The chemicals in question - dibutyl phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP) – are phthalates, which are commonly used to make coatings pliable enough to be applied to solid oral dosage forms during pill production.
However, studies have linked the chemicals to developmental problems in animals and some early epidemiological research suggests they may have similar effects in people as the Center for Drug Evaluation and Research (CDER) explained in industry guidance issued in the Federal Register.
“Phthalates have been studied extensively in animals, and DBP and DEHP have been shown to be developmental and reproductive toxicants in laboratory animals. While the data in humans are less clear, epidemiological studies suggest that certain phthalates may affect reproductive and developmental outcomes.
“While it is recognized that drug products may carry inherent risks, DBP and DEHP are used as excipients, and safer alternatives are available. Therefore, the Agency recommends avoiding the use of DBP and DEHP as excipients in CDER-regulated drug and biologic products.”
The CDER advises manufacturers check for alternatives in the US Food and Drug Administration’s (FDA) inactive ingredients database and advises those which can find replacements to consult relevant scale-up and post approval changes guidelines to see how best to make the switch.
If a manufacturer concludes that an alternative cannot be used the CDER wants the firm in question to justify its decision with supportive data and a risk/benefit analysis.
The inclusion of the CDER Guidance in the Federal Register comes just a month after phthalates in drug excipients were discussed in Environmental Health Perspectives (EHP), a monthly journal published with support from the US Department of Health and Human Services (HHS).
In an article entitled “Identification of Phthalates in Medications and Dietary Supplement Formulations in the United States and Canada” by Kelley et al, the authors suggest that although DBP and DEHP are common in the environment, drugs may be a major source.
“Human studies show widespread population exposure to background levels of phthalates. Limited evidence suggests that particularly high exposure levels may result from orally ingested medicinal products containing phthalates as excipients.
The conclude that: “Numerous RX and OTC drug products and supplements from a wide range of therapeutic categories may use DBP or DEP as excipients in oral dosage forms” and said more study is needed to assess what effect the widespread use of these compounds in drugs may have.
Kelley et al’s article prompted industry criticism. Writing on behalf of the International Pharmaceutical Excipients Council of the Americas (IPEC Americas) Dale Carter said that the blanket use of the term phthalate had created ‘unsubstantiated safety concerns.'
He argued that while DBP and DEHP are true phthalates other chemicals mentioned in the article - like diesters of isophthalic or terephthalic acids which are also used in drug excipients – are distinct, particularly when it comes to any safety concerns.
“Kelley et al. (2012) failed to acknowledge these important distinctions and incorrectly grouped isophthalic and terephthalic acid derivatives with the ortho-phthalates. This colloquial use of “phthalates” has created unsubstantiated and erroneous safety concerns. The specific toxicological concern with DEHP and DBP arises from their metabolic conversion to their corresponding monoesters.”
Whether the new CDER guidance provokes a similar reaction remains to be seen, although the care with which the agency specifies that DBP and DEHP are the only pthalates that need to be replaced indicates it is keen to avoid any similar criticism.