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VII.SUMMARY This document suggests approaches for the evaluation of the risk of viral contamination and for the removal of virus from product,thus contributing to the production of safe biotechnology products derived from animal or human cell lines,and emphasizes the value of many strategies,including:
A.Thorough characterization/screening of cell substrate starting material in order to identify which,if any,viral contaminants are present;
B.Assessment of risk by determination of the human tropism of the contaminants;
C.Establishment of an appropriate program of testing for adventitious viruses in unprocessed bulk;
D.Careful design of viral clearance studies using different methods of virus inactivation or removal in the same production process in order to achieve maximum viral clearance;and
E.Performance of studies which assess virus inactivation and removal.
GLOSSARY
Adventitious Virus.See Virus.
Cell Substrate.Cells used to manufacture product.
Endogenous Virus.See Virus.
Inactivation.Reduction of virus infectivity caused by chemical or physical modification.
In Vitro Cell Age.Ameasure of the period between thawing of the MCBvial(s)and harvest of the production vessel measured by elapsed chronological time in culture,population doubling level of the cells,or passage level of the cells when subcultivated by a defined procedure for dilution of the culture.
Master Cell Bank(MCB).An aliquot of a single pool of cells which generally has been prepared from the selected cell clone under defined conditions,dispensed into multiple containers,and stored under defined conditions.The MCBis used to derive all working cell banks.The testing performed on a new MCB(from a previous initial cell clone,MCB,or WCB)should be the same as for the original MCB,unless justified.
Minimum Exposure Time.The shortest period for which a treatment step will be maintained.
Nonendogenous Virus.See Virus.
Process Characterization of Viral Clearance.Viral clearance studies in which nonspecific “model”viruses are used to assess the robustness of the manufacturing process to remove and/or inactivate viruses.
Process Evaluation Studies of Viral Clearance.Viral clearance studies in which “relevant”and/or specific “model”viruses are used to determine the ability of the manufacturing process to remove and/or inactivate these viruses.
Production Cells.Cell substrate used to manufacture product.
Unprocessed Bulk.One or multiple pooled harvests of cells and culture media.When cells are not readily accessible,the unprocessed bulk would constitute fluid harvested from the fermenter.
Virus.Intracellularly replicating infectious agents that are potentially pathogenic,possess only a single type of nucleic acid (either ribonucleic acid (RNA)or DNA),are unable to grow and undergo binary fission,and multiply in the form of their genetic material.
Adventitious Virus.Unintentionally introduced contaminant virus.
Endogenous Virus.Viral entity whose genome is part of the germ line of the species of origin of the cell line and is covalently integrated into the genome of animal from which the parental cell line was derived.For the purposes of this document,intentionally introduced,nonintegrated viruses such as EBVused to immortalize cell substrates or Bovine Papilloma Virus fit in this category.
Nonendogenous Virus.Virus from external sources present in the MCB.
Nonspecific Model Virus.Avirus used for characterization of viral clearance of the process when the purpose is to characterize the capacity of the manufacturing process to remove and/or inactivate viruses in general,i.e.,to characterize the robustness of the purification process.
Relevant Virus.Virus used in process evaluation studies which is either the identified virus,or of the same species as the virus that is known,or likely to contaminate the cell substrate or any other reagents or materials used in the production process.
Specific Model Virus.Virus which is closely related to the known or suspected virus (same genus or family),having similar physical and chemical properties to those of the observed or suspected virus.
Viral Clearance.Elimination of target virus by removal of viral particles or inactivation of viral infectivity.
Virus-like Particles.Structures visible by electron microscopy which morphologically appear to be related to known viruses.
Virus Removal.Physical separation of virus particles from the intended product.
Working Cell Bank(WCB).The WCBis prepared from aliquots of a homogeneous suspension of cells obtained from culturing the MCBunder defined culture conditions.
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