Biotech Manufacturing Grows Up - The industry, now 30 years old, is undergoing an important transition. - BioPharm International

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Biotech Manufacturing Grows Up
The industry, now 30 years old, is undergoing an important transition.


BioPharm International
Volume 20, Issue 10

STANDARDIZING FACILITIES AND PROCESSES

Adapting manufacturing capacity to shifting demands in the market is like piloting a supertanker; one must anticipate changes in direction and initiate responses well in advance. Manufacturing facilities take up to five years to build and validate, and up to $800 million in capital investment. Thus, there is little ability to respond quickly to unpredictable markets that sometimes change on a weekly basis.

A case in point can be found in recombinant factor VIII, developed in the 1990s for the treatment of hemophilia A. Three companies, Baxter International, Bayer, and Wyeth had each developed a competing product, and initially could not meet growing demands. New manufacturing facilities were built to meet this demand. However, by the time the facilities came online, their total capacity exceeded the market needs and the companies had to manage overcapacity. For Wyeth, that meant making the tough decision of selling one of its plants to another biotechnology company in need of capacity. It has been said that over 50% of existing plants are manufacturing different products than those that were initially intended for them.

The ability of companies to predict and anticipate clinical as well as market demands throughout discovery, development, and commercialization remains elusive. Most drugs today are targeted to so-called "blockbuster" markets consisting of large patient populations. Larger manufacturing facilities require several years' lead time to come online, and during that time a successful clinical outcome is not ensured. In fact, with less than one in five drug candidates surviving clinical trials to reach the market, investing in manufacturing facilities before regulatory approval becomes a strategic gamble. Even drugs predicted to be "blockbusters" could end up serving niche markets if results from pivotal clinical trials lead to indication restrictions.

The industry has adapted to these conditions by making frequent use of contract manufacturing or in some cases by establishing partnerships with competing companies to share capacity to offset the risk of idle plants (due to overcapacity) or lost sales (due to insufficient capacity). Such a partnership was formed between Wyeth and Genentech in 2005 when Wyeth was contracted by Genentech to produce an antibody against the HER2 protein (used in the treatment of breast cancer). This arrangement allowed the companies to react quickly to surges in product demand and offset the cost and risk of idle manufacturing plants.

The economic solutions of contract manufacturing and capacity-sharing are only possible because of extensive standardization that has taken place in the industry. Standardizing manufacturing technology and equipment has emerged as the result of two major factors: (1) a limited number of engineering companies that have experience in designing biotechnology facilities have been building similar facilities for each customer, and (2) a limited number of high-capacity contract manufacturing facilities have implemented a similar technology base in order to serve clients with a wide variety of products. While standardization has enabled a more flexible response to markets through capacity sharing, many manufacturing processes still have low yields resulting in products that are expensive to produce.

PLATFORM TECHNOLOGY IMPLEMENTATION

In addition to biology and process technologies, improvements in manufacturing efficiency have been achieved through workflow improvements and platform implementation. The implementation of a consistent platform technology has been driven by the fact that the large majority of biotechnology products are antibodies. In a sense, most products have similar requirements in process development, and optimizations can be more easily translated from one product to the next. At Wyeth, the development of a pipeline candidate may be approached in a fairly standard fashion: production cell line candidates are identified using a high-throughput technology; the final choice of production cell line is based on performance in the "platform process" using standardized culture medium, culture conditions, and duration, with certain variations. Similarly, the downstream purification process uses a platform approach. The purification conditions for each molecule can be identified using high-throughput methodology resulting in high product yields and purity from a two-column process. Raw materials, production equipment, quality procedures, fermentation technology and methods as well as batch monitoring and documentation, are generally kept consistent. This is especially important when a product is manufactured at multiple locations, facilitating technology and knowledge transfer between sites. It is also an advantage for rapidly switching and optimizing products at a single facility.


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