ICH Q5A(R2) VIRAL SAFETY EVALUATION OF BIOTECHNOLOGY PRODUCTS DERIVED FROM CELL LINES OF HUMAN OR ANIMAL ORIGIN

Feb 21 , 2025

1. INTRODUCTION

This guideline describes the evaluation of the viral safety of biotechnology products including

viral clearance and testing, and it outlines what data should be submitted in marketing

applications for those products. Biotechnology products include biotherapeutics and certain

biological products derived from cell lines of human or animal origin (e.g., mammalian, avian,

or insect). In this document, the term virus excludes nonconventional transmissible agents like

those associated with mammalian prions (e.g., bovine spongiform encephalopathy, scrapie).

Applicants are encouraged to discuss transmissible spongiform encephalopathy associated

issues with the appropriate regulatory authorities as they are not in scope of this guideline.

This guideline includes products such as cytokines, monoclonal antibodies (mAbs), and subunit

vaccines produced from in vitro cell culture using recombinant DNA technologies. The

guideline also includes certain genetically engineered viral vectors and viral vector-derived

products (e.g., viral vaccines and gene therapy products), provided they are amenable to viral

clearance, without a negative effect on the product. These products may include viral vectors,

for example, adeno-associated virus (AAV), produced using transient or stable transfected cell

lines, or by infection using a recombinant virus. It also includes viral vector-derived products,

for example, baculovirus-expressed virus-like particles (VLPs), protein subunits and

nanoparticle-based protein vaccines and therapeutics. AAV gene therapy vectors include those

that depend on helper viruses such as herpes simplex virus or adenovirus for their production.

Specific guidance on genetically engineered viral vectors and viral vector-derived products is

provided in Annex 6.

Inactivated viral vaccines and live attenuated viral vaccines containing self-replicating agents

are excluded from the scope of this guideline. Cell therapies are out of the scope of this

guideline; however, the principles may be used as applicable (e.g., for biological starting or raw

materials).

It is no longer encouraged that materials be manufactured from hybridoma cells grown in vivo

as ascites due to the contamination risk as well as to the ongoing global initiative to replace,

reduce, and refine the use of animals. Where this situation exists the principles of this guideline

should be followed, including replacement of the in vivo assay by Next Generation Sequencing

(NGS).

The risk of viral contamination is a concern for all biotechnology products derived from cell

lines and needs to be reduced, because such contamination could have serious clinical

consequences. This risk can arise from the contamination of the source cell lines themselves

(cell substrates) or from exogenous introduction of adventitious virus during production.

However, biotechnology products derived from cell lines have not been historically implicated

in the transmission of viruses. The viral safety of these products has been reasonably assured

by applying a comprehensive virus testing program and assessing virus removal and

inactivation achieved by the manufacturing process, as outlined below. Three principal,

complementary approaches are applied to control the potential viral contamination of

biotechnology products: