Lessons Learned Based on Genentech Experiences with Virus Contamination in Mammalian Cell Culture Processing
| Raw materials–focused lessons learned |
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| Raw materials represent a significant vulnerability to cell cultures at very large scales |
| • Tens of millions of liters of complex media and process gases used annually |
| • Any raw material could be contaminated with a rodent virus |
| Testing of raw materials alone is not an effective barrier to viral contaminants |
| • Unless contaminant is at very high titer and homogeneously distributed |
| • Unless assay has adequate sensitivity to a broad spectrum of viruses |
| • Unless any false-positives can be promptly adjudicated |
| • Unless raw materials are not inhibitory to the assay used |
| Other raw material safeguard considerations to take into account |
| • Source and traceability at supplier |
| • Potential for adventitious virus contamination of raw material (cleanliness of facility & segregation practices) |
| • Method of RM production (exposure to conditions known to reduce viruses) |
| Pro-actively institute raw material barriers even in the absence of contamination events |
| • Heat treatment is the simplest efficacious virus barrier step for implementation at large scales of operation, and is likely to be feasible for most cell culture media/feed solutions |
| • Barriers are raw material treatment steps that constitute business risk mitigation, and are one element of several overlapping barrier approaches |
| • When unexpected operational issues arise, treatment is not mandated as a regulatory requirement, and decisions can be risk-based |
| Additional important lessons learned |
| In-process testing for specific, high-risk viruses by PCR at the production culture stage can serve as an effective early warning of viral contamination |
| • Employing this approach as a hold step protects your downstream facility from costly contamination and cleanup |
| Contamination response preparedness is crucial |
| • Proactively establish written virus contamination response procedures to enable Manufacturing and Quality to respond quickly to contain any events and prevent indecisiveness in dealing with emerging situations |