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W-33: Evaluation Process for Bulk Drug Substances for use in Pharmacy Compounding at the FDA: Weighing in the Nonclinical Assessment

Poster Presenter

      Wafa A. Harrouk

      • Pharmacology/Toxicology Reviewer
      • FDA
        United States


To describe the process for evaluation, and an outcomes analysis, of publicly available nonclinical data for substances nominated for inclusion on the list of bulk drug substances that can be used in compounding under section 503A of the Federal Food, Drug, and Cosmetic (FD&C) Act (503A bulks list).


Nonclinical data were obtained from literature sources such as the National Toxicology Program website, Pubmed, ToxNet, Embase, Web of Science, NIH dietary supplement label database, Google Scholar, GRAS notice inventory, US Pharmacopeia/NF monographs, and Drugs@FDA.


To determine whether a given substance will be recommended for inclusion on the 503A bulks list, FDA evaluates and balances four factors: quality, safety, efficacy and historical use. Nonclinical data are evaluated as part of the safety factor and encompass the following aspects: pharmacology, pharmacokinetic and toxicokinetic profile, acute toxicity, repeat dose toxicity, genotoxicity, developmental and reproductive toxicity and carcinogenicity. A retrospective analysis was undertaken of the findings of the nonclinical evaluations for over 46 substances nominated to be included on the 503A bulks list that were presented during seven PCAC meetings held since July 2014. Our preliminary analysis shows that many nominated substances lacked nonclinical data related to some or all the various parameters listed above. For many substances, available data were limited to the lethal dose information (LD50). Data quality issues were identified in association with nonclinical parameters other than LD50, such as small number of animals studied, inadequate or absent histopathology reports, and inadequate or absent description of the toxicities found.


A thorough review of public databases revealed that nonclinical data for substances which are nominated to be placed on the 503A bulks list are substantially lacking, limiting FDA’s ability to recommend safety margins to help prevent toxic effects in humans for many compounded drugs.