Historically, the development of novel excipients has been hampered by the global regulatory review system, including but not limited to the United States. A novel excipient is not reviewed by the US Food and Drug Administration until it is formulated by a pharmaceutical manufacturer in a finished drug product and submitted to the agency as part of a new drug or abbreviated new drug application (NDA, ANDA). Because the approval of a novel excipient for human use incurs an additional safety risk, it is not surprising that pharmaceutical drug manufacturers have been reluctant to use novel excipients until they are reviewed by FDA and listed in the FDA inactive ingredient database (IIG) (1). As a consequence, the acceptance and use of novel excipients for drug formulations has been a significant challenge within the industry.
Only a few drug manufacturers have formulated drug products containing novel excipients in recent years. Some examples of brand drugs include: GlaxoSmithKline's (London) use of Vit E TPGS (d-α-Tocopheryl Polyethylene Glycol 1000 Succinate) in Agenerase (Amprenavir); Pfizer's (New York) use of Sulfobutyl Ether β-Cyclodextrin in VFEND (Voriconazole); Bristol Myers Squibb's (BMS, New York) use of Cremophor EL (Polyoxyl 35 Castor oil NF) in Taxol (paclitaxel); and Abbott's (Chicago) Norvir (Ritonavir) and Kaletra (Lopinavir; Ritonavir)(2–4).
In May 2005, FDA published a guidance document to help clarify the safety data requirements, including nonclinical studies, for novel excipients (5). These noncritical studies mirror those required for preclinical evaluation of new molecular entities (NMES). Although the definitions of these studies have significantly helped in developing novel excipient innovation and regulatory strategies, they have proven to require a significant financial investment for excipient manufacturers. As a result, the guidance has failed to pave the way for innovation and may have further discouraged excipient manufacturers interested in developing novel excipients.The situation is similar in Europe. A draft note for guidance on excipients was issued in 2003 by the European Medicine Agency's (EMA) Committee for Proprietary Medicinal Products (6). Similar to the FDA guidance, the European note also contained a long list of required preclinical studies for novel excipients. Furthermore, the International Conference on Harmonization's (ICH) common technical document (CTD) stipulates for noncompendial excipients (i.e., novel excipients) a complete workup of chemistry, toxicology, specification, and analytical methods. Validation of these methods must begin with the clinical trial application.
It is not surprising, therefore, that pharmaceutical drug manufacturers have been reluctant to introduce a noncompendial excipient in their regulatory applications. Yet, when adequate safety information is provided to the authorities, it is the experience of the authors that FDA has accepted novel excipients through their regulatory approvals of products that contain the novel excipients.
The development of combination excipients, which comprise several approved excipients and encompass a multitude of functionalities, also has gained popularity among excipient manufacturers based on positive experiences with regulatory approvals. Examples of such excipients include: ProSolv (JRS Pharma, Germany) containing silicified microcrystalline cellulose; Ludiflash (BASF) containing mannitol, crospovidone and polyvinyl acetate; Ludipress (BASF) containing lactose, povidone, and crospovidone; and polyvinyl acetate and povidone-based Kollicoat SR 30D and Kollidon SR (BASF).
The irony of the current regulatory environment is that new excipients are a crucial means to advancing new therapies. NMEs may need novel excipients. For example, compound-enabling excipients are varied (e.g., an antioxidant for an oxygen-labile compound or lactose as a carrier for dry-powder inhalation for lung delivery). Most notable among compound enabling excipients is a class of solubilizers that enable the oral delivery of insoluble compounds for improved oral bioavailability. They also can help with intravenous delivery of insoluble compounds in solution or dispersion formulations using excipients that are safe for injection into the bloodstream (7). Such excipients are often used in the preclinical setting to deliver a drug into animals at a dose 10 to 100 times that of a therapeutic dose in order to assess a compound's safety and delineate its target organ toxicity (8, 9). However, if the preclinical evaluation is successful, questions arise regarding the continued use of such a novel excipient in human clinical trials because of the perceived regulatory barriers.
In some cases, even when a regulatory authority allows an investigational new drug (IND) to contain a novel excipient during early Phase I or Phase II clinical trials, questions remain about the excipient's use in Phase III trials because of the anticipated high cost and risk in NDA filing. It is this experience of the authors that encouraged the exploration of an alternative pathway offered by the International Pharmaceutical Excipient Council (IPEC), a trade association of excipient manufacturers and users. IPEC developed a novel excipient safety evaluation procedure in 2007 to allow for a more informed decision on the part of regulators regarding a novel excipient's safety profile.