Type of Posting: General Announcement
Posting Date: 29-Sep-2023
Targeted Official Date: To be Determined
Expert Committee: Complex Excipients
In accordance with the Rules and Procedures of the Council of Experts, this is to provide notice that the Complex Excipients Expert Committee intends to revise the USP Polyethylene Glycol monograph by including a Limit of Ethylene Glycol and Diethylene Glycol (EG/DEG) test in the Identification (ID) section to address the risk of EG/DEG contamination in Polyethylene Glycol. The Complex Excipients Expert Committee is considering various approaches to implement this intended revision. The intended revision would be consistent with a request documented in a letter from the U.S. Food and Drug Administration (FDA) on February 10, 2023.
USP previously revised seven excipient monographs with a high risk of EG/DEG contamination (Glycerin, Propylene Glycol, 3 Sorbitol Solutions, Maltitol Solution and Hydrogenated Starch Hydrolysate) by including Limit of EG/DEG tests in the ID sections of these monographs between 2010 – 2013, which were all referenced in the recent FDA Guidance (May 2023), 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 notes the requirement of testing for EG/DEG in the aforementioned seven excipients. In addition, the FDA Guidance recommends that for EG/DEG in high-risk drug components where the EG/DEG tests are not included in the identification test of USP-NF monograph for the component, a suitable and equivalent procedure is used to test for DEG and EG.
The current Polyethylene Glycol (PEG) monograph has no Identification test and there are two EG/DEG tests in the Impurities section for PEG MW < 450 and MW 450 - 1000, respectively. Unfortunately, both existing EG/DEG tests have some disadvantages that make them impractical for ID testing.
For liquid and semi-solid PEGs (MW ≤ 1000), the current USP General Chapter <469> Ethylene Glycol, Diethylene Glycol, and Triethylene Glycol in Ethoxylated Substances has a validated gas-chromatography (GC) testing procedure that is suitable for impurity analysis of EG/DEG. However, this procedure needs long incubation time at high temperature after each injection of sample solution to remove deposited PEG polymers, resulting in short GC column lifetimes which may not be ideal for frequent ID testing. For solid PEGs (MW > 1000), USP has engaged with stakeholders to develop a validated gel permeation chromatography (GPC) test method to detect EG/DEG in solid PEGs.
As pointed out above, the EG/DEG GC test in chapter <469> has disadvantages of short column lifetime and long run time, so USP is currently collaborating with multiple stakeholders and the FDA to optimize the EG/DEG GC method, but it will take some time and effort to develop and validate an optimal EG/DEG ID method for PEGs MW <= 1000. Therefore, to meet a pressing stakeholder need at this moment, USP is considering a proposal to add the validated EG/DEG GC test in chapter <469> to the ID section of the Polyethylene Glycol monograph for PEGs MW ≤ 1000 in the interim. USP may also propose to add an ID test using infrared spectroscopy for PEG, as there is no ID test in the current PEG monograph.
Please note that EG/DEG test methods developed by stakeholders, in accordance with USP General Notices 6.30. Alternative and Harmonized Methods and Procedures, may also be considered for use in Polyethylene Glycol.
USP is publishing this General Announcement to inform stakeholders of the anticipated future revisions to the Polyethylene Glycol monograph and to prepare industry for the potential operational and compliance implications that may be associated with this revision that may include a rapid implementation timeframe. An extended official date may also be considered based on the comments received; however, USP intends to encourage early adoption by stakeholders as outlined in the USP General Notices 3.10. Applicability of Standards.
USP encourages stakeholders to provide feedback by October 30, 2023 on any impact that may result from these potential revisions; please direct any such feedback to the email jyl@usp.org. You are also welcome to provide your feedback by answering a few questions through the link:
As indicated in FDA Guidance (May 2023), “If any testing of any drug component identifies DEG or EG levels at or above the USP-NF monograph limit, the manufacturer should notify CDER-DEG-EG-Reporting@fda.hhs.gov of the finding. Manufacturers should also contact the appropriate Division of Pharmaceutical Quality Operations if any drug product batches made with components whose testing identifies DEG or EG levels at or above the USP-NF monograph limit are already in distribution, to discuss appropriate next steps, such as voluntary initiation of a recall.”