Policy for Testing of 
Alcohol (Ethanol) and 
Isopropyl Alcohol for 
Methanol 
Guidance for Industry 
 
 
 
 
 
 
This guidance is for immediate implementation. 
 
FDA is issuing this guidance for immediate implementation in accordance with 21 CFR 
10.115(g)(2).  Submit one set of either electronic or written comments on this guidance at any 
time.  Submit electronic comments to https://www.regulations.gov.  Submit written comments to 
the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.  You should identify all comments with the docket number 
listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this document, contact (CDER) Office of Compliance at 301-796-3400. 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
Center for Veterinary Medicine (CVM) 
 
October 2023 
Current Good Manufacturing Practice (CGMP) 
 
   
Policy for Testing of 
Alcohol (Ethanol) and 
Isopropyl Alcohol for 
Methanol 
Guidance for Industry 
Additional copies are available from: 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD  20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
and/or 
Office of Communication, Outreach, and Development  
Center for Biologics Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 71, Room 3128 
Silver Spring, MD  20993-0002 
Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances 
and/or 
Policy and Regulations Staff, HFV-6 
Center for Veterinary Medicine 
Food and Drug Administration 
7500 Standish Place, Rockville, MD  20855 
https://www.fda.gov/animal-veterinary/guidance-regulations/guidance-industry 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
Center for Veterinary Medicine (CVM) 
 
October 2023 
Current Good Manufacturing Practice (CGMP) 
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 3 
III.  POLICY ON TESTING FOR METHANOL ................................................................. 6 
A.  Drug Products, Generally ............................................................................................................. 6 
B.  Compounded Drug Products, Generally ..................................................................................... 8 
 
  Contains Nonbinding Recommendations 
Policy for Testing of Alcohol (Ethanol) 
and Isopropyl Alcohol for Methanol 
Guidance for Industry1 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
I.  INTRODUCTION 
 
This guidance is intended to alert pharmaceutical manufacturers2 and pharmacists in State-
licensed pharmacies or Federal facilities who engage in drug compounding3 to the potential 
public health hazard of alcohol (ethyl alcohol or ethanol) or isopropyl alcohol contaminated with 
or substituted with methanol.  During the Coronavirus Disease 2019 (COVID-19) public health 
emergency (PHE),4 the Food and Drug Administration (FDA) became aware of reports of fatal 
methanol poisoning of consumers who ingested alcohol-based hand sanitizer products that were 
manufactured with methanol or methanol-contaminated ethanol.5  FDA has also received 
numerous reports of dermal toxicity associated with such products.   
 
FDA also is concerned that other drug products containing ethanol or isopropyl alcohol 
(pharmaceutical alcohol6), which are widely used ingredients in a variety of drug products, could 
 
1 This guidance has been prepared by the Center for Drug Evaluation and Research  in cooperation with the Center for 
Biologics Evaluation and Research and the Center for Veterinary Medicine at the Food and Drug Administration. 
2 For the purposes of this guidance, references to manufacturers include registered outsourcing facilities because 
outsourcing facilities are subject to current good manufacturing practice requirements.  See section 503B(a) of the 
Federal Food, Drug, and Cosmetic Act (FD&C Act); see also the draft guidance for industry Current Good 
Manufacturing Practice  Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of 
the FD&C Act (January 2020).  When finalized, this guidance will represent the FDAs current thinking on this 
topic.  For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  References to manufacturers also 
include repackers, relabelers, and suppliers of alcohol.  
3 See section 503A of the FD&C Act (21 U.S.C. 353a).  
4 The Department of Health and Human Services (HHS) Public Health Emergency Declaration is available at 
https://www.phe.gov/emergency/news/healthactions/phe/Pages/2019-nCoV.aspx. 
5 Yip L, Bixler D, Brooks DE, et al., 2020, Serious Adverse Health Events, Including Death, Associated With 
Ingesting Alcohol-Based Hand Sanitizers Containing Methanol  Arizona and New Mexico, MayJune 2020, 
MMWR Morb Mortal Wkly Rep, 69(32):10701073, doi: http://dx.doi.org/10.15585/mmwr.mm6932e1external 
icon. 
6 For the purposes of this guidance, we use the term pharmaceutical alcohol to mean either ethanol (ethyl alcohol) or 
isopropyl alcohol (2-propanol).  Both are used as an active ingredient in alcohol-based hand sanitizer products and are 
used in other drug products as an active or inactive ingredient. 
  1  Contains Nonbinding Recommendations 
be similarly vulnerable to methanol contamination.  For example, certain inhalation products, 
mouthwashes, cough and cold products, and many topical drug products include pharmaceutical 
alcohol.  As the COVID-19 pandemic increased the demand for hand sanitizer products, the 
demand for pharmaceutical alcohol as the active ingredient of those products also increased.  In 
the past, increased stress on supply chains has made ingredients more vulnerable to economically 
motivated adulteration. 
 
For these reasons, the policy outlined in this guidance applies to pharmaceutical alcohol used as 
an active or inactive ingredient in a drug product regardless of whether the drug product is a 
hand sanitizer product. This policy will help pharmaceutical manufacturers and pharmacists who 
engage in drug compounding avoid using pharmaceutical alcohol contaminated with or 
substituted with methanol in drug products.7 
 
This guidance replaces the guidance for industry Policy for Testing Alcohol (Ethanol) and 
Isopropyl Alcohol for Methanol, Including During the Public Health Emergency (COVID-19) 
published in January 2021.8  
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required. 
 
 
 
7 In this guidance, the terms drug and drug product include both human and animal drugs and biological products. 
8 The Agency issued this guidance in January 2021 to communicate its policy for the duration of the PHE declared 
by the HHS Secretary on January 31, 2020, including any renewals made by the HHS Secretary in accordance with 
section 319(a)(2) of the Public Health Service Act (42 U.S.C. 247d(a)(2)).  As stated in the 2021 guidance, at such 
time when the PHE was over, as declared by the Secretary, FDA intended to reassess this guidance.  The COVID-19 
PHE ended May 11, 2023.  See the HHS COVID-19 PHE web page at https://www.hhs.gov/coronavirus/covid-19-
public-health-
emergency/index.html#:~:text=Based%20on%20current%20COVID%2D19,day%20on%20May%2011%2C%2020
23.  
  2  Contains Nonbinding Recommendations 
II.  BACKGROUND 
 
On January 31, 2020, the Secretary for Health and Human Services (HHS) issued a declaration 
of a PHE related to COVID-19 and mobilized the Operating Divisions of HHS.9  In addition, on 
March 13, 2020, the President declared a national emergency in response to COVID-19.10  
Although the COVID-19 PHE ended May 11, 2023,11 FDA has determined that the policy in this 
guidance still applies. 
 
Since the beginning of the COVID-19 PHE, FDA observed an increase in reports of serious 
adverse events, including deaths, related to ingestion (both unintentional and intentional) of 
alcohol-based hand sanitizer products.  FDA also received numerous reports of dermal toxicity 
associated with such products.  In the spring of 2020, FDA began finding numerous hand 
sanitizer products that were labeled to contain ethanol but tested positive for methanol 
contamination, and the drinking of some of these hand sanitizer products resulted in methanol 
poisoning.  In some instances, manufacturers of hand sanitizer products labeled their products as 
containing methanol, even though methanol is not an acceptable ingredient in any drug 
product.12  At the same time, methanol was detected in hand sanitizer products from multiple 
manufacturers through the screening and sampling of hand sanitizer products being imported into 
the United States.13    
 
FDA has reviewed many methanol substitution and/or contamination cases, and our investigation 
revealed the following commonalities and trends among these cases: 
 
  Multiple manufacturers, while manufacturing hand sanitizer products, were neither 
complying with drug current good manufacturing practice (CGMP) requirements under 
section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act)14 nor 
 
9 Secretary of HHS Alex M. Azar II, Determination that a Public Health Emergency Exists (originally issued 
January 31, 2020, and subsequently renewed), available at 
https://www.phe.gov/emergency/news/healthactions/phe/Pages/default.aspx.   
10 Proclamation on Declaring a National Emergency Concerning the Novel Coronavirus Disease (COVID-19) 
Outbreak (March 13, 2020), available at https://trumpwhitehouse.archives.gov/presidential-actions/proclamation-
declaring-national-emergency-concerning-novel-coronavirus-disease-covid-19-outbreak/.  On February 24, 2021, 
there was a Presidential Declaration continuing the national emergency concerning the COVID-19 pandemic beyond 
March 1, 2021.  See Continuation of the National Emergency Concerning the Coronavirus Disease 2019 (COVID-
19) Pandemic (Feb. 24, 2021), available at https://www.federalregister.gov/documents/2021/02/26/2021-
04173/continuation-of-the-national-emergency-concerning-the-coronavirus-disease-2019-covid-19-pandemic.  The 
national emergency related to the COVID-19 pandemic ended on April 10, 2023.  See the Joint Resolution 
Terminating a National Emergency, available at https://www.congress.gov/118/plaws/publ3/PLAW-118publ3.pdf.  
11 See footnote 8.  
12 Methanol is not an acceptable ingredient in any drug product and should not be used due to its toxic effects (see p. 
5).  See, for example, 21 CFR 330.1(e) (requiring that inactive ingredients in over-the-counter (OTC) monograph 
drug products be safe and suitable); see also Centers for Disease Control and Preventions National Institute for 
Occupational Safety and Health web page for methanol 
https://www.cdc.gov/niosh/ershdb/emergencyresponsecard_29750029.html.  
13 See the FDA Updates on Hand Sanitizers Consumers Should Not Use web page at 
https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-hand-sanitizers-methanol.  
14 Manufacturers of drugs, as defined in section 201(g) of the FD&C Act (21 U.S.C. 321(g)), must comply with drug 
CGMP requirements in section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351(a)(2)(B)) and, for finished drug 
products, the regulations at 21 CFR parts 210 and 211 as well. 
  3  Contains Nonbinding Recommendations 
manufacturing their products in a manner consistent with FDAs temporary policies for 
alcohol-based hand sanitizer products.15   
 
  Many manufacturers of the hand sanitizer products in which the ethanol was 
contaminated with methanol or was substituted with methanol did not perform any testing 
or performed inadequate testing16 on the ethanol component, including tests to verify the 
purity of the ethanol lots received and to quantify the amount of methanol present. 
 
  Many of the manufacturers of hand sanitizer products failed to adequately test each 
incoming component lot for identity,17 as well as to properly evaluate identity testing 
data. 
 
  The testing performed on incoming lots of the ethanol active pharmaceutical ingredient 
(API) by some firms was inadequate to detect that methanol (i.e., methanol at levels 
exceeding allowable limits)18 was present, either as a contaminant or as an intentional 
substitution.  In other instances, the firms lacked testing of their incoming ethanol API 
altogether. 
 
  Many of the manufacturers of hand sanitizer products in which the ethanol was 
contaminated with methanol or substituted with methanol relied on the certificate of 
analysis (COA) provided by the ethanol supplier, or a test result sheet provided by the 
supplier, without adequately validating the suppliers COA.19 
 
  The origin of the ethanol used in the products was not readily apparent to many firms 
manufacturing hand sanitizer products.  When queried about how they had qualified 
 
15 On December 31, 2021, FDA withdrew the following three guidances for industry because the Agency 
determined that the temporary policies were no longer needed to meet the demand for alcohol-based hand sanitizer 
products (Federal Register document (86 FR 56960) published Oct 13, 2021): Temporary Policy for Preparation of 
Certain Alcohol-Based Hand Sanitizer Products During the Public Health Emergency (COVID-19); Policy for 
Temporary Compounding of Certain Alcohol-Based Hand Sanitizer Products During the Public Health Emergency; 
and Temporary Policy for Manufacture of Alcohol for Incorporation Into Alcohol-Based Hand Sanitizer Products 
During the Public Health Emergency (COVID-19). 
16 To comply with CGMP regulations, each component of a drug product shall be tested for conformity with all 
appropriate written specifications for purity, strength, and quality, unless the certificates of analysis provided by 
suppliers have been appropriately validated (21 CFR 211.84(d)(2)).    
17 To comply with CGMP regulations, identity testing must be conducted to verify each component of a drug 
product (21 CFR 211.84(d)(1)). Under that provision, specific identity tests, if they exist, must be used.  Identity 
testing confirms that the component is what it is labeled to be.  A components identity can be described as its 
chemical structure and its physical form (e.g., polymorph, solvate, appearance) including, if appropriate, its 
stereochemistry or immunochemistry. See the guidance for industry Questions and Answers on Current Good 
Manufacturing Practices  Control of Components and Drug Product Containers and Closures at 
https://www.fda.gov/drugs/guidances-drugs/questions-and-answers-current-good-manufacturing-practices-control-
components-and-drug-product.  In addition, a drug with a name recognized in the United States Pharmacopeia-
National Formulary (USP-NF) must comply with compendial identity standards or be deemed adulterated, 
misbranded, or both (section 501(b) (21 U.S.C. 351(b)) and 502(e)(3)(B) and (g) of the FD&C Act (21 U.S.C. 
352e(3)(B) and (g)); see also 21 CFR 299.5(a) and (b)).  In such cases, the identity is determined by the official 
tests, procedures, and acceptance criteria in the applicable USP-NF monograph.  See USP-NF General Notices 2.30. 
18 See 21 CFR 211.160; see also footnote 21. 
19 See footnote 16.  
  4  Contains Nonbinding Recommendations 
ethanol suppliers used in the manufacture of contaminated hand sanitizer products, many 
hand sanitizer manufacturers could not identify the true source of the alcohol used in their 
hand sanitizer production.20   
 
  Ethanol contaminated with or substituted with methanol was seen in hand sanitizer 
products imported into the United States from multiple countries.  FDA is also aware of 
reports of methanol substitution in hand sanitizer products distributed in several countries 
outside the United States.  FDA is also aware of methanol substitution for pharmaceutical 
alcohol outside of hand sanitizer production. 
 
As a result of these various practices, methanol-contaminated ethanol and hand sanitizer 
products contaminated with or substituted with methanol have entered the pharmaceutical supply 
chain.  FDA is concerned that other drug products containing pharmaceutical alcohol could be 
similarly vulnerable to methanol contamination, including drugs in oral dosage form 
presentations.  For these reasons, the policy outlined in this guidance applies to pharmaceutical 
alcohol used as an active or inactive ingredient of a drug regardless of whether the drug product 
is a hand sanitizer product.  
 
Methanol is not an acceptable ingredient in any drug product and should not be used because of 
its toxic effects.  When methanol is present as an impurity in a component of a drug that is 
recognized in an official compendium, it must be below acceptable maximum levels set forth in 
the official compendium (e.g., in a United States Pharmacopeia (USP) monograph) for the drug 
to meet applicable quality standards and specifications.21  Skin exposure to methanol can cause 
dermatitis, as well as transdermal absorption with systemic toxicity.  Substantial methanol 
exposure can result in nausea, vomiting, headache, blurred vision, permanent blindness, seizures, 
coma, permanent damage to the nervous system, or death.  Although all persons using drugs 
contaminated with methanol via any route are at risk of methanol toxicity, oral or systemic 
administration of methanol may lead to death.  We are aware of reports of young children who 
unintentionally ingest hand sanitizer products and adolescents and adults who drink these 
products as an ethanol substitute.22 23  When the pharmaceutical alcohol in hand sanitizer 
 
20 In previous instances of contamination for other drug products (e.g., diethylene glycol in glycerin), a similar 
pattern was observed. The COA for glycerin obtained by the pharmaceutical manufacturers was often a copy of a 
COA on the letterhead of the distributor and not the COA provided by the manufacturer of the glycerin.  The chain 
of custody or distribution history of the glycerin was also not readily known because the glycerin may have been 
sold several times between its manufacture and its use in medicinal syrup or other drug products.  See the guidance 
for industry Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol 
Solution, and other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol (May 2023). 
21 Section 501(b) of the FD&C Act.  The USP is an official compendium and its monographs establish identity 
testing for drugs listed therein in addition to tests and methods for strength, quality, and purity for those products.  
See sections 201(g)(1) and (j) and 501(b) of the FD&C Act.  To meet the requirements of the USP monographs for 
alcohol (ethyl alcohol or ethanol) and isopropyl alcohol for use in an application product (i.e., a new drug 
application, abbreviated new drug application, biologics license application, new animal drug application, or 
abbreviated new animal drug application) or a product marketed in conformity with an OTC drug monograph, the 
product must contain no more than 200 parts per million of methanol.   
22 McCulley L, Cheng C, Mentari E, et al., 2020, Alcohol-Based Hand Sanitizer Exposure and Effects on Young 
Children in the U.S. During the COVID-19 Pandemic, Clin Toxicol (Phila), epub ahead of print Aug 27, 2020, doi: 
https://doi.org/10.1080/15563650.2020.1811298. 
23 Santos C, Kieszak S, Wang A, et al., 2017, Reported Adverse Health Effects in Children from Ingestion of 
Alcohol-Based Hand Sanitizers  United States, 20112014, MMWR Morb Mortal Wkly Rep, 66(8):223226.  
  5  Contains Nonbinding Recommendations 
products is contaminated with or substituted with methanol, people who have ingested the hand 
sanitizer product are most at risk for serious methanol poisoning.  
 
 
III.  POLICY ON TESTING FOR METHANOL 
 
Because of the serious hazards associated with methanol, to prevent pharmaceutical alcohol used 
in drug products from being contaminated with or substituted with methanol, it is critical that all 
pharmaceutical manufacturers, as well as pharmacists who engage in drug compounding using 
pharmaceutical alcohol, are aware of the importance of properly testing pharmaceutical alcohol 
to detect methanol contamination or substitution. 
 
A.  Drug Products, Generally 
 
Manufacturers of drugs are subject to CGMP requirements under section 501(a)(2)(B) of the 
FD&C Act and, for finished drug products, the regulations at 21 CFR parts 210 and 211 as well.  
These drug products include those marketed under a new drug application, abbreviated new drug 
application, drug products marketed in conformity with an over-the-counter (OTC) drug 
monograph,24 drug products manufactured by outsourcing facilities,25 and others.  Compliance 
with drug CGMP requirements includes certain analytical testing procedures that must be 
performed on all lots of pharmaceutical alcohol before use in drug manufacturing.26  As 
described below, manufacturers of drug products that include pharmaceutical alcohol must 
perform a specific identity test that includes a limit test for methanol, on each container within 
each shipment of each lot of pharmaceutical alcohol before the component is used in the 
manufacture or preparation of drug products.27 28   
 
The USP monographs for alcohol (ethyl alcohol or ethanol) and isopropyl alcohol establish a 
limit for methanol in alcohol of 200 parts per million (ppm).  Therefore, any ethanol or isopropyl 
alcohol found to contain more than 200 ppm methanol is considered adulterated under section 
 
24 Certain nonprescription drug products (commonly referred to as OTC drugs) can be legally marketed without 
review and approval of a product-specific premarket application under section 505 of the FD&C Act (21 U.S.C. 
355) if they satisfy applicable requirements under section 505G of the FD&C Act.  The requirements in section 
505G for marketing OTC monograph drugs include conformity with applicable conditions of nonprescription use for 
the drug or class of drug, such as specified active ingredients and dosage strengths.  Such drugs also must meet the 
general requirements for nonprescription drugs, which include requirements that these drugs contain only safe and 
suitable inactive ingredients and be manufactured according to CGMP.  See, for example, 21 CFR 330.1(a). 
25 See the draft guidance for industry Current Good Manufacturing Practice  Guidance for Human Drug 
Compounding Outsourcing Facilities Under Section 503B of the FD&C Act.   
26 21 CFR 211.84(d). 
27 The CGMP regulations at 21 CFR 211.84(d) require that each lot of a component undergo testing to confirm its 
identity before use in drug product manufacturing.  A specific identity test must be used.  In addition, a drug with a 
name recognized in USP-NF, such as alcohol, must comply with compendial identity standards or be deemed 
adulterated, misbranded, or both. (See section 501(b) and 502(e)(3)(B) and (g) of the FD&C Act; see also 21 CFR 
299.5(a) and (b).)  In such cases, the identity is determined by the official tests, procedures, and acceptance criteria 
in the applicable USP-NF monograph.  See USP-NF General Notices 2.30.  
28 21 CFR 211.84(b).  Knowledge of shipping controls can help in the determination of a representative sample.  
See, for example, section XVII (17) of the International Council for Harmonisation guidance for industry Q7 Good 
Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (September 2016).   
  6  Contains Nonbinding Recommendations 
501(b) of the FD&C Act because its quality or purity falls below the standards prescribed in the 
USP.   
 
On July 30, 2020, FDA sent a request to the USP to include a test for methanol in the 
Identification sections of the alcohol, isopropyl alcohol, and any related USP-National 
Formulary (NF) monographs to help prevent methanol contamination.29  On July 31, 2020, the 
USP posted a Notice of Intent to Revise for the Alcohol Monograph and the Dehydrated Alcohol 
Monograph to include the test for Limit of Methanol as an additional Identification C Test.30  On 
September 1, 2020, the revised Alcohol Monograph and Dehydrated Alcohol Monograph 
became official.  On February 1, 2022, a revised Isopropyl Alcohol Monograph containing the 
same test for Limit of Methanol as an additional Identification C Test became official.  
Therefore, manufacturers of products in which alcohol (ethyl alcohol) or isopropyl alcohol is 
used as an ingredient must test the alcohol or isopropyl alcohol ingredient using the limit test for 
methanol that appears in the Identification section of the USP Alcohol Monograph or USP 
Isopropyl Alcohol Monograph, respectively.31  As a result, FDA may consider use of any 
identity test conducted for ethanol (ethyl alcohol) or isopropyl alcohol under 21 CFR 211.84 that 
does not contain a limit test for methanol using the USP method to be a violation under section 
501(a)(2)(B) and/or 501(b) of the FD&C Act. 
 
Additional Considerations 
 
  Drug product manufacturers are responsible for knowing the entities in their supply chain 
for all the drug product ingredients, including for pharmaceutical alcohol (i.e., knowing 
the identities and appropriately qualifying the manufacturer of the pharmaceutical 
alcohol, the manufacturer(s) of any other ingredients used in their products, and any 
subsequent distributor(s)).32 
 
  Manufacturers must establish finished drug product test methods adequate to ensure that 
when testing for ethanol or isopropyl alcohol content (assay), the method also 
distinguishes between the active ingredient and methanol.33  CGMP requires assay testing 
to be conducted on all batches of finished drug products before release or distribution 
decision.34  
 
 
29 See https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/usp-nf-notices/fda-letter-alcohols-nitr-att.pdf. 
30 See https://www.uspnf.com/notices/methanol-testing-nitr-20200731. 
31 A drug with a name recognized in USP-NF must comply with compendial identity standards or be deemed 
adulterated, misbranded, or both (section 501(b) and 502(e)(3)(B) and (g) of the FD&C Act; see also 21 CFR 
299.5(a) and (b)).  In such cases, the identity is determined by the official tests, procedures, and acceptance criteria 
in the applicable USP-NF monograph.  See USP-NF General Notices 2.30.  
32 See section 501 of the FD&C Act, which states, For purposes of paragraph (a)(2)(B), the term current good 
manufacturing practice includes the implementation of oversight and controls over the manufacture of drugs to 
ensure quality, including managing the risk of and establishing the safety of raw materials, materials used in the 
manufacturing of drugs, and finished drug products. 
33 21 CFR 211.160(b).  See also the guidance for industry Analytical Procedures and Methods Validation for Drugs 
and Biologics (July 2015).  
34 21 CFR 211.165. 
  7  Contains Nonbinding Recommendations 
  All personnel in pharmaceutical manufacturing facilities (especially personnel directly 
responsible for receipt, testing, and release of pharmaceutical alcohol) should be made 
aware of the importance of proper testing and the potential hazards if the testing is not 
done. 
 
  Repackers and others who distribute and prepare ethanol or isopropyl alcohol API for use 
in drug products should test pharmaceutical alcohol that is used, sold for use, or intended 
for use in drug products. 
 
  Bulk or repackaged ethanol or isopropyl alcohol intended as an excipient or other 
component of a drug product is a drug as defined by section 201(g)(1) the FD&C Act (21 
U.S.C. 321(g)(1)).  Section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351(a)(2)(B)) 
requires that the methods used in, or the facilities or controls used for, a drugs 
manufacture, processing, packing, or holding conform to CGMP.  Testing bulk or 
repackaged ethanol or isopropyl alcohol for methanol content is consistent with CGMP 
required under the FD&C Act. 
 
B.  Compounded Drug Products, Generally 
 
A drug product compounded by a licensed pharmacist in a State-licensed pharmacy or Federal 
facility or by a licensed physician consistent with the conditions in section 503A of the FD&C 
Act, or in an outsourcing facility consistent with section 503B of the FD&C Act, can qualify for 
certain exemptions from the FD&C Act.35  Components, both bulk drug substances and other 
ingredients, used in compounding must comply with the standards of the applicable USP or NF 
monograph, if such monograph exists, for the drug to qualify for the exemptions provided in 
sections 503A and 503B of the FD&C Act.36      
 
In addition, drugs prepared, packed, or held under insanitary conditions are deemed to be 
adulterated.37  For example, FDA observed facilities that compounded drugs using active 
ingredients, inactive ingredients, or processing aides that have or may have higher levels of 
impurities compared to compendial or pharmaceutical-grade equivalents (e.g., ingredients with 
potentially harmful impurities, ingredients labeled with not for pharmaceutical use or an 
equivalent statement).38   
 
 
35 See sections 503A(a) and 503B(a) of the FD&C Act.  
36 See sections 501(b) and 502(e)(3)(B) and (g) of the FD&C Act; see also sections 503A(b)(1)(A)(I) and (b)(1)(B) 
and 503B(a)(2)(B) and (a)(3) of the FD&C Act. 
37 See section 501(a)(2)(A) of the FD&C Act. 
38 See the guidance for industry Insanitary Conditions at Compounding Facilities (November 2020). 
  8  Contains Nonbinding Recommendations 
As discussed above, the USP monographs for alcohol (ethyl alcohol or ethanol) and isopropyl 
alcohol establish a limit for methanol of 200 ppm.  Thus, compounded drugs containing ethanol 
or isopropyl alcohol with more than 200 ppm methanol may be considered adulterated under 
section 501(a) or (b) of the FD&C Act and would not qualify for the relevant exemptions in 
section 503A or section 503B of the FD&C Act because they do not comply with the standards 
in the applicable USP monograph. It is important to confirm the identity of ingredients used in 
compounding, and compounders should establish the reliability of the original manufacturer and 
subsequent manufacturers or suppliers of components, including any repackers, relabelers, and 
distributors. 
  9