Composite assay/impurity testing

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. 

Figure 6.11. An example of a composite assay (combining both assay and impurity testing in one method) for a drug substance in early development. Note that the absorbance of the API must be <1.5 absorbance units (AU) to prevent detector saturation. Since the method has some deficiencies (e.g., partial resolution between several peaks), an improved gradient method was thus developed (Chapter 8).

Numerous methods are required to characterize drug substances and drug products (Chapter 10). Specifications may include description identification assay (of composite sample) tests for organic synthetic process impurities, inorganic impurities, degradation products, residual solvents, and container extractables tests of various physicochemical properties, chiral purity, water content, content uniformity, and antioxidant and antimicrobial preservative content microbial tests dissolution/disintegration tests hardness/friability tests and tests for particle size and polymorphic form. Some of these tests may be precluded, or additional tests may be added as dictated by the chemistry of the pharmaceutical or the dosage form. 

Table 9.9 shows a summary of validation results for the composite test method for a drug substance shown in Figure 9.9. The development process of this particular method is described in Chapter 8, Section 8.8.2. The key analytes of this assay are the API, an impurity eluting (impurity 1) at 6.4min that has been identified as an isomer of the API and the immediate synthetic precursor eluting at 7.6min. 

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