Guidance for Industry 

Testing of Glycerin for 

Diethylene Glycol 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

May 2007 

Compliance 
Guidance for Industry 

Testing of Glycerin for 

Diethylene Glycol 

Additional copies are available from: 

Office of Training and Communications 

Division of Drug Information, HFD-240 

Center for Drug Evaluation and Research 

Food and Drug Administration 

5600 Fishers Lane 

Rockville, MD 20857 

(Tel) 301-827-4573 

(Internet) http://www.fda.gov/cder/guidance/index.htm 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

May 2007 

Compliance 
Contains Nonbinding Recommendations 

i

TABLE OF CONTENTS 

I. INTRODUCTION............................................................................................................. 1

II. BACKGROUND ............................................................................................................... 1

III. RECOMMENDATIONS.................................................................................................. 2
Contains Nonbinding Recommendations 

Guidance for Industry1

Testing of Glycerin for Diethylene Glycol 

This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It 

does not create or confer any rights for or on any person and does not operate to bind FDA or the public. 

An alternative approach may be used if such approach satisfies the requirements of the applicable statutes 

and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for 

implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate 

number listed on the title page of this guidance. 

I. INTRODUCTION 

This guidance is intended to alert pharmaceutical manufacturers, pharmacy compounders, 

repackers, and suppliers to the potential public health hazard of glycerin contaminated with 

diethylene glycol (DEG), a poison. FDA has received and continues to receive (most recently in 

October 2006) reports about fatal DEG poisoning of consumers who ingested medicinal syrups, 

such as cough syrup or acetaminophen syrup, that were manufactured with DEG-contaminated 

glycerin. This guidance provides recommendations that will help pharmaceutical manufacturers, 

repackers, and other suppliers of glycerin, and pharmacists who engage in drug compounding, 

avoid the use of glycerin that is contaminated with DEG and prevent incidents of DEG 

poisoning. 

FDA's guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the Agency's 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. 

II. BACKGROUND 

In 1937, an outbreak of DEG poisoning occurred in the United States, which resulted from 

people ingesting elixir of sulfanilamide that contained DEG as a solvent. A total of 107 people 

died, many of them children. This event led to the enactment of the Federal Food, Drug, and 

Cosmetic Act (the Act), which included a provision requiring that drugs be demonstrated to be 

 

1

 This guidance was developed by the Office of Compliance in the Center for Drug Evaluation and Research 

(CDER), Food and Drug Administration. 
Contains Nonbinding Recommendations 

2

safe before marketing. In late 1995 and early 1996, many children were admitted to hospitals in 

Port-au-Prince, Haiti, with sudden kidney failure, resulting in at least 80 fatalities. An 

investigation by Haitian health officials, the Centers for Disease Control (CDC), and FDA 

discovered that the cause was DEG-contaminated glycerin in acetaminophen syrup manufactured 

in Haiti. Between 1990 and 1998, similar incidents of DEG poisoning occurred in Argentina, 

Bangladesh, India, and Nigeria and resulted in the deaths of hundreds of children.2

 In October 

2006, an outbreak of DEG poisoning occurred in Panama, resulting in multiple cases of illness 

and death. 

These cases reveal the following similarities: 

• The pharmaceutical manufacturers of the syrups that contained contaminated glycerin did 

not perform full identity testing on the glycerin raw material, including tests to quantify 

the amount of DEG present and to verify the purity of the glycerin received. 

• The pharmaceutical manufacturers of the syrups containing contaminated glycerin relied 

on the certificate of analysis (COA) provided by the supplier. 

• The origin of the glycerin was not easily apparent from the COA. The COA obtained by 

the pharmaceutical manufacturers of the syrups 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 product. 

As a result of these practices, DEG-contaminated glycerin entered the pharmaceutical raw 

material supply chain. 

III. RECOMMENDATIONS 

To avoid the use of DEG-contaminated glycerin, certain analytical testing procedures must be 

performed on all lots of glycerin (21 CFR 211.84(d)(1)). It is critical that all manufacturers and 

others using glycerin to manufacture or prepare drug products be aware of the importance of 

properly testing glycerin to detect DEG contamination. 

The Agency recommends that: 

1. Drug product manufacturers perform a specific identity test that includes a limit test for 

DEG on all containers of all lots of glycerin before the glycerin is used in the 

manufacture or preparation of drug products because of the serious hazard associated 

with DEG contamination.3

 The relevant safety limit for DEG is 0.1%, as recognized by 

 

2

 World Health Organization (WHO), Report of the Diethylene Glycol Contamination Prevention Workshop, 1997, 

p. xi.

3

 FDA’s regulation at 21 CFR 211.84(a) requires testing of each lot of components; 21 CFR 211.84(b) requires that 

a representative sample of each shipment of each lot be collected for testing and describes that the number of 

containers to be sampled shall be based upon appropriate criteria. Because DEG contamination presents a serious 

hazard, the Agency recommends that the representative sample collected for testing is of each container of each lot. 
Contains Nonbinding Recommendations 

3

the USP monograph for glycerin. The Agency recommends that a manufacturer perform 

the identity tests, including the limit test for DEG, which appear in the USP monograph 

for glycerin. Alternatively, a manufacturer may use an equivalent identification 

procedure that includes a test to detect and quantify DEG provided it meets the relevant 

safety limit. One alternative procedure is a thin-layer chromatography (TLC) method 

published in the Journal of AOAC International.

4

 

 This identification test is done in accordance with the CGMPs, which require that each 

lot of a component undergo testing to confirm its identity before use in drug product 

manufacturing (21 CFR 211.84(d)(1) requires that “[a]t least one test shall be conducted 

to verify the identity of each component of a drug product. Specific identity tests, if they 

exist, shall be used”). A specific identity test for glycerin is found in the United States 

Pharmacopeia (USP) monograph.5

 The USP monograph for glycerin provides a two-part 

identity test: test A using “Infrared Absorption” and test B using gas chromatography 

that references the “Limit of Diethylene Glycol and Related Compounds.” The infrared 

absorption test identifies glycerin and DEG, but does not distinguish between the two. 

Test B distinguishes glycerin from DEG.6

 

2. Drug product manufacturers know their supply chain for glycerin (i.e., the manufacturer 

of the component and any subsequent distributor(s)). 

3. All manufacturers take every opportunity to ensure proper testing of glycerin for DEG 

contamination. All personnel in pharmaceutical manufacturing facilities (especially 

personnel directly responsible for receipt, testing, and release of glycerin) should be made 

aware of the importance of proper testing and the potential hazards if the testing is not 

done. 

4. Repackers, and others who distribute and prepare glycerin for use in drug products, test 

glycerin that is used, sold for use, or intended for use in drug products. 

 Alternatively, knowledge of shipping controls can help in the determination of a representative sample. See, for 

example, section XVII (17) of FDA’s guidance for industry on Q7A Good Manufacturing Practice Guidance for 

Active Pharmaceutical Ingredients (Q7A). The Q7A guidance is available at 

http://www.fda.gov/cder/guidance/index.htm. We update guidances periodically. To make sure you have the most 

recent version of a guidance, check our Web site. 

4

 Kenyon et al., J. AOAC Int’l, vol. 81, no. 1, 1998, pp. 44 -50, available at 

http://www.fda.gov/cder/offices/otr/default.htm. 

5

 The United States Pharmacopeial Convention, Inc., United States Pharmacopeia 29––National Formulary 24, 

2006. The current good manufacturing practice (CGMP) regulations recognize the use of USP and NF methods (see 

21 CFR 211.194(a)(2)). Although a method other than that in the USP-NF may be used, the suitability of the testing 

method must be verified under actual conditions of use and must be accurate and reliable (21 CFR 211.194(a)(2) and 

(b)). 

6

 While the USP method is effective, there may be a potential for variability in the composition of products labeled 

as glycerin. Therefore, method modifications may be needed to the preparation of the Resolution, Standard, and 

Sample solutions and to the Chromatographic system to achieve suitable performance. Method modifications in 

analyses performed by FDA have included preparation of all solutions in methanol with appropriate modifications to 

the chromatographic system, as needed, such as temperature ramps and hold times. 
Contains Nonbinding Recommendations 

4

5. Pharmacies that use glycerin in compounding drug products either test the glycerin for 

DEG content or ensure that such testing was properly done by a reliable supplier. 

Bulk or repackaged glycerin intended as an excipient or other component of a drug product is a 

drug as defined by section 201(g)(1) the Act (21 U.S.C. 321(g)(1)). Section 501(a)(2)(B) of the 

Act (21 U.S.C. 351(a)(2)(B)) requires that the methods used in, or the facilities or controls used 

for a drug’s manufacture, processing, packing, or holding conform to CGMP. Testing bulk or 

repackaged glycerin for DEG content is consistent with good manufacturing practice required 

under the Act. 

For other components, such as propylene glycol, that in the past were found to be contaminated 

with DEG, precautions should also be taken to identify reliable suppliers and secure shipment to 

prevent similar occurrences.7

 

7

 The August 2, 1996, CDC Morbidity and Mortality Weekly Report describes DEG-contamination of propylene 

glycol. The report is available at http://www.cdc.gov/mmwr/mmwrpvol.html. The TLC test mentioned in 

recommendation #1 will distinguish DEG from propylene glycol.