George Collins is vice president, Vanderbilt Chemicals LLC. 

George Collins

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

) General Notices are not appropriate for excipients due to the complex nature of excipient composition (1).

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 

 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).

This article explores challenges of understanding concomitant components as part of the excipient composition profile. As described in the 

, 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).

Excipient concomitant components vs. impurities

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:

ICH Q3A—“Any component of the new drug substance that is not the chemical entity defined as the new drug substance” (5)

ICH Q3B—“Any component of the new drug product that is not the drug substance or an excipient in the drug product” (6)

ICH Q7—“Any component of the intermediate or API that is not the desired entity” (7).

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.

 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).

 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.

Characterization of concomitant component in excipients

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 

 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).

Concomitant components and alternate sources of excipients

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.

 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 

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 

 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.

Compendial requirements for concomitant components

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. 

 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).

 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 

 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 

 General Chapter (i.e., >1000) for characterization of excipient composition. Further, the 

 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.

 54-63 (October 2017).
2. G. Collins, et al., 

Pharmaceutical Technology APIs, Excipients, and Manufacturing Supplement

The International Pharmaceutical Excipient Council Composition Guide for Pharmaceutical Excipients

Good Manufacturing Practice Guideline for Active Pharmaceutical Ingredients

Significant Change Guide for Bulk Pharmaceutical Excipients

 38 (Rockville, MD, June 1, 2020).
10. B. Carlin, et al., 

The International Pharmaceutical Excipient Council Qualification of Excipients for Use in Pharmaceuticals

The International Pharmaceutical Excipient Council of the Americas U.S. Drug Master File Guide for Pharmaceutical Excipients

The IPEC Significant Change Guide for Pharmaceutical Excipients

 32, (Rockville, MD, 2014).
16. USP, Petrolatum Monograph, 

 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,’” 

, 46(5) (Sept. 1–Nov. 30, 2020).
18. ICH, 

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.

Articles

Viewpoint: Continued dialogue among pharma stakeholders is needed to achieve consensus regarding excipient composition.


Understanding Concomitant Components in Pharmaceutical Excipients

Advances in analytical methodology and increased sensitivity have facilitated detection by pharmaceutical manufacturers of low levels of previously undetected components in well-established, widely used excipients. Unfortunately, this increased awareness has led to potential concerns that excipients and pharmaceutical products containing these excipients with previously undeclared additives, processing aids, and/or concomitant components could now be considered adulterated and/or misbranded. 

This is, in part, due to these new identified components being considered erroneously by some as impurities in excipients. In addition, compendial excipients having 

) monographs could face further issues because 

 General Notices 5.20 (1) specifically prohibits the presence of such non-disclosed components.

A version of this article was published in 

Pharmaceutical Technology Europe’s APIs, Excipients, and Manufacturing 

Many additives, processing aids, and concomitant components have always been present and have had a long precedence of acceptable use in excipients. In addition, excipients containing these additives and processing aids have been safely used in pharmaceutical products for many years (sometimes decades) without incident. However, the identity of these additives and processing aids, as well as their presence, was often not disclosed in excipient composition profiles. In certain cases, excipient manufacturers have not been willing to disclose the identity of such components due to the proprietary nature of their use. As a result, there are a large number of excipients in approved medicines that contain undeclared additives, processing aids, and/or concomitant components.

There is typically a justifiable technical need for additive and processing aid inclusion in excipients. Additives and processing aids should not be reduced or eliminated, or considered as impurities, nor should excipients containing additives or processing aids be avoided without understanding the impact to pharmaceutical product safety or efficacy.

This article expands on a previous publication (2) and a US Pharmacopeial Convention (USP) stimuli article (3) and addresses:

History and use of additives and processing aids in excipients

Current regulatory position including acceptance of concomitant components as part of excipient composition

Recommendations to ensure pharmaceutical products are not being deemed adulterated and/or misbranded.

This article focuses on the use of additives and processing aids in excipients with established safety profiles and precedence of use and the concerns with compliance to US Food and Drug Administration (FDA) labelling and USP General Notices requirements. The presence of additives, processing aids, and concomitant components has not been well understood by regulators and pharmaceutical manufacturers. A follow up article will address concomitant components which, based on USP’s stimuli article (3), are now recognized as a natural part of excipient composition and not as impurities.  

 provides the International Pharmaceutical Excipients Council (IPEC) definitions of common terms (4).

	Most excipients are not pure substances, but rather, multi-component ingredients that likely would not perform the same if any of the components were removed. Inherent residual and trace components present in excipients are important and can impact key excipient functional characteristics when used in pharmaceutical formulations. These components in excipients are not considered impurities by excipient manufacturers and could vary from supplier to supplier due to different raw materials and manufacturing processes. Although for APIs high purity is deemed a superior product, for excipients high purity is not necessarily better and may lead to decreased functional performance.

	Examples of excipient components can be found in 

Additives and processing aids in excipients

Additives are important components commonly used at low concentrations in excipients. Additives provide certain functions such as enhancing stability, modifying pH, preventing microbial growth, etc. For many excipients currently containing additives, the absence of additives could adversely impact excipient performance and/or stability.

Processing aids are used by excipient manufacturers to support excipient manufacturing processes. Examples of processing aid functions might include reducing excipient adherence to manufacturing equipment, increasing powder flow through piping and hoppers/bins, and decreasing viscosity to facilitate pumping.

The benefits from process aid inclusion in excipient composition realized by excipient manufacturers might also be advantageous to pharmaceutical manufacturers.  Often, the relationship between excipient composition, physical form, and performance is not fully understood. Removal of undeclared additives and/or residual processing aids could have unintended negative consequences, and the impact of the removal would have to be evaluated in all pharmaceutical products containing excipients with additives and/or processing aids. For example, switching from butylated hydroxytoluene (BHT) stabilized polyethylene glycol (PEG) to an additive-free PEG could compromise pharmaceutical product stability if the pharmaceutical product is unknowingly stabilized by the undeclared antioxidant contained in the excipient. Fully understanding excipient composition profiles, including potential undeclared additives or residual processing aids, via early dialog with excipient manufacturer, would avoid such problems. Additionally, having this information could help to avoid similar future problems should a new excipient and/or supplier be qualified where the substituted excipient comprises different additive or processing aid types or levels or is free of additives or processing aids altogether.

Many pharmaceutical excipients are also manufactured for non-pharmaceutical applications. These applications do not always require identification of additives and/or processing aids. Due to the multitude of industries that excipient manufacturers support, historically, they may not have understood how important it is for pharmaceutical manufacturers to know if additives and processing aids exist in their ingredients. In addition, intellectual property confidentiality concerns may be a factor in non-disclosure of these components.  As a result, unlike APIs, which are typically single entities, excipients are often complex substances that may contain components not appearing on labelling or in monographs. Differences in additives and/or processing aids due to raw material sourcing or manufacturing processes can result in different excipient composition profiles for seemingly identical excipients that meet the same pharmacopeial specifications. For pharmaceutical products, excipient substitutions from one supplier to another supplier could have an adverse impact on product performance and could pose potential risks by compromising safety, stability, or efficacy.

Additives and processing aids can serve a variety of functions. These include, but are not limited to:	

Anti-adherent agents. Additives such as silica or talc may be used as anti-caking agents.

Antioxidants. Antioxidants are agents that prevent the oxidation process, thus avoiding its deterioration.

Potential antioxidants found in excipients might include ascorbic acid, butylated hydroxyanisole (BHA), and BHT.

Buffering agents. Designed to control the pH drift. Examples of buffering agents might include sodium bicarbonate and calcium biphosphate.

Diluents/fillers. Some excipients may contain diluents or fillers such as calcium carbonate and lactose.

Emulsifying agents. Emulsifying agents might be added to an excipient (e.g., simethicone emulsion) to enhance the emulsion stability, thus avoiding separation between two phases. Examples include sodium lauryl sulfate and polysorbate 60	

Glidants. Glidants may be added to powders or granules to enhance their flowability. Examples of glidants might include silica and/or silica derivatives.

Preservatives. Preservatives may be added to excipients in order to prolong their shelf life by protecting them from micro-organism deterioration. Examples of preservatives might include benzoic acid and butylparaben.

Based on excipient good manufacturing practices (GMPs) (5), IPEC-Americas believes that additive and processing aid use should be controlled. The USP stimuli article (3) supports IPEC-Americas’ position, as stated in their conclusion: “A distinction must be made between excipient impurities that detract from the quality of the excipient (including safety), and those components which can be present, have always been present, and which may need to be present to achieve the necessary performance in the application.”

Therefore, it should be clearly understood that additives and processing aids are not impurities.

The pharmaceutical industry is currently facing a dilemma where FDA and USP expect more detailed composition information in monographs and labelling.

Due to excipient sourcing globalization and increased need to detect and prevent supply of adulterated ingredients, many new and modernized test methods are now finding previously undetected components in excipients. Historically, excipient manufacturers have used common techniques that measure single-variable characteristics, like solution pH, to confirm desired endpoints. These techniques do not detect the presence of multiple components of a product. With the concern for adulterated ingredients, more sophisticated methods, such as high-performance liquid chromatography (HPLC), are employed and can detect the presence of multiple components within a given sample. Although they are now being detected, these components have always been present but undetectable by older, less sophisticated methods.

Further, preclinical toxicology studies conducted on excipients containing additives and processing aids have not exposed any health or safety issues or any other adverse impact due to the presence of these excipient components.

FDA expects pharmaceutical manufacturers to have a thorough understanding of composition and impurities in pharmaceutical products. As a result, because these components had not been disclosed in the past, and because pharmaceutical manufacturers are analyzing for and finding these components due to advances in analytical techniques, it is not well understood if these components have been added intentionally or in the case of concomitant components, are inherent to excipient composition and are not impurities.

 IPEC-Americas is concerned that discovery of additives or processing aids present in excipients could result in undue alarm and potentially trigger consequences that could negatively impact availability of pharmaceutical products when there is no safety concern. As a result, IPEC-Americas completed a survey to identify additives and/or processing aids that are integral to excipient composition. The survey identified a list of more than 70 additives currently undeclared in commonly used excipients with all but five of the additives currently listed as excipients in the FDA Inactive Ingredient Database (IID). Examples include, but are not limited to, silica, BHT, and propyl gallate.

Based on the survey results, IPEC-Americas developed a backgrounder document (6) that includes a list of additives and processing aids used in excipients, submitted a formal request to FDA in July 2017 (7) for a meeting to develop a strategy for handling undeclared additives and processing aids in excipients, and continues to look forward to dialoging with them.

 The excipient manufacturers have concerns about 

 General Notices 5.60, which states, “the presence of an unlabelled other impurity in an official substance is a variance from the standard if the content is 0.1% or greater” (8). This is further complicated by 

 General Notices 5.20 requirements that state, “Official substances may contain only the specific added substances that are permitted by the individual monograph. Such added substances shall not exceed the quantity required for providing their intended effect. Where such addition is permitted, the label shall indicate the name(s) and amount(s) of any added substance(s)” (1).

 General Notices 5.60 and 5.20, presence of undeclared additives or processing aids, at or above 0.1%, is not allowed. This is a major concern to excipient manufacturers because undeclared additives or processing aids are present in many 

-grade excipients currently used in pharmaceutical products and typically this has been the case for many years.

Ensuring drugs are not being deemed adulterated and/or misbranded

The pharmaceutical industry is currently facing a dilemma where FDA and USP expect more detailed composition information in monographs and labelling. In addition, pharmaceutical manufacturers need a better understanding of excipient composition. However, excipient manufacturers may need to keep certain additive and processing aid information confidential for intellectual property or trade secret reasons. Resolving this issue will require collaboration by all impacted stakeholders.

Historically, there has not been a consistent approach to disclosure of additives and processing aids in excipients, even though they have been used for many years without adversely impacting product safety. Given the large number of excipients currently in approved medicines containing undeclared additives or processing aids, and the much greater number of pharmaceutical products potentially affected, there is an urgent need for the pharmaceutical and excipient industries, FDA, and USP to collaborate in developing a strategy for addressing additives and processing aids in excipients. This approach should allow excipient suppliers to share confidential information with FDA without direct disclosure of the identity and level of additives and/or processing aids to pharmaceutical manufacturers.

Specific recommendations from IPEC–Americas include:

1. To avoid restricting current, safe excipient use, FDA should review and acknowledge additives and processing aids not listed in the IID, but which have historically been present in and demonstrated to be safely used in excipients.

2. FDA should exercise enforcement discretion to allow additives and processing aids, listed in the IID and present in excipients, as well as individually in pharmaceutical product formulations to exceed IID maximum potency limits in final pharmaceutical products, if it can be shown that there is a precedence of use in excipients having been used in the route of administration being reviewed.

3. FDA, USP, and industry stakeholders should collaborate to develop a strategy that addresses how intellectual property and labelling issues related to additives and processing aids might be handled. One such approach could include a bridging justification, reference to use in food, or generally recognized as safe (GRAS) position to justify the safety.

	4. USP should include identified excipient additives and processing aids in the exclusion list for compliance with USP General Notices 5.60.10 impurity labelling requirements. Current list of exclusions includes:

Fermentation products and semi-synthetics derived therefrom

Crude products of animal or plant origin.

	5. USP should create a new General Notice section 5.20.15 that exempts excipients from declaring specific additive and processing aid types and levels on labelling unless the excipient manufacturer desires to do so. This information, when considered confidential by the excipient manufacturer, can be shared with FDA using a Type IV drug master file (DMF) and referenced in drug applications using a letter of authorization. The excipient manufacturer, however, would need to identify that an additive or processing aid was present.

Many excipients contain additives and/or processing aids to enhance performance or facilitate manufacture. While additives can be used for such purposes as pH buffering, controlling microbial contamination, preservation, etc., processing aids are used to improve manufacturing processing and efficiency. Many additives and processing aids contained in excipients may not be found on labelling or in monographs, and additive and processing aid concentrations and types may differ among excipient manufacturers. Generally, additives and processing aids are themselves excipients or food additives and have been used safely in pharmaceutical products for years and sometimes decades. As a result, their presence in pharmaceutical products poses no risk to patient safety. However, while additive and processing aid use pose no safety risk, absence of these components could compromise pharmaceutical product stability and efficacy.

 General Notices 5.20 and 5.60, in their current language, require additives and processing aids to be on labels and reported when used at levels >0.1% (based on International Council for Harmonization Q3B). Such a requirement(s) may present challenges for excipient manufacturers due to confidentiality concerns and for pharmaceutical manufacturers who may not understand the complete excipient composition profile. IPEC-Americas recommends changes to 

 General Notices 5.20 and 5.60 regarding labelling requirements for additives and processing aids.

IPEC-Americas takes the position that excipient and pharmaceutical manufacturers should have open communication regarding the potential for the presence of additives and processing aids (9–11). This can include use of confidentiality disclosure agreements during excipient/supplier qualification. Details for accessing information regarding additive and processing aid use also may be via DMF, when appropriate. However, in other regions (e.g., Europe) where excipient DMFs are not applicable, the need for further discussion with regulators may be required.

Lastly, stakeholders, USP, and FDA, need to collaborate and develop a path forward that would affect the following:

Ensure that identification of low levels of additives and processing aids in established excipients does not lead to pharmaceutical products being deemed adulterated and/or misbranded.

Ensure that excipients containing additives and/or processing aids comply with revised USP requirements (as proposed).

Create a means to share the above information in a manner that does not compromise excipient manufacturer’s intellectual property.

 [Official May 1, 2017], p. 5.20.10 (USP, Rockville, MD, 2015).
2. Carlin et. al, 

 41 (10) 54-63 (October 2017).
3. USP, “The Complexity of Setting Compendial Specifications for Excipient Composition and Impurities,” USP 

 44 (3) 1 May 2018
4. IPEC, “General Glossary of Terms and Acronyms,” (Arlington, VA, 2014).
5. NSF/IPEC/ANSI 363–2016 Good Manufacturing Practices (GMP) for Pharmaceutical Excipients.
6. IPEC-Americas backgrounder document for “Additives in Pharmaceutical Excipients.”
7. IPEC-Americas letter to Dr. Lawrence Yu, Deputy Director OPQ, FDA, July 25, 2017.
8. USP, 

 [Official 1 May 2017], p. 5.60.10 (USP, Rockville, MD, 2015.
9. IPEC, 

 (2009).
10. J. Zeleznik and G. Collins, “Additives & Concomitant Components vs Impurities in Pharmaceutical Excipients,” IPEC-Americas Webinar, March 2018.
11. B. Carlin and R.C. Moreton, “ The Importance of Excipient Composition and Complexity,” IPEC-Americas Webinar, November 2018.


Supplement: APIs, Excipients, and Manufacturing
October 2019
Pages: s16–s19

When referring to this article, please cite it as G. Collins et al., “Additives and Processing Aids in Pharmaceutical Excipients," 

Pharmaceutical Technology APIs, Excipients, and Manufacturing

This article seeks to encourage continued dialogue among stakeholders to achieve consensus regarding excipient additives and processing aids.

) General Notices combined, it could be interpreted that API requirements apply to excipients. In 

 General Notices, an API equals the labeled entity plus impurities. Applying this logic to excipients, anything NOT the labeled entity would be an “impurity.” Most excipients are more complex and less well defined than APIs. The excipient name may not reflect its complete composition. The named entity may be a minor component. The other components may be essential for functionality. This article seeks to promote dialogue among stakeholders to facilitate consensus regarding this topic. 

Due to excipient diversity, including highly complex mixtures from animal, botanical, mineral, and/or synthetic sources, differing approaches to characterizing excipient properties may be required. More complex excipients, including excipients produced by biotechnological methods, may require extensive physico-chemical characterization to fully understand their composition.

Excipients are a diverse group of materials, which are used for a vast range of available drug products. Excipients intended for use by different routes of administration may require different understanding of the composition profile. Excipient manufacturers should seek to establish how their ingredients will be used. However, in commerce, this information is not always available from or shared by the user.

IPEC-Americas and IPEC Europe have published an 

, which describes the complex nature of excipients (1).  There are many excipient types, which have different compositional profiles. These include standard excipients, sometimes referred to as conventional or traditional excipients, mixed excipients, and co-processed excipients.

The excipient composition profile may be defined as a description of the components present in a typical excipient lot produced by a given manufacturing process. The main components of an excipient are those, which in most cases; contribute to the excipient being able to perform its intended function within the drug product(s) in which it is used (also known as “nominal” components). Other necessary components also may be present (i.e., concomitant components, additives, and processing aids). Unreacted starting materials, by-products, degradants, and residual solvents also may be present as a direct result of the excipient’s manufacturing process. These components may arise at different stages in excipient processing (

) and are considered part of the excipient composition profile. 

Finally, contaminants may be present (i.e., substances not directly resulting from the excipient manufacturing process [synthesis and/or purification], but as a consequence of extraneous factors such as personnel, equipment, packaging, other products, etc.). Contaminants would not be regarded as part of the composition profile; however, they should be controlled through good manufacturing practices (GMPs). 

As excipients are used typically without further purification, excipient manufacturers should identify and set appropriate limits for components as appropriate. These limits should be based on appropriate safety data, limits described in official compendia, or other requirements and sound GMP considerations. Manufacturing processes should be adequately controlled to ensure that undesirable components do not exceed established limits. 

For many excipients, classifying and quantifying all components may not be possible. Composition-related methods and specifications should be justified. There are many traditional, well-established (qualified by use) excipients for which it is neither feasible, nor necessary, for safety purposes to identify all components. Evaluating (re-evaluating) their safety, unless scientific evidence becomes available that suggests otherwise, is generally unnecessary. Where feasible, generating composition profiles should involve each component’s identification, classification, and quantification (expressed as a range). If unidentified, an appropriate qualitative description such as a chromatographic peak retention time should be made available. A reasonable reporting threshold is available from the International Council for Harmonization (ICH) Q3A (R2) guideline (2).

In addition to the “nominal” component, excipient components may comprise the following:

Unreacted starting materials such as monomers in polymerization

Reaction by-products (e.g., isomers and side reactions)

Raw material components (especially for naturally sourced materials).

Establishing an excipient composition profile 

Where possible, excipient manufacturers should establish composition profiles where the main excipient components are identified and their normal concentration variability determined. Acceptable limits, where required, should be based on a risk assessment using sound science. It is typically not necessary to have limits for all components in the composition profile, but the profile should be understood. Limits should only be established when justified by risk assessment to address safety and/or customer-specific concerns. 

An excipient composition profile evaluation should be performed by the excipient manufacturer using their manufacturing process knowledge and understanding, which may lead to identifying associated potentially undesirable components. Excipient components (i.e., main/concomitant components, additives, processing aids, and undesirable components) should be identified and quantified using suitable analytical techniques, wherever possible. Appropriate analytical methods may be compendial or suitably qualified manufacturer-specific methods. The materials used for composition profile development should be representative of the excipient, and sampled in a manner consistent with that used for lot release by the quality control unit (i.e., same sampling technique and sampling point(s) in the manufacturing process). 

The United States Pharmacopeial Convention (USP) merged the General Notices for both the 


) in early 2000. In effect, this means that the same General Notices restrictions apply to both APIs and excipients. It could, therefore, be argued that API requirements also apply to excipients. In the General Notices, an API equals the labeled entity plus impurities. If the same logic is applied to excipients, anything other than the labeled entity could be considered an “impurity.”
	
The current 

“impurity” or “concomitant component” definitions only apply to drug substances and drug products but not excipients. Similarly, ICH addresses impurities in new drug substances and drug products as follows: 

Any component of the new drug substance that is not the chemical entity defined as the new drug substance (2)

Any component of the new drug product that is not the drug substance or an excipient in the drug product (3)

Any component present in the intermediate or API that is not the desired entity (4). 

	These definitions do not specifically apply to excipients and cause confusion when inappropriately applied to them. Excipient-specific definitions are therefore required and should be included in future issues of the 

The situation regarding excipients is put forth in an excerpt from the International Pharmaceutical Excipients Council (IPEC) Composition Guide:
	“For excipients, the situation is more complex as they are frequently multicomponent, and their composition may be less well defined. Their functionality may be dependent on the presence of components other than the labeled entity. The definition of the term ‘impurity’ as used above for drug product and/or drug substance is thus misleading when applied to excipients. To distinguish these components from true impurities, the appropriate term for describing excipients should be ‘minor component’ or ‘concomitant component’ (e.g., the water of crystallization in magnesium stearate required for optimum lubricant effectiveness)” (1). 

Advances in analytical technologies can give excipient manufacturers, users, and regulators more quantitative excipient composition detail, but not necessarily increased understanding of excipient functionality. Increased analytical capabilities are to be encouraged, but, taken out of context, can cause confusion and inappropriate or counterproductive actions by users and regulators.

Significant differences between APIs and excipients

FDA defines an “Active Ingredient” (here used interchangeably with the term API) as “any component that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or animals” (5). FDA does not have an official definition for “excipient,” but rather uses the term “Inactive Ingredient,” which they define as “any component of a drug product other than the active ingredient” (6).

 General Chapter <1078> Good Manufacturing Practices For Bulk Pharmaceutical Excipients defines an excipient as “Any substance, other than the active pharmaceutical ingredient or drug product, that has been appropriately evaluated for safety and is included in a drug delivery system to aid the processing of the drug delivery system during manufacture; to protect, support, or enhance stability, bioavailability, or patient acceptability; to assist in product identification; or to enhance any other attribute of the overall safety and effectiveness of the drug delivery system during storage or use” (7). 

Some of the general differences between APIs and excipients are summarized (

). Exceptions exist (e.g., in the case of small-molecule synthetic API-like excipients and naturally derived APIs such as digitalis and fish oil). 

In the case of APIs, the labeled entity is generally well-defined and quantified by assay to ensure purity. Other components are considered impurities, that is, the balance of 100% minus the assay. For excipients, the labeled entity can be nominal, and there is not always a specific assay (e.g., microcrystalline cellulose). The labeled entity itself may not even be the predominant component. For example, stearic acid 50 NF can contain as little as 40 wt. % stearic (octadecanoic) acid and as much as 50 wt. % palmitic (hexadecanoic) acid.  The latter major component is a concomitant component, not an impurity. There may also be up to 10 wt. % other components. The labeled entity may also be nominal for polymeric excipients, usually reflecting an average molecular weight.

, “The presence of any unlabeled other impurity in an official substance is a variance from the standard if the content is 0.1% or greater. The sum of all other impurities combined with the monograph-detected impurities may not exceed 2.0% unless otherwise stated in the monograph” (8). 

This statement is not appropriate for excipients. If a distinction is not made between concomitant components, additives, residual processing aids, and impurities, there is likely to be confusion regarding excipient applicability of specific impurity identification and quantification requirements typical for APIs. This could encourage attempts to set inappropriate specifications by users and result in excipient shortages, if the specifications are outside the process capability of excipient manufacturers.  

The authors propose that the following excipient-specific definitions be adopted by 

Concomitant component-A substance found in an excipient that is not the intended chemical entity, may be necessary for assuring the proper performance of the excipient in its intended use, and is not an impurity or a foreign substance. (Formerly referred to as minor component) (9) 

Additives-A substance added to the excipient to improve or maintain a characteristic such as a preservative, flow agent, antimicrobial, etc. (9)

Processing aids-A material added to a manufacturing step for the purpose of facilitating the completion of that step or subsequent step (9) 

Impurity-An undesirable material found in an excipient as a consequence of the raw materials, excipient manufacturing process, or excipient degradation (9).

Excipient composition example-Polyethylene Glycol 600

Excipients can be complex mixtures of substances, some or all of which may affect functionality.

Polyethylene glycol 600 NF (PEG 600), which is a complex mixture of the tridecamer (mol. wt. 590), other oligomers (concomitant components), and impurities, is a good example. It is by no means the only example. Other examples include polymeric excipients, some excipients derived from natural fats and oils, and mineral ores. 

Polyethylene glycols are polymers of ethylene oxide and water. In the NF, the number after polyethylene glycol or PEG indicates the mean molecular weight of the polymer. PEG 600, which has been safely used as an excipient for many years, is used (among other applications) in hard and soft gelatin capsule formulations to enhance active substance solubility (10). 

While the “600” nomenclature indicates mean molecular weight, other higher and lower molecular weight oligomers present impact performance. In addition, the specified impurities ethylene glycol and diethylene glycol must not jointly exceed 0.25 wt. %. A suitable antioxidant (additive) may also be present. The antioxidant would be a stabilizer and thus an additive, not an impurity.

Historically, polyethylene glycol grades were specified by viscosity, but their multicomponent nature is now revealed by modern chromatographic techniques. The Cleaver chromatogram (11) shows multiple oligomers present, most of which are present at levels well in excess of 0.1 wt. %, and the sum of which exceed 2 wt. %. Given the current impurity limits and “definition” put forth in the 

 General Notices, these oligomers could be construed as “impurities.”

However, since finished pharmaceutical formulations using PEG 600 have been based on PEG 600 functionality, which is predicated on the presence of the oligomers shown in the chromatogram, the effect of removing all oligomers except the tridecamer is unknown, even if it were possible to do so. The presence of these oligomers may provide essential contribution to PEG 600 drug delivery properties.  In addition, their presence does not pose a health or safety risk. 

This article seeks to promote dialogue among stakeholders to facilitate consensus regarding requirements for excipients. 
