USFDA Warning letters, 483s, WHO Alerts on Diethylene Glycol (DEG), Ethylene Glycol (EG) contamination in Drug Products (Pharmaplast Egypt; Champaklal, India and others).

Potential contaminants Diethylene Glycol (DEG), Ethyelene Glycol (EG) in different drug products (cough syrups, cold syrups), homeopathic medicines are a critical issue and has led to several USFDA Warning letters and WHO Medical alerts.

USFDA issued Warning letter to Pharmaplast, Egypt (FEI: 3003767891) in April 2023 on the issue. Pharmaplast did not test incoming component Glycerin, which is used in several of its drug products, for presence ofdiethylene glycol (DEG) or ethylene glycol (EG). The Warning letter also cites that Pharmaplast did not include a detailed plan for testing of raw materials, test methods that will be used, impact on previously manufactured distributed drug products. Pharmaplast is put under Import Alert (4 April 23)

USFDA issued a Warning letter to Champaklal Maganlal Homeo Pharmacy Private Limited, India (Champaklal), also in April 2023. Champaklal is a manufacturer of Homeo drug products and OTC products. Several products contain high percentage of Glycerin. But Champaklal did not have test for DEG, EG impurities in Glycerin. In response to FDA request Champaklal tested retain samples of some finished products for presence of DEG and EG impurities using an Indian Pharmacopeia (IP 2018) monograph for Glycerin; but the test is not suitable for identifying levels of DEG or EG in finished drug product. In the Warning letter, FDA mentions – “Use of glycerin contaminated with DEG or EG has resulted in various lethal poisoning incidents in humans worldwide” and has asked Champaklal to:

Provide test results of DEG, EG levels in reserve samples for all glycerin lots used in drug products (for U.S. market), risk assessment of all drug products that contain glycerin and actions there on, measures to secure supply chain for glycerin, describe how it will test each component for conformity to appropriate specifications, establish reliability of supplier results through initial and periodic validation, commitment to perform at least one identity test. (FDA has asked for similar actions from Pharmaplast as well).

Champaklal was also put under an Import Alert (March 2023)

WHO has issued several alerts on cough syrups, expectorants, cold syrups with high levels of Diethylene glycol (DEG), Ethylene glycol  (EG)  – 4 alerts between Oct 2022 to April 2023 itself; latest of which has been in April 2023 – Medical Product Alert N°4/2023). Other alerts:      

• Medical Product Alert N°1/2023    
• Medical Product Alert N°7/2022    
• Medical Product Alert N°6/2022

WHO alert states – “Diethylene glycol and ethylene glycol are toxic to humans when consumed and can prove fatal; Toxic effects can include abdominal pain, vomiting, diarrhoea, inability to pass urine, headache, altered mental state, and acute kidney injury which may lead to death” and advised regulatory authorities and public – DO NOT use them..(the specific drug products with DEG, EG contamination).

Cough syrups, cold syrups and other drug products commonly use excipients such as Glycerin (Glycerol), Propylene Glycol (PG), Sorbitol, which can have contaminants Ethylene Glycol (EG) or Diethylene Glycol (DEG). Spurious drugs could be contaminated with Diethylene glycol, a highly toxic chemical as a cheap substituent for common excipients like Glycerin. Raw materials like Propylene glycol, Sorbitol can also have DEG, EG contaminants as related impurities; and also due to handling, repacking operations

USP (United States Pharmacopeia) monograph for Glycerin limits Diethylene glycol and Ethylene glycol to 0.1% each, by the Identification test B. The USP adopted the above limits for Glycerin, Polyethylene Glycol and Sorbitol based on specific requests from USFDA in 2009 / 2010. Though the European Pharmacopeia (EP) monographs and International Pharmacopeia (WHO) monographs for Glycerin, Propylene Glycol, Sorbitol do not prescribe a limit for DEG and EG, it is prudent for companies to adopt same test and limit for DEG and EG as per USP, considering the toxicity and risk associated with DEG ad EG contamination.

USFDA has also issued a specific guidance for Testing of Glycerin for Diethylene Glycol.

The guidance states – “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”. A key point to note is that USFDA specifies the Test for DEG as an identification test in each container of Glycerin in a lot. This is because of the supply chain traceability complexity of Glycerin. If the test for DEG was captured as a test for related substances or impurities, companies may test the same in a representative composite sample. However this has a risk that certain containers with higher DEG could get released, due to effect of averaging out. Hence the test for DEG is specified as an Identification test. Accordingly, the USP monographs for Glycerin as well as Propylene Glycol and Sorbitol identifies the test for DEG and EG as an Identification test (Test B) with a limit of 0.10% each for DEG and EG. The USFDA guidance also specifies that “ Drug product manufacturers know their supply chain for glycerin (i.e., the manufacturer, of the component and any subsequent distributor(s)).

The above incidents, regulatory expectations clearly show that for testing and release of Glycerin (Glycerol), Propylene Glycol (PG), Sorbitol Companies should implement adequate procedures and controls:

• Sampling & Testing procedure defining sampling each container and testing sample of each container separately for Diethylene Glycol and Ethylene glycol with a limit of 0.10% each in every sample.
• Appropriately validate /verify the test method. Establish specificity, accuracy, limit of detection & quantification. (If USP method is adopted verify the method; if an alternate test method is used validate the method in line with guidelines for method validation covering all parameters and also establish equivalency with USP method).
• If all identification samples from a lot (i.e. each container) complies for the Identification test B, the lot can be considered complying for the test. But if one or more samples report Out of specification (OOS), then the entire lot is suspect and should be subjected for full investigation before any decision to release the lot.
• Procedure for qualification of vendors for Glycerin (as well as Propylene Glycol and Sorbitol). Full traceability of the supply chain – manufacturers, repackers, distributors should be established and assessed for risk of contamination / cross contamination. Particular attention should be given to repackers, as many industrial solvents are repacked multiple times in the supply chain. Considering the risks of contamination, it will be prudent to procure the material in original containers from the source of manufacture.
• If the companies have not yet established controls on testing for DEG, EG on Glycerin (Glycerol), Propylene Glycol, Sorbitol raw materials, perform an impact evaluation on all batches of drug product manufactured and distributed where one or more of the materials are used.
  • Cover all drug products within valid expiry in scope of assessment
  • Test all batches / lots of glycerin used in all drug products within valid expiry. Or alternatively, test each batch / lot of the drug product reserve samples for presence of DEG and EG with a test limit of 0.10%. The method shall be appropriately validated for detection and estimation of DEG / EG.
  • Based on the test results initiate appropriate remediation action (Recall / Stop distribution / Alert to the regulatory agencies).