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40 April 2014 Tablets & Capsules mas, 1982; Gray and Gangolli, 1986; Albro et al., 1989; Saillenfait et al., 1998). As a case in point, consider the in - accurate and misleading statements in the article "Identification of phthalates in medications and dietary supplement formulations in the United States and Canada" by Kelley et al. (EHP 120(3), March 2012), which has contributed to the confusion. In that article, Kelley et al. inappropriately refer to three polymers (PVAP, HPMCP, and CAP) as "phthalates" and inappropriately imply that they too are "phthalates" simply because they have the word phthalate in their names. HPMCP, PVAP and CAP are poly- mers that have been modified by esterification with orthophthalic acid groups. These high-molecular-weight polymers differ markedly from the short-chain alcohols used to produce DEHP and DBP, and thus these poly- mers are not orally bioavailable and their chemical properties are very dif- ferent. In fact, any metabolism of these phthalate ester polymers that might occur would not produce the monoesters about which people are concerned. Regulatory guidance on phthalate excipients The December 2012 FDA "Guid - ance for Industry—Limiting the Use of Certain Phthalates as Excipients in CDER-Regulated Products" recom- mended that the pharmaceutical industry avoid the use of two specific phthalates as excipients in CDER- regulated drug and biologic products: DBP and DEHP. In the Guidance, the FDA is careful to note that its recommendations apply only to DBP and DEHP. Nonetheless, suppliers of excipients have received inquiries from customers about the applicabil- ity of the Guidance to unrelated pro - ducts that include "phthalate" in their chemical name. This confusion is not limited to the marketplace, but is seen even in the scientific literature. In the EMA's draft "Guideline on the use of phthalates as excipients in human medicinal products," the Agency proposes "Permitted Daily Exposures (PDE) values of 0.01, 4 and 2 mg/kg/day for DBP, DEP and PVAP respectively." The EMA also concluded that there was "no data indicating that the presence of CAP and HPMCP in human medicinal products constitutes a potential risk for human safety." New GLP-compliant safety studies for PVAP from Colorcon, submitted to and under evaluation by EMA, support a significantly higher PDE for PVAP. Enteric polymer applications Enteric polymers (phthalate ester polymers) are more soluble at a higher pH than at a low pH. The deleterious effects of stomach acid on a variety of orally administered pharmaceutical products have been known for decades. The enteric coat- ing remains intact in acidic media and dissolves in the relatively neutral envi- ronment of the intestines, where dis- solution and absorption of the prod- ucts occur. Some of the earliest materials to be developed for this pur- pose were polymers containing orthophthalic acid as a substituent, and many of these same materials continue to be used extensively today. The typical application of the enteric polymer coating is approxi- mately 5 to 10 percent of the tablet or capsule core's weight. Phthalate ester polymers may also be used in the man- ufacture of modified-release products, e.g. extended- or prolonged-release formulations. Depend ing on the me - chanism of prolonging or extending the release of the drug, the amount of polymer in the final formulation may approach 30 percent. Safety information for phthalate enteric polymer excipients CAP. In the first chronic safety studies for CAP, conducted in 1944, groups of rats and dogs were fed CAP daily for a period of 1 year (Hodge, 1944). In the rat study, four groups of 20 rats each were fed diets *OEVTUSJBM1BSL3Et̓$FOUFSCSPPL$5tXXXUPXFSMBCTDPN $FOUFSCSPPL$5t.POUBHVF.*t1' r#"5)4)08&3r05$%36(4 r#&7&3"(&4r03"-$"3& r13&4$3*15*0/.&%4 r#"5)4)08&3 r05$%36(4 We are the Fizz! Tower Labs is the premier effervescent product manufacturer in the U.S. t1SJWBUF-BCFMt$POUSBDU.BOVGBDUVSJOH t'%"3FHJTUFSFEtD(.1$PNQMJBOU i-EOE_38-45_Masters 4/3/14 2:58 PM Page 40