Joseph Zeleznik is technical product director, IMCD US

Joseph Zeleznik

Scientist Examining Medical Documents Near Ampoules and Pills | Image Credit: ©PixelPulse-stock.adobe.com

Traditionally, supplier questionnaires from pharmaceutical companies have been an essential part of most quality management systems to ensure that information related to an ingredient and its supplier is documented. This information can include almost anything from the raw materials used in manufacturing to packaging materials, as well as the distribution channels used for sourcing. Questionnaires have historically been used to assist excipient users with qualifying and periodically reassessing a supplier’s potential risk. Questionnaires present numerous challenges, including those related to time requirement for completion, consistency with the information shared, and the ability to have version control. The sheer number of questionnaires submitted by pharmaceutical companies for completion by suppliers is immense and nonstandardized. Conversely, the number of questionnaires to which suppliers must respond, as well as the varied questionnaire formats submitted, exacerbates the challenge. This often results in slowed response times, decreased information accuracy, and a non–value-added increased workload. To overcome the challenges, the International Pharmaceutical Excipients Council (IPEC) has established the Excipient Information Package (EIP) User Guide and Templates to streamline information exchange, reduce response times, and increase accuracy through a standardized information-sharing format.

IPEC’s EIP addresses the most commonly requested information by clearly articulating the type and level of information that users need to support use of the excipient. EIPs and the associated templates are also organized in a standardized format that can be shared quickly and efficiently and updated easily. The EIP has another benefit: the ability for excipient makers to update excipient users with changes that may affect a previously completed questionnaire, keeping key information current.

The EIP is not new. Introduced 20 years ago, the EIP continues to improve as the scope of requested information evolves. For instance, in 2023, a new section on sustainability was included. More importantly, EIP development is, and has been, a collaborative effort among excipient stakeholders, specifically manufacturers, distributors, and users. Since its inception, the EIP has undergone some modest changes while maintaining a standardized approach to information sharing. Further, the EIP has been adopted globally, making it easier to share information internationally.

Key benefits of the EIP include the following:

Excipient users can receive complete information in a standardized format to support their regulatory filings.

Change control is facilitated through periodic reviews and updates.

The opportunity for electronic data transfer makes information exchange more effective and efficient.

Streamlines what is otherwise a labor-intensive activity and enables quick delivery of information to the user.

Distributors can respond to information requests expeditiously and independently while ensuring consistent, accurate information.

EIP document templates, currently in 4 parts, are designed to provide relevant information to individuals experienced and knowledgeable with excipient supplier evaluation. The EIP is not intended to replace audits. EIP review may serve as preaudit preparation to assist with a supplier audit, particularly if it is the first time visiting an excipient manufacturing site. The EIP documents are intended to generate a detailed, comprehensive information package. Each EIP part or section is designed as a standardized, stand-alone document that addresses information requests typical of questionnaires. Some information may, therefore, be common among the documents.

Part I: Product Regulatory Datasheet. The Product Regulatory Datasheet is designed to communicate important physical, manufacturing, and regulatory information specific to the excipient.

Part II: Site Quality Overview. The Site Quality Overview is intended to communicate a summary of the quality systems and good manufacturing practices/good distribution practices used to manufacture/distribute the excipient(s) at a particular site or sites.

Part III: Supply Chain and Security Overview. The Supply Chain and Security Overview is designed to provide users with information concerning the product supply chain from the manufacturing site through delivery to the user site, including security of the product.

Part IV: Sustainability Guide. The Sustainability section facilitates the communication of the excipient supplier's information on sustainability policies and related matters.

What Is the Value of the EIP to Stakeholders?

An accurately prepared EIP is dependent on a suitable interpretation of IPEC’s Excipient Information Package User Guide and Template, commonly referred to as the EIP Guide. A regulatory reference page is provided on the IPEC–Americas website (https://ipecamericas.org) to assist excipient manufacturers with preparing EIP documents.

The EIP provides an efficient process for sharing information compared with completing a questionnaire, which is labor-intensive and time-consuming. Many companies have elected to maintain EIPs on their company website, making the retrieval process even more efficient.

The EIP streamlines the sharing of information for excipient maker, distributor, and user by eliminating the need to develop, submit for completion at defined frequencies, and track the return of completed questionnaires. Response times for EIP requests are shorter than those for traditional questionnaires. Depending on the receipt of the information request, the EIP can typically be furnished within 24 to 48 hours or less. Questionnaires, on the other hand, can take months from receipt to return and may not be complete. Missing or inadequately completed questionnaires can delay supplier or excipient qualification, which can delay drug product development, manufacture, and commercialization.

It is important that the information shared between the excipient supplier and the user is up to date. The EIP offers an important advantage over completing traditional questionnaires in this regard. Because the EIP can be integrated into the excipient supplier’s change management process, updates to the EIP, when required, become routine. Although requested by pharmaceutical companies, questionnaires provide no mechanism for updating in the event of changes by the excipient manufacturer. The EIPs are version-controlled, with an established revision process to ensure that information provided in the EIP remains current. EIPs are standardized, similar to a Safety Data Sheet, which facilitates preparation, maintenance, and use of information.

What Is the Benefit to Excipient Manufacturers?

EIPs offer significant benefit to excipient manufacturers as well. The challenge of receiving, completing, and returning numerous customer questionnaires is time-consuming and labor-intensive. Aside from differences in questionnaire formatting, questions can be vague, difficult to interpret, or not applicable to excipients. The level of information requested can be as simple as yes/no to providing detailed information that may have limited value to the user. The result is often incomplete questionnaires or sharing incorrect or irrelevant information. When questionnaires are completed by multiple individuals within an excipient company, there can be inconsistencies in what information is shared and how it is shared. Additionally, due to the manual nature of the process, “hand-completed” questionnaires are typically not incorporated into the excipient manufacturers' quality management systems.

The EIP was designed and developed by subject matter experts to expedite information sharing, transforming the process from inadequate to a system of reliable, peer-reviewed documents that are managed within the quality management system. EIP’s can easily identify confidential information that would need to be shared by an NDA or a drug master file (DMF). As such, excipient users can be assured that EIPs are prepared and internally reviewed for accuracy by qualified personnel.

What Are the Benefits of Distribution Channels?

Increasingly, excipient supply chains rely on distribution channels, particularly for smaller pharmaceutical companies. Distributors routinely facilitate the delivery and follow-up of customer questionnaires for internal use and between their suppliers and customers. This process consumes numerous resources and creates delays for the customers. The supplier EIP can directly provide excipient-related information to all customers rather than requiring the distributor to complete and route customer-specific documentation.

EIP streamlines the handling of this essential function to provide meaningful information rather than dedicating many hours to tracing a single questionnaire. Increasingly, upon receipt of a questionnaire from a distributor, the excipient manufacturer can respond in a timely manner with a product-specific EIP. The EIP provides direct information from the supplier on the supplier’s letterhead, ensuring direct transfer of information without interpretation or additional information from the distributor.

The EIP provides the type of information users require to support their intended use. This information is provided directly to the user in an efficient manner, preventing delays typically seen with questionnaires. EIPs are document-controlled with periodic review. Changes are managed through revision history and version control. Integration into the quality management system and the management of change process ensures that the EIP is always current and meets the needs of the excipient user.

Other benefits of the EIP process include the following:

The EIP can be used as preaudit information to facilitate the audit process. However, EIPs should not be used in place of performing audits.

Excipient users can easily compare suppliers because information is provided in a common, standardized format.

Users can quickly identify changes by reviewing EIP revision history.

New, industrywide information requirements can easily be incorporated into the EIP.

Resource consumption from redundant activities can be minimized.

IPEC’s Excipient Information Package User Guide and Templates facilitates a streamlined, consistent approach to information sharing among stakeholders (excipient manufacturers, distributors, and pharmaceutical companies). The EIP provides information using an international standardized format and addresses the requirements common to many questionnaires. EIPs shorten response times, which helps expedite supplier qualification. EIPs are not a substitute for audits but can help with audit preparation and risk assessment. The EIP facilitates the rapid exchange of key excipient information throughout the supply chain. The EIP content is routinely updated and managed with version control.

The IPEC EIP was developed as a means of efficiently communicating a significant amount of information about the excipient (Part I), the excipient manufacturer (Part II) and the distribution and supply chain (Part III), and sustainability (Part IV).

 The information provided facilitates and aids the excipient user in their qualification of the excipient supplier and the excipient.

IPEC Americas encourages the use of EIPs throughout the industry to improve rapid information exchange, reduce costs, and improve timely distribution of key excipient information. Utilizing EIPs would be a significant improvement over the use of customer questionnaires to obtain necessary information. The EIP Guide and Templates are available for no charge by visiting the Public Library of the 

IPEC Federation announces the revised IPEC Excipient Information Package Guide. IPEC Federation. Accessed June 23, 2026. 

https://ipec-federation.org/ipec-federation-announces-the-revised-ipec-excipient-information-package/

Regulatory references. IPEC Americas. Accessed June 23, 2026. 

https://ipecamericas.org/reference-center/regulatory-references

Guidelines. IPEC Federation. Accessed June 23, 2026. 

Joseph Zeleznik is director of technical service at IMCD US LLC. Joseph brings nearly 4 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 the IPEC-Americas Executive Committee, currently serving as immediate past chair.

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. He is a former chair of IPEC-Americas and is currently the chair of the IPEC-Americas QbD/Composition Committee.

Candy Reynolds-Cummings is the regulatory and product stewardship manager at Evonik Corporation. Candy spent 15 years at GlaxoSmithKline, starting as an analytical chemist and QA validation manager in the OTC area (specifically oral care). She is currently working at Evonik as the regulatory and product stewardship manager for the Silica business line, supporting regulatory compliance in the US, Canada, and Mexico, and is the chair of the IPEC-Americas Excipient Qualification Committee.

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 health care business, as well as regulatory manager of the Dow Corning Healthcare Industries Materials Site. Kathy is a technical specialist for IPEC-Americas.

Charlotte McIlvaine is senior manager, North America Pharma Quality at Univar Solutions. Charlotte is an analytical chemist experienced in quality control and quality assurance. Charlotte joined Univar Solutions over 9 years ago to oversee quality in 2 districts, focusing on the quality needs for Univar Solutions’ pharmaceutical customers.

Articles

Supplier questionnaires remain central to pharma quality systems but are increasingly inefficient due to nonstandard formats, high volume, slow turnaround, inconsistent responses, and weak version control. IPEC’s Excipient Information Package (EIP) offers a standardized, globally adopted, document-controlled alternative that accelerates information exchange, supports regulatory submissions, and integrates with supplier change management. The EIP comprises four modular templates covering product regulatory data, site quality systems, supply chain/security, and sustainability. It streamlines qualification workflows for manufacturers, distributors, and excipient users while complementing, not replacing, audits.

IPEC’s EIP user guide streamlines information exchange and response times while increasing accuracy through standardization.

IPEC’s Excipient Information Package: A Standardized Communication Platform for Sharing Excipient Information as an Alternative to Questionnaires

-Nitrosodimethylamine molecular structure (3-dimensional model); dimethylnitrosamine structural chemical formula.

| Image Credit: ©Сергей Шиманович -stock.adobe.com

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 (

Figure 1. Recognized Nitrosamine Formation Pathway. Figure courtesy of the authors. 

From the studies, stakeholders have identified 7 nitrosamine compounds (

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

Figure 2. Seven Known Nitrosamine Compounds. Figure courtesy of the authors.

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).

Table I: APIs Identified as Having Potential Nitrosamine Formation

Table II: Acceptable Intake Level Based on Nitrosamine Type

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 (

Figure 3. Mannitol Chemical Structure. Figure courtesy of the authors.

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 (

Figure 4. Compaction Profile for Standard and Low Nitrite Avicel PH. Figure courtesy of the authors.

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 (

Figure 5. Impact of Drug Product Manufacturing Process and Temperature and Humidity on Nitrosamine Formation. Figure courtesy of the authors.

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.

Figure 6. Three-step Nitrosamine Mitigation Strategy. Figure courtesy of the authors.

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.

Figure 7. Nitrosamine Reduction Using Scavengers. Figure courtesy of the authors.

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.

Figure 8. IPEC Questionnaire for Excipient Nitrosamine Risk Evaluation. Figure courtesy of the authors.

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.

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

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

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

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

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

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

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

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

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

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

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

Why are material properties so important? 

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

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

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

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

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

Powder properties that impact unit operations in CM. 

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

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

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

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

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

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

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

Characterization technique considerations. 

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

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

Having standardized methods offer several benefits:

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

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

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

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

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

Impact of material properties and variability on continuous manufacturing

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

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

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

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

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

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

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

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

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

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

Excipient traceability in drug product batches manufactured by CM

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

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

The need for excipients designed for purpose

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

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

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

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

High regulatory uncertainties related to CPEs.

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

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

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

Regulatory and industry perspective on how to mitigate risks

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

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

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

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

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

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

Continuous Manufacturing of Drug Substances and Drug Products

Incorporation of Pharmaceutical Excipients into Product Development Using QbD Guide

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

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

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

Understanding Excipient Characteristics to Ensure Robust Continuous Manufacturing 

This article is the third in a series related to excipient composition authored by members of the International Pharmaceutical Excipients Council of the Americas (IPEC-Americas). The first article, “

The Real Complexity of Excipient Composition

” described types of excipients, which vary from simple single-chemical entities to co-processed materials to complex natural or synthetic polymer mixtures. The article also discussed excipient composition profiles, which may include concomitant components, additives, processing aids, by-products, degradants, residual starting materials, solvents, catalysts, and reagents in addition to the nominal (labeled) component. It concluded that the current labeling requirements in the 

United States Pharmacopeia–National Formulary

) General Notices are not appropriate for excipients due to the complex nature of excipient composition (1).

Additives and Processing Aids in Pharmaceutical Excipients

,” revealed that many excipients with a long history of safe use contain additives and/or processing aids required for the excipient to function as intended. The article asserted that drug products manufactured with such excipients should not be considered adulterated/misbranded and made specific recommendations for inclusion of exemptions in the 

 General Notices labeling requirements for additives and processing aids. IPEC-Americas believes this provides a means for FDA to ensure the safe use of additives and processing aids while protecting excipient manufacturers’ intellectual property and allowing excipients already demonstrated to be safe to continue to be used (2).

This article explores challenges of understanding concomitant components as part of the excipient composition profile. As described in the 

, concomitant components are components other than the nominal component that are inherent/integral to excipient composition and are often required for functional performance (3). The USP stimuli article, “The Complexity of Setting Compendial Specifications for Excipient Composition and Impurities,” also describes concomitant components:

“The term ‘concomitant component’ is used in this Stimuli article to encompass all components that are a necessary part of the excipient, and hence should not be considered impurities unless they are shown in some way to compromise the quality of the excipient. Concomitant components of an excipient include substances that either are known to promote excipient function or have an unknown contribution to excipient function and are clearly not deleterious to excipient quality” (4).

Excipient concomitant components vs. impurities

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