FDA comes full circle with new guidance on testing products for toxic ingredients DEG and EG
The FDA has a long and sordid history with the toxic compound diethylene glycol (DEG), having received much of its original regulatory authority after a major poisoning event in the 1930s attributable to it. But what’s past is prologue, and FDA is once again expressing concerns and the need for companies to test for the compound – and a similar one, ethylene glycol – following major international incidents and a string of recent FDA Warning Letters on the topic.
- Sponsors typically formulate small molecule drug products with excipients to improve the delivery of an active pharmaceutical ingredient (API) to its intended site of action. While excipients on their own do not usually exert a pharmacological response, they can modify the solubility, targeting ability, stability, and biotransformation of the product after its administration. Selection of excipient depends on the intended use of a product and the physiochemical characteristics of the active pharmaceutical ingredient.
- Sugar alcohols (also called polyhydric alcohols or polyols) are commonly used excipients. For example, benzodiazepines (e.g., lorazepam) are commonly prepared for intravenous administration in inpatient settings using the solvent propylene glycol to improve its solubility of hydrophobic compounds. Unlike solvents, which are liquids used to dissolve APIs in solid form, diluents are used to dilute the concentration of another chemical in the same form. For example, another sugar alcohol that is a commonly used as an excipient is sorbitol. Sorbitol can be added to other powders prior to tablet compression to improve the drug product’s weight and uniformity of the content or to improve palatability of chewable drugs (like calcium carbonate) sorbitol’s sweet taste. Likewise, for products intended to be used on the skin where sustained dermal and transdermal drug delivery is desirable (e.g., in numbing ointments) an API might be combined in an emulsion with glycerin. Overall, several compounds within this family of polyols are favorable excipients to be used in pharmaceuticals, especially for increasing oral and injectable drug solubility. They are also commonly used in personal care products, such as toothpaste and mouth wash.
- Ethylene glycol (EG) and diethylene glycol (DEG) are chemicals that are extremely similar to these sugar alcohols. However, in contrast to excipients that are considered generally recognized as safe (or “GRAS”) by the FDA for use in foods and medications, ethylene glycol (EG) and diethylene glycol (DEG) are toxic compounds that have been linked to hundreds of deaths. Despite sharing many commonalities—such as being colorless, odorless, syrupy, and sweet-tasting—these chemicals are commonly used for industrial purposes such as petroleum solvent extraction and as ingredients in antifreeze, lubricants, bookbinding adhesives, mold release agents, brake fluids and inks; and as a plasticizer for adhesives, papers, packaging materials, and coatings.
- Because of the sweet taste of DEG/EG, dogs and cats are typically considered at highest risk of poisoning due to improper storage of these chemicals. In humans, these chemicals are ingested rapidly absorbed (within 1 to 4 hours).
- Technically, the compounds themselves are not toxic; it’s the metabolites they are broken down into once ingested and oxidized in the liver that are harmful. For example, DEG is metabolized in the liver by an alcohol dehydrogenase (ADH) enzyme into two known toxic metabolites, 2-hydroxyethoxyacetic acid and diglycolic acid. We are not certain of the true minimum toxic or lethal DEG dose, but doses equating to 0.5–1.0 g/kg in humans have been linked to acute kidney and liver failure and even death. Likewise, EG is minimally toxic but is broken down to toxic chemicals such as glycolic acid, glyoxylic acid, and oxalic acid once in the gastrointestinal system. The complete oxidation of ethylene glycol also depresses the citric acid cycle, generating lactic acid, resulting in eventual metabolic acidosis with increased anion and osmol gaps. However, DEG and EG are generally considered only mildly irritating to skin and mucous membranes and are not absorbed well through the skin or by inhalation.
- We first learned about the dangers of DEG in 1937, when over one hundred people in the United States died from taking a product called “elixir sulfanilamide.” While sulfanilamide was commonly used at the time in tablet and powder form to treat streptococcal infections, a company decided to reformulate the product using diethylene glycol as a solvent to create an oral suspension. This deadly incident ultimately led to the passage of the Federal Food, Drug and Cosmetic (FD&C) Act of 1938, which allowed FDA to require sponsors conduct safety studies before a new drug product could be marketed to consumers. Since then, DEG and EG have regularly popped up in pharmaceutical products as a dilutant in place of pharmaceutical-grade glycerin or other polyols used as excipients (which are more expensive) in medications. DEG has even been used in the past as a fraudulent additive in wine to increase the sweetness of the alcohol.
- In May 2007, FDA announced a direct-to-final guidance titled, Testing of Glycerin for Diethylene Glycol recommending that pharmaceutical manufacturers, pharmacy compounders, repackers, and suppliers take certain steps to avoid the use of DEG-contaminated products, primarily (as indicated in the title) in the context of glycerin. The 2007 guidance was issued in response to repeated instances of fatal DEG poisonings that resulted from consumers (mostly not in the U.S.) ingesting medicinal syrups manufactured with DEG-contaminated glycerin.
- The World Health Organization (WHO) published several product alerts in the last six months regarding medicines manufactured with DEG and/or EG. The first of these was published in October, alerting consumers that several substandard children’s cough syrups were being sold in The Gambia. Soon after, WHO issued a report on eight additional products manufactured with unacceptable amount of DEG and/or EG in Indonesia and throughout the WHO Region of South-East Asia. Next, WHO announced that two products containing DEG and/or EG were identified in Uzbekistan at the end of December 2022.
- At the end of January 2023, the World Health Organization announced more than 300 fatalities resulting from contaminated cough syrups for children, with most deaths occurring in young children under the age of five. Along with this news, WHO issued an “urgent call to action to countries to countries to prevent, detect and respond to incidents of substandard and falsified medical products.” The call to action petitioned regulators, suppliers, and manufacturers of pharmaceutical products to take additional precautions to prevent the production and distribution of any substandard medical products.
- According to a recent publication by leading medical officers at the U.S. CDC, the incidence of medication-associated diethylene glycol mass poisonings (MDMPs) persists, despite the known detrimental effects of diethylene glycol on human health. The article highlights that even although we know of some cases, there are likely many that go uncounted due to inadequate resources for public health activities in low- and middle-income countries, patients not having access to (or not seeking) medical care, occurrence of acute DEG toxicities that do not result in death, and lack of healthcare provider knowledge on recognizing DEG poisoning. Even though the root causes of MDMPs are unclear in many cases, the authors suggest they may be caused by “unintentional or intentional adulteration of medications at some point in the manufacturing or distribution supply chain and poor quality-control procedures and processes during manufacturing (often attributable to cost-saving efforts).” Finally, the article urges pharmaceutical manufacturers and regulators to use existing guidance to prevent future MDMP-associated illnesses and deaths.
- Now, FDA has published an updated version of the guidance (also issued as direct-to-final) on testing for and preventing DEG/EG contamination in pharmaceutical products. In the introduction, FDA explains that the guidance is similar in intent to the 2007 version. Basically, there have been several recent reports of suspected or confirmed DEG or EG contamination of pharmaceutical products around the world. While (thankfully) there have not been reports of this occurring in the United States, FDA wants drug manufacturers to be on the lookout for potential sources of contamination and to take extra precautions to prevent use of contaminated products.
- One major change from the 2007 guidance is the specific mention of ethylene glycol (EG) as a potential contaminant. Unfortunately, contamination of pharmaceutical products with toxic glycols continues to be a problem which seems to have expanded since 2007 beyond DEG contamination. Stakeholders should note that the title is not exhaustive; FDA explains in a footnote that the new recommendations are intended to apply to all components (beyond just those mentioned in the title), which from “historical experience, have been found to be at higher risk of DEG or EG contamination compared to other drug components.” To determine whether a specific additive should be tested for potential DEG or EG contamination, the Agency recommends review of the United States Pharmacopeia (USP) or National Formulary (NF) compendia.
- Secondly, the scope of products FDA has identified as high risk for DEG or EG contamination has expanded significantly. Previously, the main concern expressed by the Agency was contamination of glycerin products. Now, the scope of products identified as high risk includes a list of common excipients including polyethylene glycol, the most commonly used polymer in the entire field of drug development. Additional high-risk products called out in the guidance include propylene glycol, maltitol solution, hydrogenated starch hydrolysate, sorbitol sorbitan solution, noncrystallizing sorbitol solution, and diethylene glycol stearates.
- Third, the language used in this version of the guidance are much more authoritative than what was contained in the previous, 2007 version. For example, Section III was previously titled “Recommendations” but is now labeled “Regulatory Requirements” in the new copy. Along the same lines, the new guidance heavily cites the Code of Federal Regulations (CFR), emphasizing that drug manufacturers are responsible for ensuring product quality and for complying with CGMP regulations. FDA drives this point home by citing Section 501 of the FD&C Act, noting that a drug is adulterated if “the methods used in, or the facilities or controls used for its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this chapter as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.” Finally, if FDA happens to sample and test any container that is labeled using a name recognized in the official USP-NF compendia and finds that a product is not in conformance with DEG/EG safety limits (no more than .10% of DEG and EG), the Agency will not hesitate to deem the product “adulterated, misbranded, or both.”
- According to the guidance, the common sources of contamination are pretty much the same today as they were in 2007. Common reasons for DEG/EG contamination in a final drug product are due to drug product manufacturers: 1) Not performing full identity testing on the glycerin raw materials, 2) Relying on the certificate of analysis (COA) provided by the supplier instead of conducting their own analysis, and 3) Failing to realize that the COA provided by the supplier did not report the origin of the glycerin or provide a complete history of its chain of custody. Alternatively, in the last scenario, the drug manufacturer could have realized the COA was not complete but still chose to rely on it, despite the distribution history of the high-risk drug component not being clear from the COA.
- So, what can be done to prevent and identify contamination? Simple: manufacturers should perform their due diligence and avoid the three pitfalls mentioned above. By performing full identity tests on product components and not just relying on the COA from a supplier, manufacturers will be positioned to identify any quality issues prior to product manufacturing. If FDA samples and tests a container and finds that a product is not in conformance with the proper DEG/EG safety limits, it will be “deemed adulterated, misbranded, or both.” If testing reveals that distributed drug products contain DEG or EG, manufacturers of products approved via NDAs or ANDAs must submit a Field Alert Report (FAR) to FDA.
- Additionally, FDA provides a new section of recommendations that are not required but are strongly suggested to reduce the risk of DEG and/or EG contamination. In addition to the requirements, there are a total of six recommendations. Some of them are common sense suggestions like, “personnel in manufacturing facilities should be made aware of proper DEG and EG contamination testing” and “drug product manufacturers should maintain current knowledge of their supply chain for high-risk drug components.”
- However, one of them presents quite a significant ask, suggesting that manufacturers ensure “the specific identity analysis for each lot, which includes a limit test for DEG and EG, incorporates testing of samples from all containers of all lots of a high-risk drug component before it is used in the manufacturer or preparation of drug products.” In a footnote, FDA explains the rationale for this suggestion is because “DEG contamination presents a serious hazard and FDA has seen wide variability of DEG and EG contamination from container to container.”
- FDA also notes that sponsors should think about components of products: The last line of page 10 states, “The foregoing recommendations are also important precautions when determining supplier and lot acceptability of other components (e.g., polyethylene glycol 40 castor oil) that may be at risk for DEG or EG contamination and are not specifically named in this guidance.”
- The guidance seems to have the biggest implications for pharmacies that compound drug products. Most of the recommendations in the guidance are a reiteration of what is already expected of sponsors per CGMP practices. However, the 2007 version was not especially clear on whether it applied to pharmacies. Furthermore, most of the terminology used in the 2007 guidance seemed targeted more towards sponsors. This time around, FDA has specifically called out pharmacies that compound drug products to ensure its applicability for this group of stakeholders is clear. This is likely reflective of where FDA believes broader U.S. supply chain risks are for EG and DEG contamination.
- Also, manufacturers of non-oral drug products should take notice. Technically, FDA only discusses fatal poisonings resulting from ingestion of drug products in liquid dosage form. This is likely because studies on DEG and EG have shown these chemicals can be lethal when ingested and metabolized in the liver. We haven’t seen strong evidence to indicate that these chemicals are readily biotransformed via dermal absorption or inhalation. Even so, FDA does cite one study in the guidance where acute intoxication due to topical application of diethylene glycol was reported. The guidance also specifically reminds manufacturers in the guidance that CGMP requirements (and identity testing) apply “irrespective of the route of administration dosage form of the finished drug product (e.g., topical).”
- CDER Director Patrizia Cavazzoni also spoke out about this issue in March. In the article, Cavazzoni highlighted FDA’s commitment to preventing contaminated drug products from entering the U.S. market, stating, “We have implemented strict safeguards to prevent DEG/EG adulterated products, including those listed in the WHO alerts, from being imported into the U.S., and we are also working with the Centers for Disease Control and Prevention (CDC), regulatory authorities in other countries, and the WHO to support investigation efforts to determine the root cause of the reported contamination.” In the article, she also mentioned a list of high-risk products for DEG/EG contamination which precisely mirror those covered in the new guidance.
- The FDA has called attention to EG/DEG vigilance in recent warning letters, which may have also prompted the guidance. Since the start of 2023, there have been at least eight warning letters making explicit mention of DEG and EG – most often FDA’s explicit concern that companies were making glycerin-based products without conducting adequate testing.