Doug Podolsky

Submitted: Aug. 25, 2020. Accepted: Sept. 8, 2020

The US Pharmacopeia and other major pharmacopoeias have established that only the combination of documentary standards and pharmacopeial reference standards (RS) is conclusive and determines compliance to their official quality requirements. Therefore, the use of non-pharmacopeial RS with pharmacopeial methods is inconclusive, and the user takes responsibility at their own risk. Secondary RS are often used for qualitative and quantitative purposes. This article provides an overview of the key risks that can be associated with the use of secondary RS based on the measurement uncertainties that are intrinsically connected to the approach, and information that might help mitigate these risks to some extent. Case study examples are included to illustrate scientific challenges associated when transitioning from pharmacopeial RS to secondary RS. The guard band principle is discussed as an evocative way to visualize risk. 

Christian Zeine, PhD,* christian.zeine@USP.org, is the senior scientific affairs manager, USP Switzerland-Science; Doug Podolsky is the technical writer; Jane Weitzel, B.Sc. (Hons), is a consultant; Ravi Reddy, PhD

 is the senior director, Reference Standards Development; and Steven L. Walfish, MBA, MS, is the principal science and standards liaison for Science-General Chapters; all are at USP except Ms. Weitzel, who is an independent consultant.

* To whom all correspondence should be addressed.


Vol. 45, No. 2
February 2021
Pages: 36-42

When referring to this article, please cite it as C. Zeine, et al., “The Value of Pharmacopeial Reference Standards,” 

Articles

This article provides an overview of the key risks that can be associated with the use of secondary reference standards (RS) and illustrates scientific challenges associated with transitioning from pharmacopeial RS to secondary RS. 

The Value of Pharmacopeial Reference Standards

Excipients play an essential role in delivering the API to patients and can comprise up to 90% of a medication. As such, excipients are critically important to how well a drug functions in the body. They are also key to advancing a formulation through drug development, according to a new US Pharmacopeia (USP) online survey conducted to better understand how drug formulators view the current state of innovation in excipients and the issues they are experiencing related to new or novel excipients.

	FDA has defined a novel excipient as one that has not been used in an FDA-approved drug product and does not have established use in food (1). FDA currently does not review the safety of novel excipients outside the context of an investigational new drug (IND), new drug application (NDA), or biologics license application (BLA) that describes a finished product to which the excipient has been added. Subsequently, drug formulators have encouraged FDA to establish new pathways for the regulatory review of novel excipients. Proponents have said that novel excipients have potential public health benefits such as improved drug delivery or utility in abuse-deterrent opioid formulations (1). Moreover, FDA’s recognition of a novel excipient would reassure drug developers that novel excipients can be used in drug development programs while minimizing the risk that FDA would raise safety concerns during application review.

	Partly in response to stakeholder input, FDA announced that it is considering a pilot review program for the toxicological and quality evaluation of novel excipients intended for use in human drugs (1). In light of FDA’s proposal, the survey results highlighted in this article are especially timely.

	This article highlights USP’s survey results in key areas concerning limitations created by currently used excipients as well as the reasons these limitations have hampered innovation and led to reformulations, discontinuations, and delays of drugs for the US market. A total of 264 respondents who formulated or supervised the formulation of generics, branded medicines, biologics, or biosimilars during the past five years at companies who manufacture/supply these drugs in the United States or abroad shared their views on the current state of excipients innovation. The overall margin of error of the survey results is +/-6% at a 95% level of confidence.

The USP survey indicates that key decisions are made regarding excipient selection across all phases of drug development. However, the current FDA regulatory approval pathway for excipients creates challenges for the use of novel excipients. Currently, use of a novel excipient can potentially risk delays or, even worse, prevent approval for the submitted drug application. Some of the major findings from survey respondents included the following:

		Ninety-one percent of US respondents are familiar with novel excipients compared with 78% of non-US respondents.

		Ninety-six percent said that excipients are at least very important in advancing a formulation through drug development and provided their reasons, ranging from efficacy to bioavailability (

		Eighty-four percent said that currently used excipients have imposed limitations on drug development either because FDA-approved drugs in the selected dosage form did not contain the excipient or the formulators were unable to overcome challenges involving stability, bioavailability, or solubility/permeability.

		Seventy-seven percent experienced challenges using novel excipients in advancing formulation through drug development for the US market. Regulatory issues such as acceptance, approvals, and other requirements were the most common challenges (25%); followed by safety (12%); cost, toxicology data needs, and trust factors (10%).

		Eighty-one percent who formulate medicines and who work for suppliers of branded small-molecule drugs or biologics said that drug development has been limited, at least some of the time, due to excipients currently used in approved drugs. The most common reason for this limitation relates to the currently used excipient not being used in the selected dosage form.

		Forty percent felt compelled to reformulate a drug product for the US market because of excipients limitations. For the majority, the delay was one to five years.

		Thirty-one percent said they were somewhat likely and 24% said they were very likely to use novel excipients in the future, assuming no change in the current US regulatory landscape; however, 29% of respondents do not expect to use novel excipients in the next five years, and of those, 43% were respondents from companies with greater than 500 employees.

		Twenty-eight percent experienced a discontinuation of drug development as a result of excipient limitations that occurred the most during the IND and pre-IND phases.

	In the USP survey, respondents who work in companies with greater than 500 employees were more likely to experience challenges (84%) than those who work in companies with 500 or fewer employees (67%). More than three quarters of respondents (77%) have experienced challenges using novel excipients in advancing formulation through drug development for the US market. Regulatory issues are the most common challenges (

	The majority of respondents (84%) indicated that currently used excipients have imposed limitations on drug development. Key reasons for these limitations were: excipient not used in an FDA-approved drug in the selected dosage form (54%); unable to maintain stability of final drug product (36%); unable to overcome bioavailability issues (33%); and unable to overcome solubility/permeability issues (32%).

	Two in five respondents (40%) said they were compelled to reformulate a drug product for the US market because they were limited to using excipients in FDA-approved drugs. Further analysis regarding reformulations highlighted some significant differences. For example, 58% of respondents who manufacture or supply branded small-molecule or biologics reformulated drug products for the US market because they were limited to excipients in FDA-approved drugs. In comparison, only 39% of respondents who do not manufacture or supply such products reported reformulating because of excipient limitations.

	For respondents who reformulated a drug product due to limitations, 64% cited the length of delay as one to five years. Survey analysis found that 34% of respondents indicated a delay of less than one year, and 2% said the delay was more than five years. Cross tabulation of results for delays by subgroup (e.g., generic suppliers) found no significant differences.

	More than half (57%) cited their inability to formulate a stable delivery of the API as the most common reason for delays, and half (51%) noted their inability to overcome API insolubility or permeability issues.

	Due to limitations in currently used excipients, 28% of respondents reported discontinuing a drug’s development for the US market. Of those, 50% of excipient manufacturers and distributors indicated that they had experienced such discontinuations compared to 22% of pharmaceutical manufacturers.

	The USP survey results indicated that discontinuation occurred most commonly during the pre-IND phase for 40% of respondents, the IND phase for 37%, and the NDA, abbreviated new drug application (ANDA), or BLA process for the remaining 32%. The most commonly selected reasons for the discontinuation of drug development were:

	Inability to formulate a stable delivery of API with the excipients used in approved drugs on the US market (52%).

	Inability to overcome insolubility or permeability of API using excipients in FDA-approved drugs for the US market (52%).

	Inability to formulate an efficacious dosing level of the API with the excipients used in approved drugs on the US market (48%).

	Subgroup analysis regarding these discontinuations highlighted some significant differences. For example, 42% of respondents who manufacture or supply generics or biosimilars were more likely to experience a discontinuation of drug development as a result of excipients limitations compared to 27% of those who do not manufacture or supply generics or biosimilars.

	Advancing formulations through drug development: Expected use of new/novel excipients in the US in the next five years

	Although more than half of respondents (55%) said they expect to use novel excipients in the next five years, assuming no change in the current US regulatory landscape, nearly a third (29%) of the respondents are not likely to use them in the next five years. Importantly, among companies with greater than 500 employees, more than two-fifths (43%) said they are unlikely to use new or novel excipients. This finding supports the exploration of a pathway for review of novel excipients outside of the existing FDA drug application review process.

	Excipients used in drug products approved outside the US

	The survey results also indicated that 44% of respondents used excipients in drug products approved outside the US (i.e., drug products not approved by FDA) for advancing formulations through drug development in the past five years for the US. Moreover, 50% of respondents said they were likely to do so over the next five years. This finding may indicate that the current offerings for excipients permitted for use in US-approved drug products are insufficient to meet the needs of US formulators in drug product development that are critical in facilitating innovation for the advancement of new medical products.

	Excipient manufacturers/distributors vs. pharmaceutical manufacturers

	Cross tabulations of survey results based on organization or company affiliation revealed significant differences between excipient manufacturers/distributors and pharmaceutical manufacturers, including contract manufacturing organizations (CMOs) and contract development and manufacturing organizations (CDMOs). For example, 92% of excipient manufacturers/distributors compared to 82% of pharmaceutical manufacturers said that excipients used in approved drugs in the US limited their ability for drug development for the US market at least some of the time.

	In addition, 50% of excipient manufacturers/distributors compared to 22% of pharmaceutical manufacturers said they have experienced a discontinuation of a drug’s development for the US market because they were limited to using excipients used in FDA approved drugs in the US.

Table II. Selected comments from survey respondents on the use of novel excipients.

					When confronted with the use of a novel excipient, the decision usually is taken to unfortunately avoid its use due to its longer development. It’s an unfortunate decision as novel excipients do provide all round advantages to what exists. We need a regulatory strategy to make the use of new excipients more attractive to the pharmaceutical industry.

					The bar to using a novel excipient is high. It would be helpful if the agencies could more explicitly differentiate between truly new excipients and those which are already used in other products (e.g., foods, consumer products) but are just new to drug product use. I believe the agencies do show some recognition of this distinction in practice, but it would be helpful if they could articulate this as a policy.

					Our experience with the company not willing to take forward the formulation using the two novel excipients is why I respond that it is unlikely that I will use novel excipients under the current regulatory guidelines. If there was a route for regulatory ease or approval for novel excipients that would reduce the risk to our company using novel excipients would reopen the possibility for using novel excipients ... and would probably reopen the project that was killed/reformulated.

					For poorly bioavailable oral small molecules, novel excipients could represent a relatively cost-effective way of performing innovation without having to develop a technology from scratch, as there are really not that many choices of pharmaceutical-grade excipients. More excipients would lead to more drug products and potentially faster approval, which would be in the best interest of patients.

					Regulatory barriers for approval. If the excipient is not already on the FDA inactive ingredients database (IID) or if the intended use is a different route of administration or at a higher level than the IID then the approval challenge has been considered to be too difficult. The second best formulation has been pursued or the project stopped.

	Current regulatory approval pathway for excipients creates challenges

	The USP survey results suggest that the current regulatory approval pathway for excipients creates challenges, particularly for the use of novel excipients, that has hampered innovation and led to reformulations, discontinuations, and delays of medicines for the US market.

	Survey respondents were offered the opportunity to provide additional information and comments regarding their views on novel excipients. The most frequently cited comments were related to regulatory challenges (

). In addition, some survey respondents provided critical comments on the current state of use of novel excipients (

	Based on USP’s survey results, USP is supportive of the FDA Federal Register Notice requesting feedback on their proposal to establish a novel excipient review program as it may provide a pathway for review of excipients outside of the existing drug application review process (2). In comments submitted to FDA in January 2020, USP noted that establishing new pathways for the development and regulatory review of novel excipients is critical in facilitating innovation for the advancement of new medical products (2).

 Notice, FDA noted that it expects any excipients that undergo complete review would be listed in the Inactive Ingredients Database (IID) after they are used in approved formulations (1). USP continues to support the agency’s efforts to provide a clearer understanding of the information and terminology provided in the IID (2,3). To that end, a USP Excipient Nomenclature Joint Subcommittee (JS) is developing an excipient nomenclature guideline. The JS intends to include standardized approaches for naming complex excipients, including mixtures and polymers in the guideline, and to publish the guideline on USP.org. As recommended by FDA’s guidance on use of IID for single ingredient substances (4), USP proposes using the Global Substances Registration System (GSRS) to promote consistency of the official names for novel excipients evaluated by FDA (2).

	USP’s expertise can help address gaps and support innovation

	USP has many existing and developing mechanisms to help support FDA’s pilot novel excipient review program. USP’s expertise can help address gaps and support continuous innovation when a novel excipient becomes part of an application for FDA approval. For example, USP can explore how the Pending Monograph Process (5) could be utilized to facilitate development of potential new excipient monographs that are being reviewed as part of an FDA drug application. The resulting monograph could provide identification, compositional, and purity specifications for the novel excipient that coincides with FDA’s review and approval in the associated FDA drug application.

	Additionally, USP is working on developing a general information chapter and guidelines that focus on quality information including chemistry, identity, and other specifications for excipients that may also support industry and FDA’s proposal for piloting a novel excipient review program. The availability of standardized identity and naming information for a novel excipient could help the industry and FDA in establishing and evaluating quality specifications for novel excipients very early in the drug development process. Furthermore, a revised USP General Chapter <1074> Excipient Biological Safety Evaluation Guidelines in the 

) could potentially help stakeholders by including general information on developing toxicological studies supporting the safety of the novel excipient at anticipated levels and duration of exposure by anticipated routes of administration (6).

	By creating standards for excipients, USP’s Excipients Expert Committees play a key role in helping to ensure the quality of the whole medication (7). USP compendial standards provide validated test procedures to establish the identity, purity, and quality of excipients, and USP Reference Standards are authentic specimens that have been tested and approved as suitable for use as comparison standards in 

United States Pharmacopeia–National Formulary

	The 264 respondents who qualified for and completed the survey had to have formulated medicines or supervised others who formulated medicines in the past five years at companies that manufacture or supply generic drugs, branded medicines, biologics, and biosimilars. The following list highlights their experience:

		Sixty-four percent worked for organizations that manufacture or supply branded small-molecule drugs; 50% worked for generic small-molecule drug makers/suppliers; 48% for branded biologics makers/suppliers; and 27% for biosimilar makers/suppliers.

		Forty-nine percent worked for pharmaceutical manufacturers; 22% worked for excipients manufacturers; 9% for pharmaceutical contract manufacturing organizations or contract development and manufacturing organizations; 6% for pharmaceutical excipient distributors; 5% in academia; and 4% for pharmaceutical contract research organizations.

		Fifty-nine percent said their company had more than 500 employees, and 41% said their firm had 500 or fewer employees.

		Fifty-eight percent worked in the US, 18% in Europe, 13% in India, and the remaining 12%, elsewhere.

		Twenty-nine percent selected formulator as their primary role; 25% selected R&D scientist, followed by 14% as quality assurance/quality control (QA/QC), and 6% as regulatory affairs manager. The remaining 26% of respondents selected from the roles of academic scientist, consultant, CEO, manufacturing manager, pharmacologist, regulatory scientist, medicinal chemist, toxicologist, and other.

		Sixty-five percent selected tablets, injections, and capsules as the dosage forms with most experience. The remaining 35% of respondents selected from among liquids, powders, emulsions, granules, solutions, suspensions, pills, creams, lotions, aerosols, foams, gels, implants, and others.

	The survey results show that the vast majority of respondents who formulate medicines-or supervise others who formulate medicines-reported that drug development had been limited, at least some of the time, due to excipients currently used in FDA-approved drugs. The specific limiting factor noted was that either FDA-approved drugs in the selected dosage form did not contain the excipient or the formulators were unable to overcome challenges involving stability, bioavailability, or solubility/permeability. Reformulation of a drug product was a consequence of excipients limitations, according to two in five respondents. More than one-fourth of respondents experienced a discontinuation of drug development as a result of excipients limitations. More than three-quarters of users have faced challenges in using novel excipients in advancing formulation through drug development for the US market. Regulatory issues represent the most frequently cited challenges, followed distantly by safety concerns. Respondents who work in large companies were more likely to experience challenges using novel excipients. While FDA does not currently review new/novel excipients outside of the drug application review process, it is currently considering a pilot review program for the toxicological and quality evaluation of novel excipients intended for use in human drugs. Based on the survey results, USP is supportive of the recent FDA proposal to explore new pathways for the development and regulatory review of novel excipients.

	1. FDA, “Novel Excipient Review Program Proposal; Request for Information and Comments,” Notice, Federal Register, 84 FR 66669-66671.
	2. USP, “Comment from USP on FDA Notice: Novel Excipient Review Program Proposal; Request for Information and Comments,” (Docket No. FDA-2019-N-5464), submitted January 27, 2020.
	3. USP, “Comment from USP on FDA Draft Guidance for Industry: Using the Inactive Ingredient Database,” (Docket No. FDA-2019-D-2397), submitted Sept. 25, 2019.
	4. FDA, 

Draft Guidance for Industry, Using the Inactive Ingredient Database Guidance for Industry

 (CDER, July 2019).
	5. USP, “Pending Monographs,” 

, accessed April 22, 2020.
	6. USP, USP General Chapter <1074>, “Excipient Biological Safety Evaluation Guidelines,” 

(Rockville, MD, 20852).
	7. USP, “Expert Committees: Excipient Monographs Collaborative Group,” 

	Catherine Sheehan is the senior director, Science–Excipients; John Giannone is the senior director of Strategic Marketing and Program Operations (SMPO), Excipients, Food Ingredients, Dietary Supplements, and Herbal Medicines; Michael Rashed is the marketing director of SMPO–Excipients; Doug Podolsky is the technical writer; and Tanya Mitchell is the Global Market Insights manager, all at USP.


	Vol. 44, No. 6
	June 2020
	Pages: 38–43, 52

	When referring to this article, please cite it as C. Sheehan, J. Giannone, M. Rashed, D. Podolsky, and T. Mitchell, "USP Novel Excipients Survey: Stakeholders’ Views on the Current State of Excipient Innovation" 

Survey results indicate that the current regulatory approval pathway for excipients creates a challenge for the use of novel excipients.