Assessment of Needs
for Virus Safety 

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Step 1

As a drug manufacturer you are required to ensure the virological safety of the biological therapeutics you have under development. Regulatory guidance advocates virus control at various stages of the drug manufacturing process, directing that you:

• Select and test source materials for the absence of viruses
• Test the capacity of the production process to remove or inactivate viruses
• Test the product at appropriate stages of production for freedom from detectable viruses

Virus Control Regulators require that an overall safety margin, such as <1 virus particles per 106 doses, be used to demonstrate the virus safety of the manufacturing process. Drug manufacturers are required to qualify the virus “load” in the process. For biotech products derived from murine cell lines, such as the Chinese hamster ovaries (CHO) and NSO, this typically translates to ~12 – 18 log10 clearance for endogenous retroviruses and ~6 log10 removal for adventitious viruses.

Composite Summary of Current Regulatory Guidance on Virus Clearance US Food and Drug Administration: Requires that manufacturers of biotech products that use murine cell lines are to demonstrate clearance capability of their manufacturing processes with one, relevant retrovirus (murine retrovirus) before starting Phase I studies. German and French Regulatory Agencies: Require that manufacturing processes be evaluated to clear non-enveloped parvoviruses in addition to retroviruses. Before marketing authorization: Manufacturers are required to assess clearance of multiple model and relevant viruses in their manufacturing processes. While customers are responsible for review of and compliance with applicable laws and regulations, Merck monitors regulatory bodies worldwide and can assist customers with the interpretation of guidelines. We strive to ensure that we have the latest information about the current and future regulatory environment. You also need to determine if your particular process requires retrovirus clearance, or retrovirus and parvovirus removal, or no viral clearance at all. When virus clearance is indicated, you need to select the filter that best fits your needs.

Select the Filter Filters are broadly classified into two categories: Filters that provide >4 or >6 log10 removal of large viruses, typically 80-100 nm endogenous retroviruses Filters that provide >4 log10 removal of small and large viruses, larger than 18-24 nm parvoviruses

As you make these determinations, keep your end goal in mind. Future changes in your process can result in costly time delays, as you await recertification by your governing regulatory body.

In addition, we have worked with many of the largest and most successful drug manufacturers in the world, helping them resolve the same issues you are facing today.

Regulatory guidelines demand a minimum of two orthogonal methods for virus clearance. To meet these requirements customers may implement a combination of virus removal techniques like filtration (size exclusion) and affinity chromatography or virus inactivation via chemical techniques like low pH, chaotropes, or detergents. There are no universal methods for Virus inactivation or removal and so most manufacturers of biopharmceuticals use both methods in a complimentary manner to meet regulatory guidelines.

Contact the Viresolve® Team so that we can share our knowledge and experience with you.