(Disclaimer: The article below includes a discussion of key points of the guidance document. It is not the guidance document, nor it is an alternative to the guidance document. The guidance document is available here: https://www.fda.gov/media/167974/download.)
Excipients, or inactive ingredients, in a drug formulation are critical components, comprising up to 90% of a drug formulation by volume and serving important functions such as improving stability and increasing bioavailability for targeted drug delivery. However, with so much focus on the quality of active ingredients in the complex pharmaceutical supply chain, the quality of inactive ingredients is, at times, overlooked.
Sadly, with devastating outcomes in 2022 and 2023, multiple countries have reported more than 300 deaths caused by patients consuming liquid drug products contaminated with diethylene glycol (DEG) and ethylene glycol (EG), including cough syrups and analgesics. (1) Unfortunately, deaths and adverse health outcomes due to DEG and EG contamination have occurred as early as 1937 in the United States and around the globe as recently as 2023.
DEG and EG are contaminants that are toxic when ingested above acceptable limits. DEG and EG creep into drug products through 1) economically motivated adulteration of high-risk components like glycerin and propylene glycol, which have a similar taste and appearance but are less expensive or 2) process impurities during the manufacture of four sugar alcohols (e.g., sorbitol and maltitol solutions) and excipients manufactured with ethylene oxide as a starting material (e.g., polyethylene glycol). Process-related impurities like EG, DEG (dimer of EG), and triethylene glycol (TEG, trimer of EG) may arise from the hydrogenation process of sugar alcohols or the reaction of ethylene oxide with water. The systemic root causes of these occurrences stem from limited control of high-risk components. Key factors contributing to the contamination of final drug products with DEG/EG include inadequate supplier qualification (lack of origin), lack of appropriate identity testing and a complex supply chain (chain of custody). Furthermore, despite the systemic issues, drug product manufacturers rely on the certificates of analysis (COA) provided by the supplier instead of testing the incoming excipient.
In May 2023, the U.S. FDA Center for Drug Evaluation and Research issued a Guidance for Industry titled Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol. The guidance requires complying with the identity standards for a drug, including drug components, with a name recognized in USP-NF. The USP has monographs and reference standards for several of the high-risk drug components, which are widely used as excipients in drugs, in USP-NF and its reference standards catalog.
The U.S. FDA guidance is an update to a guidance from 2007 and identifies not only DEG but also EG as potential contaminants in high-risk components including those listed in the title. The guidance notes that the incidents in liquid drug products prior to 2020 were because the drug product manufacturers: (2)
- Did not perform full identity testing on the glycerin raw material, including tests to quantify the amount of DEG present and to verify purity of the glycerin;
- Relied on the COA provided by the supplier of the glycerin; and
- Had limited information on the entire supply chain and chain of custody of the glycerin raw material as it was not noted on the COA.
The guidance further observes that the 2022 incidents were due to similar over-reliance on COAs provided by suppliers. The drug manufacturer must verify the supplier testing protocols to ensure they have a quality system in place to provide accurate results. The chain of custody or distribution history of the high-risk drug component was not readily known or apparent from the COA, leading to, on one occasion, DEG and EG contaminated propylene glycol (3) entering the pharmaceutical supply chain.
The guidance includes sections on Regulatory Requirements and Recommendations.
In the Regulatory Requirement section, the guidance requires drug formulation manufacturers (including outsourcing facilities) to: (2)
- Ensure that the drugs they manufacture comply with current Good Manufacturing Practice (CGMP) regulations codified in 21 CFR Parts 210 and 211.
- Test bulk or repackaged high-risk drug components for DEG and EG content per the CGMP requirement under section 501(a)(2)(B) of the FD&C Act, stressing that bulk or repackaged high-risk drug components intended as excipients or other components of a drug product are drugs as defined by section 201(g)(1)(D) of the FD&C Act.
- Have a quality unit responsible for approving or rejecting incoming lots of materials (including components) used for manufacturing operations.
- Comply with the CGMP regulations codified in 21 CFR Part 211.84, and thus test the identity of each component of a drug product, using specific identity tests, if they exist, on each shipment of each lot before use in drug product manufacturing.
- Comply with identity standards for a drug, including drug component (e.g., excipients), with a name recognized in USP-NF (i.e., if the drug or components has a USP-NF monograph). If failed to do so, as per the U.S. FDA, a drug, including drug components, will be deemed adulterated, misbranded or both.
- Perform the DEG and EG limit test included in the identity section of a USP or NF monograph on representative samples of each shipment of each lot of the component. The acceptable limit for DEG and EG is no more than 0.10 %.
- For example, it is not sufficient to only perform identity test A in the USP monograph for glycerin and establish the component as glycerin. The manufacturer must perform test B “Limit of Diethylene Glycol and Ethylene Glycol” to check whether DEG and EG content is no more than 0.10 % prior to use, and not use it if the level is higher than 0.10 %.
Further, pharmacies that compound drug products, which satisfy the conditions specified in section 503A of the FD&C Act, are required to compound drug products using bulk drug substances that comply with the standards of an applicable USP or NF monograph, if a monograph exists. They must also use ingredients (other than bulk drug substances) that comply with the standards of an applicable USP or NF monograph, if available.
Compliance with DEG and EG limits when specified in an applicable USP-NF monograph is crucial for the quality and safety of compounded drug products.
The guidance document also makes six recommendations to drug product manufacturers, repackers, preparers and distributors of high-risk drug components, and for pharmacies. The following recommendations have been underscored:
- Drug product manufacturers must perform identity tests on samples from all containers of all lots of high-risk drug components.
- For high-risk drug components where the DEG and EG tests are NOT included in the identification test of the USP-NF monograph, a manufacturer uses a suitable and equivalent procedure that includes a test to detect and quantify DEG and EG, with a recommended safety limit of no more than 0.10%*.
- Repackers, preparers and distributors of high-risk components for use in drug products, must test the high-risk components that are used, sold for use, or intended for use in drug products, providing the details of the original manufacturer in the COA of each lot.
The guidance document from U.S. FDA comes at a very critical time as both industry and regulators worldwide continue to address this issue.
Regulatory agencies in different countries can use the U.S. FDA guidance document, the World Health Organization draft working document on GMP for excipients used in pharmaceutical manufacturing, and other similar resources from other regulatory agencies and industry organizations to develop requirements for excipients. For such guidance to be effective, it must require the testing of drug components using appropriate pharmacopeial standards, and address prevention at different points in the complex pharmaceutical supply chain.
The USP has over 500 monographs for excipients in the USP-NF, including, as mentioned earlier, for several of the high-risk drug components where the DEG and EG test is either in the identification section or the impurities section of the monograph. Also, USP general chapter <469> Ethylene Glycol, Diethylene Glycol, and Triethylene Glycol in Ethoxylated Substances lists the impurity test for 17 ethoxylated substances.
USP published a general chapter <1083> Supplier Qualification, which became official on August 1, 2023. The chapter provides a framework for vetting, approving, and monitoring suppliers of pharmaceutical materials and services, thus strengthening the integrity of global supply chains. This chapter complements the current USP excipient GMP related chapters (<1078> GMPs for Bulk Pharmaceutical Excipients, <1080> Bulk Pharmaceutical Excipients - Certificate of Analysis, <1197> Good Distribution Practices for Bulk Pharmaceutical Excipients and <1195> Significant Change Guide for Bulk Pharmaceutical Excipients) that provide additional information for the manufacture of pharmaceutical excipients. In addition, USP Verification Services can aid both excipient and drug product manufacturers in maintaining the quality of excipients.
Toolkits to measure and control DEG and EG
- A full list of USP resources to support excipient and raw material manufacturers, drug manufacturers, distributors, regulatory bodies, governments, and country pharmacopeias, and testing laboratories on measuring and controlling levels of DEG and EG can be found in USP’s DEG and EG toolkit.
- The Asia Pacific Economic Cooperation (APEC) Supply Chain Security Toolkit is another global resource to establish effective training programs, best practices, and processes for securing the global supply chain of medical products. The toolkit includes the entire supply chain and product lifecycle, from raw materials to patient use, and focuses on enhancing medical product quality and supply chain security through the implementation of robust procedures, practices, and tools.
As we know, excipients form up to 90% of the volume of a drug and have very important functions in drug formulations. Any lapse in their quality affects not only the integrity of the drug but also its efficacy. The inherent variations in the sources of raw materials for an excipient, its manufacturing process and the complex supply chain make it imperative to test ALL excipients using the appropriate analytical methods at different stages in the supply chain and prior to use in pharmaceutical manufacturing. The devastating outcomes due to DEG and EG contamination are a stark reminder of what happens when we take excipient quality for granted.
- WHO urges action to protect children from contaminated medicines, World Health Organization, Jan 23, 2023
- The U.S. FDA guidance document on the testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol
- Indonesia revokes firms' fever syrup licences amid inquiry into 150 deaths, Reuters, Oct 31, 2022
* The USP-NF monograph on Polyethylene glycol (PEG) has a test for DEG and EG in the impurities section. The U.S. FDA sent USP a letter requesting that the DEG and EG test be included in the Identification section of the PEG monograph for PEG above molecular weight of 1000.The USP Excipients Expert Committee is revisiting these two methods to determine if they are still relevant and if a test for molecular weights over 1000 should be developed based on newer technology. We are in the process of discussing with the U.S. FDA to get clarification for monographs that may have different specifications. Since the U.S. FDA did not submit a request to USP to change the acceptance criteria, at this point, the compendial specifications for PEG are still what is listed in the monograph "NMT 0.25% of the sum of ethylene glycol and diethylene glycol" or "The absorbance of the Sample solution does not exceed that of the Standard solution, corresponding to NMT 0.25% of combined ethylene glycol and diethylene glycol" depending on the molecular weight.