Recently in month of May 2023, FDA issued Guidance for Industry for the testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and other high risk drug component for Di-ethylene Glycol and Ethylene Glycol.
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In this guidance copy, FDA recommended to perform
testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch
Hydrolysate, Sorbitol Solution, and other high risk drug component to detect
and quantify the content of Di-ethylene Glycol (DEG) and Ethylene Glycol (EG). Because of these both components are poisonous
in nature if it consumed above the defined limit resulting fatalities can occurred.
FDA has taken decision to issue this guidance copy based on received data related to fatal poisoning of consumers who ingested drug products in a liquid dose form such as cough syrup, allergy, analgesic and antiemetic drug product which are manufactured by using DEG and EG contaminated drug component. Hence FDA issued this guidance on immediate effect.
FDA not binding to any of drug manufacturer to follow only this guidance however, manufacturer can use any alternative procedure to quantify the DEG and EG in their drug component which must be satisfied the requirements of the applicable statues and regulations. This guidance is only the current thinking of FDA on this topic. FDA also mentioned in this guidance as if any alternative approach is available; to discuss the same can be contact with FDA office responsible person. The communication address is mentioned below as:
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
This guidance is applicable for all pharmaceutical manufacturers, compounders, repackars, and suppliers to the potential public health hazard of glycerin and other high risk drug component which are contaminated with DEG or EG.
As a background FDA explain and give some example of poisoning fatal. They explained about DEG poisoning case of US in 1937 where people ingesting the elixir of Sulphanilamide which contains DEG as a solvent. Total of 107 dead happened and most of children are suffered. Similarity in late of 1995 and start of 1996 many children are admitted in hospital in Port- au- Prince in Haiti, with the reported case of Kidney failure and about 80 fatalities are occurred. Based on FDA investigation it was identified as DEG contaminated Glycerin was used in manufacturing of Acetaminophen syrup in Haiti and same was consumed by people.
Similar cases DEG poisoning are also reported in Argentina, Bangladesh, Nigeria and India in period of 1990 to 1998.
FDA provides some scenario as why often such types of fatality are occurred.
1- The manufacturer of liquid drug content which having Glycerin as a drug content they are not performing complete testing to identify any contamination of DEG or EG.
2- Some of manufacturer of drug component which are used Glycerin in their drug component are direct trusted on COA of Glycerin supplier.
In the year of 2022 and 2023 numerous country reported the incidence in Oral liquid drug products with confirmed or suspected contaminations with high level of DEG or EG. And more than 300 fatalities are reported in children below the age of 5 years. In October 2022, the investigation performed by Indonesia health authority and they found the presence of DEG and EG in Propylene Glycol excipient which was used in manufacturing of Oral liquid drug products.
By considering the regulatory requirements the FDA mentioned in this guidance as "The FD&C Act and its implementing regulation contain many drug manufacturing requirements. This guidance highlight certain key provision that are critical to ensuring the detection of DEG and EG contaminated drug product and avoiding additional poisoning incidents. However, this guidance is not intended to be an all-inclusive list of drug manufacturing requirements. Drug manufacturer are responsible to ensuring their drug products are manufactured in compliance with all applicable FDA law and regulations".
FDA gives the reference of USP-NF monographs for testing of DEG and EG and its limit as NMT 0.10%. In this guidance it was explained by giving the example as The USP monograph for glycerin provide three method to perform identity test. Method A is identification by IR, Method B is by Gas chromatography procedure that references the limit of Diethylene Glycol and Ethylene Glycol. As per method A, by Infrared adsorption only be Glycerin can be identified however with Gas Chromatography method the limit of Diethylene Glycol and Ethylene Glycol can be determined on quantitative basis. Which is best way to find out the DEG and EG solvents and to avoided for contamination from DEG and EG.
FDA recommended as how to safeguard the drug product from contamination from DEG and EG. The some main recommendations from FDA side is below:-
* Ensure the specific identity analysis for each lot which include the limit test of DEG and EG has been performed for sample from all containers of all lots of a high risk drug component before the high risk drug component is used in the manufacturing of drug product.
* For high risk drug component where the DEG and EG test is not included in USP monograph then manufacturer use suitable procedure to identify and quantify the DEG and EG. The recommendation from FDA is the safety limit to be follow for DEG and EG is as NMT 0.10%.
* Drug product manufacturer maintain the current knowledge of supply chain for high risk drug component. Means to identify the current manufacturer of the component and subsequent supplier.
* All personnel in pharmaceutical manufacturing unit especially those person who direct involve in receipt, testing and release of component are must be aware about the importance of DEG and EG contamination testing and ensure before release the drug component either this is performed or not. Because of this test is too important and direct impact on patient safety.
In the last the FDA mentioned as if any testing of any drug product identified the DEG and EG content on or above the USP monograph i.e. NMT 0.10% the manufacturer notify to CDER-DEG-EG-Reporting@fda.hhs.gov of the finding. Manufacturers should also contact the appropriate Division of Pharmaceutical Quality Operations if any drug product batches made with components whose testing identifies DEG or EG levels at or above the USP-NF monograph limit are already in distribution, to discuss appropriate next steps, such as voluntary initiation of a recall.
The above guidance are published by FDA to avoid any poisonous fatality due to contamination of drug product with DEG and EG. If any other alternative methods are available by which such type hazardous components are identified, then it can be acceptable based on it follows the required regulatory requirements.
Abhishek Singh is the author of Pharma technical support. He is pharmaceutical professionals, having experience of more than 12 years in Quality.