Regulatory Focus™ > News Articles > FDA Issues Guidance Meant to Limit use of Potentially Dangerous Substances in Medication

FDA Issues Guidance Meant to Limit use of Potentially Dangerous Substances in Medication

Posted 05 December 2012 | By Alexander Gaffney, RAC

The US Food and Drug Administration's (FDA) Center for Drug Evaluation and Research (CDER) has published a guidance document on the use of phthalates in products it regulates, saying it is looking to limit their use as excipients.

In the guidance, announced on 5 December in a Federal Register notice, the agency said the health risks associated with exposure to Di-n-butyl phthalate (DBP) and di(2ethylhexyl)phthalate (DEHP), were concerning enough to lead it to recommend against their usage in all CDER-regulated products, including prescription and non-prescription drugs and biologics.

The two compounds are widely used as plasticizers. When added to other materials, such as polyvinyl chloride (PVC), phthalates cause the harder material to become more soft and pliable, allowing it to be molded into more useful shapes. Though phthalates are relatively ubiquitous in industrial applications, they have also long been used in cosmetic products and as coatings on pills.

"Phthalates are found in certain pharmaceutical formulations, primarily as a plasticizer in enteric coatings of solid oral drug products to maintain flexibility, but they also may be used for different functions in other dosage forms," CDER explained. "Phthalates also are found in other products for uses such as softeners of plastics, solvents in perfumes, and additives to nail polish, as well as in lubricants and insect repellents."

The problem, continued CDER, is that the compounds have been shown be developmentally and reproductively toxic-at least in laboratory animals. Though the data for humans is a bit les clear, CDER said it would prefer to reduce human exposure to the chemical in light of its "potential risk" to humans. Such risks have been known since at least June 2000, when a National Institutes of Health (NIH) panel said it was concerned about the substance's effects on pregnant women. CDER referenced that same study in its Federal Register notice, noting that the population is widely exposed to phthalates "by multiple routes, including inhalation, ingestion, and absorption through the skin."

Under the new guidance, CDER will recommend against the use of phthalates in medications it regulates, including those under review and those already marketed to the public. It remained unclear if FDA would put into place an action plan or a timeframe by which all products containing phthalates would need to be reformulated or risk expulsion from the market.

CDER did say that the Inactive Ingredients Database (IID) would prove useful for manufacturers hoping to substitute excipients on a case-by-case basis. Both DBP and DEHP are set to be removed from that database, CDER wrote.

Any manufacturer unable to substitute DBP or DEHP for another excipient will be required to justify their rationale, FDA wrote in the guidance.

The guidance does not address exposure to either phthalate due to leaching from packaging materials or the delivery system, such as biological products stored in a PVC bag.

FDA's Center for Devices and Radiological health (CDRH) has already moved to make similar voluntary prohibitions against the use of phthalates in CDRH-regulated products, issuing a recommendation meant to minimize patients' exposure to devices containing PVC.


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