Bulk production of the antiviral lectin griffithsin

Fuqua, Joshua L.; Hamorsky, Krystal; Khalsa, Guruatma; Matoba, Nobuyuki; Palmer, Kenneth E.

The requirement for qualification of drug substance is common to all technologies used for protein production. Although the regulatory path for PMPs versus mammalian, insect cell, or microbial systems may exhibit some difference, the basic tenets of GMP hold true across the board: All pharmaceuticals are required to be manufactured and released according to cGMP. In an effort to provide guidance for future PMPs, we have included the certificate of analysis (CofA) for GRFT and a stability plan with an overview of techniques applied to assess product stability. In this review, we specifically discuss protein oxidation as a potential issue when producing and assessing the long-term stability of biologics because protein oxidation can have detrimental impact on activity, stability and safety (Singh, 2011) . Of course, oxidation is only one of many potential product degradation pathways that must be considered, but oxidation has been raised as a potential concern for GRFT because the cervicovaginal compartment and to a lesser extent the anal compartment, both of which are potential routes of administration for GRFT-containing microbicides, maintains hydrogen peroxide producing bacteria (Zegels et al., 2010) . With such potential for oxidation upon delivery, it is necessary to monitor oxidation at the level of the active pharmaceutical ingredient (API), formulated product, and in subject samples after delivery. This review is focused on the production and quality characterization of GRFT and therefore will focus on the API. We have provided our contingency plans and reasoning for dealing with protein oxidation in the event GRFT demonstrates oxidation issues. Our first product that we will evaluate in the clinic is a topical formulation designed for rectal use. We have not yet submitted the investigational new drug (IND) application to FDA, so cannot say definitively that what we present here is acceptable to the agency, but this article details some of our regulatory efforts to date. Therefore, the authors request that the regulatory position taken in this article be read as opinion and not as practice known to be acceptable to FDA.