3
Benchmarking: Status of U.S. Bioprocessing and Biotechnology

Bioprocess engineering enables translation of biotechnology into products that benefit society. Biotechnology-derived products are an important source of revenue and commercial growth throughout the world and hence are related to issues of international competitiveness. In this context, the Committee on Bioprocess Engineering generated a comparison of the state of U.S. biotechnology with that of Japan and Europe based on the recently published Japanese Technology Evaluation Center (JTEC) panel report on Bioprocess Engineering in Japan sponsored by the National Science Foundation (JTEC, 1992).

3.1 BIOPROCESS ENGINEERING IN JAPAN

Bioprocess engineering in Japan has changed substantially during the last 10 years as a result of Japan's entry into applications of bioprocessing to higher-value products obtained through recombinant-DNA and cell-culture technology. This change was achieved differently in Japan and the United States. In the United States, the new biotechnology is pursued by both large and small (startup) biotechnology companies, but the small companies are virtually nonexistent in Japan, research and development being conducted primarily in large companies. Japanese beverage, food, and pharmaceutical companies are diversifying into high-value products—a trend just now being initiated in the United States. Chemical, polymer, steel, and electronic companies in Japan have also initiated moves into the pharmaceutical sector. Industry-government relationships in Japan are different from those in the United States. In many instances, the government has provided both directions for research and development and financial sup-



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Putting Biotechnology to Work Bioprocess Engineering 3 Benchmarking: Status of U.S. Bioprocessing and Biotechnology Bioprocess engineering enables translation of biotechnology into products that benefit society. Biotechnology-derived products are an important source of revenue and commercial growth throughout the world and hence are related to issues of international competitiveness. In this context, the Committee on Bioprocess Engineering generated a comparison of the state of U.S. biotechnology with that of Japan and Europe based on the recently published Japanese Technology Evaluation Center (JTEC) panel report on Bioprocess Engineering in Japan sponsored by the National Science Foundation (JTEC, 1992). 3.1 BIOPROCESS ENGINEERING IN JAPAN Bioprocess engineering in Japan has changed substantially during the last 10 years as a result of Japan's entry into applications of bioprocessing to higher-value products obtained through recombinant-DNA and cell-culture technology. This change was achieved differently in Japan and the United States. In the United States, the new biotechnology is pursued by both large and small (startup) biotechnology companies, but the small companies are virtually nonexistent in Japan, research and development being conducted primarily in large companies. Japanese beverage, food, and pharmaceutical companies are diversifying into high-value products—a trend just now being initiated in the United States. Chemical, polymer, steel, and electronic companies in Japan have also initiated moves into the pharmaceutical sector. Industry-government relationships in Japan are different from those in the United States. In many instances, the government has provided both directions for research and development and financial sup-

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Putting Biotechnology to Work Bioprocess Engineering port to a group of companies to pursue projects that it believes are critical for the commercial development of biotechnology, e.g., in cell culture, bioreactor design, membrane processing, and protein engineering. The types of products derived from the new biotechnology in Japan are the same as those already developed in the United States (JTEC, 1992). They include interferon, growth hormone, tissue plasminogen activator, erythropoietin, and interleukins. The bioprocess know-how is often similar to that in the United States, inasmuch as the process technology is in many cases licensed from U.S. companies. Priority is given to process development for the fine tuning of fermentation processes through strain improvement and medium formulation. In contrast, fundamental engineering research appears to be secondary in the university, government, and industry sectors, with a major focus on applied research. The acceptance of and rewards for performing applied research in all sectors are apparent; both government and industry provide financial support to universities to perform applied research. Another element of Japan's applied research is technology transfer, which is accomplished by placing industrial personnel in the university and government laboratories both in Japan and abroad. Japan appears to have a leading position in automation for both upstream and downstream processing, with a focus on eliminating or reducing the human-process interface, and in hardware development to effect automation that will ensure product quality. Japanese upstream bioprocess engineering is also heavily involved in strain selection, medium development, and environmental control—particularly strain selection, which is believed to be a major spinoff from the amino acid and antibiotic industries. Control of the production environment through medium development is given far more attention than the implementation of completely new engineering concepts. Personnel performing research in the upstream sector are mostly from the departments of agricultural chemistry, fermentation technology, applied biochemistry, and biological chemistry, rather than chemical engineering. Research with recombinant organisms for the production of biologics from prokaryotes, such as E. coli, does not appear to be very different from that in the United States, although there is a heavy emphasis on the refolding of recombinant proteins from E. coli. Substantial activity in Japan is directed to exploring animal cells for the production of therapeutic proteins. However, innovative bioprocess research on the upstream side is not noted. For example, the animal-cell bioreactors are similar to their U.S. counterparts. In contrast, there is observable and intense activity in animal-cell culture medium development, possibly as part of a national effort to reduce the raw-material cost for animal-cell cultivation. Japan also has a notable emphasis on biosensor development. Again, research and development focus is on known concepts (e.g., related to en-

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Putting Biotechnology to Work Bioprocess Engineering zymes, microorganisms, and antibodies) to be incorporated into biosensor development. Some interesting trends in biosensor research in Japan are reflected in the miniaturization of biosensors with microelectronic technology and the development of disposable and discrete sensors for consumer-oriented biomedical applications. In downstream processing, as in upstream processing, the development of new concepts or principles is secondary. Most of Japan's bioprocess-engineering activities are devoted to development and refinement of existing technologies, many of which are based on technology developments in the United States and Europe. The U.S. lead in process validation and Food and Drug Administration (FDA) compliance reflects a serious commitment of time and funds. Japan recognizes the importance of this area for the commercial development of biotechnology, although much of its present knowledge in this field is obtained through technology licenses from the United States. 3.1.1 Education and Training Japan has a strong educational and training program in applied biology and chemistry. Its strength in traditional fermentation technology results from a long-standing emphasis on applied biology, including agricultural biochemistry, industrial chemistry, and fermentation technology. Continued emphasis on strengthening applied biology seems to support the effective transfer of technology from basic molecular biology to commercially important biotechnology, as well as the industry's success in many branches of bioprocess technology. 3.1.2 University-Industry Cooperation Japanese industry has supported university research in numerous cases, largely through long-term grants-in-aid. With that kind of support, universities have been able to conduct much long-term exploratory research and to support graduate students and postdoctoral trainees on a sustained basis. 3.1.3 Scientific and Technological Information-Gathering Japan seems to have established and be able to maintain a well-organized network for scientific and technological information-gathering. The committee recommends that the United States strengthen its effort along those lines with many different approaches. They could include more vigorous examination of technology assessment in Japan, more support for exchange-scholar and exchange-student programs, collaborative research programs, and establishment of a centralized coordinating and networking

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Putting Biotechnology to Work Bioprocess Engineering infrastructure with its own objectives, policy, and strategy. For bioprocess engineering, particular emphasis should be placed on tracking developments in bioprocess technology for manufacture of new bioproducts. 3.1.4 Summary of Comparison With United States A recent mission through the Japan Technology Evaluation Center was made by U.S. panel members to assess the status of bioprocess engineering and biotechnology in Japan. Present and likely future Japan-U.S. comparisons related to the various elements of bioprocessing are summarized in Figure 3.1. The present status is indicated by ''+,'' "O," and "-" to show that Japan is ahead of, even with, or behind the United States, respectively. The future trends are indicated by arrows pointing up (Japan's capabilities will surpass those of the United States), horizontal (capabilities will be similar), and pointing down (U.S. capabilities will exceed Japan's). 3.2 BIOPROCESS ENGINEERING IN GERMANY AND EUROPE One of the charges of the committee was to benchmark bioprocess engineering in Europe. The committee emphasized Germany, because some of the members were familiar with Germany's programs; and two members visited Germany in the fall of 1991. However, other countries in Europe are also very strong in bioprocessing and biotechnology, including Switzerland, the United Kingdom, France, Sweden, Denmark, Norway, Italy, France, Austria, and the Netherlands. 3.2.1 Education The education of bioprocess engineers in Germany is usually accomplished mainly within a few departments of chemical engineering or chemical technology. Scientific departments, such as those in microbiology and biochemistry, also contribute to the education of bioprocess engineers in Germany. Germany has traditionally directed more of its efforts in education to the chemical and biological sciences than to engineering. The major difference in educational training in universities between Germany and the United States lies in the German system in which a single professor is in charge of a department. Assistant, associate, or full professors who might be part of the educational program in a department in the United States and add diversity to educational programs are not prevalent in Germany. Most of the bioprocess engineers are trained at the graduate level, as is the case in the United States, Japan, and other western European countries.

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Putting Biotechnology to Work Bioprocess Engineering FIGURE 3.1 Comparison of Japanese with U.S. Bioprocessing. 3.2.2 University Research in Germany German research universities have components of applied and basic research. That differs from the United States, where the fundamental principles are stressed at the graduate level. Research programs in Germany encompass practical and applied research, in addition to fundamental engineering research. Another major difference between the United States and Germany, in terms of university research, is the Fraunhofer institutes, or bioprocess engineering centers, supported by the German states and placed throughout Germany. Those institutes, directly associated with universities, address both fundamental bioprocess engineering and process development. Most of the Fraunhofer institutes are well equipped with bioprocess equipment for laboratory to pilot-scale operations. An important element of a Fraunhofer institute is the close association between the state government,

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Putting Biotechnology to Work Bioprocess Engineering the university, and industry. Much of the research and development at the Fraunhofer institutes are conducted to meet industrial needs, and it is possible to conduct research with confidentiality for a company in the confines of a Fraunhofer institute. A number of national centers in bioprocess engineering deal with bioprocess engineering. The National Research Center for Biotechnology (GBF) at Braunschweig and the bioprocess engineering center at Julich are examples. The national centers are associated with universities, and student training, as well as research, takes place there. Like the state Fraunhofer institutes, the federally supported centers house activities ranging from basic research and process development to scaleup with small-scale and pilot-scale equipment. Both the Fraunhofer institutes and the national centers often examine process development or process feasibility for industrial processing. Like the state-supported centers, GBF and Julich are able to collaborate with industry and perform research on behalf of industry with a high degree of confidentiality. The budgets of state and federal centers are provided for long periods. For example, the GBF in Braunschweig has been in existence for over 10 years. Bioprocess-engineering research is conducted in the industrial sector. Many biotechnology companies in Germany focus heavily on the new biotechnology of recombinant DNA, as well as the traditional fermentation technology, such as that for antibiotics and large-volume chemical production. Industrial research in Germany is similar to that in the United States. A major difference between the United States and Germany is a gradual tendency for the production activities of major German companies to gravitate from Germany to the United States. For example, the acquisition of Miles Laboratory by Bayer has established a strong foothold in recombinant-DNA technology for Germany within the United States. Other examples are BASF and Henkel. The environmental and "green" policies have made it more difficult for German industry to enter the recombinant market with manufacturing based in Germany. Therefore, much of the bioprocess engineering in the major German multinational companies will be developed in part in the United States, and much of the manufacturing for the companies will also take place on U.S. soil. Figure 3.2 summarizes the opinions of the committee on the present and future states of European biotechnology processing relative to that in the United States. The comparison includes Germany, Switzerland, Austria, United Kingdom, France, Scandinavia, Italy, and the Netherlands and represents an aggregate estimate of status and direction based on committee members' experience and knowledge of European biotechnology. Given some of the excellent biotechnology products and services available from these countries and the upcoming economic unification of Europe, we recommend a separate study on bioprocessing in Europe.

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Putting Biotechnology to Work Bioprocess Engineering FIGURE 3.2 Comparison of European with U.S. Bioprocessing. 3.3 BIOPROCESS ENGINEERING IN UNITED STATES The current status of bioprocessing in the United States provides a useful reference against which the estimated magnitude of future developments can be gauged. The commercialization of products that use or are obtained from the new biotechnology is relatively recent. Within only the last 5 years, sales of biotechnology products have grown from approximately $100 million a year to $4 billion a year. Sales in 10 years are expected to be 10 times today's. Consequently, the committee undertook to estimate the current status of U.S. bioprocessing and particularly bioprocess engineering to provide a reference point for estimating future needs. 3.3.1 Education and Training Bioprocess engineering faculty in U.S. departments of chemical, biochemical, agricultural, civil, and mechanical engineering in 1990 numbered about 250. About 200 of them are in chemical-engineering departments

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Putting Biotechnology to Work Bioprocess Engineering (ACS, 1991). In addition, faculty involved in bioprocess development in allied fields—including biology, applied microbiology, molecular biology, medicinal chemistry, and industrial pharmacy—are estimated to number about 50–75. On that basis, the total current U.S. faculty in bioprocess engineering and bioprocess technology number upwards of 300 engineering and science faculty. Those faculties are estimated to be able to award about 150–200 master's degrees and doctorates in biotechnology processing and bioprocess engineering a year in the coming 10 years. The numbers just cited do not include faculty involved in graduate training in departments of food science, biomedical engineering, or electrical engineering. The education and training of bioprocess engineers in the United States is carried out primarily on the graduate level, although many engineering seniors have had one or two courses in introductory bioprocessing or biochemical engineering. According to sales of major textbooks used in the relevant courses and general chemical-engineering enrollment figures, it can be estimated that about 10,000 engineering seniors and graduate students have had at least an introductory exposure to bioprocess engineering during the last 15 years. Of those students, the committee estimates that less than 10% ultimately pursued graduate (M.S. or Ph.D.) or other specialized studies related to bioprocess engineering since 1977. About 3,000 bioprocess development technologists and engineers (B.S., M.S., and Ph.D.) are employed in an industry that uses new biotechnology for the manufacture of biotherapeutics and intermediate-value products, including enzymes, and for waste treatment (principally through bioremediation). They are probably increasing by fewer than 180 per year. The aggregate growth of bioprocess engineers over the next 10 years, if sustained at current levels, would be 75%. The projected growth rate of the industry is estimated to be 1,000%. There is a clear disparity between the need for manufacturing capability and the engineers and technologists who are likely to be prepared to provide the capability. 3.3.2 Government Initiative and Support The biotechnology initiative of the National Science Foundation defines bioprocessing as encompassing the spectrum of events that produce a substance of biological origin. Bioprocessing research is defined in more detail as including: A fundamental understanding of the formation of the product. Knowledge of separation and purification methods. Process monitoring and control, systems analysis, and integration of upstream and downstream processing.

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Putting Biotechnology to Work Bioprocess Engineering Vignette 5 Bioprocess-Industry Needs: A Moving Target Staffing needs in bioprocessing are a moving target in an industry in which 1 year represents 10%–20% of the life history of many companies. As little as a year ago (in the first part of 1991), a survey of small to medium U.S. biotechnology firms (of which there are now about 750) showed that government regulation and availability of scientific personnel were causing substantial concern; the availability of fermentation and bioprocessing expertise was not viewed as an immediate issue (Dibner, 1991). The average U.S. biotechnology firm appears to have 98 employees, of whom 19 are in basic research, 17 in product development, 22 in production, and nine in marketing. Genentech had an estimated 780 production employees among a total of 2,020. In about 750 biotechnology firms, production jobs are likely to account for 12,000 employees. When the biotechnology-related production employees of larger corporations are added, the number is likely closer to 17,000. The survey (by Dibner, 1991) was taken in the spring of 1991, when few biotechnology firms were showing profitability (Thayer, 1991). It targeted primarily the biopharmaceutical sector and did not include the substantial impact of agriculture-derived and value-added products or the engineering requirements for second-generation biotechnology products, which will need to be produced at higher volume and lower cost than the first-generation ones (see Vignettes 3 and 4). Rapid changes in perceived needs are inevitable in the rapidly growing biotechnology industry (Clemmitt, 1992). Hence, many issues will need to be addressed quickly. Abelson (1992), in assessing the 1991 Office of Technology Assessment (OTA) report, suggests that "the United States will remain a substantial factor in the commercialization of biotechnology. However, a dominant role is being frittered away." The committee believes that basic planning and allocation of resources to ensure availability of a well-trained group of bachelor's-, master's-, and doctorate-level bioprocess engineers would moderate such a trend. Therefore, expanded activities in training must be an immediate concern, given the 2-to 5-year interval that passes between initiation and completion of training. A basic understanding of molecular, genetic, metabolic, and cellular function and regulation in culture and bioreactors. Development of new approaches to bioprocessing. The committee concurs with the assessment given in the Federal Coordinating Council for Science, Engineering, and Technology (FCCSET) report (1992, p. 44): "Manufacturing/Bioprocessing is an area in which biotechnology offers vast potential rewards. The total federal investment of $99 million in FY 1992 is small in proportion to its potential.... It is a priority of the Biotechnology Research Initiative to significantly enhance research in this area." The funding in bioprocessing will need to be gradually in-

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Putting Biotechnology to Work Bioprocess Engineering creased, as the industry grows past the level reflected by the funding requested for FY 1993. Assuming a 4% average inflation rate and a 6% growth rate, an increase of around 10% per year would be needed. That is equivalent to growth of the programs from $43 million per year (budget request for FY 1993) to $110 million per year 10 years from now. The application of bioprocess-engineering principles to separation and purification methods has high priority, because separation and purification costs are often 50% or more of processing costs. Ancillary contributions to improving productivity and product quality and decreasing costs of purification will come from improvements in process-monitoring control, systems analysis, and integration of upstream and downstream processing. Research and development on those topics, if structured to address techniques that affect industrial manufacturing processes, will complement fundamental research in developing needed biological and biochemical tools for assays and downstream processing discussed in Chapter 4. Combined with improvements in the basic understanding of the productivity of cell culture and bioreactors, research on downstream processing, systems integration, and process monitoring could contribute substantially to the manufacturing technology base and at the same time provide training for bioprocess engineers who would work in the industry. Given the opportunities for training and having a major impact in the industry, strong government support of research in bioprocess engineering for separation and purification is appropriate, if not critical, to U.S. bioprocessing industries. Research in purification and separation will be most effective if structured to foster cross-disciplinary approaches that seek the application of biological, chemical, and biochemical principles. To that end, sustained increases in NSF resources for bioprocessing programs need to be maintained. Another key challenge for the protein-pharmaceutical industry is the effective analysis of the final product and product intermediates. The product must consistently be shown to be identical with the product that was demonstrated as safe and effective in human clinical trials. Proteins are large complex molecules, so the task is often difficult and expensive and might be rate-limiting in a product-development effort. The relationship between analytical characterization of a molecule and clinical performance is particularly difficult to determine. For example, it is not now possible to know whether a molecular form will be immunogenic or even to know what characteristic of the molecule determines its immunogenicity. Such limitations also often make it expensive and difficult to improve a process after a product is approved for marketing. To address that need, it is recommended that greater cooperation be established between the protein-pharmaceutical industry and FDA. Conveyance of industrial viewpoints to FDA can now occur through committees of the Pharmaceutical Manufacturers Association and the Industrial Bio-

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Putting Biotechnology to Work Bioprocess Engineering technology Association. Similar arrangements should be established to foster and support active communication and research aimed at developing more effective and less expensive methods for protein-pharmaceutical characterization. 3.4 SUMMARY The excellent basic-research program in the biological sciences has benefited the U.S. biotechnology industry, as well as being a valuable source of information for development of bioprocessing technology in both Japan and Europe. The committee feels that, in product discovery and genetics, as related to molecular biology, both Europe and Japan are behind the United States and will continue to be behind for the foreseeable future. That reflects, in part, the important long-term commitment that has been made to the basic sciences (at $3.0 billion per year) as they are related to the new biotechnology through government-funded research programs (FCCSET, 1992). In many of the other fields illustrated in Figure 3.2, Europe and the United States are approximately equivalent, and their competitive positions are likely to be maintained for the foreseeable future. Japan, in contrast, is ahead and will remain ahead for the foreseeable future (see Figure 3.1) in monitoring and control, biocatalysis, applied training, and university-government-industry relations. If the U.S. biotechnology industry is to remain competitive with those of Japan and Europe, a major commitment is needed to develop engineering staffing in bioprocess development and to support manufacturing technologies. We recommend a major commitment to developing the manpower base through funding of research programs in universities, continuing-education programs, and research directed toward industrial problems (applied-engineering research). New resources must be provided to increase the infrastructure for bioprocess engineering and biotechnology in this context. 3.5 REFERENCES Abelson, P. H. 1992. Biotechnology in a global economy [editorial]. Science 255(5043):381. ACS (American Chemical Society). 1991. Directory of Graduate Research. Washington, D.C.: American Chemical Society. 1561 pp.. Clemmitt, M. 1992. Maturing biotech firms face new challenges. The Scientist 6(8):1. Dibner, M. D. 1991. Manpower—Present and Future—in Bioprocessing: Perspectives from the Biotechnology Industry, Report to the Committee on Bioprocess Engineering, Board on Biology, National Research Council, Washington, D.C. FCCSET (Federal Coordinating Council for Science, Engineering, and Technology). 1992. Biotechnology for the 21st Century. A Report by the FCCSET Committee on Life Sciences and Health, Office of Science and Technology Policy, Executive Office of the President, Washington, D.C.

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Putting Biotechnology to Work Bioprocess Engineering JTEC (Japanese Technology Evaluation Center). 1992. Bioprocess Engineering in Japan. NTIS Report No. PB92-100213, Washington, D.C. OTA (Office of Technology Assessment). 1991. Biotechnology in a Global Economy, B. Brown, ed. Office of Technology Assessment, U.S. Congress, Report No. OTA-BA-494. Washington, D.C.: U.S. Government Printing Office. Thayer, A. M. 1991. Revenues grow for biotech firms but few show profitability. Chem. Eng. News 69(36):17–18.