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General Chapter Prospectus: <477> User-Determined Reporting Thresholds

Type of Posting: General Chapter Prospectus
Posting Date: 30-Dec-2021
Expert Committee: General Chapters—Chemical Analysis 
Proposed New Title: <477> User-Determined Reporting Thresholds
Input Deadline: 29-Jan-2022

Suggested audience: Suppliers and manufactures of drug substance and drug products, contract manufacturing organizations, drug testing organizations, drug products-related regulatory agencies, and QA/QC specialists

Estimated proposal PF: Pharmacopeial Forum 48(4) [Jul.-Aug. 2022]

Background and objectives: This potential proposed chapter would provide an approach for determining an appropriate numeric value for the reporting threshold (aligned with the definition in the Glossary in Impurities in Drug Substances and Drug Products <1086>) in chromatographic test procedures and would be applicable when a user-determined reporting threshold is specified in the individual monograph. 

Description of scope and application: USP may specify user-determined reporting thresholds in monographs for chemically derived drug substances and drug products. User-determined reporting thresholds are generally not applicable in monographs for biological/biotechnological products, peptides, oligonucleotides, radiopharmaceuticals, fermentation products and semi-synthetic products derived therefrom, herbal products, and crude products of animal or plant origin. Monographs that specify user-determined reporting thresholds will typically provide a note, as supplemental information that is not required for regulatory compliance, to aid users who are not product application holders in identifying a numeric value for the reporting threshold that may be suitable.

Preliminary outline: The following represents the sections for the proposed General Chapter <477>:

  • INTRODUCTION. For some users of the monograph with product applications approved by a responsible regulatory authority, the appropriate numeric value of the reporting threshold will be that which has been established in the approved product application. For other users of the monograph, the information provided in this chapter can support the determination of an appropriate numeric value. 
  • RELEVANT PRODUCT FACTORS. The relevant product factors supporting the determination of an appropriate numeric value for the reporting threshold for either a drug substance or a finished drug product include, the maximum daily dose (MDD) (i.e., the maximum amount of drug substance intended for administration per day) and route of administration of the related drug product. For many drug products, the maximum daily dose is the primary factor to be considered in the determination. 
  • MAXIMUM DAILY DOSE-BASED REPORTING THRESHOLDS. The numeric values for reporting thresholds corresponding to different maximum daily doses are established in the International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Q3A(R2) Impurities in New Drug Substances and Q3B(R2) Impurities in New Drug Products guidelines, for drug substances and finished drug products, respectively, and are reproduced in this section. 
  • ADDITIONAL CONSIDERATIONS. The numeric value of the reporting threshold should not exceed the numeric acceptance criterion for unspecified impurities, e.g., the numeric acceptance criterion for Any unspecified impurity in a drug substance monograph or the numeric acceptance criterion for Any unspecified degradation product in a drug product monograph.  Lower reporting thresholds can be appropriate for individual organic impurities that are known to be unusually potent or to produce toxic or unexpected pharmacological effects. The responsibility for ensuring the suitability of compendial chromatographic test procedure down to the level of the user-determined reporting threshold remains with the monograph user. 

Anticipated proposed design phase activities: USP is requesting early input from stakeholders on this  potential proposed General Chapter <477> which is anticipated to be published for comment in the Pharmacopeial Forum.

Contact: Antonio Hernandez-Cardoso, Senior Scientific Liaison (301-816-8308,