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Without an independent approval pathway for novel excipients, true pharmaceutical innovation could be stymied.
Excipients are essential to the formulation of drug products because they enable the effective delivery of drug substances and can account for as much as 80–90% of the drug product formulation. Despite the exposure that excipients pose to patients, currently there is no independent pathway for approval or assessment of novel excipients.
Other materials, which have higher levels of exposure, have established approval procedures. For example, food additives—including flavorants and colorants—can be approved via a petition to FDA or through the Flavor and Extract Manufacturers Association generally accepted as safe (GRAS) process. Cosmetic ingredients undergo the Personal Care Products Council’s well-accepted Cosmetic Ingredient Review process.
Many excipients used in approved drugs are listed in FDA’s Inactive Ingredient Database (IID); however, most have been used for decades and few were initially developed specifically for use as pharmaceutical ingredients. Novel excipients are those compounds not listed in the IID or compounds listed in the IID, but intended to be used for a new route of administration, at a higher dosage level or modified in some way, such as co-processed excipients that have been combined and enhanced in a physical manner through particle engineering.
The lack of an independent approval pathway for all of these types of novel excipients is creating significant challenges for drug formulators. “In recent years, there have been astonishing advances in the fundamental understanding of disease biology leading to remarkable treatments for once deadly diseases. Many drug candidates for these transformative and breakthrough treatments suffer from very poor physical and/or chemical properties,” observes Eric A. Schmitt, senior director of pharmaceutics at AbbVie and co-leader of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium) Working Group on novel excipients.
For oral drug candidates, excipients that can mitigate challenges associated with poor aqueous solubility and/or permeability can enable drug development for these otherwise potentially undevelopable candidates, Schmitt notes. For parenteral delivery, driven by the growth of macromolecules, there are significant needs for excipients that can improve solubility and chemical and physical stability, and reduce viscosity, he says.
“Similarly, tolerability (e.g., pain on injection for parenteral medicines), acceptability (e.g., taste for pediatric patients), and manufacturability challenges can all hinder the development of innovative medicines,” Schmitt says. “These challenges occur across therapeutic modalities, routes of administration, and dosage form types. Novel excipients, or expanded use scenarios of existing excipients, can provide formulation scientists much needed tools to address these challenges,” he concludes.
Novel dosage forms in use and under development today also have unique needs. “The industry as a whole is evolving to different methods for dosage and delivery—transdermal, mucoadhesive, and targeted immunotherapies for instance—that require unique solutions that in many cases cannot be provided by IID-listed options and will only be possible through the introduction and acceptance of novel excipients,” says Meera Raghuram, director of regulatory and sustainability with Lubrizol Life Science.
The bottom line, according to David R. Schoneker, president/owner/consultant with Black Diamond Regulatory Consulting, is that drugs today present different formulation challenges, and the numerous excipients used for 100 years no longer resolve these issues, nor do they enable optimization of new manufacturing methods such as continuous processing and 3D printing.
“It is important,” stresses Nigel Langley, global technology director for pharma solutions at BASF, “to think about novel excipients as offering a means for designing functionality to address specific problems given the challenges that drug developers currently face. Without fit-for-purpose excipients, many unmet needs will simply remain unmet,” he states.
Novel excipient approvals, however, are tied to new drug approvals, which adds risk to an already high-risk endeavor. It is natural that adding additional risk with an unapproved excipient will be avoided and only pursued as a very last resort, according to Schmitt. “Tying a new drug product approval to a novel excipient approval essentially doubles the risk of regulatory approval and significantly increases the cost of development. Even worse, if either one fails, the investment in both is lost,” he says.
There have also been examples in the past, notes Priscilla Zawislak, global regulatory affairs advocacy manager at IFF and immediate past-chair of the International Pharmaceutical Excipients Council (IPEC)-Americas, of drug developers being told by FDA that they really should use only excipients listed in the IID. “Hearing such comments can be very discouraging for pharmaceutical companies that have invested time and effort with novel excipients,” she says.
It is also frustrating for companies producing novel excipients, adds Langley. “Drug developers may want to use novel excipients in formulations that can be developed without them to provide improved quality or performance. Without an independent approval process, however, they rarely do so unless the potential reward outweighs the higher risk. Excipient manufacturers therefore don’t have any incentive to develop new products that may not bring a return for 15–20 years,” he asserts.
Some of the risk is perceived, because most novel excipients have more supporting toxicity data than the older approved excipients ever had, according to Schoneker. “It is the uncertainty that results from the lack of an established pathway that is the problem,” he states.
There is real risk, though, asserts Raghuram, due to FDA’s silence on the issue, the lack of any specific policy, and the chance that an application containing a novel excipient might land in the hands of an new drug application reviewer that doesn’t really understand how to do this type of assessment. “The awareness of issues related to safety of novel excipients is limited, and this is not surprising as there is no guidance available. It also cannot be expected that considerations related to innovation or an assessment of the positive impact of a novel excipient on the drug landscape will be part of a drug regulatory review process. An independent safety review process is, therefore, very important for novel excipients.”
A 2020 US Pharmacopeia (USP) survey of 264 respondents who formulated or supervised the formulation of generics, branded medicines, biologics, or biosimilars during the past five years revealed the extent to which drug developers find the lack of access to novel excipients a problem (1). Eighty-four percent said that currently used excipients have imposed limitations on drug development. Seventy-seven percent experienced challenges using novel excipients in advancing formulations through drug development for the US market, with regulatory acceptance, approvals, and other requirements the most common challenges. Forty percent felt compelled to reformulate a drug product for the US market because of an excipient’s limitations, while 28% experienced a discontinuation of drug development as a result of excipient limitations.
The internal structure of pharmaceutical companies that says risk must be managed has led to limited use of novel excipients, even if it means lower performing formulations are pursued, according to Langley. Today, Schmitt agrees, there is a high barrier to using novel excipients in drug development, which can stifle drug product design and potentially lead to suboptimal products with respect to pill burden, injection volume, stability, etc., as well as less efficient and/or robust manufacturing processes.
“What we have today is product development by IID and acceptance of ‘good enough’, rather than quality by design,” Schoneker asserts. In some cases, development projects have actually been halted because to move forward would require the use of novel excipients, meaning patients have therefore not had access to medications that could help them, he adds. In many cases, novel excipients have been available and shown to solve the specific issues, but the drug developers could not justify the perceived risk of using them.
While there is no lack of ideas or energy around the concept of novel excipients, given the hesitancy on the part of drug developers to use them and the lack of a path to market, the business model for excipient suppliers has become impractical, according to Raghuram. “Very few excipient companies are willing to invest resources in innovation and development,” she observes.
“At a time when we have never needed novel excipients more, there is too much uncertainty about using them and thus little reason for anyone to actually develop them. Due to the lack of an appropriate pathway for bringing products forward, very few companies are making decisions to get involved in real novel excipients any more. The only advances we are seeing are minor modifications to existing excipients, and in a few cases, co-processed excipients,” comments Schoneker.
If an independent approval or qualification pathway for novel excipients was established, then the requirements would be defined and everyone would know what must be done, says Zawislak. “FDA expectations would be clearer and more interest would be created in using novel excipients,” she says. For excipients that have FDA opinions generated and made public, drug developers would also know that there is safety data to support their use, at least for certain intended levels, Schoneker adds.
“Not only would an independent approval pathway encourage pharmaceutical companies to evaluate novel excipients, it would also give excipient suppliers a path to market that does not involve waiting 15–20 years,” observes Langley. Indeed, once an excipient receives a favorable review, suppliers can present that product to pharmaceutical companies and show that it has already been reviewed and therefore represents a higher likelihood of success, according to Zawislak.
Langley also believes such a pathway would act as a catalyst to stimulate innovation and collaboration between pharmaceutical companies and excipient suppliers. “An independent approval or qualification pathway for novel excipients could facilitate development, not only potentially reducing the attrition rate, but would also allow for a more cost-effective development process,” he states.
Access to more patient-friendly delivery solutions could also improve patient compliance, adds Katherine Ulman, principal consultant at KLU Consulting. Meanwhile, a new pathway may also lead to an update of the FDA guidance related to excipient safety, which was issued more than 15 years ago. In fact, IPEC is currently working on the revision of the 1996 Safety Guide for Pharmaceutical Excipients to incorporate current thinking related to safety evaluation techniques. IPEC hopes to publish this revised guide later in 2021.
For branded drugs, novel excipients could be used to optimize drug product performance and presentation, and possibly develop candidates that were deemed undevelopable, leading to transformative medicines with optimized patient presentations, according to Schmitt.
For generic drugs, novel excipients based on new chemical entities may not be appropriate for use; they would be best suited for use with innovator drugs that must go through clinical studies rather than bioequivalence studies. But other types of excipients including co-processed excipients and existing excipients used at higher levels or via different routes of administration, as well as food ingredients used for the first time as excipients, should be suitable for generic drugs. Because these materials have much less safety risk associated with them, the level of safety data required for assessment is typically lower.
“Novel excipients based on new chemical entities should go through a more drug-like approval process, while those based on existing excipients should have a less rigorous approval process that would enable their use by the generic-drug industry,” Schoneker asserts. If this approach was taken, generic-drug developers could make better quality products more efficiently and leverage advances in manufacturing techniques. Co-processed excipients or excipients used at higher levels, for example, might allow more cost-effective manufacture or improve patient compliance while still ensuring bioequivalence of generic formulations.
In early December 2019, FDA published a Federal Register Notice requesting comments on a proposed pilot program for reviewing the toxicology studies of a limited number of novel excipients via and process independent of the investigational new drug, new drug application, and biologics license application processes (2). Any novel excipient found to be safe under the proposed Novel Excipient Qualification Pilot Program would be listed in the IID with acceptable use levels. In the Federal Register Notice, the agency sought input on seven topics, including what criteria should be evaluated for novel excipients and whether such a program would help overcome the hesitancy of pharmaceutical companies to use them.
By the time the docket closed in early February 2020, 26 respondents had provided overwhelming support for the program (3). There has since, however, been no official public announcements from the agency regarding next steps. “We know FDA is working on the program, but we don’t know what they are going to do or when,” observes Schoneker.
The pharmaceutical industry’s perspective, according to Schmitt, is that in the past 20 years, tremendous advances have been made with respect to both small- and large-molecule drug substances, but formulators are still limited to the same excipients that were available two decades earlier with very few new excipients approved.
“We believe this situation is a direct consequence of the historical approval process for novel excipients and are excited to partner with FDA in this pilot program. We are very encouraged and hope to capitalize on this momentum by seeing the program implemented and novel excipients enter the assessment process in 2021. We also urge readers to encourage their organizations to consider novel excipients when they can make a difference and take advantage of the pilot program if/once it is implemented,” Schmitt states.
The proposed FDA pilot program is the first solid development following many years of effort on the part of excipient suppliers, pharmaceutical companies, IPEC-Americas, the IQ Consortium, and USP to reach out to and educate the agency on this important issue. “For the first time, we are seeing the possibility of a path forward that will encourage excipient innovation and in turn drug product innovation in ways that haven’t been possible before,” Schoneker asserts.
“That is tremendously exciting, and we are eager to work together with FDA to bring the program to fruition,” adds Langley. IPEC-Americas is also willing to provide suggestions for possible candidates for the pilot program that could serve as a means for seeing how the process might work. “We would love to have that kind of discussion with the agency once the decision is made to take the next steps,” Schoneker says. In addition, IPEC also has a team of toxicologists from around the world developing a new safety guide with information FDA might find useful for the proposed assessment process, according to Ulman.
Longer term, there is hope that ultimately some level of global consistency can be achieved regarding the approval of novel excipients. Doing so will be critical to realize the benefits of the US pilot program for patients, according to Schmitt. “The biopharmaceutical industry develops treatments for patients across the globe and a harmonized approach will be required,” he explains. One possible solution would be to have the topic addressed by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use.
1. T. Mitchell, et al., Pharm Tech, 44, (6) 38-43 (June 2020).
2. FDA, “Novel Excipient Review Program Proposal; Request for Information and Comments,” Notice, Federal Register, 84 FR 66669, 66669-66671.
3. FDA, “Comments on FDA Novel Excipient Review Program Proposal,” FDA Docket Number FDA-2019-N-5464-0001, www.regulations.gov, accessed Feb. 12, 2021.
Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology.
Vol. 45, No. 3
When citing this article, please refer to it as C, Challener, "Novel Excipients Needed More Than Ever Before," Pharmaceutical Technology 45 (3) 2021.