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biopharmaceuticals biochemistry and biotecnology - Walsh G.

Walsh G. biopharmaceuticals biochemistry and biotecnology - John Wiley & Sons, 2003. - 572 p.
ISBN 0-470-84327-6
Download (direct link): biochemistryandbiotechnology2003.pdf
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Contaminant-clearance validation studies are of special significance in biopharmaceutical manufacture. As discussed in the previous section, downstream processing must be capable of removing contaminants such as viruses, DNA and endotoxin from the product stream. Contaminant-clearance validation studies normally entails spiking the raw material (from which the product is to be purified) with a known level of the chosen contaminant, and subjecting the contaminated material to the complete downstream processing protocol. This allows determination of the level of clearance of the contaminant achieved after each purification step, and the contaminant reduction factor for the overall process.
THE DRUG MANUFACTURING PROCESS 185
Viral clearance studies, for example, are typically undertaken by spiking the raw material with a mixture of at least three different viral species, preferably ones that represent likely product contaminants, and for which straightforward assay systems are available. Loading levels of up to 1 x 1010 viral particles are commonly used. The cumulative viral removal/inactivation observed should render the likelihood of a single viral particle remaining in a single therapeutic dose of product being greater than one in a million.
A similar strategy is adopted when undertaking DNA clearance studies. The starting material is spiked with radiolabelled DNA and then subjected to downstream processing. The level of residual DNA remaining in the product stream after each step can easily be determined by monitoring for radioactivity.
The quantity of DNA used to spike the product should ideally be somewhat in excess of the levels of DNA normally associated with the product prior to its purification. However, spiking of the product with a vast excess of DNA is counter-productive in that it may render subsequent downstream processing unrepresentative of standard production runs.
For more comprehensive validation studies, the molecular mass profile of the DNA spike should roughly approximate to the molecular mass range of endogenous contaminant DNA in the crude product. Obviously, the true DNA clearance rate attained by downstream processing procedures (e.g. gel-filtration) will depend to some extent on the molecular mass characteristics of the contaminant DNA.
Other manufacturing procedures requiring validation include cleaning, decontamination and sanitation (CDS) procedures developed for specific items of equipment/processing areas. Of particular importance is the ability of such procedures to remove bioburden. This may be assessed by monitoring levels of microbial contamination before and after application of CDS protocols, to the equipment item in question.
FURTHER READING
Books
Butler, M. (1996). Animal Cell Culture and Technology. The Basics. IRL Press, Oxford.
Carpenter, J. (2002). Rational Design of Stable Protein Formulations. Kluwer Academic, Dordrecht.
Dass, C. (2000). Principles and Practice of Biological Mass Spectrometry. Wiley, Chichester.
Desai, M. (2000). Downstream Protein Processing Methods. Humana, New York.
Flickinger, M. (1999). The Encyclopedia of Bioprocess Technology. Wiley, Chichester.
Frokjaer, S. (2000). Pharmaceutical Formulation Development of Peptides and Proteins. Taylor and Francis, London. Grindley, J. & Ogden, J. (2000). Understanding Biopharmaceuticals. Manufacturing and Regulatory Issues. Interpharm Press, Denver, CO.
Harris, E. (2000). Protein Purification Applications. Oxford University Press, Oxford.
Janson, J. (1998). Protein Purification. Wiley, Chichester.
Kellner, R. (1999). Microcharacterization of Proteins. Wiley, Chichester.
Martindale, The Extra Pharmacopoeia, 31st edn (1996). Rittenhouse Book Distributors, USA.
Merten, O. (2001). Recombinant Protein Production with Prokaryotic and Eucaryotic Cells. Kluwer Academic, Dordrecht.
Oxender, D. & Post, L. (1999). Novel Therapeutics from Modern Biotechnology. Springer-Verlag, Berlin.
Ramstorp, M. (2000). Contamination Control and Cleanroom Technology. Wiley, Chichester.
Roe, S. (2001). Protein Purification Techniques. Oxford University Press, Oxford.
The European Pharmacopoeia, Vol. 4 (2002). Council of Europe, Strasbourg.
The Pharmaceutical Codex, Vol. 12 (1994). Pharmaceutical Press, Wallingford, UK.
The Rules Governing Medicinal Products in the European Community. (a multi-volume work; various publication dates).
European Commission, Brussels.
The United States Pharmacopoeia, 26-NF 21 (2003). United States Pharmacopoeial Convention, USA.
Venn, R. (2000). Principles and Practice of Bioanalysis. Taylor and Francis, London.
Walsh, G. & Headon, D. (1994). Protein Biotechnology. Wiley, Chichester.
186 BIOPHARMACEUTICALS
Walsh, G. (2002). Proteins: Biochemistry and Biotechnology. Wiley, Chichester. Whyte, W. (2001). Cleanroom Technology. Wiley, Chichester.
Articles
Sources of biopharmaceuticals and upstream processing
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