Formulation of Biotech Products, Including Biopharmaceutical Considerations
This chapter deals with formulation aspects of pharmaceutical proteins. Both technological questions and biopharmaceutical issues such as the choice of the delivery systems, the route of administration, and possibilities for target site-specific delivery
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Formulation of Biotech Products, Including Biopharmaceutical Considerations Daan J.A. Crommelin
INTRODUCTION This chapter deals with formulation aspects of pharmaceutical proteins. Both technological questions and biopharmaceutical issues such as the choice of the delivery systems, the route of administration, and possibilities for target site-specific delivery of proteins are considered.
laminar airflow that is filtered through HEPA (highefficiency particulate air) filters. Last but not least, the “human factor” is a major source of contamination. Well-trained operators wearing protective cloths (face masks, hats, gowns, gloves, or head-to-toe overall garments) should operate the facility. Regular exchange of filters, regular validation of HEPA equipment, and thorough cleaning of the room plus equipment are critical factors for success.
MICROBIOLOGICAL CONSIDERATIONS Sterility Most proteins are administered parenterally and have to be sterile. In general, proteins are sensitive to heat and other regularly used sterilization treatments; they cannot withstand autoclaving, gas sterilization, or sterilization by ionizing radiation. Consequently, sterilization of the end product is not possible. Therefore, protein pharmaceuticals have to be assembled under aseptic conditions, following the established and evolving rules in the pharmaceutical industry for aseptic manufacture. The reader is referred to standard textbooks for details (Halls 1994; Groves 1988; Klegerman and Groves 1992; Roy 2011). Equipment and excipients are treated separately and autoclaved or sterilized by dry heat (>160 °C), chemical treatment, or gamma radiation to minimize the bioburden. Filtration techniques are used for removal of microbacterial contaminants. Prefilters remove the bulk of the bioburden and other particulate materials. The final “sterilizing” step before filling the vials is filtration through 0.2 or 0.22 μm membrane filters. Assembly of the product is done in class 100 (maximum 100 particles > 0.5 μm per cubic foot) rooms with D.J.A. Crommelin, Ph.D. Department of Pharmaceutical Sciences, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Arthur van Schendelstraat 98, Utrecht 3511 ME, The Netherlands e-mail: [email protected]
Viral Decontamination As recombinant DNA products are grown in microorganisms, these organisms should be tested for viral contaminants, and appropriate measures should be taken if viral contamination occurs. In the rest of the manufacturing process, no (unwanted) viral material should be introduced. Excipients with a certain risk factor such as blood-derived human serum albumin should be carefully tested before use, and their presence in the formulation process should be minimized (see Chap. 3). Pyrogen Removal Pyrogens are compounds that induce fever. Exogenous pyrogens (pyrogens introduced into the body, not generated by the body itself) can be derived from bacterial, viral, or fungal sources. Bacterial pyrogens are mainly endotoxins shed from gram-negative bacteria. They are l
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