Since the late 1980s, studies have shown that plants can manufacture functional transgenic pharmaceutical compounds. Advantages attributed to plant-made pharmaceutical (PMP) approaches are compelling, and PMP production continues to attract interest from investors and the biopharmaceutical industry (Table 1). Proposed PMP benefits include proven scalability, high production capacity, limited exposure to human or animal pathogens, lower capital expenditures (CapEx), and decreased operating costs. Those putative advantages have proven to be significant business forces driving continued investor support for PMP ventures. PMP production's lower cost relative to cell culture provides an opportunity to subsidize more research for additional product development.

Table 1: PMPs in clinical trials as of March 2010*

Table 1: PMPs in clinical trials as of March 2010* (Click to enlarge)

Placed in wider context, the business value, for example, of potentially large production capacity coupled to lower CapEx requirements and manufacturing costs is underscored by concerns over the expanding gap between production volume and patients’ needs for potentially life-saving drugs. In 2010, 178 drug shortages were reported to the US FDA, 132 of which involved sterile, injectable drugs. In 2011, the agency has continued to see an increased number of shortages, especially those involving older sterile injectable drugs (1). So the disparity between production and capacity continues to expand.

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Photo 1: (Click to enlarge)

Many situations can create a drug supply shortage, including natural disasters, limited profitability, regulatory activities, and population-based demands. One compelling solution to the growing difference between drug production capacity and patient needs is taking advantage of the simplicity, lowered cost of goods (COGs), increased speed, and greater capacity offered by PMPs.

Other PMP manufacturing advantages are operational and relate, for example, to the risk of animal by-product exposure to cultures, feed streams, and/or active pharmaceutical ingredients (APIs). Manufacturers must demonstrate that their processes and APIs are free of biologically active animal by-products if they are to be approved. For example, prions and viral particles associated with animal-based products may cause serious adverse reactions in humans when injected or ingested. Such exposure can be minimized in well-designed processes using plant-based production cultures and USP Class VI certified components.

With PMP systems, however, the serious concern over animal by-product contamination is reduced or removed completely. They have less inherent animal by-product exposure, thereby eliminating the need for the additional expense of removing associated contaminants. The end result can be simpler, less-expensive processes with more rapid production and development timelines. Historical Perspective of PMP Industry Growth

The possibility of transgenic plant-based pharmaceutical production emerged in the 1980s as advances in genetic engineering reached a critical point and plant genetic transformation became possible. Initial success in transforming plants with genes encoding pharmaceutical compounds engendered a great deal of speculation about the future of PMP manufacturing and its potential benefits to human health, global nutrition, veterinary medicine, and so forth (2).

Since the successful production of the first PMP compound in 1986, plant transformation strategies, upstream processes, and PMP-related regulatory laws have been redefined and improved continually. Although conventional pharmaceutical manufacturing platforms such as yeast and mammalian cell culture continue to yield approved drug products, PMP products have been a rarity. It is not unusual for new technologies to take some time to affect pharmaceutical markets. Despite the acknowledged gradual evolution of the PMP sector, a number of plant-based recombinant drug products are currently poised to move into the final stages of drug approval (Table 1).

Experts have suggested several explanations for the differences between the PMPs’ outlook in the late 1980s and current projections. During the late 1980s and 1990s, PMP opportunities seemed vast and immediate because scientists in industry and academia focused primarily on yield rather than regulatory aspects. Early business models that sprang from this initial excitement proved incomplete. Early PMP researchers envisioned an open, field-based production factory that could be rapidly implemented with simplified scalability, resulting in an equally rapid turnaround in investment capital. That initial vision was gradually brought down to Earth during the following decade because of mounting concerns over genetic containment.

Because of documented incidents of accidental release of or contamination by genetically modified organisms (GMOs, plants in this case), the public has become quite sensitive to the potential for unchecked genetic contamination of the environment. That concern arises from uncertainty regarding what potential damage or catastrophic consequences the release of putative artificial genetic material may cause. Such concerns are legitimate, and manufacturers must verify that proper precautions are in place to contain their GMOs. The necessary containment measures for a given enclosed process are dictated by individual system and facility requirements. Open systems must consider the requirements for proper and sufficient buffer areas — where these requirements have been or can be established. Some requirements for open systems are still in development, making open GMO production systems particularly challenging from a regulatory standpoint.

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