is nevertheless assumed that the safety of these products with regard to viral contamination can only be ensured by applying a virus testing programme and assessing the virus removal and inactivation achieved by the manufacturing process through appropriate measures described in this guidance document.
Summarized is the purpose of this document to provide a general framework for viral testing, experiments for the assessment of viral clearance and a recommended approach for the design of viral testing and viral clearance studies.
The guideline mentions three different, complementary approaches to controlling the potential viral contamination of biotechnology products:
For more details, read the previous document and the new version for commenting on "ICH Guideline Q5A(R2) on viral safety evaluation of biotechnology products derived from cell lines of human or animal origin"