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Research ArticleConference Proceeding

Apparent Virus Contamination in Biopharmaceutical Product at Centocor

Linda C. Hendricks, Jarrat Jordan, Tong-Yuan Yang, Paul Driesprong, Gert Jan Haan, Mareike Viebahn, Thomas Mikosch, Henri Van Drunen and Anthony S. Lubiniecki
PDA Journal of Pharmaceutical Science and Technology September 2010, 64 (5) 471-480;
Linda C. Hendricks
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Jarrat Jordan
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Tong-Yuan Yang
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Paul Driesprong
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Gert Jan Haan
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Mareike Viebahn
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Thomas Mikosch
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Henri Van Drunen
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Anthony S. Lubiniecki
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Abstract

Out-of-specification (OOS) results were reported by a contract lab in the in vitro adventitious agent assay (AVA) for two products manufactured using mouse myeloma cells in perfusion bioreactors. Cytopathic effect observed for test article-inoculated MRC-5 monolayers resembled foci seen in tissue culture cells infected with transforming viruses. All reasonable known technologies, including highly sensitive, state-of-the-art methodologies and multiple, redundant, and orthogonal methods, were deployed to screen broadly for potential viral and microbial contaminants. Due to the appearance of apparent foci, testing for murine, bovine, and human polyomavirus contamination was heavily represented in the analytical investigation. The results obtained in this extensive screening provided convincing evidence for the lack of an infectious viral or other biological agent. Although the initial investigation produced no reason to invalidate AVA yielding OOS results or to suspect an assay artifact, an extended evaluation revealed several irregularities at the contract test lab reporting the OOS results. The extended investigation also included attempts to reproduce OOS results at alternate contract testing labs and an inter-laboratory study in which methodological differences in the AVA at the three different contract labs were investigated. Only the contract lab initially reporting the OOS results reported foci during this extended evaluation. The results of the inter-laboratory study suggested that the foci artifact might be attributed to the prolonged exposure of the MRC-5 monolayer to cell debris present in the test article. Confocal immunofluorescence microscopy and transmission electron microscopy were subsequently used to provide convincing evidence that the foci observed in test article-inoculated AVA wells were composed of a core of degraded myeloma cell debris covered by one or more layers of MRC-5 cells. The observation that the foci were detected in the AVA at a contract lab where the MRC-5 monolayer is exposed to production cell line debris for a prolonged period strongly suggests that these foci form when MRC-5 grow over the cell debris present in the test article. The cumulative results of the investigation supported the conclusion that the OOS results were artifacts of the AVA test system and not a result of contamination with a virus or other biological agent. Testing was discontinued at the contract lab generating the OOS results and validated at a second contract lab. Manufacturing resumed in consultation with health authorities. The lots were retested following a standard operating procedure (SOP) already in place and ultimately dispositioned for use in normal distribution channels.

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PDA Journal of Pharmaceutical Science and Technology: 64 (5)
PDA Journal of Pharmaceutical Science and Technology
Vol. 64, Issue 5
September/October 2010
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Apparent Virus Contamination in Biopharmaceutical Product at Centocor
Linda C. Hendricks, Jarrat Jordan, Tong-Yuan Yang, Paul Driesprong, Gert Jan Haan, Mareike Viebahn, Thomas Mikosch, Henri Van Drunen, Anthony S. Lubiniecki
PDA Journal of Pharmaceutical Science and Technology Sep 2010, 64 (5) 471-480;
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  • Article
    • Abstract
    • Introduction
    • OOS Results Obtained in an In Vitro Adventitious Agent Assay
    • CPE Observed Resembled Foci Seen in Polyomavirus-Transformed Cells
    • Initial Steps in Investigation into the OOS Results
    • OOS Results Attributed to Biological Agent Most Likely Introduced through Contaminated Medium
    • Broad, All-Inclusive Analytical Investigational Plan to Identify the Putative Contaminant
    • Negative Results Obtained in Extensive Testing for Polyomavirus
    • Positive Result for SV40 Attributed to Expression Vector Sequence
    • Nucleic Acid–Based Screening Assays for Additional Rodent and Bovine Viruses
    • Screening for Potential Contaminants of Human Origin
    • Non-Specific, Broad Screening Tests
    • Extended Laboratory Investigation
    • Comparison of AVA Parameters in Attempt To Induce Formation of the Foci Artifact
    • Further Evaluation of Biological Nature of Putative Contaminant
    • On-Site Evaluation of AVA at Three Contract Labs
    • Identification of Potential Root Cause for Foci Artifact
    • Overall Conclusion, Outcomes, and Lessons Learned
    • References
  • Figures & Data
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Apparent Virus Contamination in Biopharmaceutical Product at Centocor
Linda C. Hendricks, Jarrat Jordan, Tong-Yuan Yang, Paul Driesprong, Gert Jan Haan, Mareike Viebahn, Thomas Mikosch, Henri Van Drunen, Anthony S. Lubiniecki
PDA Journal of Pharmaceutical Science and Technology Sep 2010, 64 (5) 471-480;

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