Regulatory Guidelines for Viral Safety

Pharma IQ

Due to some high profile contamination cases, viral safety and clearance is high on the agenda for manufacturers of biological therapeutic products. “Viral safety and viral clearance evaluation are high-profile areas for product safety. Regulators are keenly focused on viral safety and expect high-quality data to support it, particularly for IND and BLA approvals. Familiarity with process and regulatory requirements, as well as expertise in the key areas of viral clearance, are essential for strategic planning and can yield savings in time, effort, and money.”1

To ensure safety regulatory guidance advocates three complementary approaches to control potential viral contamination of biologicals:

  • Selecting and testing source material for the absence of detectable viruses
  • Testing the capacity of the production processes to remove or inactivate viruses
  • Testing the product at appropriate stages of production for freedom from detectable viruses

S. Steve Zhou, Ph.D. Microbac Laboratories, Inc., said in Biopharmaceutical Process Evaluated for Viral Clearance:  “Regulatory expectations on viral safety for biopharmaceutical products have evolved over the past several decades. Original concerns focused on a relatively small number of known viruses associated with the production cell lines. Today, the concerns are much broader, encompassing unknown and uncharacterized agents. These increasingly stringent standards are intended to decrease the risk of transmitting viruses.”

He revises the guidelines as follows:

  • ICH Q5A, Viral Safety Evaluation of Biotechnology Products Derived from Cell lines of Human or Animal origin 1, (1997) specifically requires that a manufacturer of biological products for human use demonstrate the capability of the manufacturing process to remove or inactivate known contaminants.
  • The FDA’s Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use 2 (1997) and  Points to Consider in the Characterization of Cell Lines Used to Produce Biologicals 3 (1993) elaborate similar principles as the ICH Q5A guideline and provide further description on viral safety evaluation methods.  Although this document focuses on a specific group of biopharmaceutical products, it provides a good general guideline for bioprocessors to consult when evaluating the viral safety of their products in development.
  • The 2008 EMEA – CHMP guidelines on viral validation,, Guideline on Virus Safety Evaluation of Biotechnological Investigational Medicinal Products 4, 1996 EMEA - CPMP guidelines, Note for Guidance on Virus Validation Studies: The Design, Contribution and Interpretation of Studies Validating the Inactivation and Removal of Viruses 5,, and CPMP’s Note for Guidance on Plasma Derived Medicinal Products 6 provide detailed recommendations for the manufacturers of biopharmaceutical products to follow when performing viral validations.  These recommendations also set specific values for virus clearance levels that had to be attained.
  • With implementation of the EU Clinical Trials Directive 2001/20/EC 7, all EU Member States now require submission of an Investigational Medicinal Product Dossier (IMPD) starting at phase 1.  The virus safety evaluation is part of the IMPD’s quality requirement for biotech products.  The International Standard ISO 22442-3: Medical devices utilizing animal tissues and their derivatives – Part 3: Validation of the elimination and/or inactivation of viruses and transmissible spongiform encephalopathy (TSE) agents 8 describes in detail the requirements on viral clearance for the medical devices.

All of these regulatory guidelines emphasize that each viral validation study should be reviewed on a case-by-case basis and that log reduction factors obtained should be viewed under experimental limitations and product-specific risk factors.


  1. Dinowitz M. Strategic Approaches to Viral Safety and Viral Clearance Assessment in Cell Culture-Derived Pharmaceutical Products. BioProcess J, 2003; 2(1): 48-50.


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