Understanding Excipient Characteristics to Ensure Robust Continuous Manufacturing

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 Product Quality Research Institute (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.

Material property impact on CM processes

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:

• Product quality: Variations in material properties can impact product critical quality attributes (CQAs) such as drug release, potency, and ultimately, patient safety.
• Process robustness and consistency: 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.
• Process/platform optimization: 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.
• Enhanced process control—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.

Inherent risk mitigation in CM processes

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 Figure 1). 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.

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.

Challenges and opportunities

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.

Conclusion

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.

References

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

2. ICH. Q13 Continuous Manufacturing of Drug Substances and Drug Products, Step 4 (ICH, Nov. 16 2022).

3. IPEC. Incorporation of Pharmaceutical Excipients into Product Development Using QbD Guide (IPEC, 2020).

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

About the authors

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.