Compendial Verification

1. Compendial Verification GADA Meeting – July 26, 2012 Michael Brent, Ph.D. David Longstaff, Ph.D.

2. USP <1226> Verification of Compendial Procedures “The verification process for compendial test procedures is the assessment of whether the procedure can be used for its intended purpose, under the actual conditions of use for a specified drug substance and/or drug product matrix.”

3. USP Method Verification • Verification requirements depend on the complexity of the procedure and the material to which the procedure is applied. • Typically a method verification should include the following: • Assays: Specificity Intermediate Precision Solution Stability • Impurities: Specificity Intermediate Precision Solution Stability LOD (limit tests) or LOQ (quantitative tests)

4. Common Deficiencies • Solution stability not evaluated. • Solution stability should be assessed during method verification. Alternatively, state that solutions will be prepared fresh immediately before use. In cases where the API is unstable to light exposure, the method should specify to protect sample and standard solutions from light. • Sample chromatograms not provided. • Sample chromatograms should be provided and should be properly scaled. • No verification provided to support a new API Supplier. • Previously verified methods may need to be shown to be specific for any new impurities that may be present, as impurities may vary depending on the route of synthesis. • The method verified is significantly different from the compendial method. • See next slide.

5. USP <621> Chromatography • USP <621> describes minor adjustments to operating parameters of a USP method, which may be allowable without requiring additional validation. For example: Column Length (HPLC, GC): 70% Particle Size (HPLC): Can be reduced by as much as 50%, but not increased Flow Rate (HPLC, GC): 50% Minor (<50%) Mobile Phase Components: 30% relative, not to exceed 10% absolute pH of Mobile Phase (HPLC): 0.2 units Column Temperature (HPLC): 10 C UV-Vis Detection Wavelength: 3 nm See USP <621> for additional allowable variations • Making multiple changes within these ranges can have a cumulative effect and may still require reassessment of some performance characteristics. • Changes to the sample or standard concentrations are not usually acceptable without additional validation.

6. Additional Notes • Foreign Compendial Methods – CVM accepts verification of E.P. and B.P. methods. Equivalence to the USP monograph method (if available) should be demonstrated. • Contact us if you have any questions.

7. References: • USP <1226> Verification of Compendial Procedures • USP <621> Chromatography • USP <1225> Validation of Compendial Procedures • Guidance for Industry 63 – Validation of Analytical Procedures: Definition and Terminology • Guidance for Industry 64 – Validation of Analytical Procedures: Methodology

8. Questions?

9. Appendix – Excerpts from <1226> Specificity: “An assessment of specificity is a key parameter in verifying that a compendial procedure is suitable for use in assaying drug substances and drug products.” “Drug substances from different suppliers may have different impurity profiles that are not addressed by the compendial procedure. Similarly, the excipients in a drug product can vary widely among manufacturers and may have the potential to directly interfere with the procedure…”

10. Excerpts from <1226> (Continued) Intermediate Precision: “Verification should include an assessment of elements such as the effect of the matrix on the recovery of impurities and drug substances from the drug product matrix, as well as the suitability of chromatographic conditions and column, and appropriateness of detector signal response, etc.”

11. Excerpts from <1226> (Continued) Limit of Detection and Limit of Quantitation: “An assessment of the limit of detection or quantitation and precision for impurities procedures may be useful to demonstrate the suitability of the compendial procedure under the actual conditions of use.”