Biotech Manufacturing Grows Up

The biotechnology industry has faced many challenges since its inception in the late 1970s. The ability to translate new discoveries into viable therapies that could be produced on a large scale and delivered to patients across the globe required overcoming many hurdles. Biopharmaceutical manufacturing, in particular, has presented major challenges, even to the industry's leaders. In addition to the inherent difficulties associated with a production platform based on molecular and cellular biology, biopharmaceutical manufacturing always has been subject to the vicissitudes of unpredictable clinical trials, regulatory requirements, product approvals, and market demand. When we add to this the need to invest in expensive manufacturing facilities before product approval, the challenges take on the multiple dimensions of technology, logistics, and economics.

Operator preparing to load excipient to process vessel during formulation process (Wyeth Biotech)

Perhaps it is reassuring that corporations, even entire industries, undergo discrete stages of development, from uncertain beginnings to a more predictable maturity. Eventually, novel and unique technologies evolve to become robust and economically viable. Although the biopharmaceutical industry is only 30 years old, it has already graduated through several stages of development and is currently undergoing an important transition. We are on the cusp of a manufacturing renaissance where companies will have the ability to produce biopharmaceuticals consistently at high yields, respond rapidly to shifts in demand and development cycles, and lower investment in production infrastructure. These changes are being driven technically, by advances in biological and process engineering, as well as economically, through facility sharing and utilization. As a result, we believe that the fundamentals of the biotechnology industry will change dramatically, resulting in product costs and flexibility equal to those currently achieved for small-molecule pharmaceuticals. Progress in biopharmaceutical manufacturing will have far-reaching consequences for industry dynamics and competitive strategies. The three drivers for this transition are:

• increased production yields through process development and biological science instead of hardware solutions

• standardization of facilities and processes

• broad implementation of common platform technologies.

A similar transition occurred in the semiconductor industry. The dramatic improvements in semiconductor manufacturing brought about by facility and process standardization, platform technologies, and scientifically based product improvements, led to rapid growth and lower costs in that industry beginning in the mid-1980s.

Michael E. Kamarck

GROWTH OF THE BIOTECHNOLOGY INDUSTRY

To get a better idea of where the biotechnology industry is situated on its path toward maturity, let's take a look at its history so far. The biotechnology industry first emerged with the advent of recombinant DNA technology, a tool that enabled scientists to envision the mass production of therapeutic proteins. Insulin, human growth hormone, hemophilia proteins, and erythropoietin were among the first protein products that were developed into biopharmaceuticals, replacing or augmenting biological pathways that had become dysfunctional through disease. These proteins were followed by the introduction of monoclonal antibodies, which could act as antagonist drugs, targeting biological molecules in a variety of disease pathways. While both types of biopharmaceuticals are of continuing importance, monoclonal antibodies have been driving the industry for the past decade.

Quick Recap

The early years of biopharmaceutical production saw scientists evolve into engineers, inventing production equipment, control systems, and analytical technology that simply did not exist in a pharmaceutical industry based on developing medicines from small chemical compounds. Unlike small-molecule drugs, protein-based drugs were produced by living cells; manufacturing cell lines had to be established and then grown under conditions that promoted viability and high cell densities. Finally, the cells needed to be separated from their products and the protein purified aseptically. The core technology used to produce and purify the protein-based drugs varied among companies and manufacturing plants. In the industry, the initial focus was on making new products, not production efficiency, and demand quickly outstripped the capacity to supply.

The birth of the biotechnology industry was accompanied by regulatory uncertainty as well. Neither regulatory agencies nor sponsors had a clear road map for the monitoring and approval of biopharmaceutical products. Questions surrounding the purity and safety of recombinant proteins were different from those associated with small molecules. As the new industry grew, regulatory agencies worked with companies to improve and standardize biopharmaceutical manufacturing, and to develop purity and safety guidelines.

Throughout the 1990s, the biopharmaceutical industry struggled to meet the needs of a growing pipeline as well as a burgeoning demand for newly released products on the market. In response to this demand, companies focused on scale, constructing more manufacturing plants and procuring additional bioreactors and equipment to satisfy the market. It was the age of stainless steel in the industry. But with unpredictability in product yields, regulatory approval, and commercial demand, essentially every company struggled with over- or under-capacity.

Like many in the industry, Wyeth has had to deal with adjusting manufacturing capacity to unpredictable requirements in demand. In 1998, when Wyeth and Immunex launched a soluble TNF receptor–fusion protein (used for the treatment of rheumatoid arthritis) the product was manufactured under contract by Boehringer Ingelheim. However, US demand alone for the new molecule exceeded the predicted worldwide demands in the first six months after launch. Neither Wyeth nor Immunex could have anticipated the tremendous demand for this drug, which could not be met through internal capacity or the capacity available at Boehringer Ingelheim. Both Wyeth and Immunex (which had merged with Amgen by 2002) responded by renovating older facilities and building up their own capacity. By 2005, three large facilities were generating ample drug product to meet market demands that continue to grow dramatically.

BIOLOGY VERSUS STAINLESS STEEL

At Wyeth, we believe that the productivity and economics of biopharmaceutical manufacturing are about to change dramatically. While the nature of clinical development and product markets will remain unpredictable, process development and manufacturing will become more efficient, less costly, and better able to adapt to rapid changes in clinical prospects and market demand. As a company, we have made it our highest priority to bring about a transformation in manufacturing processes and technology. Currently, more than one-third of our research and development pipeline consists of biopharmaceuticals (vaccines and protein-based drugs), while our commercial biotech portfolio brings in annual revenues of approximately $7 billion. This number is expected to grow in the coming years. Thus, it became a strategic imperative to reject the status quo and find a better, more efficient way to manufacture our products. We needed to find a better way to manage the direct costs associated with biopharmaceutical manufacturing, as well as the potential costs related to product development delays (due to process modifications, batch variability, and non-robust operational systems) and lost sales due to insufficient capacity. To continue with business-as-usual was untenable.

Over the past five years, we have been working on innovations in cell biology, bioprocess engineering, and workflow, resulting in dramatic increases in yields and efficiencies that will eventually filter through to the rest of the industry. Our objective is to break through the paradigm that biotechnology drugs are expensive to produce. Here, the biopharmaceutical industry has an opportunity that is not available to manufacturers of small-molecule therapeutics: improving production efficiency through biology.

In the past 10 years, we have been successful in increasing the volumetric productivity of our clinical monoclonal antibody processes more than 10-fold and as much as 30-fold for next-stage processes, where new technology has been applied.^1,2,3 We can achieve volumetric productivity levels of 10 grams per liter in fed-batch cultures. These results have been achieved through cell engineering efforts, increasing the amount of protein produced per cell, as well as increasing the viable cell density of the production culture through proprietary fermentation technology. A single 5,000-L bioreactor can now produce the same amount of product (about one metric ton per year) equal to that produced by 100,000 L of fermentation capacity using previous technology. In addition, advances in purification technology have led to streamlined processes that use limited chromatography steps, resulting in high process yields (80%) and purity, while reducing water and buffer usage, suite labor, and ultimately, lowering the cost of goods.

The goal is to replace stainless steel with biology, to put more resources and efforts into improving the efficiency of biological expression rather than building more reactors and more manufacturing plants. A 10- to 30-fold improvement in manufacturing efficiency has the potential to transform the business model of the entire biopharmaceutical industry, influencing decisions about whether or not to build facilities and about how to allocate resources, plan product portfolios, and respond to shifting market landscapes.

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.

Generally, large organizations such as Wyeth can take on the risk of experimenting with manufacturing and process engineering. Since 2000, Wyeth has invested $3.5 billion in building or renovating more than 20 manufacturing suites at six sites around the world. Two of these sites, Grange Castle, Ireland, and Andover, Massachusetts, have become models for integrated process development and manufacturing. The co-location of process development and manufacturing groups helps foster close collaboration and creates an atmosphere of innovation. Basic research is conducted to improve and push the limits of biopharmaceutical production by methods such as assessing alternative expression and operational systems, as well as enhancing workflow efficiencies. Through standardization and improvements in the biology of protein expression, Wyeth is significantly increasing yields while enabling single bioreactors to handle more products, and reducing the need to expand equipment and facilities. The ability to increase capacity and flexibility in current internal manufacturing facilities has been instrumental in Wyeth's strategy to increase its portfolio of biologics and its ability to put as many as eight to ten biopharmaceutical candidates into the clinic each year.

Within the biotechnology industry, there has been little incentive to develop a deeper scientific understanding of manufacturing processes in an effort to improve quality and efficiency. This may be due in part to strict requirements on the part of regulatory authorities, who are concerned that any process change could present an unacceptable risk. Recently, however, the FDA, in the form of its Critical Path Initiative, has signaled a desire to foster innovation in manufacturing and other stages of drug development to get valuable drugs to patients sooner. Such policy changes have paved the way for new technologies that have gained prominence for boosting efficiency. For example, disposable bag bioreactors simplify processing, inoculum trains, scale-up, and turnaround times while saving the time and cost of sterilization, cleaning and validation; innovative expression systems secrete proteins or concentrate proteins within cells for later extraction at high yield; and precise control of bioreactor environments can lead to high cell densities.

THE FUTURE MAY HAVE ALREADY BEEN HERE

In the computer industry, one can always state with confidence that the next year will bring improvements in manufacturing: faster processors, more memory storage, and higher performance. This has rarely been the case for biopharmaceutical manufacturing. Today, however, there is a palpable sense that a significant improvement in production efficiency is imminent. Wyeth is implementing these improvements for its entire biopharmaceutical product portfolio with the ultimate goal of leading the industry. In the future, we will see other major pharmaceutical and biotechnology companies increase their manufacturing capacity and flexibility through the use of improved biological expression systems, innovative process technologies, optimized workflows, and standardization, all without having to invest in additional stainless steel.

To get a glimpse of what the future may hold for the biopharmaceutical industry, one need only look back to the transformation that took place in semiconductor manufacturing. Similar to the biotechnology industry, the technology for semiconductor manufacturing was initially highly specialized and expensive. Competitive pressures and the need for large-scale production required the construction of large plants, at costs that were prohibitive for most industry companies. The investment in such large plants led to a compromise in the ability to rapidly respond to new technological advances. To better respond to markets and compete with lower cost operations in Asia, semiconductor companies began to form consortia to share capacity and hire contract manufacturers. As in the biotechnology industry today, shared capacity in semiconductor manufacturing was only possible through the standardization of processes and technology. Technology standardization became more firmly established as the small number of companies, which held the dominant intellectual property required for the design and manufacture of state-of-the-art semiconductors, became the industry leaders.

The biopharmaceutical manufacturing renaissance has many implications. Companies will need to re-think their strategies and capital investment in manufacturing facilities. More flexible capacity and higher yielding processes will reduce the need to construct large plants for product launch. In addition, increased manufacturing flexibility will provide companies with a higher level of protection against risks associated with lack of product efficacy in clinical trials or the redefinition of its market through narrowed or expanded indications. For large companies with their own manufacturing facilities, issues of managing plant utilization through capacity sharing or outsourcing may become less relevant. For emerging companies without manufacturing infrastructure, outsourcing will remain an important resource. In addition, intellectual property for high-yield manufacturing could become concentrated among a few industry players, who would then extend and disseminate standards in facilities and processes through licensing, contract manufacturing, or building plants, in a process similar to what occurred in the semiconductor industry. Lastly, the economic viability of targeted or small-market therapeutics will improve, possibly paving the way for migration away from blockbuster drugs, which carry their own risks (e.g., major loss of revenue at patent expiration, or withdrawal due to serious adverse events). The ability to serve smaller markets cost-effectively will also support the movement toward personalized medicine, in which treatments are tailored to genetically defined subpopulations.

Many changes will occur as high production efficiency becomes the norm. So get ready, because it looks like the biopharmaceutical industry is about to grow up.

Michael E. Kamarck, PhD, is the senior vice president of technical operations and product supply at Wyeth Biotech, Collegeville, PA, kamarcm@wyeth.com. At the same company, Louane E. Hann, PhD, is a senior program manager for strategic oversight of biotech process development, and S. Robert Adamson, PhD, is vice president of biotech process development.

REFERENCES

1. Charlebois T. Frontiers and economics of mammalian cell expression. BIO 2006 Annual International Convention; 9–12 April 2006; Chicago, IL.

2. Kelley B et al. Designing a 10-ton mab process: Is conventional chromatography limiting? BiogenIDEC Manufacturing Seminar Series; Feb 2007; Cambridge, MA.

3. Luan Y-T. defined medium development for high yielding mammalian cell culture processes. BioProcess International Conference and Exhibition; Nov 2006; San Francisco, CA.