USDA also offers a quality recognition system for field production activities called Biotechnology Quality Management System (BQMS). This system is similar to ISO9001 certification but specific for plant biotechnology operations. A history of safety in these activities has been proven, and biopharmaceutical companies can capitalize on the experience and expertise of their platform technology partner in designing and implementing manufacturing and regulatory protocols.
The drug regulation question is noteworthy in the context of the FDA’s recent clearance of the first plant-made pharmaceutical product, Elelyso™ (taliglucerase alfa). This industry milestone by Protalix demonstrates that plant-manufactured protein therapeutics can successfully be taken through the drug approval process by channels familiar to biologics manufacturers.
The technical challenges of producing recombinant proteins in plants are essentially similar to those of other expression systems. Any development program will follow the basic steps of transformation, expression testing, and expansion of clones that demonstrate high expression levels over multiple generations (Figure 2B).
At this stage, master and working seed banks are created, analogous to the master and working freezer stocks of a cultured cell line.
Biomass production (plant growth and harvest) occurs according to an agricultural process defined by the needs of the host plant. As in standard biomanufacturing, the development of an extraction and purification process is worked out empirically.
Bulk biomass-processing steps such as cleaning, milling, extraction, and separation of extract are performed before chromatography, product formulation, packaging, and QC analysis. While the contaminants that must be removed are specific to the plant species used, this is similar to removal of background contaminants specific to expression systems like E. coli or CHO cells.
Scaleup is generally dictated by protein expression level in the seed (or biomass) and by target batch size. For rh-lactoferrin, we have progressed from a bench-scale of several grams of protein product to clinical-scale of approximately 4 kg per batch.
For Phase III clinical and early commercial material we will use a single commercial process train build-out for an approximately 200 kg batch size. Completion of the second process train and an increased production schedule will bring us up to commercial metric-ton quantities.