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Commercial production of monoclonal antibodies. A guide for scale-up
Journal of Controlled Release, 9 (1989) 281-288 Elsevier Science Publishers B.V.. Amsterdam - Printed
287 in The Netherlands
BOOK REVIEW (Ed.), Commercial Production of Monoclonal Antibodies. A Guide for Scale-up, Marcel Dekker, New York, Basel, 1987, 327 pages, US$99.75.
S.S. Seaver
Overall, this is a very useful volume of 14 chapters on the subject of commercial antibody production and purification. Although the field of antibody (and, especially, monoclonal antibody, MAb) production and applications is moving at a very fast pace, it is quite likely that many chapters in this volume will remain relevant and useful for years to come. As such, this volume would be recommended for both the industrial researcher and the academic teacher/ investigator. In fact, some chapters in the volume (such as, primarily, chapters 1,4,6,10 and 13) are excellent material for an advanced course on the subject. The volume is divided into three logical parts: (I ) Before scaling-up production (chaps. l-4); (II) production in large-scale systems (chaps. 5-10); and (III) purification of monoclonal antibodies (chaps. 11-14). It also contains five very useful appendixes dealing with federal regulations on the production and uses of MAb, and detailed procedures for cell culture and purification. Chapter 1, by W.R. Shek, deals with the detection of murine viruses in hybridoma cultures and its products, and also with decontamination of hybridoma lines from fungi, bacteria or mycoplasma. It is well written and very useful background for all researchers in the area, especially for those that still treat hybridoma cells like innocuous microbial cultures. Chapter 2, by S.R. Adamson et al., examines quantitative aspects of hybridoma cell growth (growth, product formation and nutrient utilization) on three commercially available media in spinner-flask cultures. Although quite detailed and interesting for a journal publication, the results are not sufficiently general to warrant inclusion in this
volume. Indeed, it is quite well known that cell growth and metabolism is very dependent on the specific cell line and small changes in the culture environment. Chapter 3, by B.L. Brown, discusses an inexpensive defined (serum-free) medium that supports effective growth of a myeloma line and its derived hybridoma lines, and also an on-line method for adapting a MAb producing hybridoma line from a serum-containing to a serum-free medium. The material is quite detailed but the procedures and results are not sufficiently general. One only wished there was a chapter to discuss exhaustively and critically what is really known today on serumfree media. This is clearly a weak point of this volume. Chapter 4, by S.S. Seaver, is a good effort to compare, based on antibody productivities, three different culture systems: a dish (static ) culture, a spinner-flask (stirred) culture, and a flat-membrane perfusion (static) culture. It contains a wealth of interesting observations and, as expected, does not proclaim a winner culture system, as cell growth and MAb production can be affected differently for each cell line by a large variety of factors. In the second part of the volume, J.P. Chandler discusses in chapter 5 MAb production in mouse ascites. This is a very well written and informative chapter on a culture method that, most likely, will be used less and less for MAb production due to cost, scale and animal welfare reasons. Chapter 6, by W.B. Lebherz III, is a detailed and thorough description of batch MAb production in large-scale suspension culture. I find this one of the best written and most useful chapters in this book for its content and organization. It discusses the creation and characterization of the hybridoma, the growth of the cells in stirred cultures of increasing size, the physical manufacturing plant, its hardware and staffing, process flow of the large-scale production, and the detailed analysis of the largescale bulk product. It also provides some cost
288
information and presents a thorough discussion of problems associated with the overall process. An excellent job! Chapter 7, by J.E. Putnam, describes the Opticell ceramic matrix production system (KC Biological) in sufficient detail and with good data. It is a useful chapter of more limited interest since this is a proprietary package system. Chapter 8, by E.G. Posillico et al., provides a useful description of the Encapsel (Diamon Biotech) microencapsulation process which uses alginate beads. The information is mostly qualitative, and a number of quantitative process and cost issues are unfortunately not discussed. The substantial information on MAb purification is relevant and useful. The list of references is also quite complete and useful. Chapters 9 and 10 discuss two commercial hollow-fiber production systems. Chapter 9 discusses the Bioresponse system. It is poorly put together, with minimal technical details, a poor if not misleading schematic (Fig. 1) , does not address any of the wellknown technical problems of hollow-fiber systems, and reads like a commercial brochure. This chapter contributes nothing to this volume. In contrast, chapter 10, by B.G. Andersen and M.L. Gruenberg, is very well written and contains a wealth of useful information. It discusses the Endotronics hollow-fiber system, and includes a clear statement of key technical problems, and a good (but not very specific) discussion of how these problems might be resolved. It openly discusses the problem of variability among production runs, and offers good strategies for improving MAb productivities. A very well written and useful chapter. The last four chapters (11-14) are devoted to the very important issue of MAb purification. Chapter 11,by S.M. Lee, discusses affinity purification of IgG using Protein A-Sepharose CL-4B. It addresses many key issues related to product evaluation (e.g., sterility, viral activity,
nucleic acid level, bovine IgG level, and endotoxin level) and includes an excellent list of references. Chapter 12, by M.P. Strickler and M.J. Gemski, discusses MAb puri~cation by anion exchange high performance liquid chromatography (HPLC) . It contains a large and relevant amount of information and detailed proIts purification. cedures on small-scale weaknesses are an almost non-existent list of references on such a literature-rich subject, and the incomplete, if not simplistic, approach to scale-up. Chapter 13, by D.R. Nau, discusses MAb HPLC purification using the ABx packing (J.T. Baker Chemical Co.), ABx is a silicabased, mixed mode ion exchanger that offers, according to the data presented in this chapter, significant advantages for MAb purification. This is a very well-written chapter and includes a good qualitative discussion of scale-up issues and a very good list of references. I like this the most among the four purification chapters. Chapter 14, by H. Juarez-Salinas et al., discusses the characterization and purification of MAb using various types of HPLC: size exclusion for analytical determinations and characterization; protein-A HPLC for puri~cation; and hy~oxylapatite HPLC for separation of biologically active IgGs (light chain variants) or MAb from polyclonal fetal calf serum IgG. The information is specific and relevant to small-scale applications. Scale-up issues are not addressed, and the list of references is small. Overall, however, this is a useful chapter. In summary, I recommend this volume enthusiastically for both industrial and academic researchers, despite a few weaknesses and omissions to cover a number of technical issues concerning the large-scale MAb production. E.T. PAPOUTSAKIS Northwestern University Evanston, IL, 1J.S.A.
287 in The Netherlands
BOOK REVIEW (Ed.), Commercial Production of Monoclonal Antibodies. A Guide for Scale-up, Marcel Dekker, New York, Basel, 1987, 327 pages, US$99.75.
S.S. Seaver
Overall, this is a very useful volume of 14 chapters on the subject of commercial antibody production and purification. Although the field of antibody (and, especially, monoclonal antibody, MAb) production and applications is moving at a very fast pace, it is quite likely that many chapters in this volume will remain relevant and useful for years to come. As such, this volume would be recommended for both the industrial researcher and the academic teacher/ investigator. In fact, some chapters in the volume (such as, primarily, chapters 1,4,6,10 and 13) are excellent material for an advanced course on the subject. The volume is divided into three logical parts: (I ) Before scaling-up production (chaps. l-4); (II) production in large-scale systems (chaps. 5-10); and (III) purification of monoclonal antibodies (chaps. 11-14). It also contains five very useful appendixes dealing with federal regulations on the production and uses of MAb, and detailed procedures for cell culture and purification. Chapter 1, by W.R. Shek, deals with the detection of murine viruses in hybridoma cultures and its products, and also with decontamination of hybridoma lines from fungi, bacteria or mycoplasma. It is well written and very useful background for all researchers in the area, especially for those that still treat hybridoma cells like innocuous microbial cultures. Chapter 2, by S.R. Adamson et al., examines quantitative aspects of hybridoma cell growth (growth, product formation and nutrient utilization) on three commercially available media in spinner-flask cultures. Although quite detailed and interesting for a journal publication, the results are not sufficiently general to warrant inclusion in this
volume. Indeed, it is quite well known that cell growth and metabolism is very dependent on the specific cell line and small changes in the culture environment. Chapter 3, by B.L. Brown, discusses an inexpensive defined (serum-free) medium that supports effective growth of a myeloma line and its derived hybridoma lines, and also an on-line method for adapting a MAb producing hybridoma line from a serum-containing to a serum-free medium. The material is quite detailed but the procedures and results are not sufficiently general. One only wished there was a chapter to discuss exhaustively and critically what is really known today on serumfree media. This is clearly a weak point of this volume. Chapter 4, by S.S. Seaver, is a good effort to compare, based on antibody productivities, three different culture systems: a dish (static ) culture, a spinner-flask (stirred) culture, and a flat-membrane perfusion (static) culture. It contains a wealth of interesting observations and, as expected, does not proclaim a winner culture system, as cell growth and MAb production can be affected differently for each cell line by a large variety of factors. In the second part of the volume, J.P. Chandler discusses in chapter 5 MAb production in mouse ascites. This is a very well written and informative chapter on a culture method that, most likely, will be used less and less for MAb production due to cost, scale and animal welfare reasons. Chapter 6, by W.B. Lebherz III, is a detailed and thorough description of batch MAb production in large-scale suspension culture. I find this one of the best written and most useful chapters in this book for its content and organization. It discusses the creation and characterization of the hybridoma, the growth of the cells in stirred cultures of increasing size, the physical manufacturing plant, its hardware and staffing, process flow of the large-scale production, and the detailed analysis of the largescale bulk product. It also provides some cost
288
information and presents a thorough discussion of problems associated with the overall process. An excellent job! Chapter 7, by J.E. Putnam, describes the Opticell ceramic matrix production system (KC Biological) in sufficient detail and with good data. It is a useful chapter of more limited interest since this is a proprietary package system. Chapter 8, by E.G. Posillico et al., provides a useful description of the Encapsel (Diamon Biotech) microencapsulation process which uses alginate beads. The information is mostly qualitative, and a number of quantitative process and cost issues are unfortunately not discussed. The substantial information on MAb purification is relevant and useful. The list of references is also quite complete and useful. Chapters 9 and 10 discuss two commercial hollow-fiber production systems. Chapter 9 discusses the Bioresponse system. It is poorly put together, with minimal technical details, a poor if not misleading schematic (Fig. 1) , does not address any of the wellknown technical problems of hollow-fiber systems, and reads like a commercial brochure. This chapter contributes nothing to this volume. In contrast, chapter 10, by B.G. Andersen and M.L. Gruenberg, is very well written and contains a wealth of useful information. It discusses the Endotronics hollow-fiber system, and includes a clear statement of key technical problems, and a good (but not very specific) discussion of how these problems might be resolved. It openly discusses the problem of variability among production runs, and offers good strategies for improving MAb productivities. A very well written and useful chapter. The last four chapters (11-14) are devoted to the very important issue of MAb purification. Chapter 11,by S.M. Lee, discusses affinity purification of IgG using Protein A-Sepharose CL-4B. It addresses many key issues related to product evaluation (e.g., sterility, viral activity,
nucleic acid level, bovine IgG level, and endotoxin level) and includes an excellent list of references. Chapter 12, by M.P. Strickler and M.J. Gemski, discusses MAb puri~cation by anion exchange high performance liquid chromatography (HPLC) . It contains a large and relevant amount of information and detailed proIts purification. cedures on small-scale weaknesses are an almost non-existent list of references on such a literature-rich subject, and the incomplete, if not simplistic, approach to scale-up. Chapter 13, by D.R. Nau, discusses MAb HPLC purification using the ABx packing (J.T. Baker Chemical Co.), ABx is a silicabased, mixed mode ion exchanger that offers, according to the data presented in this chapter, significant advantages for MAb purification. This is a very well-written chapter and includes a good qualitative discussion of scale-up issues and a very good list of references. I like this the most among the four purification chapters. Chapter 14, by H. Juarez-Salinas et al., discusses the characterization and purification of MAb using various types of HPLC: size exclusion for analytical determinations and characterization; protein-A HPLC for puri~cation; and hy~oxylapatite HPLC for separation of biologically active IgGs (light chain variants) or MAb from polyclonal fetal calf serum IgG. The information is specific and relevant to small-scale applications. Scale-up issues are not addressed, and the list of references is small. Overall, however, this is a useful chapter. In summary, I recommend this volume enthusiastically for both industrial and academic researchers, despite a few weaknesses and omissions to cover a number of technical issues concerning the large-scale MAb production. E.T. PAPOUTSAKIS Northwestern University Evanston, IL, 1J.S.A.