Viral Clearance Strategy Using a Three-Tier Orthogonal Technology Platform - How to implement a risk-based approach to eliminate viruses using orthogonal technologies. - BioPharm International

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Viral Clearance Strategy Using a Three-Tier Orthogonal Technology Platform
How to implement a risk-based approach to eliminate viruses using orthogonal technologies.


BioPharm International


REGULATORY REQUIREMENTS REGARDING VIRAL INACTIVATION AND CLEARANCE

Viral contamination is a risk to all biotechnology products derived from cell lines of human or animal origin. Contamination of a product with endogenous viruses from cell banks, or adventitious viruses from personnel can have serious clinical implications.3 To ensure maximum viral safety, the ICH Q5A regulatory guideline mandates that manufacturers of therapeutic biological products for human use implement adequate technologies in their manufacturing process and demonstrate the capability of their processes to remove or inactivate known or adventitious contaminants based on a process-specific virus clearance strategy.3 According to the latest draft on regulatory guidance from the European Agency for Evaluation of Medicinal Products (EMEA), potential contaminants may be enveloped or nonenveloped, small or large, DNA or RNA, labile or resistant viruses.4

Viral safety of licensed biological products must be assured by three complementary approaches: (i) thorough testing of the cell line and all raw materials for viral contaminants, (ii) assessing the capacity of downstream processing to clear infectious viruses, and (iii) testing the product at appropriate steps for contaminating viruses.3 The first study is required before Phase 1 clinical trials, in which the process should be evaluated for inactivation or removal of an enveloped and a small nonenveloped virus and at least two orthogonal steps should be used for achieving the same.3–4 A second and more complex study is then conducted before manufacturing Phase 2/3 materials to provide evidence of the effective and adequate clearance of relevant and known viruses, as well as the removal of a range of novel and unpredictable viruses.5 A viral clearance study with at least four viruses for late stage is state-of-the-art and lower-range values (LRV) of four or higher are perceived as robust and effective safety measures.1 At least one of these clearance steps evaluated in a validation study must be effective against nonenveloped viruses, such as porcine parvovirus (PPV), canine parvovirus (CPV), or minute virus of mice (MVM). As for enveloped retroviruses, although no cases of infection or transmission of Chinese hamster ovary (CHO) cell-related type A and C virus particles have been reported so far, retrovirus-like particles theoretically pose safety concerns to humans because of their morphological and biochemical resemblance to tumorigenic retroviruses, and therefore, have to be completely removed or inactivated.6–9

METHODS FOR VIRAL INACTIVATION AND CLEARANCE

The robust and reliable capability to eliminate viruses must be demonstrated by a risk-based approach.10 Today's requirements demand a statistically independent combination of methods (orthogonal technologies) for removing enveloped and nonenveloped viruses based on the different physical principles of removal and inactivation, and yet are complementary to each other.11–12

Several methods can be used for virus clearance in bioprocessing. These include inactivation methods such as solvent and detergent (SD) or chemical treatments, low pH, microwave heating, adsorption by chromatography, and removal by mechanical or molecular sieving using normal and tangential-flow filtration methods. The first three of these, treatments with solvents and detergents, low pH, or microwave heating, all have significant limitations in their ability to inactivate small nonenveloped viruses. SD treatments were commonly used for plasma proteins and were considered the gold standard for inactivating enveloped viruses.13 It has been shown that SD treatments of a recombinant protein can completely and rapidly inactivate enveloped viruses like PI-3, XMuLV, IBR, and MCF.14 However, small nonenveloped viruses are not being eliminated substantially by this virus-clearance technology. Low pH inactivation of murine retroviruses is reported to be highly dependent on time, temperature, pH, and relatively independent of the recombinant protein type or conductivity conditions outlined.15 Heating is not considered one of the most reliable methods for virus inactivation because of the variation in stability of each viral genome to heat or temperature.


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