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The unprocessed bulk constitutes one or multiple pooled harvests of cells and culture media. When cells are not readily accessible (e.g., hollow fiber or similar systems), the unprocessed bulk would constitute fluids harvested from the fermenter. A representative sample of the unprocessed bulk, removed from the production reactor prior to further processing, represents one of the most suitable levels at which the possibility of adventitious virus contamination can be determined with a high probability of detection. Appropriate testing for viruses should be performed at the unprocessed bulk level unless virus testing is made more sensitive by initial partial processing (e.g., unprocessed bulk may be toxic in test cell cultures, whereas partially processed bulk may not be toxic).
In certain instances, it may be more appropriate to test a mixture consisting of both intact and disrupted cells and their cell culture supernatants removed from the production reactor prior to further processing. Data from at least three lots of unprocessed bulk at pilot-plant scale or commercial scale should be submitted as part of the marketing application/registration package.
It is recommended that manufacturers develop programs for the ongoing assessment of adventitious viruses in production batches. The scope, extent, and frequency of virus testing on the unprocessed bulk should be determined by taking several points into consideration, including the nature of the cell lines used to produce the desired products, the results and extent of virus tests performed during the qualification of the cell lines, the cultivation method, raw material sources, and results of viral clearance studies. In vitro screening tests, using one or several cell lines, are generally employed to test unprocessed bulk. If appropriate, a PCR test or other suitable methods may be used.
Generally, harvest material in which adventitious virus has been detected should not be used to manufacture the product. If any adventitious viruses are detected at this level, the process should be carefully checked to determine the cause of the contamination, and appropriate actions taken.