Adaptation of the WHO guideline for residual DNA in parenteral vaccines produced on continuous cell lines to a limit for oral vaccines.
Although there is a WHO guidance for a limit on residual DNA for parenterally administered vaccines produced on continuous cell lines, there is no corresponding guidance for oral vaccines. To help determine an oral limit, we performed a study of Vero cell DNA uptake in rats, in which the relative uptake and persistence of Vero cell DNA administered orally was compared to its uptake when delivered intramuscularly (IM). The results of this study allowed the generation of an empirically derived IM versus oral factor (10(6)) representing the relative inefficiency of DNA uptake by oral administration. This factor was then applied to the WHO recommended parenteral limit of 10 ng/dose to determine a corresponding upper limit on the level of residual Vero cell DNA for an oral vaccine of 10 mg. As a conservative approach, this empirically determined limit was reduced 100-fold to 100 microg. Thus, the results of this animal study, together with additional evidence in the literature, support a residual DNA safety limit of 100 microg per dose for an oral vaccine produced on a continuous cell line.
Biologics Safety Assessment, 2 Acute Toxicology, Merck Research Laboratories, Merck & Co., Inc., West Point, Pennsylvania 19486, USA. Jose_lebron@merck.com
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Lebron
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Pacchione
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Harper
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Mixson
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Jackson
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Barnum
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Denisova
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Johnson
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Maurer
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Morgan-Hoffman
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Niu
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D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D004247:DNA / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D003851:Deoxyribonucleases; D004705:Endocytosis; D011992:Endosomes / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D017410:Practice Guidelines as Topic; D014612:Vaccines / Q000008:administration & dosage / Q000592:standards*; D014709:Vero Cells; D014944:World Health Organization
D014612:Vaccines; D004247:DNA; D003851:Deoxyribonucleases