(T1430-05-29) Critical System Suitability Test Established in Regulatory Analytical Procedures for Testing Organic Impurities in Drug Substance and Drug Product and Relevant Changes in Recently Revised USP < 621 >

Purpose: In Abbreviated New Drug Applications (ANDAs) for small molecular drug products, the organic impurity method serves as a critical quality test to control process impurities and degradation products in the drug substance and drug product. Commonly, an organic impurity method uses liquid or gas chromatographic separation techniques (e.g., HPLC, UPLC, GC) where the system suitability test (SST) represents an integral part of the analytical procedure and ensures that the entire system (e.g., column, instrument, operations and controls to be analyzed) will function correctly at the time of use. Submitted validation data by applicants usually were collected in a narrow time window using only limited numbers of column lots, instruments, analysts, laboratories etc. As expected, more variables will be encountered in the routine analysis, where poorly established SSTs will not serve as adequate controls to retain the same or similar method validity as demonstrated in the validation study submitted in ANDAs. This variability may lead to unreliable results in the routine quality testing. Such inadequate SSTs established by the applicants may generate CMC deficiencies often requiring additional amendment submissions and review cycles to resolve. This study summarizes the observed relevant deficiencies in recent ANDA submissions, and the SST requirements defined in ICH/FDA guidance and recently revised USP < 621 >.

Methods: Original ANDAs submitted in recent years for solid and liquid drug products were reviewed. With reference to scientific rationale and relevant regulatory guidance from ICH, FDA and USP, deficiencies were identified for SSTs established in organic impurity procedures submitted in the Module 3.2.S.4.2 and Module 3.2.P.5.2 (Analytical Procedures).

Results: The regulatory organic impurity procedures may be USP-based or in-house developed/validated by the applicants, where injection precision, resolution and sensitivity tests are key SSTs. However, such tests/acceptance criteria are often loosely established or missing in the routine procedures submitted by the applicants.For example, the applicant’s resolution test was performed using a pair of widely separated peaks with a criterion far looser than the values obtained in submitted validation data. However, known/unknown degradation products may closely elute before or after the main peak. In such cases, the loosely-established resolution SST cannot ensure adequate separation (e.g., no co-elution) of closely eluted degradation products from main peak and would lead to the uncertainty if those potential degradants have been observed in the applicant’s stability testing of the drug product. Similarly, for a compendial-based procedure, USP resolution test/acceptance criterion may not be enough to ensure the separation among peaks (USP impurities, non-USP impurities, unknown impurities, API, placebo etc.), therefore additional justified resolution control would be required to add in the applicant’s procedure. Missing sensitivity SST is also observed in some organic impurity procedures, which would lead to uncertainty about whether impurities (≥ reporting threshold) can be detected in the drug substance and drug product during the release/stability testing. In this study, the observed deficiencies related to SSTs will be discussed in detail. Corresponding SST requirements in regulatory guidance, especially, the new SST requirements in the latest USP < 621 > will be summarized.

Conclusion: To address the described deficiencies in this study, applicants are typically requested to propose well-justified SSTs to ensure that the same or similar method performance (specificity, sensitivity and precision/accuracy) demonstrated in validation, is retained in the ongoing quality testing (release, stability, investigation etc.) Such method performance ensures the reliability of reported organic impurity results of drug substance and drug product lots. The examples covered here point to the need to communicate SST-related concerns and recent revisions to USP < 621 > to the generic industry.