Manufacturers Urged to Take Steps to Avoid DEG and EG Contamination
Ongoing issues in the Asian pharma sector prompt an unequivocal response from the FDA and the IPEC Federation
Stephanie Sutton | | 4 min read
Contaminated cough medicines and the deaths of young children continue to make media headlines. The Indian drug regulator has reportedly identified more dangerous products. Cough syrups and anti-allergy products from Norris Medicine (reportedly shut down, according to Reuters) were allegedly found to be toxic. In addition, cold medicines made by Fourrts India were contaminated with diethylene glycol (DEG) and ethylene glycol (EG).
DEG and EG have also been mentioned in recent FDA warning letters. The Chinese company Zhao Qing Longda Biotechnology, which manufactures OTC products and has imported products into the US, was noted to be using ingredients “susceptible” to DEG and EG substitution. The FDA sent multiple requests for records and other information related to manufacturing – and eventually received a reply stating that the company was “not prepared to allow the FDA to audit and inspect” the premises. The FDA has since placed all shipments of products manufactured at the company on import alert.
Other warning letters also relate to high risk ingredients. For example, Green Pharmaceutical, based in South Korea, received a warning letter stating: “You manufactured over-the-counter (OTC) drug products, including (b)(4). Based on the records and information you provided, you did not demonstrate that you adequately tested each shipment of each lot of the incoming component at high-risk of (b)(4) contamination.”
Earlier this year, the FDA issued a new guidance document: “Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol.” Although no mass DEG poisonings have occurred in the US since the 1990s, the agency wanted to draw attention to the potential risks, given the increasing incidents in other countries. When analyzing previous poisoning cases, the FDA identified a number of similarities in cases that allow DEG- and EG-contaminated materials to enter pharmaceutical supply chains. In many cases, manufacturers did not perform full identity testing on glycerin raw materials, including tests to quantify the amount of DEG present and further tests to verify purity.
In addition, manufacturers relied on the certificate of analysis (COA) provided by the supplier. However, the origin was not readily apparent from the COA. In many cases, the COA was from the distributor rather than the original glycerin manufacturer, with the chain of custody or distribution history not readily known.
The FDA guidance says, “The 2022 outbreak resembles previous ones, as manufacturers of oral liquid drug products relied upon COAs provided by suppliers where the chain of custody or distribution history of the high risk drug component was also not readily known or apparent from the COA. For example, in one instance, the appearance of the label and COA of propylene glycol, used as a component of a drug product, suggested the component container’s content might differ from what the container label and COA stated. As a result of these practices, DEG- and EG-contaminated components, such as propylene glycol, entered the pharmaceutical raw material supply chain.”
The latest cases have also prompted a response from the IPEC Federation, which has updated its position paper, “Latest fatal incidents with contaminated medicinal syrup during 2022/2023.” The paper states: “Since 1937, when the first similar adulteration case of this kind was identified, there have been numerous cases that have caused several hundred deaths due to the use of excipients of inappropriate quality in pharmaceutical formulations.”
As with the FDA guidance, the IPEC Federation believes there are similarities between previous cases and the more recent ones. “In general, the blending or falsification of well-known pharmaceutical excipients such as propylene glycol, glycerin, maltitol, sorbitol and polyethylene glycol with industrial products seems to be the underlying principle of all the cases referred to in this Position Paper. The majority of reported cases since 1937 is in connection with the contamination of medicinal products with ethylene glycol and diethylene glycol.”
The IPEC Federation says it will consider the findings of the WHO investigation and the FDA guidance. In the meantime, the IPEC Federation position paper states that pharma manufacturers should consider the following:
- “Awareness and robust application of guides, standards and regulatory requirements
- Starting materials to be purchased from qualified and approved suppliers
- Purchase of ingredients suitable for use in pharmaceutical products/pharmaceutical grade excipients, no use of industrial grade chemicals as pharmaceutical excipients
- Robust incoming goods inspection, quality control testing and product release according to applicable monographs or equivalent validated and appropriate internal method(s)
- Full traceability of the supply chain back to the original excipient manufacturer
- Awareness and application of Risk Management principles
- Training system and records”
The IPEC Federation also said: “Ethylene glycol and diethylene glycol are chemicals for use in industrial applications only, such as, for example, industrial solvents, coolants and antifreeze agents. Ethylene glycol and diethylene glycol are not approved for use in pharmaceutical applications. When consumed by human beings, especially young children, e.g., as components of a medicinal syrup or other liquid pharmaceutical formulations, they lead to significant toxicity effects. Depending on the dose, these effects may include severe kidney damage potentially resulting in death.”
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