Commercial‐scale biotherapeutics manufacturing facility for plant‐made pharmaceuticals

Abstract

SummaryRapid, large-scale manufacture of medical countermeasures can be uniquely met by the plantmade-pharmaceutical platform technology. As a participant in the Defense Advanced Research Projects Agency (DARPA) Blue Angel project, the Caliber Biotherapeutics facility was designed, constructed, commissioned and released a therapeutic target (H1N1 influenza subunit vaccine) in <18 months from groundbreaking. As of 2015, this facility was one of the world's largest plantbased manufacturing facilities, with the capacity to process over 3500 kg of plant biomass per week in an automated multilevel growing environment using proprietary LED lighting. The facility can commission additional plant grow rooms that are already built to double this capacity. In addition to the commercial-scale manufacturing facility, a pilot production facility was designed based on the large-scale manufacturing specifications as a way to integrate product development and technology transfer. The primary research, development and manufacturing system employs vacuum-infiltrated Nicotiana benthamiana plants grown in a fully contained, hydroponic system for transient expression of recombinant proteins. This expression platform has been linked to a downstream process system, analytical characterization, and assessment of biological activity. This integrated approach has demonstrated rapid, high-quality production of therapeutic monoclonal antibody targets, including a panel of rituximab biosimilar/biobetter molecules and antiviral antibodies against influenza and dengue fever.

Vaccination via Chloroplast Genetics: Affordable Protein Drugs for the Prevention and Treatment of Inherited or Infectious Human Diseases

“…Advantages associated with plant-made biopharmaceuticals have been recognized by the United States government, whose Defense Advanced Research Projects Agency (DARPA) funded construction of four pilot-scale commercial hydroponic plant-made-biopharmaceutical facilities (54). The initial investment was in Fraunhofer CMB, which was constructed with a 100 kg/day processing capacity and has since been used for pilot studies on industrial-scale hydroponic production of transplastomic therapeutic plants (54, 124).…”

“…The initial investment was in Fraunhofer CMB, which was constructed with a 100 kg/day processing capacity and has since been used for pilot studies on industrial-scale hydroponic production of transplastomic therapeutic plants (54, 124). After Fraunhofer, additional projects were funded in Kentucky, North Carolina, and Texas (54).…”

Animal component‐free Agrobacterium tumefaciens cultivation media for better GMP‐compliance increases biomass yield and pharmaceutical protein expression in Nicotiana benthamiana

“…Therefore, the fermentation volume must be equivalent to at least 20% of the bacterial suspension volume used during infiltration. The latter is typically 1500−7000 L for large transient expression processes handling 50−7000 kg of biomass [13,14, and our unpublished data], so fermenter volumes of 300−1400 L are required for the cultivation of A. tumefaciens. This increases both the upfront and operational costs for the preparation of bacterial cultures when scaling up transient expression to industrial levels.…”

Recent achievements obtained by chloroplast transformation

“…The high cost of protein drugs is due to their production in prohibitively expensive fermentation systems, prohibitively expensive purification from host proteins, the need for refrigerated storage and transport, and the short shelf-life of the final product [66, 67]. Protein drugs made by plant chloroplasts overcome most of these challenges as they do not require such expensive production process and can be stored without losing efficacy [68, 69] As listed in Table 4 numerous vaccine antigens and biopharmaceuticals have been engineered via chloroplast genome of higher plants.…”