- Why did USP revise its Alcohol and Dehydrated Alcohol monographs?
Recently, FDA alerted the public to a sharp increase in hand sanitizer products that are labeled to contain ethanol (also known as ethyl alcohol) but that have tested positive for methanol (References below). These recent reported incidents of products labeled as ethanol testing positive for methanol could create risks to public health beyond hand sanitizers since ethanol is extensively used in many other drug products. FDA's letter to USP regarding this issue indicates that since Alcohol and Dehydrated Alcohol are widely used as pharmaceutical ingredients, the Agency is concerned that this critical contamination risk is poised to have a broad impact on the supply chain. To address this public health issue, FDA has requested that USP revise the Identification section of the USP Alcohol and Dehydrated Alcohol monographs by including Identification C Test for “Limit of Methanol” (acceptance criteria of 200 µL/L). A similar compendial approach previously has been used to address public health crises in several other cases, including glycerin products that tested positive for diethylene glycol (DEG).
- Why is the Limit test for methanol in the Identification (ID) section?
The Limit test was added to the Identification section consistent with the recommendation from the FDA. As stated in FDA’s letter to USP regarding this issue, from a regulatory standpoint, it makes a difference whether the detection and quantification of methanol is considered part of the Identification test or is considered solely a standard for strength, quality or purity. Under the Federal Food, Drug, and Cosmetic Act (FD&C Act), a drug with a name recognized in USP-NF must comply with compendial identity standards, or be deemed adulterated, misbranded, or both.
As per FDA’s letter, If Methanol detection and quantification is part of the Identification test, the CGMP regulations at 21 CFR 211.84(d)(l) would require that manufacturers of drug products detect and quantify any Methanol present for each lot of Alcohol received. Furthermore, manufacturers of Alcohol could not deviate from the Methanol limit since this would be an aspect of identity. In contrast, if Methanol detection and quantification is part of an impurity test, a manufacturer need not include as part of its identity testing the detection and quantification of Methanol in the Alcohol. In addition, a manufacturer could deviate from the impurity requirements established in the monograph by labeling the product to indicate that it deviates from the USP test requirements in this regard. The agency would, however, consider such deviation from the impurity test requirements to render the drug adulterated under the Federal Food, Drug, and Cosmetic Act.
- Do all three Identification (ID) tests in the Alcohol and Dehydrated Alcohol monographs need to be performed to demonstrate conformance to the USP standard?
In order to demonstrate conformance to the USP monographs for Alcohol and Dehydrated Alcohol, the requirements for all three Identification tests must be met. USP General Notices defines Identification as follows:
A compendial test titled Identification is provided as an aid in verifying the identity of articles as they are purported to be, e.g., those taken from labeled containers, and to establish whether it is the article named in USP–NF. The Identification test for a particular article may consist of one or more procedures. When a compendial Identification test is undertaken, all requirements of all specified procedures in the test must be met to satisfy the requirements of the test. Failure of an article to meet all the requirements of a prescribed Identification test (i.e., failure to meet the requirements of all of the specified procedures that are components of that test) indicates that the article is mislabeled and/or adulterated.
- Will the Limit of Methanol test appear in both the Identification and the Organic Impurities sections of these monographs?
Yes. Because methanol is used in the Standard solution B for calculating resolution of system suitability in the Organic Impurities test, it needs to remain in the organic impurities section of each monograph. In addition, the Organic impurities test is a harmonized attribute in the Pharmacopeial Discussion Group (PDG) harmonized Alcohol and Dehydrated Alcohol monographs, and stakeholders need to include the methanol specification in Organic impurities for compliance in other regions outside of the U.S.
- Since the Limit of Methanol test is referring to the relevant section of the Organic Impurities test, do the solutions of acetaldehyde, acetal and benzene need to be prepared and injected?
No. As specified in the monograph revisions, only Standard solution A, Standard solution B, and Sample solution need to be prepared and injected for the Limit of Methanol test in the Identification section.
- Is USP Methyl Alcohol Reference Standard (RS) suitable for use in the Limit of Methanol and Organic Impurities tests?
Yes. USP Methyl Alcohol RS was evaluated by USP and found suitable for use in the Standard solution A and Standard solution B in both Limit of Methanol and Organic Impurities tests.
- What is the official date of the Revision Bulletins?
The official date of the Revision Bulletins for Alcohol and Dehydrated Alcohol Monographs is September 1, 2020. These Revision Bulletins supersede the currently official monographs.
As indicated in FDA's letter to USP, manufacturers should evaluate their supply chain and if stakeholders encounter difficulties to implement this standard by September 1, they should contact CDER Drug Shortage Staff at firstname.lastname@example.org
- When can I start to implement the Revision Bulletin revisions?
Early (i.e., immediate) adoption is allowed per USP General Notices
3.10 Applicability of Standards:
Early adoption of revised standards in advance of the official date is allowed by USP unless specified otherwise at the time of publication. Where revised standards for an existing article have been published as final approved “official text” (as approved in section 2.10 Official Text), but have not yet reached the official date (6 months after publication, unless otherwise specified; see “official date”, section 2.20 Official Articles), compliance with the revised standard shall not preclude a finding or indication of conformance with compendial standards, unless USP specifies otherwise by prohibiting early adoption in a particular standard.
USP has not specified any prohibition on early adoption in these Revision Bulletins.
- Will the changes specified in the Revision Bulletins also be applicable for Alcohol used as an active pharmaceutical ingredient (API)?
Alcohol is one of several excipients that are used as dual actives (i.e., that can be used as inactive and active ingredients). Other examples include Glycerin, Dextrose (glucose), Povidone, Hypromellose, Carboxymethylcellulose Sodium, etc. A single USP standard (monograph) exists and applies to both active and inactive uses. As such, the USP Alcohol monograph applies to both API and excipient uses.
- Is the revision proposal published in Pharmacopeial Forum (PF) 46(4) [Jul.–Sep. 2020] included in the Revision Bulletins?
No. The Alcohol revision proposal published in PF 46(4) proposes to add a note to the Specific Gravity test referring to the revision of Alcoholometric table that also appears in the same PF issue, 46(4). This revision proposal is not included in the Revision Bulletin, and it will still proceed through the in-process revision pathway.
- How do these Revision Bulletins affect harmonization of the Alcohol and Dehydrated Alcohol monographs?
Both the USP Alcohol and Dehydrated Alcohol monographs are currently harmonized through the (PDG) process. However, based on public health concerns and informed by the recommendation from FDA, USP has communicated with PDG that the Limit of Methanol test is added as a local requirement in the ID section. A local requirement is only applicable to specific regions of PDG, and in this case, it will be only applicable for drugs intended for the U.S. market.
USP will follow up with PDG to discuss opportunities to harmonize the Identification section of these monographs with the inclusion of ID C.
- Are any other USP monographs implicated by this issue?
USP has identified additional related monographs in the USP–NF and Food Chemicals Codex (FCC), namely the USP Isopropyl Alcohol, USP Azeotropic Isopropyl Alcohol, FCC Ethyl Alcohol, and FCC Isopropyl Alcohol monographs.
USP has published a Notice of Intent to Revise (NITR) for FCC Ethyl Alcohol monograph that describes the proposed changes to the monograph. USP will announce potential compendial revisions to these monographs at a later date.
- Will the FCC Ethyl Alcohol and Isopropyl Alcohol monographs have an Impurity limit of 200 µL/L Methanol or just an ID test for methanol?
USP has engaged stakeholders, including FDA’s Center for Food Safety and Applied Nutrition (CFSAN), to develop a suitable testing procedure and acceptance criteria for testing methanol in the FCC Ethyl Alcohol monograph. The NITR of the FCC Ethyl Alcohol monograph proposes to include the same methanol testing procedure and acceptance criteria as the USP-NF Alcohol monographs.
- Why and how does Methanol acceptance criteria (NMT 0.5) correspond to 200 µL/L?
In Table 2 of Organic impurities test in the USP Alcohol monographs, it specifies that the acceptance criteria for methanol is “NMT 0.5, corresponding to 200 μL/L,” where NMT 0.5 indicates the peak ratio - Result (ru/rs) ≤ 0.5.
As shown below in Organic impurities test (also Limit of Methanol test) of the Alcohol monographs, Standard solution A is prepared using Sample solution A (Alcohol sample) as diluent.
- Standard solution A: 200 μL/L of methanol in Sample solution A
In Methanol Calculation, it specifies that
Result = (ru/rs )
ru = peak area of methanol from Sample solution A
rs = peak area of methanol from Standard solution A
Thus, rs = ru + peak area of spiked 200 µL/L methanol, as shown in the Standard solution A preparation.
The Methanol acceptance criteria in Table 2, which is Result (ru/rs) NMT 0.5, corresponds to less than or equal to (≤) 200 µL/L of methanol in the Sample solution A. For example, if ru is half of rs which means the Result (ru/rs) equals to 0.5, then the Sample solution A contains 200 µL/L of methanol and the Standard solution A contains 400 µL/L of methanol (200 µL/L in Sample solution A + 200 µL/L spiked) . If the Result (ru/rs) is below 0.5, then there is less than 200 µL/L of methanol in the Sample solution A.
In addition, if Cu = methanol concentration in Sample solution A and Cs = methanol concentration in Standard solution A, then Cs = Cu + 200 µL/L.
As described above, Result (ru/rs) = ru/(ru + peak area of spiked 200 µL/L methanol), then
Result (ru/rs) also equals Cu / (Cu + 200 µL/L).
To explain this more explicitly using numbers, the table below is created as an example:
Methanol Peak area Ratio
Result = ru/rs
Methanol Concentration in Sample Solution A
Methanol Concentration in Standard Solution A
0.00 0 0 0.20 50 250 0.33 100 300 0.43 150 350 0.50 200 400 0.60 300 500 0.67 400 600
- Are these compendial revisions anticipated to create or exacerbate drug shortages of hand sanitizers or other products?
USP recognizes that we are making significant compendial revisions on a very tight timeline, which will likely have broad-ranging implications for manufacturers, suppliers, testing labs, and others across a global supply chain.
In addition, consumers, manufacturers or distributors who have questions for the FDA regarding hand sanitizers should email COVID-19-Hand-Sanitizers@fda.hhs.gov
Updated September 21, 2020