The pharmaceutical industry faces the challenge of balancing science and innovation with patient safety. Among the issues affecting drug product manufacturers, nitrosamine impurities stand out due to their inherent risk to patient health. Why the concern? Evidence shows nitrosamines to be carcinogenic and associated with numerous cancer forms, including esophageal, stomach, liver, lung, and bladder.

 Still, other cancer forms, such as nasopharyngeal, colorectal, and brain, may be attributed to nitrosamine exposure.

 With this in mind, it is important to understand how nitrosamines form.

Pharmaceuticals—APIs and excipients—and their manufacturing processes can pose exposure risks. It is here that pharmaceutical companies can limit patient nitrosamine exposure.

The nitrosamine issue first emerged in June 2018, when 

-nitrosodimethylamine (NDMA) was detected in valsartan. This was followed in the larger group of sartans in July 2018. Ranitidine and metformin followed in 2019.

 The initial focus was on tablets; however, other routes of administration, such as topical, transdermal, and parenteral, may also be a nitrosamine exposure risk. At-risk APIs include secondary and tertiary amines and some amides.

Nitrosamine formation has been studied by industry, academia, and regulators hoping to better understand nitrosamine formation. Research shows that nitrosamines form through complex chemical pathways involving nitrosating agents (

From the studies, stakeholders have identified 7 nitrosamine compounds (

), specifically N-nitroso compounds (NOCs) associated with an increased health risk.

Today, more than 300 APIs have a potential for nitrosamine formation (


While some drug products have been withdrawn from the market, not all have. Regulators have worked with industry to determine acceptable exposure levels and have published acceptable intake levels that vary from 26.6 ng/day to 1500 ng/day (

 The European Medicines Agency (EMA) has also established acceptable intake levels through their own studies, as have PDMA (Japan), Health Canada, TGA (Australia), NMPA (China), and ANVISA (Brazil).

Mitigation Strategies: Excipient and Process Selection

Several nitrosating agent sources were mentioned earlier. There are others, and they can include packaging materials (nitrocellulose-based), process water, solvents (recovered and recycled solvents), and excipients. Knowing that excipients may contribute to nitrosamine formation, excipient stakeholders are collaborating to better understand excipient impact. Excipient suppliers are examining manufacturing processes to reduce the use of nitrosating agents. Excipient manufacturers actively assessing nitrosating agent levels are BASF, DFE Pharma, Evonik, Lubrizol, and Roquette. Case studies show how excipient selection mitigates nitrosamine formation and patient risk.

Pearlitol (mannitol) is one example. Pearlitol’s chemical structure is nitrogen-free, and the manufacturing process does not introduce nitrosamines or nitrosating agents during production (

Another question is whether there is a change in performance when controlling nitrite levels in excipients. Avicel PH exists in standard and low-nitrite forms. The manufacturing process used to produce Avicel with low nitrite levels has been assessed and determined not to alter the compaction performance compared to the standard offering (

Process selection for drug product manufacture is also fundamental in mitigating nitrosamine formation. API characterization and a risk assessment can determine if the manufacturing process is a contributing factor. For example, wet granulation processes can prompt formation for at-risk APIs. Additionally, elevated temperatures and humidities have demonstrated increased nitrosamine formation.

 Recovered and recycled solvent use, which has become more common, has demonstrated increased risk due to impurities present. Direct compression and dry granulation avoid conditions that might initiate formation (

and the US Food and Drug Administration (FDA)

, in their respective guidance documents, provide a strategy for nitrosamine mitigation (

). This approach provides a strategy toward risk evaluation, identification and level determination, and mitigation implementation, which can include excipient and process selection, as well as using scavengers.

Scavengers have shown to reduce nitrosamines (

The amino acids lysine, arginine, L-cysteine, and histidine have demonstrated nitrite scavenging as well as pH modification using caffeic and ferulic acid.

 Yet, not all scavengers are equally effective and should be assessed on their own merit, as one study showed. For the model compound, ascorbic acid showed greater nitrosamine reduction than α-tocopherol, with other options somewhere between.

The International Pharmaceutical Excipients Council (IPEC) developed a questionnaire to provide information on excipients, assisting pharmaceutical companies in evaluating the risk of nitrosamine impurities in the final drug product (

 The questionnaire was adapted from the EMA assessment report 

Nitrosamine Impurities in Human Medicinal Products

, the related EMA document "Questions and Answers for Marketing Authorization Holders," and the FDA Guidance for Industry 

Control of Nitrosamine Impurities in Human Drugs

. The questionnaire was developed as a harmonized approach to share information with drug product manufacturers.

With advances in instrumentation to aid with API characterization and nitrosamine detection, formulators are more prepared to implement nitrosamine mitigation strategies. Knowing whether an API is at risk is the first step and assists with excipient and process selection. Additionally, excipient manufacturers have responded to the pharmaceutical industry’s needs by making low-nitrite excipients available, as well as those used as scavengers. Excipients for direct compression and roller compaction can also be used to avoid wet processes that promote nitrosamine formation.


1. Akkaraju H, Tatia R, Mane SS, Khade AB, Dengale SJ. A comprehensive review of sources of nitrosamine contamination of pharmaceutical substances and products. 

2. Wichitnithad W, Nantaphol S, Noppakhunsomboon K, Rojsitthisak P. An update on the current status and prospects of nitrosation pathways and possible root causes of nitrosamine formation in various pharmaceuticals. 

 2023;31(2):295‑311. doi:10.1016/j.jsps.2022.12.010

3. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. 

Control of nitrosamine impurities in human drugs: guidance for industry.

4. US Food and Drug Administration. CDER nitrosamine impurity acceptable intake limits. Table 1. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cder-nitrosamine-impurity-acceptable-intake-limits#compound. Accessed April 10, 2026.

5. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. 

Recommended acceptable intake limits for nitrosamine drug substance–related impurities (NDSRIs): guidance for industry.

6. Moser J, et al. N‑nitrosamine formation in pharmaceutical solid drug products: experimental observations. 

Questions and answers for marketing authorization holders/applicants on the CHMP opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products.

 EMA/409815/2020 Rev.23. October 10, 2025.

8. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. 

9. Homšak M, Trampuž M, Naveršnik K, et al. Assessment of a diverse array of nitrite scavengers in solution and solid state: a study of inhibitory effect on the formation of alkyl‑aryl and dialkyl N‑nitrosamine derivatives. 

10. Bayne ACV, et al. N‑nitrosamine mitigation with nitrite scavengers in oral pharmaceutical drug products. 

11. International Pharmaceutical Excipients Council. 

IPEC questionnaire for excipient nitrosamine risk evaluation.

 https://ipecamericas.org/viewdocument/questionnaire-for-excipient-nitrosa. Accessed April 10, 2026.

Joseph Zeleznik, MA, is the technical director – North America at IMCD. Zeleznik brings nearly 4 decades of experience in pharmaceutical excipients and formulation development. His expertise spans high-functionality and novel excipients, continuous manufacturing, and advanced formulation strategies.

Sydney Badger, MS, is a technical development manager at IMCD. With over 7 years of experience in the pharmaceutical excipient industry, Badger has a strong background in oral solid dosage forms and formulation development. Leveraging her previous experience as an R&D formulator, she brings application-oriented technical expertise to her current role.

Manish Ghimire, PhD, is the director of technical development – North America at IMCD. Ghimire brings over 20 years of experience in pharmaceutical R&D and technical marketing, with deep expertise in solid dosage forms and advanced formulation strategies. He is a recognized thought leader known for translating complex scientific concepts into practical, commercially relevant solutions.

Articles

Nitrosamine impurities represent a high-priority quality and safety risk because many are potent carcinogens and can form during API/excipient manufacture, processing, storage, or from packaging. Following NDMA findings in valsartan (2018) and later ranitidine and metformin, scrutiny expanded beyond tablets to topical, transdermal, and parenteral products. Formation involves nitrosating species (eg, nitrites, NOx-derived acids) reacting with susceptible amines/amides; >300 APIs are potentially at risk. Acceptable intakes are nanogram/day-range and jurisdiction-specific. Mitigation emphasizes risk assessment, excipient/process selection (low-nitrite grades, dry processing), solvent/water controls, and scavengers; IPEC provides an excipient questionnaire.

Understanding how factors such as excipient choice affect nitrosamine formation is essential to developing safer, lower-risk pharmaceutical formulations.

Excipient Selection Strategies to Mitigate Nitrosamine Risks

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 (

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 (

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.

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.

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

Sustainability has become a core consideration in pharmaceutical manufacturing. It is driven by evolving global regulations, consumer expectations, and increasingly complex supply chains, which all demand a shift toward greener practices. Industrial sustainability efforts often focus on reducing emissions, optimizing resource efficiency, and minimizing waste across the product life cycle, without compromising human rights. From a manufacturing perspective, these efforts include responsible and sustainable sourcing, innovative product design, efficient manufacturing and shipping, and waste reduction.

Excipients can play a meaningful role in achieving sustainability goals in the pharmaceutical industry. Sourcing excipients that have a low carbon footprint and are derived from renewable sources is just part of the equation. Excipients designed to enable simpler, lower-energy processes are often overlooked for improving sustainability. This article explores the diverse ways excipient companies can support sustainable pharmaceutical production across the life cycle of a drug product.

How Is Environmental Impact Reduced at the Source?

The environmental impact of pharmaceuticals can be reduced by responsible sourcing, efficient manufacturing, waste reduction, life cycle assessment, and collaboration.

 At the heart of sustainability is responsible and sustainable sourcing. With a global perspective, these programs ensure ethical and environmental practices in procurement and implementation of traceability of raw materials, such as wood pulp and seaweed, which are widely used in the pharmaceutical industry. Many excipient manufacturers are prioritizing renewable feedstock and local and traceable supply chains through collaborations with raw material suppliers and external programs focused on ethical practices. For example, wood pulp, a starting material for cellulose-based excipients, including microcrystalline cellulose and hypromellose, can be responsibly sourced from suppliers that are certified by organizations such as the Forest Stewardship Council, Sustainable Forestry Initiative, or Programme for the Endorsement of Forest Certification. Key practices required for these certificates include sourcing from responsibly managed forests, protecting the rights and dignity of indigenous communities, and managing high conservation–value areas, while avoiding controversial sources like mature-growth forests to achieve deforestation-free value chains.

Each raw material going into plant-based excipients has its own set of needs to ensure an environmentally-friendly supply. Seaweed, a raw material used in the manufacturing of alginates, alginate-based materials, and carrageenan, does not require use of fertilizers or arable land like many land-based crops. However, minimal disruption to aquatic life is key to the responsible harvesting of seaweed, especially in a time of climate change. To maintain aquatic biodiversity, it’s important to develop and follow a sustainable harvest management plan. Many countries where seaweed is harvested, such as Norway and Iceland, have strict regulations on harvesting, requiring a 5-year growth cycle and rotating zones in harvest fields.

Excipients coming from crop raw materials (corn, wheat, pea, and potato) can be certified from the field to customers through chain-of-custody processes. Excipient manufacturers can guarantee these excipients are coming from fields without deforestation and farms using good agricultural and ethical practices. By participating in regenerative agricultural programs (eg, Covalo in France and Truterra in the US), excipient companies are dedicated to strengthening the resilience of farms facing climate change and securing more sustainable sources for raw materials.

Excipient companies (eg, Roquette, BASF, Ashland, and JRS) have implemented transparent sourcing protocols for raw materials and ensure compliance with responsible sourcing certificates.

Green chemistry and energy-efficient manufacturing

. Excipient companies are increasingly adopting greener production technologies to achieve energy efficiency. Process optimization, predictive modeling, and adoption of continuous manufacturing can increase yields and decrease the energy required per kilogram of material produced.

Solvent selection is another critical factor. The choice of solvent within a chemical process can affect both potential toxicity and environmental impact if not properly controlled. Some Class 2 solvents are also volatile organic compounds that can react with nitrogen oxides in the presence of sunlight to form ground-level ozone (smog). Replacing a Class 2 solvent with a safer Class 3 alternative may reduce toxicity and environmental hazards associated with some chemical syntheses.

Biocatalysis is gaining traction as a scalable solution for lowering carbon footprints in the production of active pharmaceutical ingredients (APIs).

 These processes use enzymes or whole cells to perform chemical reactions that produce molecules with highly precise chemical and stereo selectivity under mild conditions. A few excipients (eg, xanthan gum and citric acid) currently use bioprocesses such as fermentation in their synthesis. Expansion of biocatalytic processes in excipient production will depend on the industry’s ability to scale these bioprocesses for production in the thousands of kilograms (excipients) compared to kilograms for API.

 Excipient suppliers are increasingly embedding circular economic principles into their operations, with a focus on reducing waste and maximizing resource efficiency. Recycling and/or recovery systems can reduce incineration and disposal of waste streams. Water reuse strategies, including advanced filtration and reverse osmosis, are effective at separating water from a range of materials from large particles down to ions, substantially reducing freshwater withdrawal and wastewater discharge.

 These efforts not only reduce environmental impact and lower operational costs but also align with good manufacturing practice (GMP) frameworks requiring validation of solvent recovery processes—covering critical parameters, impurity monitoring, and annual requalification.

Excipient packaging is another area where suppliers can make changes to reduce waste. Companies are shifting from traditional fiber drums to recyclable, lightweight packaging formats (eg, bag-in-box), thereby cutting packaging waste by over 85% and improving pallet loading efficiency.

 Boosting pallet density lowers the emissions per unit with regard to shipping of the material around the world. These improvements come as regulatory initiatives such as Packaging and Packaging Waste Regulation (PPWR) (EU) 2025/40 set out sustainability requirements for packaging through its life cycle, including production, use, and waste management.

Excipient packaging selection can have more impact on waste management than just the physical packaging material waste. Properly selected packaging can extend the shelf life of the excipient material, allowing for more flexible supply chain maintenance and resulting in less unusable material making its way to landfills or incinerators.

Regulatory frameworks—spanning EU directives, US standards, and international GMP guidelines—are driving excipient suppliers and pharmaceutical manufacturers to invest heavily in circular infrastructure; the outcome is reduced waste, reduced greenhouse emissions, and compliance readiness. The EU PPWR 2025/40, effective from August 2026, mandates that all packaging across industries—including pharmaceuticals—must be designed for recyclability by 2030 and be recyclable at scale by 2035. It also imposes minimum recycled-content requirements for plastic packaging, with potential exemptions for primary pharmaceutical packaging until 2035. New obligations such as harmonized recycling symbols and QR codes (due by 2028) further support clear end-of-life handling.

 Extended Producer Responsibility under PPWR compels excipient and pharmaceutical producers to finance reverse logistics, such as packaging end-of-life collection, sorting, and recycling, with fees modulated by environmental performance. In the United States, the FDA’s International Council for Harmonisation (ICH) Q3C guideline and companion residual solvents guidance emphasize minimizing residual solvents in drugs—including excipients—encouraging manufacturers to recover and reuse solvents instead of disposing of them, because reducing solvent use also lowers residual risk.

 The US Environmental Protection Agency Subpart P (40 

Part 266) enforces strict controls on hazardous pharmaceuticals—including excipient residues—banning sewer disposal and requiring safe management, which motivates facilities to implement closed-loop solvent and water systems to avoid discharges and protect the environment.

 To enhance transparency with customers and suppliers, pharma industry companies work relentlessly on conducting life cycle assessments (LCAs) for their products. LCAs play a central role in quantifying and communicating the environmental impact of excipients across their entire value chain—including raw material sourcing, production, distribution, and end-of-life. Pharma companies often conduct product carbon footprint calculations in alignment with the International Organization for Standardization (ISO) standards and the Greenhouse Gas Protocol. In support of these efforts, excipient companies are providing their own LCAs on their products. Many companies publish sustainability reports detailing carbon footprints, energy usage, and progress toward emission reduction targets—providing transparency to regulators and customers alike. 

Roquette has aligned its operations with various climate regulatory and circular economy frameworks,

 including the principles of the Product Sustainability Assessment, published by the World Business Council for Sustainable Development. SPARQ provides a sustainability score based on the environmental footprint through quantitative LCA and the extent to which the product provides environmental and societal benefits when used. One of Roquette’s targets by 2030 is to cover 100% of their products with an LCA.

BASF has developed a rigorous methodological framework for product carbon footprinting, adhering to ISO 14067:2018. Individual LCAs assess carbon emissions, resource use and waste generation across the product life cycle, enabling optimized formulations and production processes.

 IMCD, a global distributor of specialty chemical ingredients (including excipients), reports annually under Global Reporting Initiative standards and frameworks, such as the UN Global Compact. Its dashboards detail supplier emissions, logistics energy efficiency, and waste performance, offering insights into environmental impacts across sourcing and distribution activities.

 By openly sharing LCA data, both BASF and IMCD demonstrate environmental accountability and empower formulators and planners with data that support sustainable decision-making, regulatory compliance, and end-product transparency. Conducting LCAs also helps companies understand their own resource use and environmental impacts focusing on product sustainability.

Collaborative sustainability frameworks. 

The pharmaceutical excipient industry is increasingly leveraging collective action—through partnerships, consortia, and cross-sector initiatives—to drive sustainable outcomes. Suppliers are collaborating with farming cooperatives and agronomists to promote regenerative agriculture practices for crops and cellulose feedstocks. These programs focus on soil health, biodiversity, and carbon sequestration, enabling a more circular and resilient agricultural ecosystem. Cross-industry audit frameworks, such as Together for Sustainability and UN Global Compact, help suppliers ensure that ethical labor standards and biodiversity-preservation practices are embedded in raw material sourcing and feedstock cultivation.

These collaborative models signify a profound transition in the pharmaceutical supply chain: Sustainability is no longer a marketing add-on but a fundamental design principle. Formulators can now source excipients that are both functionally robust and aligned with environmental, social, and governance (ESG) objectives, bolstered by verified traceability, environmental integrity, and social responsibility. Industry consortia and partnerships are fostering shared standards for sustainable excipient development. Initiatives include joint programs for regenerative agriculture supporting crops and cellulose feedstocks and cross-industry audits to ensure ethical labor practices and biodiversity preservation.

To go further, Roquette decided to target a 25% reduction in emissions by 2030. This target aligns with the Science Based Targets initiative and the Paris Agreement, ensuring that Roquette’s efforts contribute meaningfully to global climate goals.

How Are Technical Advancements in Excipients Reducing Energy, Water, and Waste in Pharma Manufacturing?

Formulation design represents one of the most impactful opportunities to reduce energy, water, and waste in pharmaceutical manufacturing. By leveraging innovative excipients, manufacturers can simplify processes, minimize waste, and enhance operational efficiency without compromising product performance or regulatory compliance. Excipients can reduce environmental impact beyond manufacturing too. By enabling smaller, more stable dosage forms, supporting recyclable packaging, and reducing environmental persistence, excipients help minimize waste and emissions from production to patient use and disposal. The following are some examples of how excipient and formulation innovation can impact sustainability initiatives.

Reducing water and energy consumption using moisture-activated dry granulation (MADG). 

Traditional wet granulation is resource-intensive, requiring significant water (20%-50% of the weight of the dry powder) and energy for drying. MADG offers a sustainable alternative by using minimal liquid (1–4 wt% water) to agglomerate powders without a heat-drying phase (

). Eliminating the heating phase reduces energy consumption by about 50% (or more) compared to conventional wet granulation processes.

 The MADG process comprises 2 main phases: agglomeration and moisture distribution. During the agglomeration phase, a small amount of water is added to a subset of ingredients, including the API, to create agglomerates with a predetermined particle size that will ensure satisfactory flow. The second step involves blending in an excipient (or 2) that will absorb and redistribute the moisture within the mixture. Subsequent addition of excipients, like lubricants, proceeds as typically done. The key to this process is selecting excipients that absorb and distribute water throughout the formulation. Avicel PH-200 LM, a low-moisture-grade microcrystalline cellulose, enables MADG by providing excellent binding, water redistribution, and flow properties under low moisture conditions.

Reducing energy consumption by direct compression with made-for-purpose excipients

. Direct compression (DC) eliminates multiple steps inherent in wet granulation, such as wet massing, drying, and milling (

). DC saves time, water, energy, and money. One study estimates that the drying stage needed in wet granulation accounts for 45% to 84% of the total energy consumption of the entire production process.

 Not all formulations are well designed for DC. The blended formulation must flow well and not segregate. Careful selection of excipients can provide good flow, consistent particle size, and good compressibility properties to aid in successful DC production with suitable API. Excipient manufacturers recognize the benefits of DC and are designing excipients for direct compression, like Avicel silicified microcrystalline cellulose (SMCC; Roquette), mannitol and hydroxypropyl methylcellulose (PEARLITOL CR-H; Roquette), and direct compression hydroxypropyl methylcellulose (METHOCEL DC2 HPMC; Roquette).

Co-processing excipients can improve the flow and reduce segregation of critical excipients within a formulation, often rendering them superior to their individual components in direct compression processes. SMCC, a co-processed excipient, flows better than both microcrystalline cellulose (MCC) and the blended mixture of silica and MCC, while also providing better tablet strength and uniformity compared to the blended combination.

 The co-processing step does not chemically change either the silica or the MCC,

 but it provides intimate integration that outperforms the simple blended mixture in direct compression. Similarly, co-processing mannitol with HPMC produces an excipient that flows well and has good compressibility in direct compression processes for controlled-release formulations.

Not all excipients made for direct compression need to be co-processed. Direct compression hydroxypropyl methylcellulose is morphologically designed for better flow than standard HPMC products without any change to chemistry or composition. The direct compression grades of HPMC show reduced tablet variability (hardness and weight) compared to the standard HPMC grades using several model API formulations in DC processes [28, 29].

One study showed that moving from a production process that includes wet granulation with HPMC to a direct compression process with direct compression grades of HPMC could save 42% in production time and 61% in production costs,

 further emphasizing that excipients and excipient manufacturers can support pharma’s goals in efficiency gains.

. Film coating is another energy-intensive process, often requiring high temperatures and long cycle times. Coating processes and formulations that can reduce the drying temperature and drying time (and thus the overall energy input to the system) are more eco-friendly. A hydroxypropyl pea starch–based coating system addresses these challenges by enabling up to 50% reduction in coating time, 25% lower processing temperatures, and half the CO

 emissions compared to traditional coating systems.

Beyond energy savings, this system simplifies cleaning cycles, reducing water usage by 45% and eliminating the need for harsh solvents, further supporting sustainability goals.

These technical advancements demonstrate how excipient innovation can serve as a catalyst for sustainable pharmaceutical manufacturing, reducing resource consumption, improving efficiency, and aligning with global climate and ESG objectives.

Excipient innovation is part of a broader eco-design strategy that integrates sustainability into every stage of product development. By reducing energy consumption, minimizing waste, and sourcing responsibly, excipients are helping the pharmaceutical industry meet their sustainability targets without compromising quality or safety.

BASF Methodology for Product Carbon Footprint Calculation

. BASF SE. August 2022. Accessed March 10, 2026. https://www.basf.com/dam/jcr:66611f85-8ae8-3714-8a66-fdecde3ccee4/basf/www/global/documents/en/sustainability/we-drive-sustainable-solutions/quantifying-sustainability/product-carbon-footprint/BASF_Methodology_for_Product_Carbon_Footprint%20Calculation_August_2022.pdf

Energy and climate protection. BASF. 2022. Accessed March 10, 2026. https://report.basf.com/2022/en/managements-report/sustainability-along-the-value-chain/safe-and-efficient-production/energy-and-climate-protection.html

. Ashland. 2022. https://cdn.mediavalet.com/usva/media/ls8qZ2jUf0OqJm2mHOJZSw/ZrMvPRm5lkuVXOHuCCNVPA/Original/COR17-1041.5-ESG-Report-FY22-Interactive.pdf

JRS integrates “sustainability management” organizational unit and completes EcoVadis rating. JRS. September 17, 2024. Accessed February 10, 2026. https://www.jrs.eu/en/news/data/sustainability-management.php

Kaul P, Banerjee A, Banerjee UC. Opportunities for the pharmaceutical industry: key biotransformation technologies of the future. 

. April 28, 2004. https://www.ddw-online.com/opportunities-for-the-pharmaceutical-industry-key-biotransformation-technologies-of-the-future-598-200404/

France SP, Lewis RD, Martinez CA. The evolving nature of biocatalysis in pharmaceutical research and development. 

Azmi LS, Jabit NA, Ismail S, Ishak KEHK, Abdullah TK. Membrane filtration technologies for sustainable industrial wastewater treatment: a review of heavy metal removal. 

. 2025;323:101321. doi:10.1016/j.dwt.2025.101321

Adden A. Optimizing supply chains to reduce pharmaceutical waste: the role of excipient packaging. Roquette. September 17, 2025. Accessed January 6, 2026. https://pharma.iff.com/blogs/optimizing-supply-chains-to-reduce-pharmaceutical-waste-the-role-of-excipient-packaging

The European Parliament and the Council of the European Union. Regulation (EU) 2025/40 on packaging and packaging waste. Published December 19, 2024. Accessed January 6, 2026. https://eur-lex.europa.eu/eli/reg/2025/40/oj/eng

Michiels L. EU Packaging Regulation 2025/40: why it matters for the pharmaceutical industry. SPG. September 15, 2025. Accessed January 6, 2026. https://www.spgl.eu/eu-packaging-regulation-2025-40-why-it-matters-for-the-pharmaceutical-industry/

Mavor C. EU packaging & packaging waste regulation: impact on healthcare. Oliver Healthcare Packaging. April 22, 2025. Accessed January 6, 2026. https://www.oliverhcp.com/news-and-resources/packtalk/eu-packaging-packaging-waste-regulation-impact-on-healthcare

Guidance for Industry: Residual Solvent in Drug Products Marketed in the United States

. FDA. November 2009. Accessed January 6, 2026. https://www.fda.gov/media/70928/download

Q3C(R8) Impurities: Guidance for Residual Solvents

. FDA. December 2021. Accessed January 6, 2026. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q3cr8-impurities-guidance-residual-solvents-guidance-industry

Code of Federal Regulations. Title 40, Subpart P — Hazardous Waste Pharmaceuticals. National Archives and Records Administration. February 22, 2019. Accessed January 6, 2026. https://www.ecfr.gov/current/title-40/chapter-I/subchapter-I/part-266/subpart-P

New Subpart P rule: what the 2025 hazardous waste pharmaceuticals regulations mean for your facility. Waste Medic. 2025. Accessed January 6, 2026. https://wastemedic.com/2025/07/15/new-subpart-p-rule-what-the-2025-hazardous-waste-pharmaceuticals-regulations-mean-for-your-facility/

Preserve the planet. Roquette. 2026. Accessed January 6, 2026. 

https://sustainability.roquette.com/preserve/

Plant-based leaders. Plant Based Product Council. August 14, 2025. Accessed January 6, 2026. https://pbpc.com/plant-based-leaders-roquette/

. IMCD; 2022. https://www.imcdgroup.com/document/sustainability-report-2022-MC5KYVBRPWSVGKRHWNORZN4QO7AU

Sustainability reports. IMCD. 2026. Accessed January 6, 2026. https://www.imcdgroup.com/about-us/sustainability/sustainability-reports

Standards and guidance. Science Based Targets; 2026. Accessed January 6, 2026. https://sciencebasedtargets.org/standards-and-guidance

Karunanayake YH, Brütsch L, Meunier V, Salman AD. Sustainability vs suitability in granulation. Chem Eng Res Des. 2024;202:272-283. doi:10.1016/j.cherd.2023.12.032

Ullah I, Corrao R, Wiley G, Lipper R. Moisture activated dry granulation: a general process. 

Ullah I, Chang J, Wiley G, Jain N. Moisture-activated dry granulation part I: a guide to excipient and equipment selection and formulation development. 

Ullah I, Wang J, Chang S-Y, Guo H, Kiang S, Jain NB. Moisture-activated dry granulation part II: the effects of formulation ingredients and manufacturing-process variables on granulation quality attributes. 

Alfa J, Odeniyi M, Jaiyeoba KT. Direct compression properties of microcrystalline cellulose and its silicified product.

. 2006;7(3):56-59. doi:10.4314/ecajps.v7i3.9714

Lin L. Sustainability by design: excipient innovation for resource-efficient formulation. Presented at: AAPS PharmSci 360; November 9-12, 2025; Philadelphia, PA.

Tobyn MJ, McCarthy GP, Staniforth JN, Edge S. Physicochemical comparison between microcrystalline cellulose and silicified microcrystalline cellulose. 

. 1998;169(2):183-194. 10.1016/S0378-5173(98)00127-6

Kodam M, Jacob K, Curtis-Fisk J, et al. Flowability evaluation of formulations involving METHOCEL. Presented at: AAPS Annual Meeting & Exposition; November 12-15, 2017; San Diego, CA.

Rogers TL, Hewlett KO, Curtis-Fisk JL, Balwinski KM, Schmitt RL, Khot SN. Direct compression of HPMC matrix tablets containing metformin HCl materials with different particle size distributions. Presented at: AAPS Annual Meeting & Exposition; November 12-17, 2017; San Diego, CA.

Baumann M. Excipient innovation requires close collaboration. ONdrugDelivery. 2018;(88):22-25.

Freed P. A new, more sustainable film coating system for the nutraceutical industry. Roquette. June 10, 2025. Accessed February 5, 2026. https://www.roquette.com/health-pharma/resources/sustainable-film-coating

Lily Lin, PhD, is a senior applications scientist at Roquette in the Health and Pharma Solutions Business Unit, specializing in formulation design and excipient innovation. She holds a PhD in polymer chemistry from Texas A&M University and completed postdoctoral training at MIT.

Prathiba Devadas is a sustainability engineer at Roquette in the Health and Pharma Solutions Business Unit, focusing on responsible sourcing, scope 3 emissions, zero waste to landfill, sustainability in research and development, and strategy development.

Sustainability in pharmaceutical manufacturing is increasingly shaped by regulation, ESG expectations, and supply-chain complexity. Excipients influence decarbonization and waste reduction through responsible sourcing of renewable feedstocks, greener synthesis, circular operations, and data transparency. Certified wood pulp, sustainably harvested seaweed, and regenerative agriculture programs support deforestation-free, ethical supply chains. Process innovations—solvent substitution, continuous manufacturing, and emerging biocatalysis—lower energy and toxicity. LCAs and standardized reporting enable product-level carbon accounting, while packaging redesign and closed-loop solvent/water systems align with EU PPWR and US solvent/hazardous-waste guidance.

Excipients contribute to more sustainable practices throughout the life cycle of a drug. 

Strengthening Sustainability Through Smarter Ingredients: Designing Resource‑Efficient Formulations

In an earlier series of articles by Wiggins and Albanese addressing the challenges of pharmacopoeia compliance, consideration was given to the global regulatory expectations and requirements, with guidance provided on how to address the potential misalignment of compendial monographs and drug product registrations.

 A subsequent article in that series provided a case study detailing the specific challenges for excipients.

 That article listed several strategies to ensure multi-compendial compliance for excipients and included a brief discussion on internal or in-house harmonization. Previous articles in this current series have introduced the concepts and provided the tools for establishing specification equivalence.

 The present article details a practical application of specification equivalence to excipients testing to achieve in-house harmonization.

Excipients are present in essentially every pharmaceutical product currently approved and marketed around the world. For most of these drug products, excipients comprise the vast majority of the dosage form content. Oftentimes, a small number of different excipients are used in a wide variety of products in a company’s portfolio. For example, many solid oral dosage forms combine the active drug substance with common excipients, including lactose, starch, microcrystalline cellulose, magnesium stearate, and titanium dioxide, among other ingredients. Pharmacopoeia monographs exist for most common excipients, and regulatory agencies require conformance with these monograph requirements.

Compliance with the quality requirements for excipients as published by pharmacopoeias around the world is a significant challenge in global registration and distribution of medicinal products (pharmaceuticals, biologics, and vaccines). Establishing appropriate specifications through in-house harmonization can help ensure compliance with excipient monographs in multiple pharmacopoeias to provide meaningful benefits. These include minimizing the testing needed to ensure compliance with pharmacopoeia requirements and health authority expectations while also enabling flexibility in filing strategies. The approach is based on the principles of specification equivalence presented in the earlier articles in this series and addresses regulatory expectations and requirements at a global level, while reducing redundant testing of multi-compendial excipients by a bio/pharmaceutical company.

Achieving multi-compendial compliance for excipients in pharmaceuticals is crucial for global distribution. In-house harmonization of excipient specifications, based on specification equivalence, can streamline compliance with various pharmacopoeias, reducing redundant testing. This involves evaluating and selecting appropriate methods and acceptance criteria from major pharmacopoeias like Ph. Eur., USP–NF, and JP. The process includes method evaluation, harmonization, and acceptance criteria assessment. Extending these principles to other pharmacopoeias can further enhance compliance. This approach ensures excipients meet global regulatory expectations while optimizing testing and filing strategies.

The authors detail a practical application of specification equivalence to excipients testing to achieve in-house harmonization.

Pharmaceutical Technology Ingredient Innovations eBook

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Strengthening Sustainability Through Smarter Ingredients: Designing Resource‑Efficient Formulations

Multi-Compendial Compliance for Pharmaceutical Excipients, Part 1: A Practical Application of Specification Equivalence