Securing a safe, economical, and reliable supply of a recombinant therapeutic protein for use in clinical trials and commercialization
is an important strategic issue that must be addressed early in the development process. Today, bacteria, yeast, and mammalian
cell cultures are routinely used for large-scale commercial production of biopharmaceuticals, but these systems are frequently
costly and lack flexibility for scaling up production. Typical unit production costs range from US$100–1,000 per gram of purified
protein product, depending on the product, volume, and production system. Capital investment is in the order of several hundred
million dollars for a large capacity (100,000 L) facility.1,2
Nancy Markley, Ph.D
The construction and validation of cGMP compliant facilities requires long lead times, typically three to five years, which
creates challenges in matching capacity to demand. As a result, companies must make manufacturing choices and a substantial
upfront investment in capacity while their products are still in the test phases. The uncertainty of regulatory approval,
and the difficulties in predicting market demand impose a significant business and financial risk. For drug developers, investing
large amounts of capital on a drug that is awaiting approval is an expensive and very risky prospect; however, having a drug
that is approved without a reliable supply of product can have equally dire consequences.
Transgenic production holds tremendous promise for dealing with the cost, capacity and scale-up limitations faced by traditional
systems. Trans-genics can substantially reduce capital investment and lower production costs through economies of scale and
more-flexible scale-up. Such advantages could enable the commercialization of proteins that would otherwise be impractical
due to cost or capacity constraints, and provide scope for pricing flexibility that could be passed on to patients and health
care systems. These benefits could allow companies to expand into new markets, such as follow-on biologics, where price is
a barrier to entry.
Transgenic technologies have made significant advances in recent years and several companies have moved products into the
clinic and validated their technologies through partnerships with well-established pharmaceutical and biotechnology companies.3,4 Transgenic systems encompass a variety of hosts and tissues from animal, plant, and avian origin. No transgenically derived
product has been approved yet. We believe that it is plausible that insulin will be the first. With that in mind, we will
discuss our technology based on oilbodies, followed by a description of recombinant protein production systems. We will wrap
up with a case study of producing insulin with these technologies.
Oilbody-oleosin technology offers several advantages for protein production and purification over traditional cell culture
and other transgenic systems. Oilbody-oleosin technology is unique, as it is the only recombinant technology that addresses
protein recovery and purification (processes that represent as much as 75% of the cost of production) contemporaneously with
bulk protein production. The capital investment in an oilseed processing facility is roughly an order of magnitude lower than
that of conventional fermentation facilities.
Beyond economics, oilseeds offer superior inventory management when compared to other transgenic systems. Unlike proteins
expressed in milk or leaves, recombinant proteins have been found to be stable in transgenic seeds for several years. Seeds
can be stockpiled and safflower, our commercial production crop, can be grown counter-seasonally, allowing maximal flexibility
for inventory management. We believe that using safflower will allow us to readily address regulatory issues associated with
transgenic crops, because safflower is a small acreage crop that is largely self-pollinating and can easily be geographically
segregated from other safflower production and from the main food and feed crops.