R. Christian Moreton, PhD, is vice-president of pharmaceutical sciences at Finnbrit Consulting and a member of Pharmaceutical Technology’s editorial advisory board.

R. Christian Moreton

Excipients are substances other than the API, which have been appropriately evaluated for safety and are intentionally included in drug delivery systems. Excipients are typically more complex than APIs, because they are frequently multi-component and less well-defined. In addition, excipient variability can present itself in various forms, compositionally, physically, or functionally.

Most excipients are not pure substances. Other residual and trace components present in excipients can impact key excipient functional characteristics when used in pharmaceutical formulations (1). The International Pharmaceutical Excipients Council (IPEC) refers to these other unavoidable substances in excipients as concomitant components (2). Performance of many excipients in a drug formulation may rely on the presence of such substances in the excipient. These excipient components are not considered impurities and could vary due to changes in raw materials, process variability, and from supplier to supplier. Excipients are not controlled at an individual parameter level. There are many degrees of freedom associated with polydispersity of particle size, molecular weight, and chemical composition, all of which may be process or supplier dependent. Particle size is usually controlled as an average or distribution, and dilute solution viscosities are often used for routine analysis to monitor batch-to-batch consistency of polymer molecular weight. The composition profile of a complex mixture may not be well defined, and the performance impact of the many components may not be well understood.

Silverstein contrasted the control of API quality versus that of excipients (3):

“API quality is improved by reducing the presence of all materials other than the desired chemical. […] Extraneous substances may be harmful to the patient in that they may lead to side effects, or they are inert, thus reducing API purity and thereby compromising efficacy.”

“Excipient quality is described quite differently. While one would again refer to compliance with the compendial monograph (if there is one) or the manufacturer’s specification, a higher assay is not always better. While this may seem counterintuitive, excipients are often complex mixtures that include constituents arising from raw materials, catalyst, solvent, initiator residue, or side reactions” (3).

Excipients are often mixtures of materials with major and minor components, and the minor components may contribute to the overall excipient performance in a particular application (4). For example, the compactibility of coarse grade dibasic calcium phosphate dihydrate is influenced by the presence of “impurities” in the crystal lattice, which cause dislocations and weakness, allowing brittle fracture to occur. Very pure coarse-grade dibasic calcium phosphate dihydrate does not compact as well. However, in general, the exact
relationship between excipient composition and excipient performance is not often well understood and will vary with each application (5).

Many excipients possess some inherent variability. Variability in the finished excipient attributes can arise from many sources such as, but not limited to those in 

Table I. Potential variability due to excipient source.

Excipient variability for some excipients can also be influenced by degradation, which also can be impacted by packaging and/or environmental conditions during storage and distribution.

As described in the IPEC quality-by-design (QbD) guide (6), “excipient manufacturers can control excipient variability only within the limits of their process capability and for which the processing equipment was designed and constructed.” Process capability is a general statistical concept based on the ratio of the specification limits to the process variability. If the variability is the same as the specification range the process capability is one, with no room for error. The higher the process capability the lower the risk of failure. Less than one means that not all batches will meet specification. Therefore, arbitrary narrowing of a specification by users may adversely impact sustainable excipient supply. Robust formulations are not critically impacted by typical excipient variabilities, not all of which may be reflected in the specification.

“In addition, the equipment train used in the process and the type of processing and unit operations included may all influence variability. Various excipients are continuously manufactured in many metric tons per annum. Results reported on a certificate of analysis (CoA) will often be a composite or average, potentially underestimating variability. Not all excipients will have the crystallization or precipitation steps typically used to purify fine chemicals. Users should discuss inherent variability with the supplier and their capability to supply product as it relates to the user’s needs (7). It is the responsibility of the user to identify potential critical material attributes (CMAs) for the excipients used in their formulations but the suppliers may be able to assist. A risk-based approach will probably be appropriate” (6).

Different excipient manufacturers are likely to use different raw material sources as well as different manufacturing processes. Therefore, variability introduced by alternate sources encompasses variability of both raw materials and processing.

Excipients from alternate sources (additional sites within a manufacturer and/or alternate supplier(s)) may not be compositionally, physically, or functionally identical, but may still demonstrate equivalent performance within the drug product depending on application. Excipient users should define functional performance requirements for alternate excipient sources (8).

When evaluating alternate excipient sources, users should not assume that all sources conforming with the same compendial requirements are interchangeable in all drug product formulations. Variability in excipient composition and other attributes among excipient sources could impact performance. To gain an understanding of the potential origin for various components that may be found in excipients from different sources, see 

Figure 1. The complexity in excipient composition. Figure courtesy of IPEC Americas.

Confirmation of equivalent performance is necessary to support interchangeability. The critical quality attributes (CQAs), including stability, of the drug product manufactured with the alternate source must be demonstrated.

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.

In a 2008 article on “Comparative Tableting Properties of Sixteen Microcrystalline Celluloses” (9), Doelker 

noted that, “Great differences in packing and tableting properties and in sensitivity to the addition of a lubricant were generally observed between
products from the various manufacturers. In contrast, lot-to-lot variability was quite acceptable.”

Mitigating the impact of excipient variability

Moreton defined a robust formulation as being “able to accommodate the typical variability seen in API, excipients, and processes without compromising the manufacture, stability, performance, or any other attribute of the product critical to the patient’s care or well-being” (5).

Qualifying multiple sources should be considered when establishing the design space to reduce the time required to switch to an alternative supply after launch (10). If the impact of an excipient variability on finished product CQAs is unacceptable, then additional controls (CMAs) should be considered. Both limits and methods for CMAs must be agreed between user and excipient manufacturer.

It may be necessary for excipient manufacturers to make changes to their processes for various reasons that have the potential to impact excipient performance and thus finished product performance. Excipient manufacturers should consult the IPEC Significant Change Guide for Pharmaceutical Excipients (11) whenever a change is to be made to excipient raw materials, manufacturing process, and/or finished excipient testing and assess the need for customer notification. Based on a risk assessment, the excipient manufacturer should apply the same reasoning (as far as is practicable) to their own suppliers of starting materials, reagent, solvents, processing aids, and additives used in the manufacture of the excipient.

When investigating potential impacts of notified changes, it is strongly recommended that a risk assessment be undertaken by the excipient user. Based on the results of the risk assessment, the excipient user should determine their need for further action.

It may be necessary for the excipient user to build product inventory, thus requiring pre-change excipient supply, because regulatory filings may be subject to extended review times. This may, in turn, require coordination between excipient manufacturer and user.

It should also be remembered that not all changes to an excipient will be detrimental to the performance of the excipient or pharmaceutical finished product. All changes should be considered as significant unless it can be scientifically justified as not a significant change. Significant changes should be notified to the excipient user (11).

Factoring excipient variability into design of experiments, control strategy, and lifecycle management will increase finished product robustness (12),
which will improve the overall product quality and performance, leading to better patient outcomes.

Excipient variability should always be a concern unless proven otherwise. Relying only on the excipient sales specification or the compendial monograph is not enough to account for potential variation(s) because many CMAs may not be part of these requirements. Drug product manufacturers should have a robust dialogue with their excipient suppliers to understand the variability of material attributes.

PharmTech APIs, Excipients, and Manufacturing 

Composition Guide for Pharmaceutical Excipients

I. Silverstein, “Excipient Quality and Selection,” PharmTech Europe, 28 (2) 2016.

Incorporation of Pharmaceutical Excipient into Product Development using Quality-by-Design (QbD) Guide,

The IPEC-Americas Quality by Design (QbD) Sampling Guide, 

E. Doelker, D. Mordier, H. Iten & P. Humbert-Droz (1987) Comparative Tableting Properties of Sixteen Microcrystalline Celluloses, 

, 13:9-11, 1847-1875, DOI: 10.3109/03639048709068696

Qualification of Excipients for Use in Pharmaceuticals

Signifiant Change Guide for Pharmaceutical Excipients

CPhI Pharma 2021 Report: Post Pandemic Legacy Trends

Brian Carlin is owner Carlin Pharma Consulting LLC. George Collins is the Vice-President for Excipient Mineral Manufacturing, RT Vanderbilt Company. Chris Moreton is partner at FinnBrit Consulting. David R. Schoneker is the President/Owner of Black Diamond Regulatory Consulting, LLC. Jennifer Putnam is a Senior Supervisor, Analytical R&D at Perrigo.Joseph Zeleznik is Technical Director, North America for IMCD US Pharma. Katherine Ulman is the owner and Primary for KLU Consulting, LLC. Stacey Bremer, Director, Product Stewardship Medical at Celanese.


Vol. 46, No. 8
August 2022
Pages: 20–23

When referring to this article, please cite it as B. Carlin et al., “Mitigating the Risk from Excipient Variability,” 

Articles

This article reviews sources of excipient variability, including raw materials and processing, both of which may vary from supplier to supplier and from plant to plant for a single manufacturer.

Mitigating the Risk from Excipient Variability

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.


Vol. 45, No. 2
February 2021
Pages: 49–53

When referring to this article, please cite it as J. Putnam et. al., “Understanding Concomitant Components in Pharmaceutical Excipients,” 

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


Understanding Concomitant Components in Pharmaceutical Excipients

Manufacturers of pharmaceutical excipients often serve other markets in addition to the pharmaceutical industry. The excipient qualification process, quality systems supporting excipient manufacture, and regulatory scrutiny associated with pharmaceutical excipients offer confidence to potential customers in other regulated industries that the pharmaceutical excipient grade material could be qualified to meet their needs. The reality, however, is that significant differences often exist between regulated industry requirements, and neither suppliers nor customers can assume a single material qualification can meet every markets’ requirements.

	Many ingredients used as pharmaceutical excipients have applications in dietary supplement or food ingredient markets. The common sugar alcohol, mannitol (HOCH

OH), for example, can be used as a pharmaceutical excipient, a non-dietary ingredient in dietary supplements, or a food additive. Mannitol monographs are accessible in the 

), as well as the Food Chemicals Codex (FCC) and the European Union (EU) Food Additive regulations (Reg. (EU) 231/2012). Mannitol, with its sweet taste and pleasant mouthfeel, may serve the same purpose in confectionaries, chewable dietary supplements, or oral medications.

	Each market application, whether food, dietary supplement, or pharmaceutical, has its own requirements, and although some of the requirements may overlap, pharmaceutical excipient manufacturers must understand and implement the requirements relevant to the intended uses before supplying into the aforementioned applications. Similarly, manufacturers of food additives and/or non-dietary ingredients need to understand and implement pharmaceutical requirements prior to supplying mannitol for drug product use. It is incorrect to assume that materials meeting food additive and/or non-dietary ingredient standards will also meet pharmaceutical excipient requirements. Likewise, it is also incorrect to assume that product approved for use as a pharmaceutical excipient will automatically comply with food or dietary supplement requirements.

	FDA’s food additive definition (1) does not include generally recognized as safe (GRAS) substances; however, all food ingredients (including food additives, GRAS substances, and non-dietary ingredients for dietary supplements) are held to the same good manufacturing practice (GMP) requirements. For the sake of brevity, in this article, food additives, GRAS substances, and non-dietary ingredients for dietary supplements will be referred to collectively as food ingredients. Pharmaceutical excipients will be referred to as excipients.

	Excipient, dietary supplement, and food ingredient markets are regulated, having requirements for quality management systems with material specifications and qualifications. Some markets have voluntary GMPs and other certification programs as discussed in the following. While there is considerable overlap in requirements for the different markets, there are also significant differences. No single quality management system or certification scheme satisfies the demands or requirements for all three markets, and some applications may have market-driven requirements not considered for the other applications. 

 lists pertinent guidelines and certification programs mentioned in this article.

: Sources for guidelines and certification programs, food and pharmaceutical excipients.

					NSF/IPEC/ANSI 363–2016 Good Manufacturing Practices for Pharmaceutical Excipients

					EXCiPACT Certification Standards for Pharmaceutical Excipient Suppliers: Good Manufacturing Practices, Good Distribution Practices

Joint International Pharmaceutical Excipient Council–Pharmaceutical Quality Group Good Manufacturing Practices Guide for Pharmaceutical Excipients

					International Food Additives Council

					Food Safety Systems Certification 22000

					International Council for Harmonization

	There are well-established GMP standards for regulated markets. For excipients, the NSF/IPEC/ANSI-363 and EXCiPACT excipient GMP standards, or the 

Joint International Pharmaceutical Excipient Council–Pharmaceutical Quality Group GMP

 guide for pharmaceutical excipients should be followed. In contrast to food ingredients, pharmaceutical products are not limited to the oral route of administration. For non-oral routes of administration, additional GMP requirements are based on intended uses.

	Food GMP conditions are mandatory for food ingredients. In Current Good Manufacturing Practice, Hazard Analysis, and Risk Based Preventative Controls for Human Food (2), FDA requires that all food must be manufactured in compliance with food GMP requirements. Finished dietary supplements are subject to Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling or Holding Operations for Dietary Supplements (3) dietary supplement GMP requirements; non-dietary ingredients are subject to 21 

) 117 Part B (2) like all food ingredients.

	The manufacture of chemical and mineral food ingredients may vary considerably from production requirements for agricultural food ingredients. Similar to excipients, food ingredients are often manufactured in chemical or mineral manufacturing facilities.

	As such, it is not always clear to these manufacturers how to apply food GMP requirements to food ingredients. For this reason, the International Food Additives Council (IFAC) developed a GMP guide (4) for the food ingredient industry. Similarly, the Global Food Safety Initiative (GFSI) recommends the Food Safety Systems Certification FFSC 22000, Safe Quality Food Institute, or International Featured Standards as applicable food safety schemes for the manufacture of (bio)chemicals. The FSSC 22000 is based on ISO 22000 Food Safety Management requirements and adds additional elements appropriate to food ingredient manufacturers. Regardless of the certification standard used, application of food ingredient GMPs is sometimes quite different than for finished foods. Appropriate controls for food ingredients are based on identified and potential material hazards.

	Although some quality management systems (i.e., GMPs) for excipients may exceed requirements needed to meet food ingredient GMPs, it is incorrect to assume excipient GMPs meet all food ingredient requirements. It is often easier to obtain acceptance of a food-grade material for use as a pharmaceutical excipient than for an excipient to comply with food regulatory requirements. Like excipients, food ingredients must undergo rigorous toxicological and safety evaluation prior to being approved for use in food; however, excipients, unlike food ingredients, may be evaluated based on their intended route of administration. In addition, whereas direct contact equipment and packaging supplies for excipients must be qualified based on the excipient being handled-including verification activities and identification of potential risks-food contact materials must follow FDA rules limiting the types of materials that can be used.

 illustrates some of the differences between food ingredient and excipient GMP requirements.

	In addition to GMPs, food ingredients and excipients are subject to other regulatory requirements including the following:

		California Safe Drinking Water and Toxic Enforcement Act of 1986 (commonly called Prop 65) for the reporting of known carcinogens

		Pesticides and potential pesticide residue

		Bovine spongiform encephalopathy/Transmissible spongiform encephalopathy (6) reporting requirements

		Applicable USP general chapters (for excipients)

		Applicable FCC general chapters (for food additives).

	Excipients and food ingredients require analytical testing, often described in published monographs. Although there may be some overlap in attributes, test methods, and specifications described in the monographs, significant differences often exist.

	For instance, food and food ingredients’ heavy metal requirements typically focus on arsenic, cadmium, mercury, and lead. For pharmaceutical products, elemental impurities (7) are emphasized, which does not apply directly to excipients, but rather, to the final dosage form of which the excipient is a component. As of Jan. 1, 2018, heavy metals specifications were no longer required for excipients in the United States and European markets unless specific metals are included in the excipient’s monograph. Excipients have requirements for residual solvents (8); however, in the United States, no specific residual solvent requirement for food ingredients exists. This is not to say that there is no consideration for solvents in food ingredients. When appropriate, food safety risk due to potential residual solvent should be evaluated.

	Regulatory agencies, such as FDA, sometimes inspect excipient and food ingredients facilities for cause; however, only food ingredient manufacturing facilities are required to register with FDA under the Bioterrorism Act of 2002 (9). Under the Food Safety Modernization Act (FSMA), food ingredient facilities are subject to additional FDA requirements intended to protect against intentional adulteration (10). FSMA requirements include implementing a food defense plan targeted at preventing intentional adulteration intended to do mass harm to the public and food fraud mitigation programs targeted at protecting against economically motivated adulteration. Although similar intentional adulteration concerns may exist for excipients, a written plan to address intentional excipient adulteration is not explicitly required.

	Importers of food ingredients must confirm foreign suppliers comply with US food requirements per the Foreign Supplier Verification Program (FSVP) (11). FSVP requires food ingredient importers to verify that their suppliers have controls in place for meeting US food safety requirements, including implementing supplier verification activities to mitigate risks identified for each imported food. There is no corresponding regulatory requirement to verify GMP of foreign manufacturers of excipients. Pharmaceutical customers should evaluate the risks associated with imported excipients.

	Because ingredients used in any of these markets could be derived from raw materials of natural origin, additional restrictions to prevent exploitation of endangered species (12,13) need to be considered. There are also more specialized requirements to address illegal logging (14) intended to protect vulnerable environments (15). In addition to controls on flora- and fauna-derived materials, conflict mineral concerns require supply chain control on some inorganic materials (16,17). These conventions and regulations are impacted by material origin and harvesting for excipients and food ingredients.

	Consumers also may want food ingredients to have attributes that are not defined by safety or quality. Despite the lack of scientific evidence, “natural,” “organic,” and “genetically modified organism (GMO)-free” are all perceived as “healthier” and verification can add significant consumer-recognized value to food ingredients. Although there is no regulatory definition of “natural” for most food ingredients, flavors have a clear regulatory definition (18). The United States Department of Agriculture (USDA) regulates organic claims, labeling, and practices (19). Furthermore, USDA defines the requirements on labeling bioengineered foods: food containing bioengineered genetic material, which consumers commonly associate with GMO (20).

	Consumer demands for natural, organic, and GMO (bioengineered food) are less likely for dietary supplements and currently are very limited for excipients. Although sustainable and fair-trade supply chain verification may be very important for foods, similar concerns for dietary supplements or pharmaceuticals are less likely.

	Some consumers desire vegan or vegetarian ingredients, and certain regions such as India (21) require vegetarian labeling on food products. These same consumers typically do not hold pharmaceuticals to the same requirement.

	Religious requirements for food are very clear to the extent that in some countries these requirements are written into law. Kosher and halal are the most common religious requirements, and recognized religious agencies provide detailed requirements on meeting these standards. Many religious scholars recognize kosher/halal alternatives are not available for all pharmaceuticals; however, the pharmaceutical’s benefits are medically necessary and may have no suitable alternatives. As such, although halal or kosher ingredients may be desirable for pharmaceutical excipients, acceptance by patients is not a strict requirement, particularly when there is no suitable halal or kosher alternative. There may be other religious dietary requirements, and the degree to which they ascribe those to dietary supplements or drug products may vary.

	Although there may be considerable overlap in quality management systems and material specifications/requirements for substances sold for use as food ingredients, non-dietary ingredients, and excipients, many significant differences remain. No single quality management system or certification scheme satisfies ingredient requirements for the three markets. Therefore, manufacturers who supply into two or more of these markets need to understand and implement quality management system requirements to meet each of the markets they serve.

	1. FDA, “Substances Generally Recognized as Safe,” Final Rule, 

 Part 117, Current Good Manufacturing Practice, Hazard Analysis, and Risk Based Preventative Controls for Human Food.
	3. 

 (Government Printing Office, Washington, DC) 275–305.
	4. IFAC, 

Quality Systems, Food Safety and Good Manufacturing Practices Guide for Food Additives and GRAS Substances

Significant Change Guide for Pharmaceutical Excipients

, 2014.
	6. FDA, “Use of Materials Derived from Cattle in Human Food and Cosmetics,” Rule, 

, 81 FR 14718, 14718-14732.
	7. ICH, Q3D, 

, Step 4 version (December 2014).
	8. ICH, Q3A, 

), Step 4 version (October 2006).
	9. 21 

Part 1, Subpart H, (Government Printing Office, Washington, DC) 5.
	10. FDA, “

 Part 1, Subpart L (Government Printing Office, Washington, DC) 6–7.
	12. US Fish and Wildlife Service, “

.
	13. Convention on International Trade in Endangered Species, “How CITES Works,” 

.
	15. Roundtable on Sustainable Palm Oil, “RSPO Certification,” 

.
	16. US GPO, Dodd Frank Wall Street Reform and Consumer Protection Act of 2010, Section 1502, Conflict Minerals (July 10, 2010).
	17. EU, Regulation (EU) 2017/821 of the European Parliament and of the Council of 17 May 2017 Laying Down Supply Chain Due Diligence Obligations for Union Importers of Tin, Tantalum and Tungsten, Their Ores, and Gold Originating from Conflict-Affected and High-Risk Areas (May 17, 2017).
	18. 21 

Part 101 (Government Printing Office, Washington, DC) 10–199.
	19. 7 

 Part 205 (Government Printing Office, Washington, DC) 400–456.
	20. 7 

 Part 66, (Government Printing Office, Washington, DC) 200–210.
	21. Food Safety and Standards Authority of India, “Draft Regulation on Labelling (Claims)” File Number 1-94/FSSAI/SP/(Labelling) 2009 (Dec. 27, 2012).

 is regulatory affairs expert–pharma food materials, MilliporeSigma; 

 is global regulatory affairs advocacy manager, DuPont; 

Vol. 44, No. 4
	April 2020
	Pages: 54–60

	When referring to this article, please cite it as L. Grocholl, et. al, “Comparison of Pharmaceutical Excipients and Food Ingredient Requirements" 

With ingredients sold to multiple markets, excipient manufacturers must understand the different regulatory requirements for pharma vs. food.

Comparison of Pharmaceutical Excipients and Food Ingredient Requirements

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

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