Manufacture of protein pharmaceuticals

Beatrice, M. (2002), Regulatory considerations in the development of protein Pharmaceuticals, in Nail, S., and Akers, M., Eds., Development and Manufacture of Protein Pharmaceuticals, Pharmaceutical Biotechnology, Vol. 14, Kluwer Academic/Plenum, New York, pp. 405 157. 

Nail, Steven L., and Michael J. Akers. Development and Manufacture of Protein Pharmaceuticals. Vol. 14 of Pharmaceutical Biotechnology. New York Kluwer Academic/ Plenum Publishers, 2002. 

VoUdn DB, Sanyal G, Burke CJ, Middaugh CR. Preformulation studies as an essential guide to formulation development and manufacture of protein pharmaceuticals. Pharm Biotechnol 2002 14 1-46. 

Nail S L, Jiang S, Chongprasert S, et al. (2002). Fundamentals of freeze-drying. In S L Nail, M J Akers, (eds.), Development and Manufacture of Protein Pharmaceuticals Kluwer Academic, New York, pp. 281-360. 

Urea is largely used as a fertilizer (ISy ), and as a non-protein feed supplement for sheep and cattle. The most important chemical use, which however accounts for only a small part of urea production, is in the manufacture of urea-formaldehyde resins. U is also used in the manufacture of adhesives, pharmaceuticals, dyes and various other materials. U.S. production 1981 7 0 megatonnes urea resins 1983 6 megatonnes. 

Organic solvents are often used in the manufacture, purification, precipitation and crystallization of protein pharmaceuticals (Sukumar et al., 2005). Water miscible solvents such as ethanol, acetonitrile and propanol have been utilized to promote the stabilization of reversible denaturation and aggregation, with recovery of the native conformation. For example, insulin has been precipitated and/or crystallized in a wide variety of solvents (Brange and Lanlqaer, 1993). 

Although there is much to be optimistic about the future of protein pharmaceuticals, there are still many unique problems with their development, production, and delivery. Among the more obvious problems with protein drugs is the fact that they are much more delicate than small-molecule drugs. Proteins such as hormones, antibodies, and enzymes cannot normally be compounded or pressed into dry pills or emulsified or concentrated into tinctures. This type of conventional pharmaceutical manufacturing and formulation would destroy the activity of most protein pharmaceuticals. Similarly most peptide hormones, antibodies, and enzymes cannot be stored indefinitely at room temperatures in nonsterile containers instead they must be kept in a cool, dark, aqueous, sterile environment for no more than a few weeks. These limitations to protein preparation and formulation have created a significant challenge to pharmaceutical chemists. Potential solutions to these problems are discussed in Chapter 4 of this book. 

Little, if any, of the expertise, analytical methods and in-house standards, specifics of the production process, historical process, and validation data or full characterization data required for comparability assessment of therapeutic proteins are available in the public domain. As a rule, they are proprietary knowledge. It is inconceivable, in most cases, that another manufacturer, on the basis of the patent or published data, is able to manufacture a protein pharmaceutical that can be assumed similar enough to the original innovative product that only a limited documentation of physico-chemical characteristics would be sufficient to show equivalence. In most cases only limited data are available in pharmacopoeial monographs and scientific papers. Moreover, even the most sophisticated analytical tools are not sensitive enough to fully predict the biological and clinical characteristics of the product. 

JF Carpenter, BS Chang. LyophUization of protein pharmaceuticals. Biotechnology and Biopharmaceutical Manufacturing, Processing and Preservation. Edited by KE Avis and VL Wu, Volume 2, 199-264, 1996. 

Human blood plasma contains over 700 different proteins (qv) (1). Some of these are used in the treatment of illness and injury and form a set of pharmaceutical products that have become essential to modem medicine (Table 1). Preparation of these products is commonly referred to as blood plasma fractionation, an activity often regarded as a branch of medical technology, but which is actually a process industry engaged in the manufacture of speciaUst biopharmaceutical products derived from a natural biological feedstock (see Pharmaceuticals). 

History. Methods for the fractionation of plasma were developed as a contribution to the U.S. war effort in the 1940s (2). Following pubHcation of a seminal treatise on the physical chemistry of proteins (3), a research group was estabUshed which was subsequendy commissioned to develop a blood volume expander for the treatment of military casualties. Process methods were developed for the preparation of a stable, physiologically acceptable solution of alburnin [103218-45-7] the principal osmotic protein in blood. Eady preparations, derived from equine and bovine plasma, caused allergic reactions when tested in humans and were replaced by products obtained from human plasma (4). Process studies were stiU being carried out in the pilot-plant laboratory at Harvard in December 1941 when the small supply of experimental product was mshed to Hawaii to treat casualties at the U.S. naval base at Pead Harbor. On January 5, 1942 the decision was made to embark on large-scale manufacture at a number of U.S. pharmaceutical plants (4,5). 

Plasma fractionation is unusual in pharmaceutical manufacturing because it involves the processing of proteins and the preparation of multiple products from a single feedstock. A wide range of unit operations are utilized to accompHsh these tasks. They are Hsted in Table 3 some are common to a number of products and all must be closely integrated. The overall manufacturing operation can be represented as a set of individual product streams, each based on the processing of an intermediate product derived from a mainstream fractionation process (Fig. 1). 

Microparticulate Systems for the Delivery of Proteins and Vaccines, edited by Smadar Cohen and Howard Bernstein Good Manufacturing Practices for Pharmaceuticals A Plan for Total Quality Control, Fourth Edition, Revised and Expanded, Sidney H. Willig and James R. Stoker... 

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