Biopharmaceutical products, aggregation

Parenteral administration is not perceived as a problem in the context of drugs which are administered infrequently, or as a once-off dose to a patient. However, in the case of products administered frequently/daily (e.g. insulin to diabetics), non-parenteral delivery routes would be preferred. Such routes would be more convenient, less invasive, less painful and generally would achieve better patient compliance. Alternative potential delivery routes include oral, nasal, transmucosal, transdermal or pulmonary routes. Although such routes have proven possible in the context of many drugs, routine administration of biopharmaceuticals by such means has proven to be technically challenging. Obstacles encountered include their high molecular mass, their susceptibility to enzymatic inactivation and their potential to aggregate. 

According to current PDA guidelines, an acceptable pharmaceutical product should exhibit less than 10% deterioration after 2 years.5 Protein biopharmaceuticals usually have to be stored under refrigerated conditions or freeze dried to achieve an acceptable shelf life. EL IS As for aggregates and product variants as discussed previously would be applicable for determining shelf life. 

In this chapter, we have reviewed some critical aspects of stoppers that are used for packaging of lyophilized biopharmaceuticals. We have listed the desirable attributes for lyophilization closures for use with protein formulations. We have discussed issues relating to preparation of stoppers. Two issues, siliconization and occluded water, have been dealt with in detail. Siliconization can be a cause of particulate generation and aggregation, as shown by our experience with recombinant tumor necrosis factor formulations. We have described methods of measurement of stopper-occluded moisture and discussed their relative merits and demerits. We further studied the kinetics of moisture removal from stoppers under selected conditions. Our approach to validation of moisture removal from stoppers has also been presented. Finally, we have discussed the usefulness of occluded moisture measurement for determination of moisture uptake by protein products under real... 

Another important topic is downstream processing. The production of biopharmaceuticals requires the highest standards of sterility and purity, including GMP [72]. Downstream requirements specific for rDNA products include, for example, the renaturation of inclusion bodies - proteins aggregated in bacterial cytoplasm. 

Formation of protein aggregates impairs protein activity both directly and indirectly and is a particularly serious concern in the biopharmaceutical industry, where its occurrence in protein drugs not only affects the production process but also raises safety concerns. Therefore, special attention was... 

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