Not so long ago, big pharmaceutical companies turned to contract manufacturing organizations (CMOs) solely to achieve efficiencies in cost, capacity, and time-to-market, or to obtain a specific expertise not available in-house. Today, these factors still also play a role, but the most dynamic driver behind the use of CMOs in the pharmaceutical industry is now rapidly becoming the unique, innovative, and state-of-the-art process and production technology they offer.

Many CMOs have gone far above and beyond the immediate needs of their customers to create innovative homegrown processes and to implement the latest, technologically advanced equipment-technology that frequently surpasses that available at Big Pharma's own facilities.

Improved process tools

The total cost of pharmaceutical production includes not only the cost of building new plants. It includes the cost to maintain them, stay up-to-date on equipment advances, and to maintain a workforce of highly-skilled operators-operators with more than just the knowledge to run them, but with the expertise and experience necessary to continually update and improve them.

As the pharmaceutical industry moves deeper into the decade, the need to keep pace with next-generation process technology and process tools will only become more challenging-not only to meet increasingly tight cost-efficiency requirements, but in the case of many emerging pharmaceutical products, to make viable commercial production possible at all.

To meet this need, CMOs are already expanding and upgrading their existing plants, as well as building totally new, next-generation facilities. And, they're also investing heavily in outfitting them with state-of the-art, highly-automated equipment. In addition, however, CMOs are applying their own expertise to advancing pharmaceutical process and manufacturing science and technology, contributing significantly to the development of new and innovative tools and systems.

One example of this innovation can be seen in the extent to which automation is being incorporated into CMO processes and operations. For example, Quintiles Preclinical and Pharmaceutical Sciences (Kansas City, MO) has implemented an automated robotic powder dispensing system that gives drug developers the flexibility to work with a broad range of drugs and dosage levels without having to per form extra formulation, analytical, or stability work.

Biotechnology has become a particular focus area for CMOs as the number and variety of new biotechnology-based drugs, moving rapidly out of development and through the final phases of clinical trials into full-scale production, continues to grow. As described by Michiel E. Ultee, senior director of biopharmaceutical development and operations at Laureate Pharma (Princeton, NJ), "biotech-based products are growing at a rate almost twice that of conventional drugs."

Though their arrival is certainly welcome to the industry as a whole, their unfamiliar and specialized manufacturing needs also present a number of new challenges for CMOs, who must not only provide the most advanced equipment and technology available to produce them, but also the expertise necessary to successfully implement and manage very complex and expensive processes. As pointed out by Ultee, "The development of the next generation of biotech-based pharmaceuticals will be very different from that of conventional small-molecule drugs."

Ultee's view was supported at the most recent national AAPS meeting in Salt Lake City, Utah, where, as observed by Norm Alworth, RPh, pharmaceutical manager at MPT Delivery Systems, "Among this year's exhibitors were a host of companies presenting specific technology and products that didn't exist in this industry five years ago."

Gala Biotech (Middleton, WI), recently acquired by Cardinal Health, focuses its attention on monoclonal antibodies and gene insertion/ expression technology. Gala's Gene Product Expression or "GPEx" technology is aimed at rapidly developing highly expressive mammalian cell culture lines and their use for the production of recombinant proteins. The company recently established a 43,000-[ft.sup.2] facility in Middleton, Wisconsin, for GPEx-based cell line development and CGMP-compliant protein production.

Galas GPEx technology is based on the use of "retrovectors," which can be thought of as disabled retro viruses. Though retrovectors look like retro viruses, they don't carry any of the protein encoding genes of the virus, but rather the gene of interest (i.e. the gene for a monoclonal antibody).

The technology has reduced the time needed to develop a stable production cell line for a target protein from as long as 18 months to just five or six. Says Michael Jenkins, PhD, Gala's director of business development and commercial operations, "In as little as three months, we can typically provide clients milligram-amounts of material from an unoptimized cell line. At the six month stage, we can provide a stable cell line in serum-free media at commercially viable expression levels"

Jenkins points to the high transformation efficiency of the GPEx approach, noting that virtually 100 per cent of the target cells are transformed. "This is a significant advantage when compared to other methods of gene expression such as transfection or electroporation, where insertion frequency can be as low as one out of every 100,000 cells and which can require additional selection steps and the use of selectable marker genes," says Jenkins.

For bicistronic (and multicistronic) applications, GPEx allows multiple genes to be carried and inserted by a single retrovector, thereby increasing efficiency.

GPEx retrovectors also target high-expressing chromosomal matrix attachment sites in the target cell genome, generating a higher expression of the gene in transduced cells and increasing yield. GPEx cell lines are also optimized via a repetitive insertion process that increases the number of inserted gene copies and proportionally increases target protein expression levels. The optimized cell lines may have a dozen or more copies of the desired gene, all of which are stably inserted and express the target protein. "With our technology, both the heavy and light chain subunits are produced from a single mRNA molecule," notes Jenkins.

Lyophilization

Concurrent with the increasing number of biotech-based pharmaceutical products entering commercial-scale production has come increased demand for freeze-drying, or lyophilization, capability. Since most proteins aren't stable in solution or powder states, they must be dried prior to storage.

However, most standard drying techniques can cause significant damage to proteins, resulting in loss of potency. To deal with this, many pharmaceutical companies are using lyophilization to stabilize their protein-based drugs and improve their shelf life.

Because lyophilization is such a complex science, subject to close FDA scrutiny, many pharmaceutical makers choose not to attempt it in-house. As a result, it has provided a lucrative opportunity for those CMOs specializing in the capability, and who have made the significant investment necessary to ensure total FDA compliance. One example is Lyophilization Technology, Inc. (Ivyland, PA), which provides product characterization, formulation, and product design through the development of optimal freeze drying cycles. Says Wendy Sunderland, a research scientist at the company, "Since we're very specialized in this one specific area, our scientists are extremely knowledgeable of the process and equipped to deal with any challenges that may arise."

The company's GMP-compliant laboratory houses seven pilot-size lyophilizers, as well as certified portable cleanrooms. The freeze dryers are equipped with automated control and data acquisition systems.

- Pharmaceutical Technology