Protein biopharmaceuticals challenges

Due to the lack of activity after oral administration for most peptides and proteins, administration by injection or infusion - that is, by intravenous (IV), subcutaneous (SC), or intramuscular (IM) administration - is frequently the preferred route of delivery for these drug products. In addition, other non-oral administration pathways have been utilized, including nasal, buccal, rectal, vaginal, transder-mal, ocular, or pulmonary drug delivery. Some of these delivery pathways will be discussed in the following sections in the order of the increasing biopharmaceutic challenges to obtain adequate systemic exposure. 

Biopharmaceutical Challenges Pulmonary Delivery of Proteins and Peptides... 

The interpretation and assessment of the pharmacokinetics of protein biopharmaceuticals often pose additional challenges compared to small-molecule drug candidates, therefore requiring additional resources. In general, these biopharmaceutical drug candidates are subject to the same general principles of pharmacokinetics, but their similarity to endogenous molecules can cause considerable complications in the evaluation of pharmacokinetics and pharmacokinetic/pharmacodynamic relationships (Meibohm, 2006). 

The cleaning of process-scale chromatography systems used in the purification of biopharmaceuticals can also present challenges. Although such systems are disassembled periodically, this is not routinely undertaken after each production run. CIP protocols must thus be applied periodically to such systems. The level and frequency of CIP undertaken will depend largely on the level and type of contaminants present in the product-stream applied. Columns used during the earlier stages of purification may require more frequent attention than systems used as a final clean-up step of a nearly pure protein product. While each column is flushed with bulfer after each production run, a full-scale CIP procedure may be required only after every 3-10 column runs. Most of the contaminants present in such columns are acquired from these previous production runs. 

Lubiniecki, A. (1998). Biopharmaceutical regulation—progress and challenges. Curr. Opin. Biotechnol. 9, 305-306. Seamon, K. (1998). Specifications for biotechnology-derived protein drugs. Curr. Opin. Biotechnol. 9, 319-325. 

Since risk analysis plays an important role in public policy decision making, efforts have been made to devise a means by which to identify, control, and communicate the risks imposed by agricultural biotechnology. A paradigm of environmental risk assessment was first introduced in the United States by Peterson and Arntzen in 2004. In this risk assessment, a number of assumptions and uncertainties were considered and presented. These include (1) problem formulation, (2) hazard identihcation, (3) dose-response relationships, (4) exposure assessment, and (5) risk characterization. Risk assessment of plant-made pharmaceuticals must be reviewed on a case-by-case basis because the plants used to produce proteins each have different risks associated with them. Many plant-derived biopharmaceuticals will challenge our ability to define an environmental hazard (Howard and Donnelly, 2004). For example, the expression of a bovine-specihc antigen produced in a potato plant and used orally in veterinary medicine would have a dramatically different set of criteria for assessment of risk than, as another example, the expression of a neutralizing nonspecihc oral antibody developed in maize to suppress Campylobacter jejuni in chickens (Peterson and Arntzen, 2004 Kirk et al., 2005). 

Considering the critical role of plant-based food to cover the future food demand by a rapidly growing worldwide population, a better knowledge of plant proteins (composition, interactions, adverse effects, allergic reactions, and biopharmaceutical discoveries) becomes a strategic challenge. 

Another challenge is the delivery of a biopharmaceutical to its site of action, as the injection of molecules in solution leads to a partitioning of the molecules according to their physicochemical properties. One approach to deliver particles injected intravenously is based on the concept of differential protein adsorption. After injection the particles adsorb blood proteins according to physicochemical surface properties of the particles. The adsorbed proteins determine the cells to which the particles will be directed (Muller and Keck, 2004). 

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