Exploring a New Approval Process for Continued Excipient Innovation

Novel excipients in the United States are only reviewed in the context of a new drug application (NDA) or, more rarely, a new abbreviated drug application (ANDA). Even if a drug manufacturer is willing to accept the risks associated with the use of a new excipient in an NDA filing and manages to receive approval of the drug product, the excipient is only approved for use at the level used in that drug and for that particular route of administration. In addition, the time required for safety testing and the drug product approval process means that excipient manufacturers have a long wait to achieve a return on their investment, and often there are few years of patent protection left. As a consequence, it is difficult to make the business case for the development of novel excipients at a time when new classes of APIs that can treat as yet untreated diseases and meet unmet patient needs are being identified. The drug products that use these APIs will only reach the marketplace if novel excipients designed to overcome undesirable physical and/or chemical properties are available to enable their effective delivery.

Strong need for novel chemistries
New excipients and improvements to existing excipients are needed both for future drug-product development and for specialized applications such as pediatric-drug development, according to Chris DeMerlis, manager of regulatory affairs at Colorcon. While there are perhaps 300 to 400 different chemical entities used as pharmaceutical excipients, many are chemically similar, such as reducing sugars, clays, cellulosics, and carbohydrates. If one member of a class is unsuitable for a particular API, then generally none of the members of that class will be effective.

In addition, a number of excipients have recently been banned by FDA (dibutyl phthalate and di(2ethylhexyl) phthalate (1), and action on similar compounds may take place in the future. As analytical techniques advance, information about impurities in excipients that may be potential issues in certain applications is becoming available, such as formaldehyde and peroxide residues in microcrystalline cellulose and polyethylene glycol. According to Chris Moreton, vice-president of pharmaceutical sciences with FinnBrit consulting, “The imminent introduction of
United States Pharmacopeia General Chapters <232> and <233> concerning elemental impurities may mean that some current excipients will no longer be suitable for certain applications.”

Perhaps most importantly, modern drug-discovery methods (including combinatorial chemistry and high-throughput screening), which target isolated receptors rather than whole animal models, have changed the paradigm regarding drug solubility, permeability, and stability, according to Moreton. “These new drug molecules are placing increasing demands on drug-delivery technologies and available excipients, and some of the more traditional formulation approaches simply are not adequate to deliver these poorly soluble compounds,” he explains.

Together, the challenges posed by newer drugs combined with the issues surrounding some of the more commonly used excipients means that the number of available excipients for a particular application (formulation project) can be considerably reduced. “We need new excipients to increase our options for the formulation and delivery of the newer molecules coming through the development pipelines, including both small-molecule and biologic drugs,” Moreton asserts. There is a particular need for excipients that can aid in the formulation of parenteral drugs, according to Nigel Langley, head of marketing for BASF’s pharma ingredients and services business. Keith Horspool, vice-president of pharmaceutical development with Boehringer-Ingelheim, adds that new functional excipients in particular have potential to address the solubility and other challenges presented by drug candidates in today’s pipelines.

Untenable situation
In the past 1520 years, less than a handful of new excipients have been launched in the US, according to Moreton. There is no independent approval process for novel excipients. They are approved as part of an NDA and then only if the drug is approved and only for that particular route of administration and the level of use approved for the NDA. For pharmaceutical companies, it is risky to use a novel excipient because doing so complicates the regulatory issues, because any problem with the new excipient could hold up the approval of the drug product. Moreton points to one recent example: the use of Captisol (sulfobutyl ether betacyclodextrin, originally from Cydex) by Pfizer. “In this case, no other excipient was found to provide an acceptable finished product, so Pfizer was willing to adopt the risk of incorporating the safety testing for the excipient into the safety testing program for the drug and drug product. The technical need overrode the concerns over the risks,” he says.

It takes many years to develop a novel excipient and perform all of the necessary safety testing. Excipient manufacturers are then faced with the challenge of finding a pharmaceutical company that is willing to accept the risks of using a new excipient and then must hope that the drug progresses through clinical trials and ultimately receives approval. If the drug fails, the excipient does not receive approval, even if the failure was not related to the excipient (and the clinical trial data are not usable, even as a reference). “With the very high attrition rate for NDAs, the outlook for getting a novel excipient approved is pretty limited, and if an excipient is approved, often there is very little patent life left by that point,” Langley notes. Moreton adds that while there are provisions for patent term extensions for drug products, there are none for novel excipient compounds.

“As a result of these combined issues, it is getting more difficult to argue that there is a business case for investing in the development of new excipient technologies,” states Langley. Pharmaceutical manufacturers are concerned. “The current system is not only stifling innovation, it is creating an untenable business environment for excipient developers. The risks are becoming so great that excipient manufacturers are coming to the conclusion that excipient development is a nonviable proposition. Real change must be accomplished before excipient producers become unwilling to invest in innovation,” he asserts.

Exploring a separate approval pathway
Modifying the approval process for novel excipients so that they can be approved on an individual basis without tying them to a particular new molecular entity (NME) would make excipients available for development efforts of other NMEs independently of the development success of any one NME program, according to Vinod Tuliani, director of product development with GlaxoSmithKline.  If this type of regulatory pathway can be established, the industry will be encouraged to develop the types of novel excipients that are required for the effective delivery of challenging new drug candidates, adds Dave Schoneker, director of global regulatory affairs at Colorcon. “An independent pathway for safety assessment of new excipients, new co-processed excipients, and new uses or levels of existing excipients would increase the likelihood for pharmaceutical companies to include new excipients into their formulations,” he says. He also believes such an approach would lead to improvements in the overall design quality of many pharmaceutical products (to address things like drug solubility issues), enhanced productivity, and reduced costs. “Such designed-for-purpose excipients would become critical tools in pharmaceutical formulation as the industry moves towards a quality-by-design world,” Schoneker comments.

Building on past efforts
The FDA Guidance for Industry, Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients (2), which became final in 2005, provides recommendations for the safety evaluation of new pharmaceutical excipients, but does not address their approval. The New Excipient Evaluation Procedure (3) established by the International Pharmaceutical Excipients Council (IPEC)-Americas in 2007 is run by Robert Osterberg, a former FDA toxicologist. Osterberg heads a panel of independent toxicologists that review the safety/tox package of a new excipient to assess whether or not, in their opinion, it would be acceptable to FDA. Several reviews have been conducted, most to justify the use of higher levels of a current excipient than is given in the FDA’s Inactive Ingredient Database (IID). The hope that the new procedure would be a major step towards the adoption and approval of new excipients has not been realized, however, in part because the review is not an official FDA assessment leading to regulatory approval of the excipient. The program has, however, been beneficial in providing good supporting information to pharmaceutical users based on the safety review by word-class experts, according to DeMerlis.

A joint approach
With widespread interest and concern over the issue of new excipient development in the industry, a new effort has been initiated that unites the forces of IPEC-Americas and the IQ Consortium, an organization of pharmaceutical and biotechnology companies with the mission of advancing science-based and scientifically-driven standards and regulations for pharmaceutical and biotechnology products worldwide. The group within the IQ Consortium working on the issue is the Novel Excipients Working Group, which comprises colleagues from the pharmaceutical development, excipient, regulatory, and other fields, according to Tuliani. Notably, the group has surveyed members and found that there is significant interest in finding a way to increase the development of novel excipients to overcome barriers in developing new drug products.

“With both pharmaceutical and excipient manufacturers working together to uncover gaps in understanding and expectations and address them, it is possible to identify best practices and the types of data that are needed,” Horspool notes. He adds that with its technology focus and large membership that well represents the pharmaceutical industry, the IQ Consortium is the ideal group to work with IPEC-Americas on this issue. “With these two organizations working together, we can present a much more powerful argument,” observes Horspool. “It is exciting that we have these two major associations representing the excipient and pharmaceutical manufacturers collaborating on this effort,” agrees Langley. “We believe that we have the opportunity to make real progress,” he adds.

The Novel Excipients Working Group and a similar group formed within IPEC-Americas are currently exploring the development of joint best practices for preclinical safety (testing and specification requirements) and creating a process for designing a well-defined pre-clinical data package for novel excipients. With IPEC-Americas, the group is assessing current challenges to excipient review and approval, and possible next steps to alleviate these challenges. Horspool and Langley are excited about the potential of these efforts. “We see unprecedented possibilities for advancing meaningful change to the adoption of new excipients for achieving the most important goal of enabling new drug products to reach patients,” says Horspool.

References
1. FDA, Guidance for Industry, Limiting the Use of Certain Phthalates as Excipients in CDER Regulated Products (Rockville, MD, December 2012).
2. FDA, Guidance for Industry, Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients (Rockville, MD, May 2005).
3. C. DeMerLis et al., <em>Pharm. Tech</em>. 33 (11) 72-77 (2009). See also: http://ipecamericas.org/content/ipec-novel-excipient-safety-evaluation-procedure