How to ensure the viral safety of cell and gene therapies

16 June 2023
Advanced Therapy Medicinal Products
Kathleen O’Hagan
Global Change Facilitator

Regulatory agencies expect cell and gene therapy (CGT) sponsors to have an adventitious agent strategy and to leverage the three pillars of ‘prevent, detect, and remove’ where applicable for a given product. Unfortunately, there is little regulatory guidance and harmonization on viral clearance requirements in CGT.

The CGT field can leverage the manufacturing knowledge of biologics, including that from monoclonal antibodies and recombinant proteins, gained over several decades to develop viral safety strategies for its products.

However, it is necessary to consider the unique nature of CGT products to maintain the potency of the viral vector while removing or inactivating adventitious and/or helper viruses. The need and extent of virus clearance studies depend on several factors, such as the stage of clinical trial phase and the risks associated with the manufacturing process.

Due to this, we have published Validation: Current approaches and considerations for viral clearance in cell and gene therapy, which proposes an approach to viral clearance for adeno-associated viral (AAV) vectors that, ultimately, would result in the harmonization of a general methodology.

It includes the major relevant guidance and advice on viral clearance for viral vectors and highlights the unique considerations and potential options for resolving viral clearance challenges.

“Until the comprehensive revision of ICH Q5A in late 2022, guidance from regulatory agencies on viral clearance study design for genetically engineered viral vectors and other modalities within the CGT space has been lacking,” said Jason Morais, Associate Director, Purification Process Development, Genomic Medicine Unit CMC at Sanofi. “This white paper from BioPhorum attempts to leverage its standing as a facilitator of industry consortia to summarize the experiences and best-practice approaches for viral clearance study design of recombinant AAV products, helping to close a gap in this fast-growing space.”

Assuring viral safety

In this paper, we assess how to apply the current understanding of viral clearance to the products and processes employed in CGT manufacture so you can ensure the viral safety of these therapies. We also highlight the unique factors for preventing contamination through raw materials risk mitigation and make recommendations based on the field’s current regulatory and technical understanding.

So, if you are new to the CGT field, our paper will allow you to start thinking about your validation approach. Also, while giving a comprehensive overview of a viral clearance validation strategy that fits all CGT products is difficult, we provide an outline to help you develop a directed approach to address this critical aspect of AAV manufacture to ensure product safety.

Other areas covered in the paper include the regulatory landscape, sources of viral entry into the manufacturing process, and the modes of viral clearance.

“CGT is an emerging field with many new players, start-ups, etc., and it is helpful to see how industry understands the guidelines that currently exist,” said Dr. Moritz Bennecke, Staff Scientist Purification Development and Virus Safety at Roche. “Since this is a fast-growing field of expertise, the authorities would also potentially be open for a dialogue to make sure industry practice and capabilities align with authority expectations. Also, many questions like ‘I wonder if someone has experience of this’, ‘I wonder how others would validate this’, and ‘What is the most recent feedback in this field,’ are constantly coming up. The BioPhorum publication provides a solid base for all companies to design their own processes in accordance with the broader community.”

The paper is aimed at scientists and technical specialists involved in biosafety, viral safety and quality assurance.

It is our intent that this paper will be used to develop and implement a viral clearance strategy that represents current industry best practice and meets regulatory expectations.

For more information, download the paper below and contact Kathleen O’Hagan, Global Change Facilitator, at

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