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U.S. Department of Health and Human Services

Drugs

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FDA Notification to Industry Regarding Potential Adulteration of Pharmaceutical Ingredients used as Emulsifying Agents and Flavorings

FDA's Center for Drug Evaluation and Research (CDER) recently learned that there have been recent instances when clouding and flavoring agents, which have been used outside the U.S. in certain food manufacturing processes, contain undeclared phthalate plasticizers, specifically diethylhexyl-phthalate (DEHP) and diisononyl-phthalate (DINP).  

CDER is not aware at this time of any intentional phthalate substitution, in part or whole, in finished pharmaceuticals or pharmaceutical ingredients used in the U.S. market. Nonetheless, significant overlap of global food and pharmaceutical ingredient supply chains raises the potential for adulterated food ingredients to enter the U.S. pharmaceutical supply chain.

CDER advises manufacturers of drug products and suppliers of pharmaceutical ingredients, both in the U.S. and abroad, to be aware of the potential substitution of phthalate plasticizers for vegetable oils in clouding and flavoring agents.  Manufacturers using emulsions containing vegetable oils should exercise caution to prevent the use of ingredients that might be intentionally adulterated with phthalates.  
 
The following recommendations apply to pharmaceutical manufacturers and compounding pharmacies:
  • Prior to use, confirm the composition of oil-in-water emulsions, such as clouding agents, and flavoring agents. 
  • Oil-in-water emulsions should be subjected to a comprehensive risk assessment with respect to phthalate adulteration unless the composition is known. [1]
  • End users should conduct appropriate testing of at-risk emulsions to assure they were not contaminated in the supply chain. [2]
CDER is continuing to monitor this situation to assess any impact on the U.S. drug supply chain. CDER is also evaluating the safety of DEHP and DINP. Manufacturers, pharmacy compounders, and distributors should determine if their supply chain is at risk. CDER will provide additional information as it becomes available. If you conduct testing and find phthalate contamination, or know of possible contamination, please email CDER_Ingredient_Adulteration@fda.hhs.gov.


[1] This is a general recommendation whenever a manufacturer uses any mixture containing undeclared or undisclosed components. See ICH Q9 for guidance on risk management.
[2] Methods for testing are not being provided since each matrix is unique. Manufacturers should refer to published methods to test for phthalates.