David Schoneker is president, Black Diamond Regulatory Consulting, LLC

David Schoneker

Beige cosmetic or make up powder isolated on white. | Image Credit:©triocean – stock.adobe.com

An essential factor to consider when developing a robust continuous manufacturing (CM) process is the impact that inherent excipient and API physicochemical variations can have on the drug product performance, CM unit operations, or CM process as a whole.

This paper examines the key information needed for excipients and their potential impact on CM processes. Much of this information is derived from several presentations made at a 

 (PQRI) workshop entitled, “Managing Excipient and API Impact on Continuous Manufacturing”, held virtually on May 17–18, 2022 (1).

CM involves continuous feeding of input materials into, the transformation of in-process materials within, and the concomitant removal of output materials from an interconnected manufacturing process in which two or more-unit operations are directly integrated. While many excipients have been continuously manufactured for decades, the use for pharmaceutical drug products, particularly oral solid dosage (OSD) forms, is relatively new. Knowing how excipient physicochemical properties impact CM, whether as a whole or in individual unit operations, needs to be understood to implement a rigorous control strategy and ensure a robust CM process. Not every excipient will have a direct impact on the overall process but may affect individual unit operations to some degree.

Most regulatory guidelines apply only to APIs and drug product manufacture but not excipients (e.g., International Council for Harmonisation [ICH] Q13 [2]). However, regulators and other organizations are discussing what impact excipients may have on CM and what controls or understanding are needed to ensure success in the development and manufacture of pharmaceutical products through continuous processes. One example is International Pharmaceutical Excipients Council of the Americas (IPEC-Americas) and how the various IPEC guides may assist in understanding the role of excipients in CM.

CM is also gaining traction in the manufacture of biologic drug substances and their dosage forms. Many biologics are liquids intended for injection and excipient considerations for CM of liquid biologic drugs are quite different than for OSDs. This article will focus on CM for OSDs.

CM offers efficiency, cost-effectiveness, and real-time quality control in a reduced footprint compared to traditional batch manufacturing. However, this shift from batch-based to continuous production hinges on one critical factor: understanding and controlling the material properties of the raw materials involved.

A growing body of knowledge is being developed on this topic for CM of liquids, semisolids, and OSDs. The majority of FDA- and European Medicines Agency (EMA)-approved commercial CM drug products are OSDs, particularly tablets, manufactured via direct compression or twin-screw granulation platforms.

The following sections focus on highlighting the importance of characterizing raw materials and understanding their variability for manufacture of OSDs. General considerations based on unit operations and specific case studies are provided.

Why are material properties so important? 

The impact of raw material properties on process performance and drug product quality has been extensively studied. Understanding this impact does not automatically translate to robust processes and products. Control strategies to accommodate the impact of raw material variability should minimize the number of alarms and process interruptions and give robustness and consistent product quality.

For continuous manufacturing of OSDs, the following are three major reasons why it is important to proactively evaluate the impact of raw material properties:

 Variations in material properties can impact product critical quality attributes (CQAs) such as drug release, potency, and ultimately, patient safety.

 Predictable material properties reduce the risk of mass flow deviations from their set point, minimizing alarms and process downtime, and maximizing process and process analytical technologies (PAT) model robustness. Robust models require less updates and, if used for real-time release, reduce downtime and supply chain disruptions.

 Tailoring process parameters based on material properties (e.g., via design spaces) can improve efficiency, yield, and overall cost-effectiveness (faster return on investment [ROI]) of the manufacturing platform.

Powder properties that impact unit operations in CM. 

CM, when optimized, allows for enhanced predictability and control. Understanding the impact of raw material variability on process performance will allow for the design of a control strategy that ensures continual high drug product quality. A comprehensive list of all the material properties that can impact formulation and process development of liquids, creams, gels, and OSDs, is outside of the scope of this article. To date, most CM approvals have been for OSDs. The following is a list of the material properties to consider for manufacturing pharmaceutical tablets or capsules:

Particle size distribution can impact flowability, cohesion, mixing dynamics, blending time, and granulation torque.

Bulk density needs to be considered in feeder design. Light, fluffy powders are more difficult to feed and compress, and may require pre-blending steps before incorporation in a continuous process line.

Surface area and morphology properties can influence electrostatics or tribocharging, tablet ejection force, drug dissolution, and film coating effectiveness.

Flowability and cohesiveness (inverse correlation) determine powder handling, feeding configurations, mass flow alarms and noise/smoothing averages, blending efficiency, pre-compression parameters, and others. A shift in excipient or API cohesion can impact its flowability and thus how efficiently it fills screw flights. These differences can require new feed factor calibrations (grams delivered per revolution) and control parameter tuning on screw speed to reach the mass flow setpoints. Additionally, poor flowing blends can introduce increased tablet and capsule weight variability and thus impact overall assay. Paradoxically, a free-flowing blend can also segregate more easily as it moves downstream to the tablet press or capsule machine and flood the dies wherein increased tablet weight variability is the system response.

Compressibility refers to changes in powder volume as an effect of applied normal force. Excipients with higher compressibility are generally more cohesive (they can function as binders) and are sensitive to shear. Increased head pressure when charging material into the feeder hopper (refill) will increase powder packing and, for highly compressible materials, this can lead to bridges and densification in the screws, ultimately negatively impacting mass flow variability. Refill limits and charging systems (manual vs. pneumatic, for example) should be designed with material compressibility in mind.

Moisture content impacts blend hold time (potential for microbiological contamination), powder flowability, tribocharging, tableting properties, and drug product stability.

Characterization technique considerations. 

Performance-related properties—the physical characteristics of excipients that may impact performance and drug product manufacturability—are generally not comparable due to multiple, non-standardized methods. Formulators are then required to test these as part of product development and include the results in risk assessments and regulatory submissions that contain the product knowledge and history.

For example, particle size distribution can be determined by laser diffraction or sieve analysis, and other techniques. Flowability can be described based on Hausner Ratio, Carr’s Index, Angle of Repose, or powder rheometry. Considering that there are multiple ways to test an attribute, the details of the method are as important as the results to allow comparability.

Having standardized methods offer several benefits:

Data comparability enables consistent comparison of data across different labs, sites, and batches.

if methods are standardized, sites can share a raw material database with known interactions with their unit operations (process performance) and drug product quality. This would allow for a prediction of process and product robustness, such that precise adjustments to process parameters like refill limits and blending speeds can be tuned based on factors like compressibility and flowability. This ensures consistent product quality throughout continuous production.

Improved communication and collaboration—standardized data creates a common language for communication among scientists, engineers, and regulators. This can allow for faster technology and product transfer amongst company sites, and clear communication from the user to the excipient supplier and vice versa in cases of investigations.

Reduced costs and risks—accurate and comparable data minimizes the need for extensive re-testing and troubleshooting, leading to cost and full-time equivalent (FTE) savings, and reduced risk of production delays associated with inconsistency in raw material behavior.

The successful implementation of CM in the pharmaceutical industry relies heavily on the reliable assessment of raw materials—both excipients and API. Inconsistency in raw material properties can have a domino effect, impacting process stability, product quality, and ultimately, patient safety. Standardizing characterization techniques can mitigate these risks and ensure successful CM implementation.

Impact of material properties and variability on continuous manufacturing

To understand excipient variability, it might be helpful to understand several factors. Excipients, particularly those that are naturally derived or quarried and refined, often have complex multicomponent compositions. Changes in seasonal growing conditions, for example, may result in varying composition, even if only slight, which could impact physical and/or functional properties. Unlike many pharmaceutical products, excipients are sometimes manufactured on a metric ton scale, often by CM. This leads not only to batch-to-batch variability (inter-batch variability), which is often monitored, but also excipient intra-batch variability, or package-to-package variability. While a well-designed, robust continuous process for drug product can manage excipient variation that might otherwise adversely affect process, product quality, or performance, understanding slight variations within an excipient (or API) batch can assist in designing a robust CM process.

Raw material properties, both physical and functional, can impact process behavior due to the particle–particle interactions taking place throughout the equipment train. Using a quality-by-design (QbD) approach to understand material attributes and their impact on the process and product can facilitate better product robustness. Individual ingredients should be characterized for their intended role in a formulation in addition to how the interactions among ingredients impact the CM process and product quality. For example, understanding segregation tendency during manufacture may help with ingredient selection before moving forward with process design. By understanding the critical material attributes, and modeling one or more continuous process designs, the best outcome can be achieved.

Excipient variability can also lead to changes in the PAT signal and consequent analysis. PAT feedback is critical in implementing an adequate control strategy and ensuring a robust CM process.Without a defined control strategy with PAT input, process drift could lead to product or process failure, affecting yield. Assessing the effect of material changes on residence time distributions and from there on, establishing actionable system responses to disturbances are key to ensuring consistent product quality and process performance. Given the limitations of material introduction into the continuous process, excipient performance then assumes greater importance in CM.

CM provides the ability to isolate non-conforming material without compromising the batch in its entirety. CM also mitigates much of the tech transfer risk associated with traditional batch manufacturing, primarily through elimination of scale-up. However, CM by itself does not mitigate raw material risk. Formulation design should be guided by the finished product CQAs regardless of whether the product is manufactured continuously or batch-wise. CM reduces the process degrees of freedom relative to batch manufacturing, but not the impact of raw material variations.

The output from a continuous manufacturing run is variable, dependent on run time, in contrast to the fixed output from a batch process, which is dependent on equipment size. The ICH Q13 guideline includes an example of a CM tablet noting that “the continuous process verification approach, coupled with appropriate regulatory action for reporting manufacturing changes, was used to validate run time extensions beyond current experience” (2). Excipient selection should consider potential risks from extended running, such as fouling of tooling.

Excipients should not need tighter specifications in CM than in batch processing. The process should be designed such that any transient disturbances associated with raw material variability are averaged out according to the residence time distribution of the CM process. Excipient variability may be more visible due to PAT, as the smaller working volumes in CM allow better temporal and spatial correlation with excipient variability.

In CM, the significance of a disturbance is a function of its magnitude and duration. The robustness of CM is demonstrated by the example in the ICH Q13 guideline where a disturbance of ±20% lasting less than 90 seconds would not cause the drug concentration in the blend to exceed the 90–110% label claim (see 

). Similarly, for a ±5% disturbance of 300 seconds or 5 minutes, the product would still meet label claim. 

It is likely that CM will provide more insight into excipient impact especially if the greater amount of PAT data associated with CM can be subjected to multivariate analysis. The IPEC QbD guideline (3) provides methods for the categorization and control of excipients.

Figure 1. Example of a funnel plot for the feeding of a drug substance. (Figure courtesy of International Council for Harmonisation [ICH]. ©ICH, used under public license.)

Excipient traceability in drug product batches manufactured by CM

In CM, traceability is defined as “the ability to track the distribution of materials throughout the manufacturing process” (2). Traceability is required so that non-conforming material can be diverted. Understanding of the residence time distribution is required for traceability to control material diversion.

Traceability is also required to determine where individual batches of an excipient occur in the output finished product stream. If a second batch of an excipient is introduced into a CM run, there will be finished product initially containing excipient batch 1 only, then product containing increasing proportions of batch 2, and finally product with batch 2 only. Products may be conforming but the location of the transition material needs to be known in the event of a subsequent investigation or recall associated with an excipient batch. For this reason, it is advisable to time slice long runs into sequential smaller batches.

The need for excipients designed for purpose

The need for new excipients has never been greater nor the benefits clearer. Novel excipients with improved properties can enable API solubilization, consistent product mass flow, more precise PAT measurements, and in some cases, better pharmacokinetic profiles with improved dosing regimens and higher product efficacy. In CM, co-processed excipients (CPEs) have emerged as a fit-for-use alternative to simplify formulations. CPEs are multi-functional and have many of the desired functionalities required to develop CM drug products. The formulation approach is simple: combine the API with the CPEs via blending, and compress. The CM process approach with CPEs is also rather simple, as the manufacturer would only require a minimum of two feeders, when appropriate, greatly reducing the complexity of the control strategy compared to traditional five- to six-component drug products.

Excipients have always played a critical role in drug product processing, and there is a need for material innovation to enable further adoption of CM from traditional batch manufacturing.

The information provided above has demonstrated how important excipient properties are to the success of CM. However, there are some challenges and opportunities with the use of current excipients in CM processes such as the following:

Ultra-low-density materials, such as fumed silica, cannot be fed unless preblended.

High regulatory uncertainties related to CPEs.

Excipients need stronger PAT signals to distinguish more easily from API spectra.

Excipients could help mitigate fouling of CM lines and enable more efficient clean in place (CIP).

There are few incentives for excipient innovation (e.g., FDA Pilot Program for the Review of Innovation and Modernization of Excipients [PRIME] [4]).

Regulatory and industry perspective on how to mitigate risks

Excipient attributes often vary between suppliers, even for the same grade. They may have differences in properties such as particle size and flowability which can affect process variability in CM runs. As such, sourcing excipients for CM will likely lead to detailed negotiations in supplier quality agreements wherein compliance with the pharmacopeia monograph tests will not be sufficient and customer-specific tests and specifications will become more important.

Considering that formulations with more excipients can potentially have more variability when raw materials are sourced from different suppliers, co-processed excipients (CPEs, combinations of two of more excipients into one) can benefit both batch and CM processes. Particularly for CM, formulating with CPEs has the advantage of reducing the number of process feeders and simplifying the control strategy. Although advantageous for accelerating formulation design and maximizing process robustness, the use of CPEs present a supply chain risk as they are sourced from a single supplier. This risk needs to be discussed during supply agreement negotiations, in addition to the compliance / testing topics described earlier.

For both batch and CM products, there is an expectation on the part of regulatory agency review staff that risks to finished product quality (CQAs) will be assessed and understood, critical material attributes (CMAs) identified, and risk mitigation strategies, including extra testing as needed, will need to be put in place. There is also an expectation that such information will be included in regulatory filings. The implementation of risk mitigation strategies to reduce the impact of the risks identified in the risk assessment, including supply chain, will likely influence the final choice of excipients.

As CM becomes more common, excipients that traditionally have been used may not provide optimal CM formulations. There will be a greater need for innovation and the use of new excipient technologies to provide enhanced properties designed for purpose in CM applications. It will be more important than ever to develop improved regulatory strategies to provide the incentives needed for this innovation.

It is hoped that the development of FDA’s PRIME program which allows for an independent safety assessment of different novel excipient types will open the door to the innovation needed to support successful implementation of CM going forward.

1. PQRI. “Managing Excipient and API Impact on Continuous Manufacturing”. PQRI Workshop May 17–18, 2022.

Continuous Manufacturing of Drug Substances and Drug Products

Incorporation of Pharmaceutical Excipients into Product Development Using QbD Guide

4. FDA. Pilot Program for the Review of Innovation and Modernization of Excipients (PRIME). FDA.gov.

Krizia M. Karry, PhD, ishead of Global Technical Marketing, Pharma Solutions, BASF. Brian Carlin is president and owner of Carlin Pharma Consulting LLC. Nigel Langley, PhD, MBA, is global technical director at Gaylord Life Sciences and Immediate Past Chair, IPEC- Americas. R. Christian Moreton, PhD, is partner, FinnBrit Consulting. David R. Schoneker is president and owner of Black Diamond Regulatory Consulting. Katherine L. Ulman is owner and president of KLU Consulting LLC. Joseph Zeleznik is technical director North America at IMCD.

Articles

Key information is needed for excipients and their potential impact on continuous manufacturing processes.

Understanding Excipient Characteristics to Ensure Robust Continuous Manufacturing 

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,” 

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.
