Type of Posting: Notice of Intent to Revise
Posting Date: 30-Apr-2021
Targeted Official Date: To be Determined
Expert Committee: Simple Excipients
In accordance with the Rules and Procedures of the Council of Experts, this is to provide notice that the Simple Excipients Expert Committee intends to revise the USP Azeotropic Isopropyl Alcohol monograph by including a Limit of Methanol test in the Identification (ID) section to address the serious public health hazards associated with the use of azeotropic isopropyl alcohol contaminated with or substituted with methanol. This is consistent with a request documented in a letter from the U.S. Food and Drug Administration (FDA) on July 30, 2020. In the recent FDA Guidance, Policy for Testing of Alcohol (Ethanol) and Isopropyl Alcohol for Methanol, Including During the Public Health Emergency (COVID-19) (January 2021), FDA also describes its concerns that drug products other than hand sanitizer containing ethanol or isopropyl alcohol, which are widely used active ingredients in a variety of drug products, could be similarly vulnerable to methanol contamination. USP previously revised the USP Alcohol and USP Dehydrated Alcohol monographs by including Identification C test for Limit of Methanol. Additional information about this topic can be found in the Frequently Asked Questions for Alcohol and Dehydrated Alcohol.
The purpose of the proposed revision to the USP Azeotropic Isopropyl Alcohol monograph is to strengthen the Identification (ID) section of the monograph by including a test for Limit of Methanol as an additional Identification test. The added Limit of Methanol test would utilize similar gas-chromatography (GC) conditions to the existing Volatile Impurities test. The limit for methanol (200 μL/L) would be the same as that in the USP Alcohol and USP Dehydrated Alcohol monographs, as recommended in the FDA Guidance.
Additionally, consistent with FDA’s request in a letter on Feb. 25, 2021, the intent of this proposed revision is also to update the Volatile Impurities GC test method in the USP Azeotropic Isopropyl Alcohol monograph to include individual specified impurities, including methanol. External reference standards will be used instead of the current area normalization approach for quantitative analysis of each individual impurity, including methanol, 1-propanol, acetone, ethyl ether, diisopropyl ether, and 2-butanol.* In general, using external reference standards to quantify the impurities produces more specific and accurate results than using the area normalization procedure. In addition, it is consistent with the approach of determining methanol and other organic impurities listed in the USP Alcohol and USP Dehydrated Alcohol monographs.
The FDA Guidance includes the recommendation to use the methanol test described in the USP Alcohol monograph to test for methanol contamination in isopropyl alcohol. The FDA Guidance also states that, “a manufacturer may use an equivalent identification procedure that includes a test to detect and quantify methanol, provided it is validated and fit for such purpose.” We note that if the revisions to the USP Azeotropic Isopropyl Alcohol monograph become official, the test described in the USP Alcohol monograph, if validated according to USP General Notices 6.30. Alternative and Harmonized Methods and Procedures, may still be considered for use in azeotropic isopropyl alcohol.
USP is publishing this Notice of Intent to Revise (NITR) to inform stakeholders about the proposed upcoming revisions to the USP Azeotropic Isopropyl Alcohol monograph via the USP Accelerated Revision Process and to prepare companies for any operational and compliance implications that may be associated with a rapid implementation timeframe. USP is planning to follow this NITR with a Revision Bulletin with a specified official date. The Revision Bulletin may have an extended implementation time based on the comments received, however, USP plans to encourage early adoption by stakeholders as outlined in the USP General Notices 3.10. Applicability of Standards.
A separate NITR regarding the revisions to the USP Isopropyl Alcohol monograph can be found here . USP is planning to publish the proposed Revision Bulletin for the USP Isopropyl Alcohol monograph first, followed by the USP Azeotropic Isopropyl Alcohol monograph at a later date, based on the availability of the method validation data.
USP encourages stakeholders to provide feedback by May 28, 2021 on any impact that may result from these proposed revisions; please direct any such feedback to the email Methanol-ID@usp.org. As indicated in FDA’s letter (July 30, 2020), manufacturers should evaluate their supply chain for this product and contact CDER Drug Shortage Staff at firstname.lastname@example.org if any access or potential drug shortage issues arise. In addition, consumers, manufacturers, or distributors who have questions for the FDA regarding hand sanitizers should email COVID-19-Hand-Sanitizers@fda.hhs.gov.
[*Note: USP Reference Standards (RS) are qualified and suitable for use in the Limit of Methanol and Volatile Impurities tests, including USP 2-Propanol System Suitability RS, USP Methyl Alcohol RS, USP Acetone RS, USP 1-Propanol RS, USP 2-Butanol RS. In addition, USP Ethyl Acetate RS may be used as a RS for calculations of unspecified impurities. However, to reduce the burden on stakeholders, the monograph revision instead, may reference the use of ACS grade as reference standards for 1-propanol, acetone, ethyl ether, diisopropyl ether, and 2-butanol (known impurities) as well as ethyl acetate (for unknown impurities) to perform the test. As such, only the USP 2-Propanol System Suitability RS and USP Methyl Alcohol RS will be required in the monograph for the Limit of Methanol and Volatile Impurities tests.]