Katherine Ulman is the owner and Primary for KLU Consulting, LLC.She retired from Dow Corning Corporation after more than 40 years of employment.While at Dow Corning, she held positions as a global regulatory compliance manager for their Healthcare business as well as regulatory manager of the Dow Corning Healthcare Industries Materials Site.

Katherine Ulman

Microcrystalline cellulose, refined wood pulp, texturizer, anti-caking agent, fat substitute, emulsifier, used in vitamin supplements or pills. | Image Credit: ©RHJ - stock.adobe.com

The International Pharmaceutical Excipients Council (IPEC) defines a co-processed excipient as a combination of 2 or more compendial or non-compendial excipients designed to physically modify their properties in a manner not achievable by simple physical mixing, and without significant chemical change.

In some instances, formation of necessary components may occur, such as in situ salt formation.

In modern pharmaceutical formulations, co-processed excipients (CPEs) enable drug product manufacturability, stability, and performance that are not achieved when the CPE components are used individually in a simple blend. With the increased functional performance, formulators are turning to CPEs, which are engineered combinations of 2 or more excipient components integrated at the particle level (

Figure 1. "Simple" microcrystalline cellulose/fumed silicon dioxide blend (top right) compared to the co-processed silicified microcrystalline cellulose (bottom right).In co-processing, fumed silicon dioxide is added to microcrystalline cellulose slurry before drying creating an integrated system. Figure courtesy of the authors.

With the demonstrated benefits of CPEs in batch processing, it was a natural progression to their use in continuous manufacturing, which enables higher throughput and patient-centric dosage forms. Understanding the nature, benefits, and regulatory implications of CPEs is becoming indispensable for product formulators and supply chain decision-makers.

Historical Context and Current Prevalence of CPEs

The idea of co-processing is not new. The pharmaceutical industry has long used co-processed excipients. Classic examples include sugar spheres (sucrose and corn starch) for multiparticulate systems and the CPE combination of carboxymethylcellulose sodium (NaCMC) and microcrystalline cellulose (MCC) grades developed to improve liquid delivery. Other widely used cellulose combinations such as MCC and lactose; lactose and powdered cellulose; and silicified microcrystalline celluloses (SMCC) are examples where combining functional materials has produced practical benefits for decades. Today, more than 100 co-processed excipients exist, many of which are reported to be in commercial use, spanning direct-compression excipients, multifunctional binders, disintegrant-binder combinations, and specialty performance excipients, such as those used for orally disintegrating tablets (ODTs). Several of the co-processed materials identified above have achieved compendial recognition within the United States Pharmacopeia (USP). The growing number of CPEs reflects both historical safety experience and the practical manufacturing advantages they offer.

It is important to recognize that the individual components used in the manufacture of many CPEs are not isolated as single, compendial excipients prior to co-processing; however, they are carefully controlled. CPE manufacturers may employ different approaches to co-processing depending on the manufacturing processes used, components comprising the CPE, and the targeted physical and functional characteristics. In principle, there are 3 manufacturing pathways to produce CPEs. Each pathway yields an excipient whose composition is designed to work synergistically without significant chemical change to the components.

In practice, co-processing can be accomplished by several manufacturing routes:

Use of commercial excipients: Finished excipients are combined and subjected to a process (eg, milling, granulation, spray drying, or agglomeration) that integrates the components into particles comprising those materials (

A commercial excipient is introduced and combined with an in-process excipient that has not yet been isolated (eg, a polymer solution or slurry), and the combined stream is processed to integrate the components into particles comprising those components (eg, spray drying) (

All CPE components are in-process excipient streams coming together for co-processing: 2 or more material streams (eg, polymer dispersions, microcrystalline cellulose slurries, sugar-based solutions) are combined, mixed, and processed into particles without isolating any of the individual components first (

Figure 2. Commercial or finished excipients used to manufacture co-processed excipient. Figure courtesy of the authors. 

These manufacturing pathways affect physical characteristics, including particle morphology (particle shape and porosity), surface properties, particle size and size distribution, and moisture level, which in turn influence performance properties such as powder flow, compressibility, and robustness in the case of tablet manufacture.

Figure 3. Commercial or finished excipient(s) are added to the in-process stream of an excipient's manufacture during co-processing. Figure courtesy of the authors.

Figure 4. During excipient manufacture, the in-process streams are combined before drying to produce a co-processed excipient. Figure courtesy of the authors.

What Are the Safety and Regulatory Considerations?

An important safety consideration for CPEs is that no new covalent bonds are formed during co-processing, and that starting material chemical identities are preserved. Therefore, the individual component safety profiles are largely carried forward into the CPE. Because co-processing integrates components at the particle level, some attributes and interactions (eg, surface chemistry, dissolution rate, or microenvironmental pH) may change and should be evaluated.

One regulatory challenge arises when CPE manufacturers cannot claim straightforward pharmacopeial compliance for the co-processed excipient, and not all co-processed excipients have established compendial standards. This gap leads to an open industry question: Would broader pharmacopeial monograph coverage increase acceptance and adoption of CPEs? Many in the field insist yes — standardized monographs could improve transparency, harmonize quality expectations, and streamline regulatory reviews — but developing those monographs requires robust, widely accepted characterization methods for composite materials.

To adopt co-processed excipients responsibly, formulators and manufacturers should apply the following core principles:

Demonstrated safety. Confirm that the component identities and toxicological profiles are acceptable and that no unintended chemical reactions have created new risks.

Consistent composition. Ensure strict control of raw material attributes and manufacturing parameters to maintain reproducible CPE composition.

Reduced variability. Leverage co-processing to achieve more consistent performance from batch to batch versus simple blends.

Process control and monitoring. Implement robust in-process controls and validated manufacturing processes to maintain quality.

Documented performance benefits. Provide evidence that the CPE delivers functionality that cannot be achieved by simple mixtures.

Benefits for Manufacturing, Sustainability, and Innovation

Co-processed excipients provide a range of benefits that address both operational and formulation challenges, such as the following:

Facilitation of continuous manufacturing. CPEs can reduce the number of feeders and simplify input streams, improving feed-rate consistency and enabling more efficient continuous processes.

Sustainability. By reducing development iterations, waste from formulation trials and rejection during production, co-processed excipients can lower environmental impact. Some CPEs support direct compression, avoiding wet granulation and the associated solvent and energy use.

Productivity and cost. Enhanced flow, compressibility, and robustness reduce downtime, rework, and rejection rates, improving throughput and lowering the cost of goods.

Formulation enablement and innovation. CPEs can overcome flow or compaction limitations, reduce strain-rate sensitivity, allow capsule-to-tablet conversions, reduce binder needs, and enhance stability — opening pathways to novel dosage forms or improved patient-centric products.

Co-processed excipients are a practical, increasingly common resource for modern pharmaceutical development and manufacture. By integrating complementary excipient functions at the particle level, CPEs deliver real performance advantages that simple blends cannot match — from enabling continuous manufacturing and improving sustainability to solving difficult formulation problems. Continued development of compendial standards and transparent characterization will further support safe, consistent adoption of these materials across the industry. For formulators and manufacturers seeking reproducible, high-performance inputs, co-processed excipients merit serious consideration to accelerate development and improve product quality.

General glossary of terms and acronyms for pharmaceutical excipients. Version 3. IPEC; 2023. Accessed April 8, 2026. 

IPEC-Americas. Co-processed excipients demystified. 

. 2024;1(2):60-63. Accessed April 8, 2026. 

https://jefc.scholasticahq.com/article/124082-co-processed-excipients-demystified

Gina Marsee is the director, Compendial Compliance and Advocacy at Merck located in West Point, PA, USA. She holds a bachelor’s degree in Chemistry & Biology from the University of Tennessee and has worked in the pharmaceutical industry for 30+ years holding various leadership roles within Quality, Compliance, and Regulatory Affairs. She is also Chair, IPEC-Americas.

Ms. Katherine Ulman is the owner and Primary for KLU Consulting, LLC. She retired from Dow Corning Corporation after more than 40 years of employment. While at Dow Corning, she held positions as a global regulatory compliance manager for their Healthcare business as well as regulatory manager of the Dow Corning Healthcare Industries Materials Site

Joseph Zeleznik is the Technical Director – North America at IMCD US LLC. Joseph brings nearly four decades of experience in pharmaceutical excipient and formulation development. His expertise spans high-functionality and novel excipients, continuous manufacturing, and advanced formulation strategies. Additionally, he is a member of IPEC-Americas Executive Committee, currently serving as Immediate Past Chair.

Candy Reynolds Cummings spent 15 years at GlaxoSmithKline starting as an analytical chemist and working up to QA Validation Manager in the OTC area (specifically oral care). Currently working at Evonik as the Regulatory and Product Stewardship Manager supporting the business line Silica for regulations in US, Canada, and Mexico.

Priscilla Zawislak is Corporate Regulatory Affairs, ROQUETTE AMERICAS, INC.
Priscilla has over 35 years’ experience in Regulatory Affairs and Quality for excipients, food additives and ingredients for personal care products. She is currently President of the IPEC Federation and the Vice Chair of Science and Regulatory Policy for IPEC-Americas and is also a past Chair of the organization.

Bob Sulouff is Sr. Manager Regulatory Affairs, Health & Pharma Solutions, ROQUETTE AMERICAS, INC. Bob has over 25 years’ experience in Regulatory Affairs and Quality, primarily focused on excipients. He is a member of Roquette’s Health and Pharma Solutions Regulatory team, where he advocates for value added pharma regulatory solutions. He is also Chair-Elect, IPEC-Americas.

David R. Schoneker is currently the president/owner of Black Diamond Regulatory Consulting, LLC, a consulting firm specializing in providing regulatory and quality consulting for the pharmaceutical, dietary supplement, food, and related industries. Dave has been involved in the excipient industry for over 48 years and is currently the Chair of the IPEC-Americas QbD/Composition Committee.

Articles

Co-processed excipients (CPEs) are engineered combinations of two or more excipients integrated at the particle level to deliver functional performance unattainable through simple blending, without significant chemical change. Longstanding examples exist, and more than 100 CPEs are now reported in commercial use, including compendial materials. Manufacture can involve processing finished excipients together or co-processing in-process streams, shaping morphology and key attributes affecting flow and compressibility. Safety expectations hinge on preserved chemical identities, while regulatory adoption is constrained by limited monograph coverage and characterization standardization.

This article details what co-processed excipients are and how they are made.

Co-Processed Excipients: Practical Engineered Solutions for Modern Pharmaceutical Challenges

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

	
	Peer reviewed:
	Submitted: Feb. 11, 2015. Accepted: April 7, 2015.

Applications for a drug product that is administered dermally must define acceptable limits for elemental impurities in the product. Current guidelines for exposure limits, however, are based on oral, parenteral, or inhalation exposure and do not adequately address other routes, such as dermal exposure. This article reviews the information available about dermal exposure to metals and considers how it differs from oral or parenteral exposure.

	The International Conference on Harmonization’s (ICH’s) 

 establishes acceptable exposure limits and defines these limits based on route of administration, but does not specifically address dermal limits (1). Thus, developers of dermally delivered drugs are challenged to establish and define those limits. Is it appropriate, for example, to transpose limits based on other routes of administration (i.e., to apply oral or even parenteral limits)? This article seeks to examine the available data relating to dermal exposure to metals and evaluate appropriate approaches to ensure that the limits established will adequately address actual risk.

	The skin is made up of several layers including 

, viable epidermis, and dermis (2). The largest organ in the body, the skin provides a formidable barrier to exogenous materials. Within the skin, the outer layer (the 

) provides the most significant barrier and is rate limiting for any substance applied to the skin, whether intentional, in the form of a deliberately applied ointment, or a contaminant to which the skin is inadvertently exposed (e.g., a metal impurity present in a dermal product). The 

is highly lipophilic and contains very little water. As a result, penetration of hydrophilic or charged molecules is particularly difficult, and such species are effectively unable to partition into the lipid layer and hence pass through the skin at significant levels.


	The skin provides a formidable barrier to any drug. Even when a formulation has been deliberately designed to facilitate transport across the dermal barrier, exposure levels are typically a fraction of those obtained when the drug is delivered by injection. Consider lidocane, for example. Using topical formulations containing lidocaine, the systemic levels that are reached are as follows (3):

		5 µg/mL, after the application of 2 g ointment to the endotracheal tube

		1.3 µg/mL, after the application of 10 g ointment to the oral mucosa for 30 minutes

		0.6 µg/mL, after an oral (ingested) dose of 10 g ointment (bioavailability 35%)

		2.5 µg/mL, after a rectal dose of 10 g ointment (bioavailability 60-70%)

		0.3 µg/mL, after the application of 10 g ointment to a partial thickness burn

		0.1 µg/mL after the application of 10 g ointment to intact skin.

	Systemic levels of lidocaine of 0.1 µg/mL were observed following the application of 10 g dermally (to intact skin). For the same dose administered orally, the level is 6 times higher.  Even when applied to burnt skin, the level (0.3 µg/mL) is still 50% lower than the level achieved through oral administration. When compared to endotracheal application, where there is no effective barrier, the level adjusted for dose is significantly below 5% of the systemic concentration level. These data clearly demonstrate the significant barrier the skin provides and indicate significant concerns for the simplistic approach of applying oral-based limits for elemental impurities.

	Similar data have been generated for polydimethylsiloxane and linear and cyclic siloxanes.

 Dimethicone, a polysiloxane polymer, is widely used in a range of cosmetics. 

human dermal absorption/penetration studies in which neat material was applied to abdominal skin showed that 0.2% and 0.1% of the applied dose of PDMS (10 cST fluid) or PDMS (350 cSt fluid), respectively, remained at the dosing site and could be considered absorbed. The percentage of applied dose that penetrated through the skin to the receptor fluid was ~0.0002% for the 10 cSt fluid and ~0.0003% for the 350 cSt fluid. Studies of its dermal absorption showed no evidence that it had penetrated the dermal barrier (4).

	Oral-dosage absorption is also challenged. In studies where an oral dose of 350-cSt 14C-PDMS was administered to rats at 1000 mg/kg body weight, more than 99% of the recovered dose was excreted by the animals (4). PDMS by the dermal or oral route is minimally absorbed.

 human dermal absorption data for cyclic siloxanes (octamethylcyclotetrasiloxane, D4; decamethylcyclopentasiloxane, D5; and dodecamethylcyclohexasiloxane, D6) again showed extremely low levels of absorption following dermal application (5,6). As the molecular weight and lipophilicity of the cyclic siloxane increased (from D4 through D5 and D6), the percutaneous absorption decreased. The percentages of applied dose absorbed following a neat application was 0.5%, 0.05%, and 0% for D4, D5, and D6, respectively. Penetration into the receptor fluid was 0.01%, 0.002%, and 0.003% for D4, D5, and D6, respectively.

	Absorption data are available in rats following a single oral administration to rats of D4 (300 mg/kg), D5 (1000 mg/kg), and D6 (1000 mg/kg). These mass balance studies indicate that 52%, 20%, and 12% of the orally administered dose was absorbed (7-9). In the case of cyclic siloxanes, a greater percentage of the administered dose was absorbed orally than dermally.


	There are several comprehensive reviews covering exposure to metals. These reviews are predominantly focused on environmental exposure from sources such as soils. In 1993, Hostynek et al. (10) sought to summarize data relevant to the qualitative and, where possible, quantitative evaluation of metal permeation through skin. They looked at assessments for 31 elements, although coverage of ICH Q3D Class 1 metals (mercury, arsenic, cadmium, and lead) is incomplete, as there is no assessment of mercury or lead.

	They concluded that dermal absorption of metals is a complex process affected by multiple factors including size, charge, and oxidation state. They did not, however, draw any definitive overall conclusions regarding generic estimates of absorption, nor does it seek to generically compare rates to other routes of administration.

	A review by the National Environmental Policy Institute, 

Assessing the Bioavailability of Metals in Soil for Use in Human Health Risk Assessments

 (11), sought to specifically examine bioavailability. This review provides a thorough assessment of the available toxicological data for soil samples containing six metals: arsenic, cadmium, chromium, lead, mercury, and nickel. This review focuses on evaluations performed using soluble salt forms of the metals and assesses main routes of administration, including dermal limits. The overriding conclusions are that there are little data available to allow for the specific calculation of dermal exposure; however, the data that are presented support the view that even when present in an aqueous soluble form, metals are poorly absorbed through the skin.

	The most comprehensive and most recent review of dermal exposure to metals is the HERAG 1 factsheet, 

Health Risk Assessment Guidance for Metals--Assessment of Occupational Dermal Exposure and Dermal Absorption for Metals and Inorganic Metal Compounds 

(12). This review, sponsored by the International Council on Mining and Metals and Eurometaux, critically examines existing models used to estimate levels of dermal exposure, and determines their value in assessing the absorption of inorganic metals. One of the most prevalent models used is the EASE (Estimation and Assessment of Substance Exposure) model, developed by the United Kingdom’s Health and Safety Executive. This model defines default dermal absorption rates of 100% or 10% depending on the properties of the substance in question.

	Without relevant experimental data, 10% dermal absorption is used when the molecular weight (MW) of the substance is > 500 and the log P

 [partition coefficient for the compound in question between octanol (o) and water (w)] is smaller than -1 or higher than 4, otherwise 100% dermal absorption is used. The major issue with such an approach is that it was developed for organic chemical compounds; this is not considered relevant for metals, for the following reasons:

 is a parameter that has no bearing whatsoever in the prediction of the properties of a metal or of an inorganic salt of a metal. Inorganic metal species do not permeate the skin by passive diffusion. Instead, the uptake of metals largely depends on the presence of specific transport systems that provide biological gateways for the metal to cross the membrane.

		The dissolution of an inorganic metal compound or the metal itself on the skin surface will intrinsically require dissociation and ultimately liberation of free metal cations. Thus, molecular weight, the second criterion for assigning a dermal absorption rate, is irrelevant for metals. Under no circumstances could any metal cation exceed the cut-off value of 500.

	The review repeatedly makes the point that such general approaches are not only scientifically flawed, but also grossly overestimate the actual levels of exposure.

	Crucially, the review cites recent studies that fundamentally challenge the EASE model, with data derived from studies performed on soluble and insoluble zinc compounds. These data show that penetration of the dermis by soluble zinc sulfate is low and that dermal penetration of insoluble zinc oxide is even lower. The review concludes that dissolution kinetics are the rate-limiting factor. The results from these and other studies are summarized in 

	The article concluded, based on these experimental data, that recent studies conducted to Organization for Economic Cooperation and Development (OECD) standards indicate dermal absorption rates to be at or below 0.3% (12). There is no clear correlation between absorption and such factors as speciation, valency, and/or water solubility. Crucially, the HERAG guidance document concluded that it should be feasible to establish default absorption factors, concluding that a default absorption rate of 1% was reasonable and adequately conservative when the skin is exposed to metals in wet or liquid media. For “dry” exposure to dusts, it proposes a default dermal absorption factor of 0.1% (12).


	The following summarizes literature references with specific data relating to ICH Class 1 metals.

 A white paper specifically focused on arsenic was developed by the New Jersey Department of Environmental Protection (13). The paper provides a useful summary of several studies pertaining to the dermal absorption of arsenic. The data presented show that significant levels of arsenic were found to penetrate the skin of mice; however, this contrasted markedly with the results obtained for human skin, for which levels were within the range of 2-6% of the dose applied. The differences were attributed to the significant intra-species variation in skin thickness, that of a human being substantively greater.

	The National Research Council (1999) (14) evaluated the available information on this subject and stated that “these results indicate a low degree of systemic absorption of arsenic via the skin.” The Agency for Toxic Substances and Disease Registry (15) concluded that “it is usually considered that dermal uptake of Arsenates and Arsenites is sufficiently low that this route is unlikely to be of health concern …, but studies to test the validity of this assumption would be valuable.” Arsenic does not act as a sensitizer upon casual skin contact due to poor skin-penetrating ability of its naturally occurring compounds.

	Further studies were reported by Wester et al. (16). These studies reported a low permeability coefficient of 2.71 x 10

 following topical application of water containing radio-active arsenic.

 Absorption of cadmium through the skin is reported to be extremely low (0.5%) (17). Specific 

 experiments reported by Hostynek et al. (10) were conducted using human skin; these involved exposure for 16 hours to 116 ppb cadmium chloride applied as 2.5 and 5 ul/cm

 solution. Only 0.1 to 0.6% was found in the receptor solution.

	The HERAG factsheet (12) cites the relative absorption rate for cadmium metal and cadmium oxide, concluding that percutaneous absorption is likely to be significantly less than 1%.

The US Occupational Safety and Health Organization (OSHA) (18) concluded that lead can be absorbed by inhalation (breathing) and ingestion (eating) lead (except for certain organic lead compounds not covered by the standard, such as tetraethyl lead). It was also concluded, however, that lead is not readily absorbed through skin, concluding that cutaneous absorption of lead is limited. The amount absorbed through the skin depends on the physical characteristics of the lead (i.e., organic vs. inorganic) and the integrity of the skin.

	The HERAG paper (12) presented data from a variety of studies concluding that dermal absorption rates greater than 0.01% were unfeasible.

 The Hostynek paper (10) concludes that mercury can penetrate the skin in all forms including its elemental form, outlining both intra and intercellular pathways. Data relating to studies performed using guinea-pig skin and limited data relating to human skin are described. The data are complex, showing an apparent non-linear dose response, which was thought to be related to significant skin retention caused by reaction with skin proteins. There are no specific conclusions as to the actual level (%) absorbed.


	The following summarizes literature references with specific data relating to ICH Class 2 metals.

 No specific studies were located regarding absorption in humans or animals after dermal exposure to vanadium, although absorption by this route is generally considered to be very low, according to the World Health Organization (19). Absorption through the skin is thought to be quite minimal due to its low lipid/water solubility.

 The dermal absorption of molybdenum (as the molybdate ion) is low to negligible at approximately 0.2% of the applied dose. These results were shown in an in-vitro percutaneous study by Roper of the absorption of sodium molybdate dehydrate, a highly soluble substance, in human skin (20).

 While the HERAG report (12) raises concerns over the methodology employed in the studies described, it reports that even in the highest example (one where data for level absorbed was combined with the level retained in the 

) the absorption of a soluble salt form was reported to be only 2%.

 There is some evidence of absorption of cobalt metal through skin. Scansetti et al. (21) found that an experimental study with four volunteers, whose skin was exposed to freshly mixed or waste powder containing 5-15% cobalt, measured a ten-fold increase of cobalt in urine. Results confirmed that absorption through skin is a potential route of entry. Later studies by Filon et al. (22) concluded that cobalt can pass through the skin only when it is oxidized to ionic cobalt (Co

 The US Environmental Protection Agency (EPA) has not developed actual toxicity values for metals based on dermal administration. Instead, the EPA has devised a process for making route-to-route (oral-to-dermal) extrapolations for systemic effects. The EPA developed 

Risk Assessment Guidance for Superfund: Volume I Human Health Evaluation Manual (Part E, Supplemental Guidance for Dermal Risk Assessment)

 (23) to address human health risk related to dermal exposures. Part E uses a consistent methodology for assessing the exposures from the dermal pathway for Superfund human health risk assessments.

	Primarily, Part E accounts for the fact that most oral reference doses (RfDs) and slope factors are expressed as the amount of substance administered per unit time and body weight, whereas exposure estimates for the dermal pathway are expressed as absorbed dose. The process uses the dose-response relationship obtained from oral administration studies and makes an adjustment for absorption efficiency to represent the toxicity factor in terms of absorbed dose. Crucially, this does not advocate direct correlation between oral and dermal exposures, which would be crude and simplistic, nor does it advocate the simple direct application of oral limits to dermal application.

European Union (EU) risk assessments, occupational dermal exposure.

 EU assessments have historically been based on the EASE model, which proposes a default absorption of 10%. This is now largely discredited (see HERAG review [12]).

Michigan Department of Environmental Quality (MDEQ)

. The review by the National Environmental Policy Institute (NEPI) (11) reports that MDEQ has had a 1% value in place as the default dermal absorption value for all inorganic compounds since 1995.

West Virginia Department of Environmental Protection (WVDEP).

 In addition, the NEPI report (11) indicates that WVDEP relies heavily on EPA in providing guidance for considering bioavailability in assessing dermal exposures. Default assumptions provided for dermal absorption of metals from soil are 3% for arsenic and 1% for cadmium and other metals.


	Although fragmentary in nature, existing data do nevertheless show that dermal exposure to metals is limited, often well below 10% of that observed when the same materials are administered orally. This conclusion is entirely consistent with the fundamental nature of the dermis and the obvious barrier it presents to charged materials in particular, such as metal ions. Reflecting on the variable approaches taken by regulatory bodies, it is clear than even the most conservative and largely discredited (in the context of applicability to charged metal species) EASE model differs substantially from assumed parity with parenteral or even oral exposure. Certainly the assumptions prescribed by MDEQ and WVDEP of exposure levels equivalent to <5% absorption correlate well with data available, even though it is limited.

	With respect to ICH Q3D and the establishment of dermal exposure limits, the available evidence and data challenge any attempt to correlate dermal limits directly with oral data.  The available evidence and data strongly support the need for a case-by-case approach that takes into consideration such factors as metal form and relevant specific data to establish scientifically justifiable limits. Ultimately, the overriding evidence to date supports the view that dermal exposure to low-level elemental impurities is unlikely to represent a substantive toxicological concern.

		R. Mehta, “Topical and Transdermal Drug Delivery: What a Pharmacist Needs to Know,” 

		Astra Zeneca internal report, “Clinical Documentation on Xylocaine Ointment 5% (50mg/mL),” 2003.	

Technical Report No. 55. Linear Polydimethylsiloxanes 

		Hostynek et al., Critical Reviews in Toxicology  23 (2) 171-235 (1993).	

		National Environmental Policy Institute, 

Assessing the Bioavailability of Metals in Soil for Use in Human Health Risk Assessments. Bioavailability Policy Project Phase II Metals Task Force Report

Health Risk Assessment Guidance For Metals--Assessment Of Occupational Dermal Exposure And Dermal Absorption For Metals And Inorganic Metal Compound

Environmental Assessment and Risk Analysis Element

 (National Academy Press, Washington, 1999).	

		US Dept. of Health and Human Services, Agency for Toxic Substances and Disease Registry, “

Toxicological Profile for Arsenic (Aug. 2007)

Vanadium. Environmental Health Criteria 8

		C. Roper, “Disodium Molybdate Dihydrate: The In Vitro Percutaneous Absorption Of Molybdenum Through Human Skin,” Unpublished study report by International Molybdenum Association (2009).	

Risk Assessment Guidance for Superfund (RAGS), Volume I: Human Health Evaluation Manual (Part E, Supplemental Guidance for Dermal Risk Assessment)


	Andrew Teasdale, PhD* is principal scientist, chair of AstraZeneca‘s Impurities Advisory Group, Hurdsfield Road, Macclesfield, Cheshire, England, SK10 2NX, andrew.teasdale@astrazeneca.com; Katherine Ulman is global regulatory compliance healthcare manager, and Jean Domoradzki is an EHS specialist, both at Dow Corning Corporation, Auburn, MI; and Phyllis Walsh is associate director, compendial affairs at Merck, Rahway, NJ.

	*To whom all correspondence should be addressed.

 When referring to this article, please cite it as A. Teasdale et al., “Establishing Limits for Dermal Absorption of Elemental Impurities,” 

Current guidance for absorption of elemental impurities does not address dermal exposure, resulting in a simplistic approach to limit setting.

Establishing Limits for Dermal Absorption of Elemental Impurities

New guidelines relating to elemental impurities from the International Conference on Harmonization (ICH), Q3D 

 (1) have presented the pharmaceutical industry with new challenges. These challenges include the complexity of introducing new analytical technology-specifically inductively coupled plasma (ICP)-based techniques replacing the wet chemical “heavy metals” limit test-along with new and specific limits for individual elements. Perhaps the most significant challenges, however, are related to the practical implementation of the guideline. 

	ICH Q3D advocates the use of a risk-based approach to assessing the potential presence of elemental impurities in drug products. While such assessments are common within other aspects of pharmaceutical development, application to elemental impurity assessment presents new challenges. Specific challenges include determining how to assess or quantify the risks associated with factors such as water, container-closure systems, and excipients. Defining where in the assessment process data may be required and identifying where risks can be determined to be negligible through a thorough scientific theoretical risk assessment also present significant questions. This article seeks to review these questions by looking at the various risk factors and, where possible, weighting the risk factors based on appropriate and relevant considerations to establish an effective framework for the systematic assessment of risk and final control strategy. 


	 The introduction of ICH Q3D (1) is one of the most complex changes in regulations pertaining to impurities seen by the pharmaceutical industry. While the guideline is ultimately intended to focus on final drug product quality, the actual risk assessment will touch all facets of the manufacture of a drug product. The guideline introduces toxicologically relevant permitted daily exposure (PDE) limits to individual elements replacing non-specific 19th century wet chemical “heavy metal” limit tests. ICH Q3D advocates the use of a risk-based approach to assessing the potential for presence of elemental impurities in drug products. The process of executing and documenting the risk assessment is a major challenge, primarily as a result of a limited global understanding about how to assess or quantify the risk associated with factors such as water, container-closure systems, and excipients.

	Defining where in the assessment process data may be required and identifying where risks can be determined to be negligible through a thorough scientific theoretical risk assessment also present a significant challenge. Where the risk assessment identifies the need for testing, the level of the PDEs for the element(s) of concern may also require the broader introduction of new, more sensitive, and specific analytical technology, adding still further to the complexity.

	This article specifically seeks to examine relevant risk factors and, where possible, the weighting of these risks based on appropriate and relevant considerations. It also seeks to specifically define where in the assessment process data may be required as well as seeking to identify where risks can be determined to be negligible simply through a thorough scientific theoretical risk assessment.

	The general principles outlined in this article are believed to address most scenarios or product types; however, ultimately any drug-product manufacturer needs to consider potential sources of elemental impurities appropriate for their specific product. 


	The evaluation of the potential risk posed by elemental impurities within a formulated drug product requires a holistic approach taking into account all potential sources of elemental impurities. 

 illustrates potential sources that should be considered in such an evaluation. 

: Sources of elemental impurities in finished drug products.

, the drug substance is a key component that can contribute elemental impurities to the finished drug product. The risk of inclusion of elemental impurities from a drug substance, therefore, needs to be considered when conducting a drug product risk assessment. Control of the elemental impurity content of a drug substance can be assured through a thorough understanding of the manufacturing process including equipment selection, equipment qualification, GMP processes, packaging components, and the selection and application of appropriate control strategies.

	A principal responsibility for any drug-substance manufacturer is to develop a strategy to ensure effective control of the levels of elemental impurities in the finished drug substance. An approach based on assessing and controlling potential sources of elemental impurities, coupled with focused, limited testing, is preferable to exhaustive testing on the finished drug substance. A scientific, risk-based approach combined with knowledge and control of the key sources of elemental impurities in the drug-substance manufacturing process such as catalysts, provides an efficient and comprehensive elemental impurity control strategy for finished drug substances. 

 shows potential sources of elemental impurities in the drug substance manufacturing process. Of the sources highlighted, the greatest risk comes from intentionally added metals (e.g., metal catalysts used in the process). Manufacturing equipment, processing aids, inorganic reagents, water, solvents, and other organic materials are less likely to serve as major contributors of elemental impurities in the finished drug substance, but do require consideration.

: Primary sources of elemental impurities in drug substances (DS).

 Metal catalysts such as palladium and platinum are often used in the drug-substance manufacturing process and can therefore be present at low levels in the finished drug substance. The synthetic route should be reviewed for intentionally added metals, and data from purging studies, including any supportive testing of appropriate isolated intermediates, should be used in the design of an appropriate control strategy.
	 The ability to remove the catalyst (purge capacity) will be influenced by catalyst loading and the nature of the catalyst used in the process (i.e., homogeneous vs. heterogeneous catalysts). Heterogeneous catalysts, such as palladium on carbon, are often easily removed from reaction mixtures by filtration, and therefore, the risk of carryover of elemental impurities into the drug substance is typically low. Even in cases where metal catalysts are used in the final stages of the process, good historical data and/or understanding of carry-over may permit reduced testing schemes. 

	Biotech products do not normally rely on the use of catalysts. As ICH Q3D points out, typical purification schemes in biotech drug substance manufacturing are well capable of clearing any elements introduced either intentionally or inadvertently “to negligible levels.” The principles outlined previously may nonetheless be relevant in some specific cases (e.g., chemically modified biotech drug substances).

	When considering the other potential sources highlighted in 

, it is recommended to focus primarily on the manufacturing steps that occur after the formation of the final intermediate. Washes, crystallizations, phase separations, chromatography, distillations, and processing aids/scavengers aid in purging of elemental impurities and, therefore, reduce the risk of carryover into the finished drug substance from stages earlier in the upstream process. Areas for further consideration include manufacturing equipment, processing aids/inorganic reagents, solvents, water, and packaging. 

 In general, GMPs, including equipment compatibility assessment and qualification, are sufficient to ensure that significant levels of elemental impurities are not leached from manufacturing equipment into the drug substance. Hastelloy, stainless steel, and glass are the most commonly used materials of construction for drug substance manufacturing equipment, due to their superior chemical resistance. Nickel, cobalt, vanadium, molybdenum, chromium, and copper are key elements in some Hastelloy and stainless-steel alloys. Under extreme/corrosive reaction conditions, such as high temperature and low/high pH, these elements could have the potential to leach from manufacturing equipment. In such cases, it may be necessary to supplement standard GMP equipment compatibility assessments with specific studies to assess the elemental impurity-leaching propensity from manufacturing equipment due to corrosive reaction conditions. 

	Other potential sources include high-energy processes such as milling/micronization equipment. These are also generally considered to be low risk, but should be addressed via appropriate GMP including cleaning records and visual inspection. Particle size reduction is discussed in the Drug Product Manufacture section.

 Processing aids such as charcoal, silica, celite, and darco, and inorganic reagents such as sodium chloride, magnesium sulfate, and sodium sulfate, are often used in drug-substance manufacturing processes and may be used in significant quantities. Depending on their specific composition, inorganic reagents should be considered within the risk assessment, especially when ICH Q3D elements are integral to the formula. The levels used should also be considered as some reagents may be employed in higher relative amounts (i.e., in stoichometric amounts). In such instances not only the elements (intentionally) present in the reagents, but also reagent purity (or lack thereof) need to be taken into account. 

	In general, the use of such reagents presents a low risk. In studies conducted within the organizations associated with this article, there is little evidence to support such materials being a significant risk. Therefore, the risk assessment should primarily focus on processing aids and inorganic reagents used late in the drug substance manufacturing process, and/or where aggressive reaction conditions exist (e.g., extreme pH/high temperatures for prolonged times).

Assessing risk factors is key to implementing the new ICH Q3D guidelines for elemental impurities.