IPEC-Americas

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 two 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 at a level not achieved using the CPE components individually in a simple blend. With the increased functional performance, formulators are turning to CPEs, which are engineered combinations of two 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 for their use in continuous manufacturing, which provides for 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.

What Are the 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 multi-particulate 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, with many reported to be in commercial use, spanning direct-compression, 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 three 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: two 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 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

IPEC-Americas. 2024. “Co-Processed Excipients Demystified.” 

International Journal of Pharmaceutical Excipients

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 that 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.