More than 37 mammalian cell-derived therapeutics entered the pharmaceutical market since the first monoclonal antibody OKT 3 was approved in 1986.1 Several hundred proteins including antibodies, growth factors, cytokines, and enzymes are currently in clinical trials. An extensive preclinical pipeline ensures sustainable product flow through clinical trials for future decades. The probability of successfully passing clinical trials is still less than 20 percent for this kind of product, and increasing competition exists among nearly all complex therapeutic proteins and in all indications. Thus flexibility and speed of Phase I and II protein supply at pilot plants are now major issues for the industry. Figure 1 illustrates the current product life cycle for mammalian cell-based proteins, which is often up to 15 years from concept to market. To ensure return on investment and reasonable profit, more than eight years of market exclusivity are required. Unfortunately, patents expire after 20 years. Therefore there is substantial pressure on timelines to obtain market approval. Availability and flexibility of pilot and commercial manufacturing plants play a crucial role in creating timelines, especially for mammalian cell products.
Rene Brecht, Ph.D
This article focuses on the construction and operation of a contract plant designed around the production of recombinant proteins for mammalian cell lines using disposable systems. With growing experience, a manifold increase of customer cell-line productivity could be achieved, boosting extrapolated plant capacities to a level of several kilograms per year. This case report summarizes our experience with the pilot plant over a three-year period and discusses challenges for commercial plants of disposable nature.
DISPOSABLE NATURE PILOT PLANT PROVIDES UNIQUE FLEXIBILITY
In 2000 we initiated a pilot plant project based on thorough analysis of market trends, product life cycles, and state-of-the-art technologies. Most "early" customer cell lines have a very low specific productivity of less than 5 pg therapeutic protein produced per cell per day (pg/c-d). As a result, about 50 percent of the customers are asking for a newly designed, high-yielding cell line. An excess of 25 g net protein are needed for toxicology tests and Phase I trials. High product throughput must be ensured to serve a large number of customers. Therefore short product change-over periods are mandatory. Facility design should also allow manufacturing of investigational viruses and cell-therapy products to broaden the company's contract manufacturing base. Consequently the following specifications were used for facilities design.
Specifications for Facilities Design
Figure 1. Life Cycle of Complex Proteins
- Cell line and process development capacity: 10 to 14 slots/year
- Portable bioreactor equipment with low space requirement
- Closed systems to reduce clean-room loads in upstream suites
- Annual capacity:more than 500 g crude product at 5 pg/c-d cell line productivity
- Flexibility: more than ten investigational medicinal products per year
To meet specifications it was decided to integrate separate cell line and process development units into the manufacturing site, and to entirely rely on bioreactor systems with disposable culture ware.