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The US Pharmacopeial Convention is proposing a policy change to the inclusion of reporting thresholds in drug substance and drug product monographs.
The US Pharmacopeial Convention (USP) announced on Aug. 3, 2019 that it is proposing a policy change to the inclusion of reporting thresholds in drug substance and drug product monographs. The proposal comes in response to FDA’s recommendation that reporting thresholds should be addressed as part of application assessments based on product-specific factors and not be included in drug product monographs.
USP is updating organic impurities testing in alignment with International Council for Harmonization (ICH) Q3A/B-based limits for identification and reporting of organic impurities and degradation products in drug substances and drug products. These impurities tests currently include, in some cases, a reporting threshold consistent with ICH guidelines. USP stated in a press release that, “In addition to setting criteria for a peak to be included in the total impurities, the reporting threshold also aligns with the approach to verify the system sensitivity. Monographs with recently modernized or new impurity procedures are expected to contain a sensitivity solution at a concentration corresponding to the reporting threshold, and a signal-to-noise requirement as a part of system suitability requirements. This approach is used for both drug substance and drug product monographs.”
According to USP, FDA is concerned that including reporting thresholds might present the risk of toxic impurities not being identified or reported. FDA commented to USP that reporting thresholds for drug products should be addressed as part of an application assessment. FDA uses ICH reporting thresholds as guidelines and deviates from them as needed based on application specific considerations. The agency believes that similar concerns apply to drug substance monographs. FDA commented that since a drug substance may be used in different products with different maximum daily doses, ICH Q3A limits (including reporting threshold) will vary due to product specific factors and should also be addressed as an application assessment issue.
USP is therefore proposing a policy change to the inclusion of reporting thresholds in drug substance and drug product monographs. The proposal includes the following changes:
The proposed revised policy is up for a 90-day public comments period that ends Nov. 12, 2019. Reporting thresholds will continue to be included until the changed policy is finalized.