Issue link: https://www.e-digitaleditions.com/i/238663
j-Excipients_38-41_Masters 12/30/13 2:08 PM Page 39 eye on January 2014 39 Tablets & Capsules excipients Matthew Knopp Editor That change comes slowly to the pharmaceutical industry is not news, but with respect to the framework for using new excipients, will change ever come? Would excipient manufacturers be willing to pay to change it? It's a chicken-or-egg problem: On the one hand, excipient manufacturers are reluctant to develop new excipients because no new excipient will be accepted for use until it's submitted within an approved new drug application (NDA) or abbreviated NDA (ANDA). On the other hand, pharmaceutical manufacturers show little interest in risking the success of their applications by including new (novel) excipients in them. Under the current regulatory framework, both stances make sense, yet both stifle innovation, which the FDA has encouraged in other areas, including its Process Analytical Technology and Quality by Design (QbD) initiatives. And yet the FDA is aware of the need for new excipients. In fact, some observers had expected the Agency to follow its April 2005 Guidance for Industry: "Clinical Studies for the Safety Evaluation of New Pharmaceutical Excipients" with an initiative that promoted conducting those studies. They're still waiting. Meanwhile, the International Pharmaceutical Excipients Council (IPEC) and others have proposed procedures for evaluating new excipients, but little has changed. Very few new excipients have been cited in NDAs or ANDAs, and fewer yet have gained approval. One example of an approved NDA that included a new excipient is a parenteral antifungal treatment that cited cyclodextrin, a doughnutshaped molecule that complexes water-insoluble actives in its central cavity. When given by injection, cyclodextrin helps to solubilize the active in the patient's blood, where it disassociates and produces the desired pharmacological effect. The FDA approved this intravenous form of voriconazole in June 2002. That was the first FDA approval for a drug product using a substituted cyclodextrin and demonstrated the value of the new excipient. That approval opened the door for other uses, and cyclodextrin is now used in several FDA-approved drug products. Another success was BASF's testing—in accordance with IPEC's newexcipient procedures—of its Solutol HS 15. That work generated a favorable response from the FDA, but there was still no way for it to approve that excipient—despite its promise in solubilizing difficult actives—because it had not been included in a drug product application. Another manufacturer, Colorcon, seeking to expand the application of its approved enteric excipient Surelease, conducted studies to demonstrate its safety in other applications and/or at higher use levels. The payoff for these companies' efforts is unclear without knowing whether the work actually enticed a sponsor to cite those products as new excipients in an approved drug application. In reality, for most excipient manufacturers, the cost of surmounting the toxicological barriers to bringing new excipients to market has all but extinguished any notion of investing in such efforts. It is simply too expensive and the odds of a payoff too long. Instead, excipient manufacturers focus on developing new grades or new combinations of existing products. That usually entails coprocessing, blending, and/or particle modification to add functionality, facilitate formulation, and boost yields. Furthermore, because many excipient manufacturers sell much larger volumes of their products to other industries, the business case for investing in the pharmaceutical segment is not strong. Nor do pharmaceutical manufacturers appear interested in experimenting with unapproved materials, despite QbD. Indeed, they seldom seek to innovate with excipients, preferring instead to minimize, if not eliminate, the regulatory aspects of excipients on the finished dosage form. Indeed, many companies will not consider buying any excipient unless it comes from their current, qualified supplier of that excipient. Understandably, they want no changes, no surprises, and no extra paperwork. A fee-based approval process? In an ideal world, the science, economics, and regulatory framework of approving new excipients would mesh, thereby enabling excipient manufacturers and pharmaceutical companies alike to innovate and thus deliver better therapies to patients in a safe manner. Children are among the patients who would benefit from new excipi-