ASTM E3259-22

3.1?Mammalian cell lines are widely used in the production of biological therapeutics, such as monoclonal antibodies and other recombinant proteins. Some of these cell lines, like rodent cell lines, are known to contain genes encoding endogenous retroviral-like particles or produce endogenous retrovirus, but there is no evidence of an association between rodent retrovirus and disease in humans. Adventitious viruses can be introduced into a drug substance manufacturing process from other sources, and contamination of human therapeutics is a safety concern 3.2?Virus filtration, an orthogonal technology in a virus clearance platform to such steps as low pH or surfactant inactivation, has traditionally been accepted as a robust method for virus clearance when well designed. Size exclusion has been shown to be the primary mechanism of virus removal by virus retentive filtration, that is, larger viruses are more easily retained than smaller viruses such as parvoviruses (4, 5). Large virus retention has also been shown to be insensitive to process fluid characteristics such as protein type, protein concentration, pH, and ionic strength 3.3?Large virus retentive filters, or retrovirus filters, are tested for removal of larger enveloped viruses like retrovirus or MuLV (80 nm to 100 nm) and have undetectable levels of the large bacteriophage PR772 (64 nm to 82 nm) 3.4?Numerous published studies and reviews encompassing data from the last 20 years have shown both large and small virus retentive filters are effective and consistent for removal of retrovirus. In published reviews of regulatory submissions from 1990 through 2010, rare occurrences of retrovirus breakthrough did occur across both large and small virus retentive filters. These anomalies, however, were not resolved and could be attributed to study design, experimental artifacts, or limitations of the meta-analyses performed on the regulatory submission 3.5?The level of justifiable LRV for a modular claim from a censored dataset, that is, all observations are below a certain LRV level, can be difficult to estimate 3.6?Implementing parameters of small virus retentive filtration established by this practice can provide robust retrovirus removal and can be used as a modular retrovirus validation of the virus filtration step. In conjunction with other clearance unit operations (for example, chromatography and inactivation by pH or surfactants), sufficient overall retrovirus clearance can be achieved 1.1?This practice assures 6.0 log₁₀ removal of retrovirus (for example, MuLV).

1.2?This practice is applicable to monoclonal antibody (mAb), immunoglobulin G (IgG) fusion proteins, recombinant proteins, or other proteins produced using mammalian cell lines (for example, Chinese hamster ovary (CHO), murine hybridomas, murine myelomas, or human embryonic kidney (HEK) 293).

1.3?The step is performed on cell-free intermediates.

1.4?The log removal claim for retrovirus by small virus retentive filters can be used in conjunction with other clearance unit operations (for example, low pH inactivation, or inactivation of virus by surfactant) to assure sufficient total process clearance of potential virus contaminants, which would be supportive of early phase (clinical phase 1 or phase 2a trials) regulatory filings.

1.5?Retrovirus removal claim by filtration is limited to small virus retentive filters, as defined in the PDA Technical Report Virus Filtration 1.6?The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard.

1.7?This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety, health, and environmental practices and determine the applicability of regulatory limitations prior to use.

1.8?This international standard was developed in accordance with internationally recognized principles on standardization established in the Decision on Principles for the Development of International Standards, Guides and Recommendations issued by the World Trade Organization Technical Barriers to Trade (TBT) Committee.