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The Biomanufacturing of Biotechnology Products

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The Biomanufacturing of Biotechnology Products Chapter 26 The Biomanufacturing of Biotechnology Products John Conner, MS*, Don Wuchterl**, Maria Lopez***, Bill Minshall, MS†, Rabi Prusti, PhD††, Dave Boclair†††, Jay Peterson‡ and Chris Allen, MS‡‡ *Vice President Manufacturing Science and Technology, Cytovance Biologics, Inc., Oklahoma City, Oklahoma, **Senior Vice President Operations, Cytovance Biologics Inc., Oklahoma City, Oklahoma, ***Vice President Quality Systems, Cytovance Biologics Inc., Oklahoma City, Oklahoma, †Senior Vice President Regulatory Affairs, Cytovance Biologics Inc., Oklahoma City, Oklahoma, ††Executive Director Quality Control, Cytovance Biologics Inc., Oklahoma City, Oklahoma, †††Manager Manufacturing Downstream Operations, Cytovance Biologics Inc., Oklahoma City, Oklahoma, ‡Manager Manufacturing Upstream Operations, Cytovance Biologics Inc., Oklahoma City, Oklahoma, ‡‡Senior Manager Facilities and Engineering, Cytovance Biologics Inc., Oklahoma City, Oklahoma What is biologics manufacturing? How is it different from effect on safety. It has been demonstrated that endogenous small molecule pharmaceutical manufacturing? Biologics adventitious viruses may result from processing changes manufacturing, or biomanufacturing for short, is a complex or the extension of the production process. Therefore, end process that produces a product largely derived from discov- of production processes and genotypic studies on the cell eries using recombinant DNA technology to develop pro- line have been required to understand the implications of cesses and analytics to manufacture biotherapeutic products. changes in the production process that can affect the prod- These recombinant products were developed from several uct’s quality attributes, impurity profiles that could impact platforms such as whole multicellular systems encompassing the safety of the therapeutic. Today’s biologic manufac- transgenic plants, animals and unicellular microbials (bacte- turing facilities incorporate analytical and process devel- ria and yeast), and insect and mammalian cell cultures. The opment capabilities to develop and test the scale-up of discovery and “proof-of-concept” from the research bench the process to deliver sufficient productivity of a quality is transferred to a process and analytical group that will use product. The development will support a Phase 1 clinical science and engineering as well as regulatory experience to study focusing on safety and efficacy of the product. If the scale-up the product efficiently with sufficient product yield product can demonstrate safety and efficacy, the product to support the clinical program and a quality product express- with regulatory agency and business-positive feedback will ing the quality attributes of the product as well as profile any continue the manufacturing of the biologics until reaching product-associated impurities. The process for different bio- final approval and licensing. logic platforms are complex and unlike traditional chemical synthesis the biologic product resulting from a living system THE HISTORY OF BIOTECHNOLOGY AND is not as an exact science as chemistry. The long-existing paradigm for biologics was “the BIOMANUFACTURING process is the product” and any variation in the process Biotechnology is technology based on biology. It utilizes could impart a change in the product’s safety and efficacy. the biology of living systems and their genetic manipula- Although today’s raw materials, process and analytics are tions of these systems and processes to develop technolo- better defined and allow a lot more flexibility in the design gies and products that help improve the lives and health and development of the process. Changes in the process of individuals worldwide. These biological processes of or materials could severely alter the product’s safety and microorganisms have been used for thousands of years characteristics, thus one may end up with a product with to make food products from fermentation, such as bread, a different profile. Changes in the manufacturing process beer, wine, pickles and cheese—these processes are still can alter the “impurity profile” of a biologic, thus imparting used today. Modern biotechnology provides discoveries changes in the product’s purity which can have an adverse of recombinant DNA technology to discover and develop Biotechnology Entrepreneurship. http://dx.doi.org/10.1016/B978-0-12-404730-3.00026-9 Copyright © 2014 Elsevier Inc. All rights reserved. 351 352 SECTION | VII Biotechnology Product Development therapeutic biologics. The following is a chronological 1993—The FDA approves Betaseron®, the first of sev- history of significance to the field of biotechnology and eral biotech products that have had a major impact on biomanufacturing (http://www.bio.org/articles/history- multiple sclerosis treatment. biotechnology?page): 1994—The first breast cancer gene is discovered. 1994—The Americas are certified polio-free by the 500 B.C.—In China, the first antibiotic, moldy soybean International Commission for the Certification of Polio curds, is put to use to treat boils. Eradication. A.D. 100—The first insecticide is produced in China 1995—Gene therapy, immune-system modulation, and from powdered chrysanthemums. recombinantly produced antibodies enter the clinic in the 1761—English surgeon Edward Jenner pioneers vaccina- war against cancer. tion, inoculating a child with a viral smallpox vaccine. 1996—A gene associated with Parkinson’s disease is dis- 1870—Breeders crossbreed cotton, developing hundreds covered. of varieties with superior qualities. 1996—The first genetically engineered crop is commer- 1870—The first experimental corn hybrid is produced in cialized. a laboratory. 1997—A sheep named Dolly in Scotland becomes the 1911—American pathologist Peyton Rous discovers the first animal cloned from an adult cell. first cancer-causing virus. 1998—The FDA approves Herceptin®, a pharmacoge- 1928—Scottish scientist Alexander Fleming discovers nomic breast cancer drug for patients whose cancer over- penicillin. expresses the HER2 receptor. 1933—Hybrid corn is commercialized. 1999—A diagnostic test allows for the quick identification 1942—Penicillin is mass produced in microbes for the of Bovine Spongicorm Encephalopathy (BSE, also first time. known as “mad cow” disease) and Creutzfeldt-Jakob 1950s—The first synthetic antibiotic is created. Disease (CJD). 1951—Artificial insemination of livestock is accom- 2000—Kenya field-tests its first biotech crop, a virus- plished using frozen semen. resistant sweet potato. 1958—DNA is made in a test tube for the first time. 2001—The FDA approves Gleevec® (imatinib), a gene- 1978—Recombinant human insulin is produced for the targeted drug for patients with chronic myeloid leukemia. first time. Gleevec is the first gene-targeted drug to receive FDA 1979—Human growth hormone is synthesized for the approval. first time. 2002—The EPA approves the first transgenic rootworm- 1980—Smallpox is globally eradicated following a resistant corn. 20-year mass vaccination effort. 2002—The banteng, an endangered species, is cloned for 1980—The U.S. Supreme Court approves the principle the first time. of patenting organisms, which allows the Exxon Oil 2003—China grants the world’s first regulatory approval Company to patent an oil-eating microorganism. of the gene therapy product, Gendicine (Shenzhen 1981—Scientists at Ohio University produce the first SiBiono GenTech), which delivers the p53 gene as a ther- transgenic animals by transferring genes from other ani- apy for squamous cell head and neck cancer. mals into mice. 2003—The Human Genome Project completes sequenc- 1982—The first recombinant DNA vaccine for livestock ing of the human genome. is developed. 2004—The United Nations Food and Agriculture 1982—The first biotech drug, human insulin produced in Organization endorses biotech crops, stating biotech- genetically modified bacteria, is approved by the FDA. nology is a complementary tool to traditional farming Genentech and Eli Lilly developed the product. methods that can help poor farmers and consumers in 1985—Genetic markers are found for kidney disease and developing nations. cystic fibrosis. 2004—The FDA approves the first antiangiogenic drug 1986—The first recombinant vaccine for humans, a vac- for cancer, Avastin®. cine for hepatitis B, is approved. 2005—The Energy Policy Act is passed and signed into 1986—Interferon becomes the first anticancer drug pro- law, authorizing numerous incentives for bioethanol duced through biotech. development. 1988—The first pest-resistant corn, Bt corn, is produced. 2006—The FDA approves the recombinant vaccine 1990—The first successful gene therapy is performed Gardasil®, the first vaccine developed against human on a 4-year-old girl suffering from an immune disorder. papillomavirus (HPV), an infection implicated in cervi- 1992—The FDA approves bovine somatotropin (BST) cal and throat cancers, and the first preventative cancer for increased milk production in dairy cows. vaccine. Chapter | 26 The Biomanufacturing of Biotechnology Products 353 2006—The U.S. Department of Agriculture grants Dow together these regulatory authorities, the International AgroSciences the first regulatory approval for a plant- Conference on Harmonization of Technical Require- made vaccine. ments for Registration of Pharmaceuticals for Human 2007—The FDA approves the H5N1 vaccine, the first Use (ICH) was formed in 1990. This organization brings vaccine approved for avian flu. together these regulatory authorities to discuss
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