Katherine L. Ulman is president of KLU Consulting.

Katherine L. Ulman

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 that are submitted by pharmaceutical companies for completion by suppliers is immense and non-standardized. 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 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 efficiently, quickly, 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. First 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 an otherwise labor-intensive activity and allows for 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 four 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 pre-audit 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, therefore, may 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 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 for developing, submitting for completion at defined frequencies, and tracking the return of completed questionnaires. Response times for EIP requests are shortened compared to traditional questionnaires. Depending on 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 information shared between excipient supplier and user is current. 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 update 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 which 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 and how information is shared. Additionally, due to the manual nature of the process, “hand-completed” questionnaires are typically not incorporated into the excipient manufacturers' quality management system.

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 to 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 handling of this essential function to provide meaningful information rather than dedicating many hours 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 pre-audit 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, industry-wide information requirements can easily be incorporated into the EIP.

Minimize resource consumption from redundant activities.

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 help 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 EIP’s throughout the industry to improve rapid information exchange, reduce costs, and improve timely distribution of key excipient information. Utilizing EIP’s 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, Technical Service; 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 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 Reyolds-Cummings is Regulatory and Product Stewardship Manager at Evonik Corporation. Candy spent 15 years at GlaxoSmithKline starting as an analytical chemist, QA Validation Manager in the OTC area (specifically oral care). She is currently working at Evonik as the Regulatory and Product Stewardship Manager supporting the business line Silica for regulations in US, Canada, and Mexico and is the Chair of 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 healthcare 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

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 

In today’s regulatory environment, and with the importance of delivering quality medicines to patients, regulators continue to place even more responsibility on pharmaceutical companies. Although more companies are outsourcing manufacturing, it remains their job to ensure that raw materials used in their medicines, including excipients, are safe, of high-quality, and sourced from reputable suppliers who adopt appropriate manufacturing practices.  

	In turn, excipient suppliers face a growing number of on-site audits and related information requests to ensure that their facilities and products meet the expectations of their customers (pharmaceutical companies) and regulators (1). The burden placed on audit teams at both suppliers and pharmaceutical companies is daunting. 

	With the introduction of the Falsified Medicines Directive (FMD) (2) in Europe and the Food and Drug Administration Safety and Innovation Act (FDASIA) (3) in the United States, regulators have made clear that the buck stops with pharmaceutical marketing authorization holders. It is their responsibility to verify that current good manufacturing practices (cGMP), ascertained from a formalized risk assessment of the excipient and its intended use, are documented and in place for excipients used in drug products.  To meet this expectation, pharmaceutical companies are emphasizing on-site supplier audits and relying less on information provided from paper audits or questionnaires filled out by suppliers.

	For decades, pharmaceutical companies have audited some of their excipient suppliers, but the audits typically took place every three-to-five years, and each one typically required only one day to complete. As cGMP requirements for excipients have become more stringent, it can be difficult to audit even the smallest excipient suppliers in one day, at least in any comprehensive way. What has typically happened is that audits have been rushed and compromised. 

	In response, pharmaceutical companies have increased requests for more and longer (i.e., one-to-two-day) on-site audits. The problem with on-site supplier audits is that they are costly, both to the company performing the audit and the supplier that is being audited. For pharmaceutical companies, audits require spending on travel and accommodations for the auditing team, plus hourly rate for any contract auditors they hire. They must also budget for writing the audit report and follow up work.  

	Suppliers often reject requests for audits due to resource constraints and because pharmaceutical customers are not their core markets and the sales value of their business is too low to justify the time required for the audit. Based on business case and customer priority, excipient suppliers have historically hosted limited on-site audits from pharmaceutical companies. However, many excipient suppliers have hundreds or even thousands of customers and find it physically and economically impossible to host on-site audits for all of them.  In addition, not all pharmaceutical company auditors are sufficiently trained in excipient GMPs, adding layers of complexity and burden to the excipient supplier.

	Based on the growing need for verified excipient quality and safety information and to help alleviate the audit burden, pharmaceutical companies, excipient suppliers, and other pharmaceutical industry stakeholders have joined together to develop voluntary excipient cGMP consensus standards (4,5). These voluntary standards facilitate the use of third-party qualified auditors who have been specifically trained to audit excipient manufacturing facilities to ensure their compliance with both cGMP and current good distribution (cGDP) practices.

	Recognized consensus standards and auditing programs 

	Today, there are two voluntary consensus standards and auditing programs designed to assess excipient GMPs (6): 

	The EXCiPACT certification scheme (7), certified against EXCiPACT cGMP and good distribution standards (5), which are published as an annex to the International Organization for Standardization (ISO) 9001:2015 Quality Systems standard. The EXCiPACT certification scheme was launched in 2012 and includes the GMP and good distribution practice (GDP) for excipients as an Annex of ISO-9001, the competency of the auditors, and the independence of the certification bodies as an annex of the ISO-17021. 

	The NSF Health Sciences Excipient Certification Program (NSF-ECP), which certifies against the NSF/IPEC/ANSI 363: Good Manufacturing Practices (GMP) for Pharmaceutical Excipients standard.  The program was launched in March 2015 and may be used by all excipient manufacturers, regardless of ISO 9001 certification status.  The program is accredited by the American National Standards Institute (ANSI) and operated with oversight of NSF Corporate Quality and Compliance.  

	The purpose of these certification programs is to apply a consistent approach to inspecting and auditing excipient suppliers for conformance to appropriate excipient cGMPs. In addition, these independent, high quality, third-party certification programs include the use of credible certification bodies (CBs) who employ qualified auditors who have been shown to be competent in the related standards, to issue audit reports and certificates.  Use of these independent CBs help to address concerns about any potential conflicts of interest.  As shown in 

, the cumulative number of excipient GMP certificates has steadily accelerated during the past five years.  

	Credible third-party certification involves both an independent assessment declaring that specified requirements pertaining to a product, person, process, or management system have been met and also that the certifying body has independent oversight to ensure impartiality and freedom from conflicts of interest. The third-party certification is more robust than first-party certification, in which an individual or organization providing goods or services offers assurance that it meets certain claims, and second-party certification, in which an association to which the individual or organization belongs provides the assurance (1). 

	Unlike the one-day excipient audit conducted by pharmaceutical companies, initial EXCiPACT and NSF-ECP certification programs require several days to complete and include annual surveillance audits. Qualification and verification of auditor competency and independence is key to ensuring the validity of the certification. Using auditors specifically trained and certified to excipient cGMP standards helps ensure consistent and relevant audits. The publication of the certification program, as well as criteria for approving certification bodies and auditors, should be considered as an added value for recognition of certification audits. In addition, in third-party audits, report findings are more likely to be based on excipient GMPs and less prone to auditor bias. 

	Regulatory acceptance of accredited third-party party audits for assessing the quality and safety of regulated products is not new.  In October 2002, FDA implemented the Medical Device User Fee and Modernization Act (MDUFA), which authorized third-party Accredited Persons (AP) to conduct medical device facility inspections (8). 

	Then, based on the agency’s recognition of the increasingly global nature of the industry, and the number of medical device manufacturers, in 2012 the International Medical Device Regulators Forum (IMDRF) designed and adopted the Medical Device Single Audit Program (MDSAP) (9) to allow for greater coverage in auditing manufacturers as opposed to relying solely on government resources from individual countries.   

	Similarly, based on pioneering work by the Global Food Safety Initiative (GFSI) to develop and implement a voluntary certification program for the food industry, the FDA Food Safety Modernization Act (FSMA) final rule, “Accreditation of Third-Party Certification Bodies to Conduct Food Safety Audits and to Issue Certifications,” established a voluntary program for the accreditation of third-party certification bodies to conduct food safety audits and to issue certifications of foreign facilities and the foods for humans and animals they produce (10).

	Relying on these third-party certification programs allows responsible parties to redirect their internal resources toward assessment of any relevant issues that may be outside the scope of the standard.  

	Although third-party excipient cGMP certification can help pharmaceutical companies verify appropriate excipient cGMPs are in-place and being followed, certification does not exempt a pharmaceutical company from executing and documenting formalized risk assessments to identify appropriate excipient cGMPs based on intended use and criticality. In addition, in some cases a certified excipient cGMP audit report may need to be supplemented with additional information (outside the scope of the standard) to justify use of an excipient. The pharmaceutical company may need to acquire further verification, including but not limited to quality agreements, special questionnaires, teleconference discussions, and even on-site meetings and/or audits to address specific issues or concerns.

	Best practices for utilizing cGMP audit reports

	Through partnering and communication with excipient suppliers, pharmaceutical companies should strive to understand whether a third-party excipient cGMP certification is in place and, if not, whether a supplier might be seeking such certification.  

	To help justify the acceptance of third-party excipient cGMP audit reports to a regulatory inspector, in lieu of a second-party audit and report, it is important for a pharmaceutical company to develop and document a standard operating procedure (SOP). Establishing SOPs would allow them to promptly utilize the audit report/certificate. 

		How the company performs and documents excipient risk assessments to identify appropriate excipient cGMPs based on intended use and criticality 

		Details for how the company qualifies the certification program(s) as well as when and how they can use an excipient cGMP certification audit report 

		How certificate expiration will be monitored and tracked to ensure its validity

		Where and how audit reports will be received, reviewed, and accepted actions to take if and when an issue arises with excipient quality.

	Note: Inappropriate application to products outside the scope of the certification must be avoided. For example, certification of other grades cannot be inferred if only NF grade product has been included in the scope of certification. 

	Critical process steps to cGMP certification

, critical steps in the certification/recertification process include:

The excipient supplier develops and documents an internal certification plan including appropriate SOPs for certification, drafting of an audit report, and certificate handling. Best practice is to ensure that the excipient supplier is ready for certification and that any gap assessment is conducted separately from the certifying body audits, to ensure the absence of bias.

The excipient supplier schedules a certification audit with a certifying body (communication between supplier and certifying body). The certifying body conducts an excipient GMP audit of the excipient supplier’s facility (this requires communication between supplier and certifying body). Within an agreed upon period of time, the qualified auditor writes a report that is reviewed by a panel of the certifying body, approved, and issued.  It is critical that the audit report not contain any confidential or proprietary information about the supplier, because this information could delay providing the report to pharmaceutical companies  (this requires communication between the certifying body and the supplier).

The certifying body issues an invoice to the excipient supplier (again, requiring communication between certifying body and supplier). Excipient suppliers pay the invoice, which will not be issued until payment has been received. This step, depends on communication between the supplier and the certifying body).

	Note:  Payment for an audit by the excipient supplier should not be viewed as a conflict of interest as long as the certification program chosen includes the use of credible, independent, registered, third-party certification bodies employing qualified auditors who are demonstrated to be competent in the relevant standard (11). 

. After receipt of payment, the certifying body issues the cGMP certificate to the excipient supplier. After receiving the cGMP certificate, the excipient supplier notifies pharmaceutical customer(s) .

. After receiving the audit report from the certifying body, the excipient supplier determines their process for sharing a copy of the report with their pharmaceutical company customer(s).

. The supplier schedules a surveillance audit with the certifying body prior to cGMP certificate expiration, allowing sufficient time for scheduling/executing the audit and invoice payment.

	Note: The frequency of certification audits (annually, as required by the EXCiPACT standard) should be compared with the traditional pharmaceutical company audit frequency, which often only occurs every three-to-five years, if at all.

	As previously stated, the pharmaceutical company is ultimately responsible for ensuring the quality and safety of the ingredients that it uses for manufacturing. Key questions that pharmaceutical manufacturers should consider when documenting, justifying, and developing a risk ranking and mitigation strategy should include the following :

		Is the certificate from an accredited third-party certification body?  

		To what standard was the audit performed?

		Has the auditor (training and report) and process been adequately assessed?

		In addition to the cGMP certificate, has a risk assessment been conducted to determine the need for further supplier audits that would cover needs not addressed in a routine audit?

		Have necessary internal SOPs been developed to document the strategy and any necessary steps taken to ensure proper execution?

		Have criticality and ranking of excipients been performed and documented?

		Where are the certificates and audit reports going to be stored?

		Who is responsible for reviewing the audit reports and determining whether the excipient supplier meets defined cGMP requirements?

		Is specific excipient product that is used included within scope of the third-party certification?

		Who is responsible for tracking certificate expiration dates and providing notification for any potential issues? 

		Have the necessary agreements/contracts been put in place (e.g., supplier certifications, audit reports, notifications of change, quality agreements, other) with the supplier to ensure a continued supply of excipients that meet the defined GMP requirements?

		Are there items outside the audit/certificate that require follow up with the excipient supplier?

		Is technical due diligence required to achieve the enhanced understanding necessary for pharmaceutical quality by design?

		Is there any additional risk involved, or are there concerns that are not stated within the scope of the cGMP audit and certifications?

	Note: Pharmaceutical companies should consider and manage for risks with suppliers and supplied excipients, and should have documented evidence that shows whether or not the supplier is addressing any potential concerns.

	When pharmaceutical manufacturers audit suppliers, results can vary depending on the training, experience, and levels of bias among those performing the audits. Third-party audits offer an standards-based alternative.

	Often, a third-party audit cannot cover all technical aspects. Therefore, certain proprietary or ad hoc issues or concerns should be addressed via followup (phone, email/mail, in-person, other) with the supplier after the audit and audit report. Suppliers who choose to use third-party certification bodies and excipient cGMP audit reports and certificates to support their conformance to excipient cGMPs will need to select certifying bodies that have been qualified and approved by EXCiPACT or NSF-ECP, because these programs will have the ability to:

		Handle confidential information securely

		Communicate when certification is suspended or withdrawn

		Conduct audits and issue reports within a predefined period of time (e.g., 30 days of audit)

		Provide excipient cGMP certificates without delay together with corresponding audit report

Increasingly stringent audit requirements will make third-party accredited GMP audits critical for pharmaceutical excipients and raw materials.