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摘要： 本文件规定了固定化葡萄糖异构酶制剂的要求、检验规则和标志、包装、运输及贮存要求，并描述了相应的试验方法。 本文件适用于固定化葡萄糖异构酶制剂的生产、检验和销售。

摘要： 范围:本文件适用于复合营养粉的生产检验;主要技术内容:本文件规定了复合营养粉通用技术要求的术语和定义、技术要求、试验方法、检验规则、包装、运输、贮存和保质期等

摘要： 1.1This practice assures effective inactivation of≥4 log10of infectious rodent retrovirus (that is, reduction from 10 000 to 1 infectious rodent retrovirus or removal of 99.99 % of infectious rodent retroviruses) in the manufacturing processes of monoclonal antibodies or immunoglobulin G (IgG) Fc fusion proteins manufactured in rodent-derived cell lines that do not target retroviral antigens. Rodent retrovirus is used as a model for rodent cell substrate endogenous retrovirus-like particles potentially present in the production stream of these proteins.1.2The parameters specified for this practice are clarification, Triton X-100 detergent concentration, hold time, pH, and inactivation temperature.1.3This practice can be used in conjunction with other clearance or inactivation unit operations that are orthogonal to this inactivation mechanism to achieve sufficient total process clearance or inactivation of rodent retrovirus.1.4This detergent inactivation step is performed on a clarified, cell-free intermediate of the monoclonal antibody or IgG Fc fusion protein.1.5The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard.1.6This 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.1.7This 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. ====== Significance And Use ======3.1Rodent-derived cell lines are widely used in the production of biopharmaceutical drugs such as mAbs and Fc fusion proteins. These cell lines have been shown to contain genes encoding endogenous retroviral-like particles or endogenous retrovirus. Despite the lack of evidence for an association between such rodent retroviruses and disease in humans, the potential contamination of human therapeutics raises safety concerns for biopharmaceutical drugs. Additionally, adventitious agents such as viruses can be introduced into a biopharmaceutical drug substance manufacturing process from other sources, and potential safety issues can be attributed to these potential unknowns. For these reasons, effective viral clearance is an essential aspect of an integrated approach combining safety testing and process characterization which ensures virus safety for biopharmaceutical drug products made using rodent cell lines.3.2Solvent/detergent inactivation has been widely used for decades to inactivate enveloped viruses in blood plasma derived biopharmaceutical therapies(1-3).3Solvent/detergent systems using the detergents Triton X-100 or Polysorbate 80 along with the organic solvent tri(n-butyl)phosphate (TNBP) have been used to inactivate enveloped viruses by disrupting the viral envelope thereby reducing the ability of the enveloped virus to attach to and then infect the host cell(4 and5).3.3Most manufacturers of mAbs, recombinant proteins, and Fc fusion proteins have focused on viral inactivation methods using the detergent Triton X-100 or Polysorbate 80 in the absence of TNBP(6), which can interfere with subsequent bioprocessing steps. The ability of the detergents alone to inactivate retroviruses has been demonstrated in monoclonal antibodies produced in rodent-derived cell lines(6-9). At a 2011 workshop devoted to viral clearance steps used in bioprocessing(7), investigators from one firm showed incubation with 0.2 % Triton X-100 for 60 min of hold time at ambient temperature inactivated >5 log10of X-MuLV across four separate mAbs in cell culture matrices.3.3.1At the same 2011 workshop(7), investigators from a second firm confirmed that levels of protein concentration and lipid concentration had no observable effect on MuLV virus inactivation at levels of 0.3 % Triton X-100. Additionally, eight different monoclonal antibody Host Cell Culture Fluids (HCCF), were treated with 0.3 % Triton X-100 for a 60 min hold time at 20?°C. Effective inactivation,≥4 log10of inactivation of MuLV virus, was seen for each antibody in these experiments.3.4Quertinmont(8)demonstrated that DNA level, total protein concentration, and lipid content (exceeding 1000 μg/mL) in a 0.45 % (w/v) Triton X-100 detergent inactivation step using HCCF were not statistically significant to the detection of MuLV virus following 60 min of inactivation using both monoclonal antibodies and Fc fusion proteins. Additionally, three Design of Experiment (DOE) robustness studies were carried out for three separate molecules varying biological drug concentration, total protein concentration, temperature, and Triton X-100 concentration.?These studies demonstrated effective viral inactivation when Triton X-100 concentration is≥0.2?%, temperature is between 15?°C to 25?°C, and hold time is≥60?min in HCCF.3.5Blumel and Tounekti(9)showed complete inactivation of MuLV across 4 mAbs [2 IgGs and 2 immunoglobulin M (IgMs)] for all time points (0, 5, 30, and 60 min) using 1.0 % Triton X-100 for a 60-min hold time. The average log reduction factor (LRF) for these 15 studies was≥3.89 log10. Analyses of the study data showed the higher level of Triton X-100 (1 %) necessitated a large dilution to mitigate cytotoxicity of the MuLV indicator cells. No detectable virus was seen at any of the time points tested across these 15 studies and the claimed LRF was completely dependent on the starting viral titer of the MuLV feed stock in these studies.3.6The extent of this retroviral inactivation could be dependent on certain reaction parameters including clarification, Triton X-100 concentration, hold time, pH, and inactivation temperature. However, managing parameters that give robust and effective retrovirus inactivation as specified by this practice, in conjunction with other clearance unit operations, can assure effective retroviral inactivation.3.7This practice incorporates parameters that give effective retrovirus inactivation, which can be used as modular validation of the viral clearance process for the specified viruses.