Bulk production of the antiviral lectin griffithsin

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

One of the primary challenges in moving from laboratory scale production to bulk production is the regulatory requirements involved with the manufacturing process and protein product qualification. There are few therapeutic proteins produced in plant systems that are approved by regulatory authorities and none of these is produced in leaf tissues. A regulatory framework for the production of recombinant pharmaceuticals in plants only existed in draft form until little more than a decade ago. Moreover, as the industry was still in its infancy, the draft guidance was based on existing knowledge and experience with regulation of pharmaceutical production in mammalian and microbial cells and was lacking in specifics that related to the use of whole plants. In principle, good manufacturing practice (GMP) should be able to be extrapolated from mammalian and microbial technologies to plant-based technologies. In practice, this may work well for products produced in plant cell culture. Whole plant-production systems, however, introduce new and separate challenges . This situation has caused the development of two divergent production pathways: plant cell culture systems and whole plant systems. Plant cell culture technologies have the advantage of allowing enough similarity in concept and process to mammalian and microbial expression systems to have a clearer and more straightforward regulatory pathway. Facilities using whole plant technologies had to work with regulators to make clear the requirements for handling new issues, such as seed banking instead of cell banking . Therefore, mechanisms for process qualifications for plant expression must be developed from a thorough understanding of regulatory requirements. In this review, we will discuss the regulatory aspects involved in the expression of GRFT using rTMV technology and outline our plan for qualification of virion and plasmid banks including long-term stability monitoring.