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Viewpoint: Continued dialogue among pharma stakeholders is needed to achieve consensus regarding excipient composition.
This article is the third in a series related to excipient composition authored by members of the International Pharmaceutical Excipients Council of the Americas (IPEC-Americas). The first article, “The Real Complexity of Excipient Composition” described types of excipients, which vary from simple single-chemical entities to co-processed materials to complex natural or synthetic polymer mixtures. The article also discussed excipient composition profiles, which may include concomitant components, additives, processing aids, by-products, degradants, residual starting materials, solvents, catalysts, and reagents in addition to the nominal (labeled) component. It concluded that the current labeling requirements in the United States Pharmacopeia–National Formulary (USP–NF) General Notices are not appropriate for excipients due to the complex nature of excipient composition (1).
The second article, “Additives and Processing Aids in Pharmaceutical Excipients,” revealed that many excipients with a long history of safe use contain additives and/or processing aids required for the excipient to function as intended. The article asserted that drug products manufactured with such excipients should not be considered adulterated/misbranded and made specific recommendations for inclusion of exemptions in the USP–NF General Notices labeling requirements for additives and processing aids. IPEC-Americas believes this provides a means for FDA to ensure the safe use of additives and processing aids while protecting excipient manufacturers’ intellectual property and allowing excipients already demonstrated to be safe to continue to be used (2).
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This article explores challenges of understanding concomitant components as part of the excipient composition profile. As described in the IPEC Excipient Composition Guide, concomitant components are components other than the nominal component that are inherent/integral to excipient composition and are often required for functional performance (3). The USP stimuli article, “The Complexity of Setting Compendial Specifications for Excipient Composition and Impurities,” also describes concomitant components:
“The term ‘concomitant component’ is used in this Stimuli article to encompass all components that are a necessary part of the excipient, and hence should not be considered impurities unless they are shown in some way to compromise the quality of the excipient. Concomitant components of an excipient include substances that either are known to promote excipient function or have an unknown contribution to excipient function and are clearly not deleterious to excipient quality” (4).
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q3A, Q3B, and Q7 guidelines define impurities in drug substances and drug products; however, these definitions, as follows, do not apply to excipients:
An API is “intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body” (8). Any components that are not the API are considered impurities because they reduce its purity, thereby potentially compromising the efficacy of the drug product (1).
Unlike most active ingredients, excipients are not typically small molecules where the goal of manufacture is to have the highest assay or purity (4). Drug substances are typically synthetic chemicals yielding a single, highly purified, chemical entity. Excipients, however, are made using many different types of manufacturing processes, from purification of natural materials to polymer synthesis, which often yield complex mixtures of components. Therefore, API “impurity” concepts cannot be applied to excipients; differentiation of concomitant components from impurities is required.
USP General Chapter <1195> differentiates concomitant components from impurities (bold type indicates authors’ emphasis):
“Excipients may contain minor components that are known to be or might be necessary for the correct functioning of the excipient. The presence of these ‘essential concomitant components’ in the excipient should not be construed as undesirable. These concomitant components are not considered part of the impurity profile but should be considered separately. Water may be a concomitant component in some excipients but may be included in the impurity profile for others” (9).
The USP Stimuli Article also provided definitions for excipient impurities and concomitant components, as follows:
“Concomitant Component: A minor component of an excipient that accompanies the nominal component, which is identified either in the title or definition of a monograph. Concomitant components are characteristic of many excipients and are not considered to be impurities if there is no negative impact on drug products. Some but not all concomitant components are defined or specified in excipient monographs. Added substances and toxic impurities are not considered to be concomitant components.”
“Excipient Impurity: Any substance that detracts from the quality of the excipient (i.e., that is not the substance appearing in the official name, or a concomitant component or added substance)” (4).
IPEC-Americas agrees that concomitant components should not be regarded as excipient impurities and that added substances are not considered concomitant components. However, concomitant components are not always “minor” and may comprise a significant amount of the overall composition. The phrase “identified in the title or definition of a monograph” presumably refers to the nominal component but should be clarified to avoid misinterpretation that concomitant components are identified in the title or definition of a monograph. Most importantly, the impact of concomitant components on drug products cannot be assessed at the raw material level. Only the drug product manufacturer can determine whether a concomitant component has a negative impact on the specific drug product formulation.
Further, the term “quality” is too broad to be useful for distinguishing a concomitant component from an impurity. IPEC-Americas asserts that an impurity is a substance that has inherent toxicity and may pose a potential negative impact on the safety of the excipient or that renders the excipient unfit for pharmaceutical uses. Any substance inherent to the excipient that does not pose a safety or a significant good manufacturing practice (GMP) concern is not considered an impurity.
An excipient’s composition profile is defined by the components present in typical excipient lots produced by a defined manufacturing process. For APIs, high purity is deemed a superior product. But for excipients, high purity is not necessarily better and could even lead to decreased functional performance (2). The excipient composition profile often includes other concomitant components that may be important for the excipient’s performance. These concomitant components could vary from supplier to supplier due to different raw materials and manufacturing processes (3).
There are many well-established excipients for which it is neither feasible nor necessary for quality or safety purposes to identify, classify, and quantify all components. However, where feasible and necessary, a composition profile should include identification, classification, and quantification of each component or, if unidentified, an appropriate qualitative description (e.g., peak retention time).
Polyethylene glycols (PEGs) are polymers of ethylene oxide and water labeled by the polymer’s mean molecular weight. PEG 600, for example, is a complex mixture of tridecamer (mol. wt. 590), and other oligomers (concomitant components). While the “600” nomenclature indicates mean molecular weight, the other higher and lower molecular weight oligomers present may impact performance. Historically, PEG grades were specified by viscosity, but modern chromatographic techniques (1) now show them to contain multiple oligomers. However, because the function of PEG 600 in pharmaceutical formulations is predicated on the presence of these oligomers, the effect of removing all oligomers except the tridecamer is unknown. The presence of these oligomers may provide essential contribution to PEG 600’s drug delivery properties and has not been shown to pose a health or safety risk.
Historically, excipient manufacturers have used non-specific techniques, which did not detect the presence of multiple components. Due to excipient sourcing globalization and the increased need to detect adulteration, advanced analytical techniques have been developed that reveal previously undetected excipient components. These more sophisticated methods (e.g., high-performance liquid chromatography [HPLC]) can detect the presence of multiple components within a given sample. These components have always been present and should not be cause for concern because historical safety studies were conducted using these materials (2).
Characterization of excipient functionality or processability may be performed by the excipient manufacturer for their intended target market and communicated directly to the excipient user (10). However, many times, excipient manufacturers do not know exactly how their excipient is being used by the excipient user. It is the responsibility of excipient users (i.e., drug product manufacturers) to establish that there is sufficient characterization, safety, and toxicological information available to support the specific intended use in their drug product formulation (11).
IPEC-Americas’ position is that excipient manufacturers and users should have open dialogue regarding concomitant components. Excipient manufacturers should understand how their materials are being used because concomitant components may be critical to the excipient’s function in a drug product. Excipient users should be aware of an excipient’s concomitant components because of the potential impact on drug product quality and/or interaction with APIs and other excipients.
For example, a non-crystalizing grade of sorbitol contains concomitant components that prevent the sorbitol from crystalizing in the container closure. Without the concomitant components, the packaging would essentially glue shut. Another example is sucrose, where the concomitant components glucose and fructose have been incorrectly defined as impurities by the USP in the recent Pharmacopeia Forum postings (12). Optimal performance of sucrose in some applications may depend on the glucose and fructose level; changes in amounts of glucose and fructose, or complete removal, could adversely impact compaction. Glucose and fructose levels could vary between suppliers due to differences in refinement and other manufacturing processes.
When necessary, limits for concomitant components should be justified and jointly agreed upon between the excipient manufacturer and excipient user to meet the needs of an individual drug product formulation.
Compositional information is often considered proprietary to the excipient manufacturer. Therefore, it may be necessary to define a mechanism for sharing information between the two parties, such as a confidential disclosure agreement (CDA) or a drug master file (13).
Communicating significant changes for concomitant component is also important. While concomitant components pose no safety risk, changes (or their absence) could impact excipient performance or drug product properties, such as stability and efficacy in a particular drug formulation. Therefore, potential changes in levels of concomitant components are an important consideration when assessing significance of change (14).
As previously discussed, concomitant components are frequently required for an excipient’s functional performance in a drug product application, and can vary in type and amount due to differences in manufacturing processes and materials used.
Excipients from alternate sources may not have the exact same composition and therefore may not demonstrate equivalent performance in all drug product applications. Excipient users should apply their understanding of the role of concomitant components (as identified and characterized by the excipient manufacturer or the excipient user) in defining functional performance requirements for alternate sources of an excipient.
USP General Chapter <1059> Excipient Performance states:
“[drug product] manufacturers should anticipate lot-to-lot and supplier-to-supplier variability in excipient properties. […] The effects of excipient properties on the critical quality attributes (CQAs) of a drug product are unique for each formulation and process and may depend on properties of excipients that are not evaluated in USP or NF monographs” (15).
These critical properties may be physical or chemical attributes, including concomitant components. When evaluating alternate sources of excipients, excipient users should not assume that all sources meeting the same compendial requirements are interchangeable in all drug product formulations.
Differences in types and amounts of an excipient’s concomitant components could result in differences in functional performance between excipient sources. Alternate excipient sources must be evaluated in the drug product formulation and process where intended to be used. Confirmation of equivalent functional performance is necessary to confirm interchangeability. For excipients with complex composition profiles, it is critical to evaluate drug product batches prior to full implementation of an alternate source. The critical quality attributes (CQAs), including stability, of the drug product manufactured with the alternate source must meet the established requirements.
Distributors should not substitute an alternate excipient source without prior notification to the excipient user to allow evaluation of the interchangeability of the alternate source in their specific drug applications. Consider the example of petrolatum used as the ointment base in a topical drug product. Per the USP monograph, Petrolatum USP is a “purified mixture of semisolid hydrocarbons obtained from petroleum” (16) having a melting point of 38–60 °C. The range in melting point results from variations in the hydrocarbon mixture from different petrolatum sources. The manufacturing process developed for a drug product formulated with petrolatum having a melting point near 38 °C would likely not adequately distribute API in petrolatum having a melting point near 60 °C due to differences in handling properties.
The potential impact of changes in concomitant components—and hence to excipient functional performance—should be considered when changes are made to the excipient manufacturing process or materials used. Because only the excipient user can confirm whether a change impacts the functional performance of the excipient in the drug product, the excipient manufacturer should notify the excipient user of any change with potential to significantly impact the excipient composition.
The current global excipient supply chain is vast and complex. When developing compendial requirements, it is important to consider that monograph requirements must be applicable to all pharmaceutical suppliers and grades. Because pharmaceutical excipient composition can vary greatly between suppliers and grades, compendial limits for concomitant components are challenging to develop and difficult for excipient manufacturers to implement. Setting acceptance criteria for concomitant components should be avoided. When included, composition-related quantitative or qualitative methods and specifications should be justified.
In response to the USP stimuli article (4), comments submitted by industry and the subsequent responses from the USP Expert Committee were published (17). Industry stakeholders and USP agreed on the complexity of distinguishing between impurities and “minor components.” Industry stakeholders commented that, due to their global use, excipient monographs should establish minimum quality standards that are applicable to all pharmaceutical grades currently being safely used in approved drug products. However, the USP response implies that new excipient monograph requirements are based on emerging detection methods:
“The USP has an obligation to investigate all components found to be present when a new analytical method is being implemented. Additionally, USP must provide clear information to allow for a quality control (QC) analyst to conduct the testing, and that would include determination of the identity of components that are readily detected using modern analytical techniques” (17).
IPEC-Americas understands that advancements in analytical technology have made it possible to develop increasingly sensitive and specific methods for studying the composition of pharmaceutical materials. Knowledge of the compositional profile is important for appropriate selection of excipients during drug product formulation development and evaluation of significant changes, including alternate sources. However, control of all components via compendial limits is not necessary to demonstrate quality of each excipient batch manufactured and distributed. In addition, developing compendial limits based on advanced technologies may impede their implementation in countries where the advanced technologies are not available.
The impact of concomitant components on drug product performance differs from product to product; the criticality of concomitant components is not universal to all applications. USP General Chapter <1059> provides an introduction for how concomitant components impact CQAs:
“… the effects of excipient properties on the quality and performance of a drug product may be unique for each formulation and process, and could depend on properties of excipients that are not evaluated in USP or NF monographs, and which may vary from supplier to supplier and batch to batch [….] The impact of excipient properties and their variability depends on the role of an excipient in a formulation and the critical quality attributes (CQAs) of the drug product”(15).
As described in ICH Q8 (18), it is the responsibility of the excipient user to determine the criticality of the excipient composition to the quality of the drug product. IPEC-Americas supports the development of an informational USP General Chapter (i.e., >1000) to provide guidance to excipient manufacturers and users for characterization of excipient composition. Attempts to develop acceptance criteria in monographs for every concomitant component create the potential for divergence from other global pharmacopeias and the inclusion of unnecessary tests and limits. Further, the USP guideline for submission of new and revised excipient monographs should be revised to clarify that limits for concomitant components are not recommended for inclusion in excipient monographs unless there is a specific quality concern that applies universally to all applications.
Concomitant components are often required for functional performance. Concomitant components are not considered part of, and must be considered separately from, the impurity profile.
Excipient composition can vary greatly between grades and suppliers. Monograph requirements must be applicable to all global pharmaceutical suppliers and grades. Limits in NF monographs for all concomitant components are not appropriate. An excipient user may establish their own limits for concomitant components, when necessary, to ensure functional performance and drug product quality for a specific drug product.
IPEC-Americas supports the development of an informational USP General Chapter (i.e., >1000) for characterization of excipient composition. Further, the USP guideline for submission of new and revised excipient monographs should be revised to clarify that limits for concomitant components are not recommended for inclusion in excipient monographs unless there is a specific quality concern that applies universally to all applications.
1. B. Carlin, et al, PharmTech 41 (10) 54-63 (October 2017).
2. G. Collins, et al., Pharmaceutical Technology APIs, Excipients, and Manufacturing Supplement, s16–s19 (October 2019).
3. IPEC, The International Pharmaceutical Excipient Council Composition Guide for Pharmaceutical Excipients (2020).
4. USP, USP Pharmaceutical Forum 44 (3) (May 1, 2018).
5. ICH, Q3A(R2) Impurities In New Drug Substances (Oct. 25, 2006).
6. ICH, Q3B(R2) Impurities in New Drug Products (June 2, 2006).
7. ICH, Q7 Good Manufacturing Practice Guideline for Active Pharmaceutical Ingredients (Nov. 10, 2000).
8. I. Silverstein, “Excipient Quality and Selection,” PharmTech.com (Feb 2, 2016).
9. USP, USP General Information Chapter <1195>, Significant Change Guide for Bulk Pharmaceutical Excipients, USP 43-NF 38 (Rockville, MD, June 1, 2020).
10. B. Carlin, et al., Pharm Tech 31 (9) (September 2007)
11. IPEC, The International Pharmaceutical Excipient Council Qualification of Excipients for Use in Pharmaceuticals (2009).
12. USP, Proposed Sucrose, Pharmacopeia Forum NF monograph 46 (4).
13. IPEC, The International Pharmaceutical Excipient Council of the Americas U.S. Drug Master File Guide for Pharmaceutical Excipients (2019).
14. IPEC, The IPEC Significant Change Guide for Pharmaceutical Excipients (2014).
15. USP, USP General Information Chapter <1059>, Excipient Performance, USP 37–NF 32, (Rockville, MD, 2014).
16. USP, Petrolatum Monograph, USP 43–NF 38 2S, (Rockville, MD, 2020).
17. C. Moreton et al., “USP Responses to Comments on Stimuli Article: ‘The Complexity of Setting Compendial Specifications for Excipient Composition and Impurities,’” Pharmacopeia Forum, 46(5) (Sept. 1–Nov. 30, 2020).
18. ICH, Q8(R2) Pharmaceutical Development(August 2009).
Jennifer Putnam is AR&D supervisor II, Perrigo; Katherine L. Ullman is president, KLU Consulting, LLC; Priscilla Zawislak is global regulatory affairs advocacy manager, DuPont Nutrition & Biosciences; David Schoneker is president, Black Diamond Regulatory Consulting, LLC; George Collins Jr. is vice-president, Vanderbilt Chemicals LLC; Douglas G. Muse is a consultant–QA, Eli Lilly and Company; Brian Carlin is director QbD/Regulatory, DFE Pharma US; Joseph Zeleznik is technical product manager, IMCD US; and Chris Moreton is partner, FinnBritt Consulting.
Vol. 45, No. 2
When referring to this article, please cite it as J. Putnam et. al., “Understanding Concomitant Components in Pharmaceutical Excipients,” Pharmaceutical Technology 45 (2) 2021.