The registration application should include documented evidence that the analytical procedures have been validated and are suitable for the detection and quantitation of degradation products (see VICH 1 and 2 guidelines on analytical validation). In particular, analytical procedures should be validated to demonstrate specificity for the specified and unspecified degradation products. As appropriate, this validation should include samples stored under relevant stress conditions: light, heat, humidity, acid/base hydrolysis, and oxidation. When an analytical procedure reveals the presence of other peaks in addition to those of the degradation products (e.g., the drug substance, impurities arising from the synthesis of the drug substance, excipients and impurities arising from the excipients), these peaks should be labeled in the chromatograms and their origin(s) discussed in the validation documentation.
The quantitation limit for the analytical procedure should be not more than (≤) the reporting threshold (See attachment 1).
Degradation product levels can be measured by a variety of techniques, including those that compare an analytical response for a degradation product to that of an appropriate reference standard or to the response of the new drug substance itself. Reference standards used in the analytical procedures for control of degradation products should be evaluated and characterised according to their intended uses. The drug substance can be used to estimate the levels of degradation products. In cases where the response factors are not close, this practice can still be used if a correction factor is applied or the degradation products are, in fact, being overestimated. Acceptance criteria and analytical procedures, used to estimate identified or unidentified degradation products, are often based on analytical assumptions (e.g., equivalent detector response). These assumptions should be discussed in the registration application. Differences between the analytical procedures used during development and those proposed for the commercial product should also be discussed.