FDA to Compounders: Know Your Bulks and Excipients Suppliers
The quality of bulk drug substances, also called active pharmaceutical ingredients (APIs), and excipients used in compounded drugs can affect the quality of the resulting drug products. FDA has previously identified several issues related to components used in compounding. The agency urges compounders to know their API and excipient suppliers and know if they are testing these components for purity and quality before they are purchased for use in compounding. FDA reminds compounders that sections 503A and 503B of the Federal Food, Drug, and Cosmetic Act contain provisions regarding bulk drug substances (APIs) use in compounding. These include provisions regarding API compliance with applicable United States Pharmacopeia (USP) or National Formulary (NF) monograph standards, sourcing API from FDA-registered facilities, and valid certificates of analysis. These sections also contain provisions regarding excipient compliance with applicable USP or NF monograph standards.
Generally, repackagers take bulk API (usually in powder form) or excipients from the container in which the API or excipient was distributed by the original manufacturer and place it into a different container without further manipulation of the API or excipient, for distribution to drug manufacturers and compounders. Improper repackaging or lack of supply chain transparency regarding API or excipients can cause serious vulnerabilities in the supply chain and may lead to patient safety issues. In addition, repackaged API and excipient labels cannot be false or misleading regarding the identity of the manufacturer of the product. (21 CFR 201.1(h)(2)).
Examples of Quality Issues with Bulk Drug Substances and Excipients
The agency has issued alerts about quality issues with baclofen API and has highlighted concerns with using dietary ingredient glutathione to compound sterile injectables. There also have been other recalls related to bulk API, including a recall of products produced by Darmerica LLC, which shipped API labeled as quinacrine dihydrochloride to compounders nationwide, but subsequent tests identified the API as artemisinin.
The agency issued an alert about serious adverse events associated with a compounded curcumin emulsion which contained an ungraded polyethylene glycol (PEG) 40 castor oil as an excipient. The PEG 40 castor oil was found to contain diethylene glycol (DEG), a toxin formed during the manufacturing process. FDA is aware of recent international incidents of DEG and ethylene glycol (EG) contamination, some of which pose severe safety risks to consumers.1, 2, 3, 4, 5
Related Guidances, Resources, and Monographs
- The guidance for industry, Testing of Glycerin for Diethylene Glycol, provides recommendations that assist compounders, pharmaceutical manufacturers, repackagers, and other suppliers of glycerin, to establish practices that prevent the use of glycerin that is contaminated with DEG.
- The guidance for industry, Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients contains information on how API, from original manufacturers as well as API repackagers and relabelers, should identify the original API manufacturer to assure transparency as the API moves through the supply chain. The guidance for industry, Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, Questions and Answers is intended to respond to requests for clarification about the Q7 Guidance.
- There are several United States Pharmacopeia (USP) monographs including monographs for glycerin, propylene glycol, sorbitol solution, noncrystallizing sorbitol solution, sorbitol sorbitan solution, and maltitol solution, that incorporate identity testing provisions for DEG and EG. Information on these pharmaceutical excipients at risk for DEG and EG contamination, including appropriate test methods and DEG and EG limits, appears in the applicable USP monographs.
FDA remains vigilant in our inspections and oversight of the supply chain. As part of this effort, we inspect API manufacturers, including repackagers and relabelers, to help identify and prevent any weaknesses in the pharmaceutical supply chain. For patient safety and supply chain transparency, repackagers must follow all quality standards pertaining to them. Repackagers should clearly identify the original bulk drug substance manufacturer to their customers who use them to make the finished drugs patients take every day.
FDA has issued warning letters to API manufacturers and repackagers for significant violations of current good manufacturing practice (CGMP) requirements, including to:
- Professional Compounding Centers of America dba PCCA, January 27, 2021
- Yino Inc.,October 28, 2019
- Asclemed USA Inc., doing business as Enovachem, June 11, 2019
- B&B Pharmaceuticals Inc., June 4, 2019
- Spectrum Laboratory Products Inc., June 4, 2019
- Vipor Chemicals Private Ltd., January 29, 2019
- Fagron Inc., August 29, 2018
- Sichuan Friendly Pharmaceutical Co. Limited, June 22, 2018
- Sal Pharma, April 20, 2017
- Huron Pharmaceuticals, Inc., April 20, 2017
- Lumis Global Pharmaceuticals Co. Ltd., March 2, 2017
Additionally, the agency has placed API repackagers, including Lumis Global Pharmaceuticals Co. Ltd. and Sal Pharma, on import alert because they failed to meet CGMP requirements.
Report a Problem
We encourage compounders, health care professionals, and patients to report adverse events or quality problems associated with compounded drug products, including adverse events that may be linked to API or excipients that may have been contaminated, to FDA’s MedWatch Adverse Event Reporting program by calling 800-FDA-1088, or electronically at www.fda.gov/medwatch/report.htm. Please include in the report any information about the potential sources of the API or excipients.
1 World Health Organization, 2022, Medical Product Alert N°6/2022: Substandard (Contaminated) Paediatric Medicines.
2 World Health Organization, 2022, Medical Product Alert N°7/2022: Substandard (Contaminated) Paediatric Liquid Dosage Medicines.
3 World Health Organization, 2022, WHO Press Conference, October 5, 2022.
4 Centers for Disease Control and Prevention, 1996, Fatalities Associated with Ingestion of Diethylene Glycol-Contaminated Glycerin Used to Manufacture Acetaminophen Syrup — Haiti, November 1995–June 1996, Morbidity and Mortality Weekly Report, 45(30):649–650.
5 World Health Organization, 2023, WHO urges action to protect children from contaminated medicines.