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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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• Various amino acids are also used as stabilizing agents for some biopharmaceutical products (Table 3.24). Glycine is most often employed and it (as well as other amino acids) has been found to help stabilize various interferon preparations, as well as erythropoietin, factor VIII,
Table 3.24. Amino acids, carbohydrates and polyols that have found most application as stabilizers for some biopharmaceutical preparations
Amino acids Carbohydrates Polyols
Glycine Glucose Glycerol
Alanine Sucrose Mannitol
Lysine Trehalose Sorbitol
Threonine Maltose Polyethylene glycol
152 BIOPHARMACEUTICALS
Glycerol Polyethyleneglycol
Figure 3.26. Structure of some polyols sometimes used to stabilize proteins
urokinase and arginase. Amino acids are generally added to final product at concentrations of 0.5-5%. They appear to exert their stabilizing influence by various means, including reducing surface adsorption of product, inhibiting aggregate formation, as well as directly stabilizing the conformation of some proteins, particularly against heat denaturation. The exact molecular mechanisms by which such effects are achieved remain to be elucidated. Several polyols (i.e. molecules displaying multiple hydroxyl groups) have found application as polypeptide-stabilizing agents. Polyols include substances such as glycerol, mannitol, sorbitol and polyethylene glycol, as well as inositol (Table 3.24 and Figure 3.26). A subset of polyols are the carbohydrates, which are listed separately (and thus somewhat artificially) from polyols in Table 3.24. Various polyols have been found to directly stabilize proteins in solution, while carbohydrates in particular are also often added to biopharmaceutical products prior to freeze-drying, in order to provide physical bulk to the freeze-dried cake. Surfactants are well-known protein denaturants. However, when sufficiently dilute, some surfactants (e.g. polysorbate) exert a stabilizing influence on some protein types. Proteins display a tendency to aggregate at interfaces (air-liquid or liquid-liquid), a process which often promotes their denaturation. Addition of surfactant reduces the surface tension of aqueous solutions and often increases the solubility of proteins dissolved therein. This helps to reduce the rate of protein denaturation at interfaces. Polysorbate, for example, is included in some g-globulin preparations and in the therapeutic monoclonal antibody, OKT-3 (Chapter 10).
THE DRUG MANUFACTURING PROCESS 153
Figure 3.27. Final product filling. The final bulk product (after addition of excipients and final product QC testing) is filter sterilized by passing through a 0.22 mm filter. The sterile product is aseptically filled into (pre-sterilized) final product containers under grade A laminar flow conditions. Much of the filling operation uses highly automated filling equipment. After filling, the product container is either sealed (by an automated aseptic sealing system) or freeze-dried first, followed by sealing
Final product fill
An overview of a typical final product filling process is presented in Figure 3.27. The bulk final product firstly undergoes QC testing to ensure its compliance with bulk product specifications. While implementation of GMP during manufacturing will ensure that the product carries a low microbial load, it will not be sterile at this stage. The product is then passed through a (sterilizing) 0.22 mm filter, Figure 3.28. The sterile product is housed (temporarily) in a sterile product-holding tank, from where it is aseptically filled into pre-sterilized final product containers (usually glass vials). The filling process normally employs highly automated liquid filling systems. All items of equipment, pipework, etc. with which the sterilized product comes into direct contact must obviously themselves be sterile. Most such equipment items may be sterilized by autoclaving, and be aseptically assembled prior to the filling operation (which is undertaken under Grade A laminar flow conditions). The final product containers must also be pre-sterilized. This may be achieved by autoclaving, or passage through special equipment which subjects the vials to a hot WFI rinse, followed by sterilizing dry heat and UV treatment. If the product can be filled into plastic-based containers, alternative ‘blow-fill-seal’ systems may be used, Figure 3.29; as its name suggests, such equipment first moulds plastic into the final product container (the moulding conditions ensure container sterility), followed immediately by
154 BIOPHARMACEUTICALS
Figure 3.28. Photographic representation of a range of filter types and their stainless steel housing. Most filters used on an industrial scale are of a pleated cartridge design which facilitates housing of maximum filter area within a compact space (a). These are generally housed in stainless steel housing units (b). Some process operations, however, still make use of flat (disc) filters, which are housed in a tripod-based stainless steel housing (c). Photos courtesy of Pall Life Sciences, Ireland
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