Excipient impurity profile

Some excipients contain a certain amount of amorphous form such as spray-dried lactose,27 and others are hygroscopic, such as microcrystalline cellulose.28 These excipients will adsorb water, which causes a change in the micro-environment of the formulation. If the drug substance is moisture-sensitive, degradation may occur quickly. Therefore, consider both drug-excipient compatibility and excipient impurity profile in selecting excipients for low-dose drug products. 

Excipient impurity profiles and how to evaluate this important aspect of excipient manufacture, particularly in light of the International Conference on Harmonization (ICH) guidance published in 1999, also are addressed. Care must also be taken that residual solvent levels do not exceed those prescribed in the ICH Guidance for Residual Solvents published in 1999. Solvents are divided into three classes ... 

The generic representation in Figure 1 illustrates the various types of impurities that may arise during the production of a dosage form. It is not all inclusive, as each dosage form has unique sources of impurities, but it includes most of the important ones. The sources of impurities increase with the increase in the number of components and the number of steps in the process. Each drug substance and excipient has its own impurity profile and the potential for interactions and reactions. 

Several dosage forms carry an increased risk of degradation or adjunct formation. Products such as injections and aerosols are more likely to interact with volatiles or extractables from packaging and closure systems. Tablets have the potential to form adjuncts with excipients (specifically, lactose has been shown to form adjuncts in tablets). Non-CFC propellants in aerosols have a large number of impurities that typically do not interact with drug substances, but the potential for these interactions does still exist. Creams, ointments, lotions, and other such products will each have specific interactions that should be considered while evaluating the impurity profile of a drug product. 

The development of an impurity profile for a dosage form follows many of the same principles as in the drug substances however, instead of identifying all precursors and intermediates, the analyst will identify and place all of the components of the dosage form (excipients, preservatives, and others) and their affiliated impurity profiles within a master profile. Here again additional method development may be needed to... 

Similarly, impurity profiles may change when the formnlation is modified or a scale-up of a specific formulation is made. Pharmacentical formnlations are a complex physiochemical system that may resnlt in impnrities due to reactions between API and pharmacentical excipients and/or packaging materials. In some cases, degradants that were generated by multiple-step degradation pathways can still react with the API leading to the formation of degradants that can be difficult to identify. 

A change in the excipient composition may change the product impurity profile. This change may make the method deficient in its specificity for the assay or impurity tests and may require redevelopment and revalidation. 

Technical Grade Technical grades of excipients differ in their specifications and intended use. Technical grades may differ in (1) specifications and/or functionality, (2) impurities, and (3) impurity profiles. 

Pharmaceutical excipients are increasingly considered important quality attributes of a drug product. They have an effect not only on product manufacturability, but also on product stability. The physical characterization of excipients has received the most attention, as discussed earlier. Excipient functionality testing and multisource excipient equivalence have been reviewed in the literature.21 However, chemical impurity profiles of excipients have not, in general, received similar attention. 

Differences between methods from Tier 1 through Tier 3 are due to the extent of validation of the analytical figures of merit that is performed [3]. During early development of the active pharmaceutical ingredient and early dosage form development, emphasis is placed on speed and quantitation of the API. At this stage, methods rely on the use of short columns, fast flows, and very minimum validation to quickly identify the most desirable synthetic route for the API that will produce an adequate impurity profile (overall yield may not be optimized at this stage) and most desirable prototype formulations and excipients that will ultimately lead to the selection of the final formula-... 

Changes in the impurity profile of the excipient owing to the change. 

The guideline also provides for consideration of objective criteria when considering changes to the impurity profile of an excipient as a result of any change. IPEC-Americas has developed a guide for... 

The content of the impurity profile varies with the nature of the excipient, the raw materials used in its manufacture, and its chemical composition. Changes are considered significant whenever a new impurity is introduced at or above the 0.1% concentration or when an impurity previously present at or above 0.1% disappears. 

Zhang, H., and Ray, K. (2007). Profiling impurities in a taxol formulation Application of a mass-dependent mass defect filter to remove polymeric excipient interferences. In Proceedings of the 55th ASMS Conference on Mass Spectrometry and Allied Topics, Indianapolis, IN. 

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