Excipient additives

Enbrel is a product now approved for medical use that is based upon this strategy. The product is an engineered hybrid protein consisting of the extracellular domain of the TNF p75 receptor fused directly to the Fc (constant) region of human IgG (see Box 13.2 for a discussion of antibody structure) The product is expressed in a CHO cell line from which it is excreted as a dimeric soluble protein of approximately 150 kDa. After purification and excipient addition (mannitol, sucrose and trometamol), the product is freeze-dried. It is indicated for the treatment of rheumatoid arthritis and is usually administered as a twice-weekly s.c. injection of 25 mg product reconstituted in WFI. Enbrel functions as a competitive inhibitor of TNF, a major pro-inflammatory cytokine. Binding of TNF to Enbrel prevents it from binding to its true cell surface receptors. The antibody Fc component of the hybrid protein confers an extended serum half-life on the product, increasing it by fivefold relative to the soluble TNF receptor portion alone. 

TABLE 10 Changes in Specification of Excipients (Addition of New Test Limit) Comparison between Guidelines... 

A variety of different artificial sweeteners have been approved for use in oral liquid dosage forms by the FDA. One general characteristic for artificial sweeteners is their very high sweetness compare to sucrose. This also results in a much lower concentration needed in the formulation, which can lower the cost and/or risk of incompatibility with the drug or other excipients. Additionally, a sugar-free formulation... 

With the passing of the FDAMA, the agency s inspection latitude was increased and its inspectional responsibility over active pharmaceutical ingredient (API) manufacturers was reiterated. The agency did increase its inspection activity over firms that manufacture APIs and excipients. Additionally, FDA s review of foreign API manufacturers increased slightly. The onus, however, remains with the sponsor company to ensure that the manufacturer of their API is cGMP compliant and the material suitable for use. 

According to ICH Guideline Q8 Pharmaceutical Development, the marketing authorization application (MAA) should discuss the excipients chosen and their concentration. The MAA should show the characteristics that can influence the medical product performance and manufacturability relative to the respective function of each excipient. Additionally, the MAA should demonstrate the ability of excipients to provide their intended functionality throughout the intended period of validity of the formulation. Use the information on excipient performance as appropriate to justify the choice and quality attributes of the excipients.26... 

In essence, the test battery should include XRPD to characterize crystallinity of excipients, moisture analysis to confirm crystallinity and hydration state of excipients, bulk density to ensure reproducibility in the blending process, and particle size distribution to ensure consistent mixing and compaction of powder blends. Often three-point PSD limits are needed for excipients. Also, morphic forms of excipients should be clearly specified and controlled as changes may impact powder flow and compactibility of blends. XRPD, DSC, SEM, and FTIR spectroscopy techniques may often be applied to characterize and control polymorphic and hydrate composition critical to the function of the excipients. Additionally, moisture sorption studies, Raman mapping, surface area analysis, particle size analysis, and KF analysis may show whether excipients possess the desired polymorphic state and whether significant amounts of amorphous components are present. Together, these studies will ensure lotto-lot consistency in the physical properties that assure flow, compaction, minimal segregation, and compunction ability of excipients used in low-dose formulations. 

A list of all components A list of usually no more than one or two pages of written information should be submitted. The quality (e.g., NF, ACS) of the inactive ingredients should be cited. For novel excipients, additional manufacturing information may be necessary. 

Figure 4.16 shows the increased generation of free salicylic acid at 37°C in the tablets containing paracetamol, it is interesting to note from this figure the effect on stability of tablet excipients. Addition of 1% talc caused only a minimal increase in the decomposition,... 

The current chapter is intended to provide an overview of the stability problems of biopharmaceuticals and their assessment as well as the formulation approaches that can be used to circumvent these problems. Presented next is a literature review on the known degradation/denaturation mechanisms of various biopharmaceuticals, followed by a general discussion on the formulation strategies using specific excipients/additives for improving the product shelf-life. 

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