5
Needs: What Must Be Done to Meet the Challenges

5.1 EDUCATION AND TRAINING

Research activities and the training of bioprocess engineers for the next decade should be broad enough to enable staffing of bioprocess research, development, and manufacturing functions for biotherapeutics and other classes of bioproducts, including intermediate-value products obtained from renewable resources through bioprocessing, value-added agricultural materials, and waste-processing products and services. This chapter treats elements of bioprocess engineering that must be addressed to meet the needs of industry and the goal of commercializing biotechnology.

5.1.1

Science-Engineering Interface

The principles, culture, and techniques of scientists (biologists and chemists) are often different from those of bioprocess engineers. The differences can place unnecessary limits on collaboration among members of a bioprocessing-development team and thereby delay engineering considerations to the later stages of bioprocess development. Hence, it is important that the bioprocess engineers' training in the next decade have a strong background in biochemistry, molecular biology, cell biology, and genetics. That will facilitate useful communication of bioprocess engineers with the bench scientists who are at the initial discovery stage of biological-product research and development. The situation can be thought of as analogous to process development in the chemical and petrochemical industries, where engineers who are knowledgeable in basic concepts in organic and physical chemistry have fostered innovations in processes developed through interactions of research chemists and engineers. Future research and training in the appli-



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Putting Biotechnology to Work Bioprocess Engineering 5 Needs: What Must Be Done to Meet the Challenges 5.1 EDUCATION AND TRAINING Research activities and the training of bioprocess engineers for the next decade should be broad enough to enable staffing of bioprocess research, development, and manufacturing functions for biotherapeutics and other classes of bioproducts, including intermediate-value products obtained from renewable resources through bioprocessing, value-added agricultural materials, and waste-processing products and services. This chapter treats elements of bioprocess engineering that must be addressed to meet the needs of industry and the goal of commercializing biotechnology. 5.1.1 Science-Engineering Interface The principles, culture, and techniques of scientists (biologists and chemists) are often different from those of bioprocess engineers. The differences can place unnecessary limits on collaboration among members of a bioprocessing-development team and thereby delay engineering considerations to the later stages of bioprocess development. Hence, it is important that the bioprocess engineers' training in the next decade have a strong background in biochemistry, molecular biology, cell biology, and genetics. That will facilitate useful communication of bioprocess engineers with the bench scientists who are at the initial discovery stage of biological-product research and development. The situation can be thought of as analogous to process development in the chemical and petrochemical industries, where engineers who are knowledgeable in basic concepts in organic and physical chemistry have fostered innovations in processes developed through interactions of research chemists and engineers. Future research and training in the appli-

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Putting Biotechnology to Work Bioprocess Engineering cation of systems engineering and bioprocess economics at the early stages of research and development are also needed; they will help to foster interactions between bioscientists and bioprocess engineers and encourage consideration of engineering factors at the onset of a research and development program. 5.1.2 Multidisciplinary Team Research Bioprocess engineering is a broad engineering field, in that it covers all the physical sciences and biological sciences. It is impossible to design and engineer bioprocesses within a single discipline. Formal coursework in other disciplines will begin to build the foundation for team research through cross-disciplinary interactions. However, coursework alone will not be sufficient for executing and implementing the actual research and development. The hands-on experience of team research must be part of bioprocess engineers' training program. It is therefore recommended that cross-disciplinary research be part of the training of the bioprocess engineer; it is probably best practiced at the postgraduate level. There is much to be gained through input from different disciplines when such team research is executed. However, to implement this type of research, cultural changes in the engineering and scientific communities will be required. For example, a doctoral candidate in chemical engineering is often viewed as performing research as a single investigator when, in fact, input from multiple disciplines is essential. Several government-agency programs foster cross-disciplinary and interdisciplinary training. They include the National Science Foundation (NSF) Engineering Research Center Initiative and the National Institutes of Health (NIH) Interdisciplinary Biotechnology Training Grant Program in the National Institute of General Medical Sciences. It is recommended that the programs continue to foster activities through cross-disciplinary interactions. 5.1.3 Industry-University Interface The education of leaders who are strong in science, engineering, business, and management skills is difficult. But the bioprocess engineer's education at the predoctoral level usually devotes little time to the management and business aspects of biotechnology. A training program must reflect the realities of the bioprocess industrial sectors. It is recommended that future programs incorporate the industry-university interface into formal training activities. Continuing education is especially critical for bioprocess engineering, because of the rapidity of advances in the biological sciences. Continuing

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Putting Biotechnology to Work Bioprocess Engineering education in the industrial sector should be part of the training offered by universities to leaders in the bioproduct industry. Such a program should be created by industry, universities, and government in a cooperative fashion. 5.1.4 Bioprocess Equipment Engineers Biochemical engineers are and should be the lead engineers in bioprocess development. They are educated uniquely to span the gap between the biological sciences and process engineering. However, the efforts of these engineers must also be integrated with those of equipment engineers, as well as bioscientists. Integration of biochemical and equipment engineering is often absent in current bioprocess engineering practice. The equipment that is used by the bioprocess engineer evolves slowly; there are few radical breakthroughs. That is probably because the most active parts of the industry are new and relatively small, and their progress has been driven by new ventures attempting to inject new technology into bioprocessing. Attempts by small, startup bioprocess equipment companies are often underfunded, and many fail. In contrast, the well-established manufacturers of bioprocess equipment spend little on research and development relative to other high-technology industries. Systems and equipment engineering, comparable with that in the aircraft, electronics, and defense industries, must be used by the U.S. bioproducts industry to make it competitive. To that end, more engineers should be trained who are seriously interested in improving bioprocess equipment, such as chromatography systems, centrifuges, membrane filters, bioreactors, and especially on-line instrumentation for monitoring and control. Their undergraduate education can be in the traditional fields of instrumentation and electrical and mechanical engineering, with a few basic courses in chemical engineering. At the graduate level, education should be structured jointly with programs in bioprocess engineering. As the biotechnology industry matures and manufacturing costs become important, the equipment engineer will assume a larger role than today. And, if biomass substantially replaces fossil fuel as a primary source of energy and materials, equipment technology will become critical. Industry and government should encourage the education of more equipment engineers for the bioproducts industry. 5.1.5 Diversification and Specialized Training Bioprocess-engineering manpower demand will continue to increase in research and development, manufacturing, biotechnology-related business

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Putting Biotechnology to Work Bioprocess Engineering and legal professions, and teaching. Specialized training with a focus on specialties will be required. Specialties in the biopharmaceutical arena are Recombinant and nonrecombinant fermentation technology. Bioseparation and purification of gene products. Animal-, plant-, and insect-cell culture and animal-tissue culture. Similarly, bioprocessing of renewable resources and environmental bioprocess engineering requires Recombinant and nonrecombinant fermentation technology. Bioseparation and purification of fermentation products or products derived through microbial activity. Applied microbiology of industrially important microorganisms. Other fields of importance are Protein chemistry and processing. Biocatalysis and enzyme technology. Biosensors, instrumentation, and process control. Future training and educational programs must be much more concentrated and focus on selected subspecialties to address anticipated staffing needs in the pharmaceutical industry, medical industry, food and agriculture, environmental biotechnology-related industry, chemical industry, and energy industry. 5.1.6 Curriculum Development A unique element in the education of some bioprocess engineers is hands-on experience in applied microbiology and molecular biology, bioreactor operation, cell culture, bioseparation (chromatography, membranes, and centrifugation), and basic analytical methods for biological materials and molecules. Such training in the context of an upper-level, undergraduate bioprocess-engineering laboratory constitutes an invaluable first experience in merging theory with experiment for biological systems. It is already being provided to some extent in a few universities. The committee recommends that competitive-grant programs be further developed to upgrade teaching laboratories for bioprocess engineering so that they can provide a high-quality training experience for a larger number of students. 5.2 RESEARCH Bioprocessing research needs differ between the biopharmaceutical, renewable-resources, and environmental sectors of the biotechnology industry. The biopharmaceutical sector currently has the strongest basis and

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Putting Biotechnology to Work Bioprocess Engineering research needs directly tied to recombinant-DNA technology. Key research needs in generic applied research are in fundamental studies on and development of Methods for rapid characterization of biochemical properties, efficacy, and immunogenicity of protein pharmaceuticals. Process control of systems involving genetically altered products. High-resolution protein-purification technologies that are economically feasible, are readily scaled up, and have minimal waste-disposal requirements. Other research needs are related to expanding the range of pharmaceuticals that can be produced by prokaryotic cells, further developing the technology for stable liquid formulations and for sustained release of protein pharmaceuticals, and increasing knowledge of chemical and biochemical reactions that modify proteins during production and storage. The latter subjects are perceived to be potentially parts of the research mission of NIH, because they involve health issues. The key bioprocess-engineering issues are consistent with the continuing programs of NSF, although sustained increases in resources will be needed to fund strong programs. The processing of renewable resources and manufacture of value-added products from agricultural commodities require bioprocess-engineering research to address fundamental understanding and development of Cellulose pretreatment and saccharification systems to convert ligno-cellulosic materials, as well as coproducts of corn processing, into appropriately priced fermentable sugars and value-added materials. Microorganisms and fermentations capable of converting pentoses to value-added products at rates and yields comparable with those obtained for glucose by yeast. Separation systems, amenable to large-scale use, for recovering and purifying bioproducts from dilute aqueous solutions. Engineering and manipulating cellular pathways for enhanced production of microbial metabolites, or microbial synthesis, of new products. Those research needs can be addressed within the framework of bioprocessing research initiatives of NSF, the U.S. Department of Agriculture (USDA), and the Department of Energy (DOE). Another engineering-research need is in the development of large-scale surface culture as might be encountered in biopulping. Other fundamental research needs are to increase the knowledge base of biochemical and microbial transformations that result in value-added nonfood products from starch and cellulose. A recent example is the genetic engineering of E. coil to enable it to produce ethanol, thereby com-

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Putting Biotechnology to Work Bioprocess Engineering bining the microorganism's ability to use pentose with its ability to yield an economically useful end product (Ingram, 1992). Other examples of potential products are poly-&x98; -hydroxybutyrate, calcium magnesium acetate (from acetic acid), glycerol, acetone, and butanol (Bungay, 1992). Research to improve methods of adding value to corn wet-milling products is also needed. Those subjects all fit within the missions of USDA initiatives to carry out applied generic research in biotechnology to add value to agricultural products and DOE programs in deriving fuels and chemicals from biomass. A sustained research effort will be required if successful process concepts are to be developed in the coming 5–10 years. Environmental applications of bioprocessing are perhaps the furthest off and need fundamental research, particularly in Specific effects of microorganisms in various ecosystems. The role of microorganisms in ex situ waste remediation. Definition and implementation of engineering standards by which bioremediation protocols and processes could be gauged. The research needs in bioremediation are subject to a number of complex technical and regulatory issues, as described in the OTA report (OTA, 1991). Concerted efforts will be particularly important as the regulatory environment for biotechnology products improves and the regulatory process is streamlined. The federal support of fundamental research in bioprocess engineering is essential, and a major increase in federal support is strongly recommended. The research goals and approaches of industry are different from those of universities. Industrial research is mission-oriented, and its emphasis is on applied research that leads to products and more efficient process technologies; the purpose of university research is to enlarge the generic and fundamental knowledge base relevant to bioprocess engineering. Consequently, federal support is a critical element of success. The challenge of coordinating government-supported research and development is recognized and is the focus of the Federal Coordinating Council for Science, Engineering, and Technology (FCCSET) Committee on Life Sciences and Health. The FCCSET report (1992) lists planned federal investments in manufacturing and bioprocessing biotechnology, which total $123.8 million for FY 1993 (Table 5.1). The committee agrees with the directions that are set, but feels strongly that more will be needed over the next 10 years. Bioprocess technology is the basis on which the products of life-science research are translated to a manufacturing environment. It is critical for bringing the industry to the profitability that will return taxes and create jobs in all sectors of our economy.

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Putting Biotechnology to Work Bioprocess Engineering Table 5.1 Federal Investment in Manufacturing and Bioprocessing Biotechnology   Investment, millions of dollars Agency FY 1991 FY 1992 FY 1993 National Science Foundation 29.5 32.3 43.0 U.S. Department of Agriculture 17.6 18.8 23.6 Department of Defense 12.7 17.4 18.4 Department of Health and Human Services 16.7 17.0 17.7 Department of Energy 5.3 6.4 13.2 National Aeronautics and Space Administration 2.6 2.6 3.7 Department of Commerce 3.5 3.5 3.5 Department of the Interior 1.0 0.8 0.7 TOTAL 88.9 98.8 123.8   SOURCE: FCCSET, 1992, p. 46. 5.3 TECHNOLOGY TRANSFER Technology transfer in biotechnology and bioprocess engineering can include dissemination of published scientific and technical literature related to biotechnology, movement of scientists and engineers between employers, training of scientists and engineers in bioprocessing technology, construction of plants to manufacture biotechnology products, joint ventures of biotechnology businesses, licensing of biotechnology products and bioprocesses, exchange of manufacturing technology, release of technical information with the sale of bioprocessing equipment, technical consulting, transfer of engineering proposals, and transfer of technical information through trade exhibits. Although there is a need for university, industry, and government research organizations to be interdependent in their research and development endeavors, effective communication and technology transfer are mutually beneficial and critically important to the national economic security. The federal government is emphasizing the need to increase cooperative activities between national laboratories, industry, and universities with emphasis on technology transfer. The committee encourages continued development of this type of interaction. The important issues that are relevant to biotechnology transfer and should be focused on are the effectiveness of U.S. university-industry relationships in bioprocess technology transfer in the context of international exploitation of biotechnology.

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Putting Biotechnology to Work Bioprocess Engineering 5.3.1 University-Industry Relationships The United States seems to have a very effective university-industry technology-transfer process, compared with other technologically advanced countries. The effectiveness of technology transfer from the U.S. university to industry can be attributed to the high degree of freedom of faculty to conduct their research and the openness of the academic community to technology transfer. Forms of technology transfer from the universities include employment of graduates, professional meetings, dissemination of scientific and technical publications, consulting arrangements, contract research for industry, collaborative research agreements, and training of industrial personnel. Thus, universities make their research available to industry by many means. It appears that, in biological science, industry carefully studies the university output and exploits it effectively. In contrast, the U.S. bioprocessing industry is slow to use information for innovation in manufacturing processes. Some of the industries involved are very conservative about changing processes and, in general, U.S. industry tends to be risk-averse because owners exert pressure to produce results in the short term, and the regulation and validation process could become a rate-limiting factor in the commercialization of pharmaceutical products. In the bioprocessing industry, many manufacturing-process innovations are developed by small companies. New chromatographic techniques, new bioreactors, new membrane filtration—all come from small to medium companies. The large users of the technology—pharmaceutical, food, and chemical companies—seem to have less of a role in innovations that lead to new manufacturing processes. Research programs that lead to innovations by universities or entrepreneurial companies are supported primarily through government funds. There are no U.S. consortia of manufacturers supporting the development of generic bioprocessing technology. Both industry and university technology transfer would benefit if industry had stronger communications with the universities. Communication would serve as a means to encourage cooperation between industry and universities to the benefit of both. The committee recommends that the issue of tax incentives be reexamined with an eye to stimulating greater risk investment by industry, improving technology transfer, stimulating university investigators to set priorities in their fundamental research according to technology that industry will use, and promoting international competitiveness in bioprocess technology. The committee strongly recommends that a strategy be developed for fostering an improvement in awareness of the importance of manufacturing technology in the research and university communities through education

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Putting Biotechnology to Work Bioprocess Engineering and training. It would be equally beneficial if industry would provide guidance to universities in selecting research and development foci. 5.3.2 International Exploitation Biotechnology companies have three ways of exploiting biotechnology in a world market: They can license the biotechnology to a foreign company. They can invest in a foreign subsidiary or joint venture. They can make the biotechnology product in their home countries and export it. Many new biotechnology firms in the United States have transferred some of their biotechnology via licensing and joint ventures to well-established large U.S. or foreign companies, because the new firms lack the capital and capability for commercial-scale manufacturing or marketing abroad. It is difficult to assess accurately the amount or extent of international biotechnology transfer, investment, and trade and their potential impact on U.S. competitiveness in biotechnology. The issue is quite complex and might warrant a separate study. 5.4 REFERENCES Bungay, H. 1992. Product opportunities for biomass refining. Enzyme Microb. Technol. 14:501–507. 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. Ingram, L. 1992. Genetic engineering of novel bacteria for the conversion of plant polysaccharides into ethanol. Pp. 507–509 in Harnessing Biotechnology for the 21st Century, M. Ladisch and A. Bose, eds. Washington, D.C.: American Chemical Society. 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.