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Understanding and overcoming excipient variation are crucial for successful continuous processes.
Continuous manufacturing is being encouraged by regulatory authorities as a means for improving product consistency and quality while also potentially reducing cost. For continuous manufacturing of oral solid dosage drugs, excipients play important roles not only in the performance of the formulated product, but also during processing. Excipients must address the specific needs of the API, such as the desired drug release rate, solubility enhancement, crystallization inhibition, or improved API uniformity while also enabling processing of the final intended dosage form. In the latter case, physiochemical properties such as flowability, density, particle morphology, and glass-transition temperature are crucial considerations for designing an optimal continuous process.
For each given excipient, the impact on a continuous process may be small or substantial depending on the quantity of excipient present and its difference in properties from that of the API. Many excipients available today are well suited for continuous processing, but there remain significant opportunities for increasing knowledge about the impact of material property changes in process output and, ultimately, drug product quality.
“The excipient impact on continuous drug product manufacture is profound,” asserts Joseph Zeleznik, technical product manager for IMCD US Pharmaceuticals. “The proper choice and use level influence product and process robustness, throughput and yield, development and manufacturing costs, and drug product quality. It is important that any excipient used is not only effective in its application within the formulation but is well-suited to maximize continuous manufacturing process efficiency,” he adds.
For oral solid dosage (OSD) drugs, excipients can have an impact on the physical characteristics (i.e., flow, density, homogeneity, and compactability) of the mixture in the equipment during processing and ultimately at compression or encapsulation, notes Anthony Carpanzano, director of R&D at JRS Pharma in the United States. Blend homogeneity is critical for achieving content uniformity in the finished tablet, according to Mark Dreibelbis, associate research scientist with DuPont Nutrition & Biosciences. “Large mismatches in particle size and flowability between excipients and the API can lead to segregation, impacting dosage consistency and possibly leading to excursions from the therapeutic window,” he explains. Inter- and intra-lot excipient variability should be understood, as well as its potential impact on process and product quality Zeleznik observes.
“Excipients can be a double-edged sword for OSD continuous manufacturing processes,” states Krizia Karry, global technical marketing manager at BASF Pharma Solutions. “They can be used to improve flowability and tabletability, but they may also affect dissolution performance if they are shear dependent, for example. My recommendation is to steer away from excipients that are very shear dependent as these can lead to inconsistent residence time distributions, and those with broad particle size ranges and/or high specific surface area, as fines are more prone to gaining static charge and bridging,” she says.
A quality-by-design (QbD) development program supported by an appropriate process analytical technology (PAT) strategy is essential in understanding and controlling excipient impact on continuous manufacture and drug product quality and performance, according to Zeleznik. Lubrication strategies also need to be rethought not only with respect to the right choice of lubricant, but the right use level and when it should be added.
In batch manufacturing, Krizia explains, there is not too much emphasis placed on flow characteristics, shear, or electrostatics because the batch dispensing process is manual (you open a bag and dispense into an [intermediate bulk container] IBC, or you use a vacuum system) and subsequent unit operations are discrete. “In continuous processing, the impact of compactability (change in volume with force) when refilling materials, flowability (how easy the material moves through the line), and shear (which also dictates your feeder screw set-up because you want to feed accurately and without breaking the material) must be considered, among other factors,” she says.
Overall, Zeleznik comments that continuous manufacture is no different than batch manufacture regarding choosing the “right” excipient. “Excipient choice is predicated on several factors, including API physicochemical characteristics, targeted dose, route of administration, and most importantly, the manufacturing equipment and process used during continuous manufacture,” he says. “Another consideration in choosing an excipient is its multifunctionality and flexibility with respect to the formulation and process. Excipients to avoid are those having limited performance attributes or that are unsuitable for continuous operations. Because of the limited feeders, more has to be accomplished with less.”
It is important, therefore, to develop a formulation with the desired functionality. The flow, density, particle size, and electrostatic properties of excipients are more important in continuous processes versus traditional batch processes, according to Mara van Haandel, innovation manager at DFE Pharma. “During continuous manufacture, it is essential that product flows in a continuous manner in the processing units (and is consistently transported from one unit to the next), as clogging of material/material build up can impact the residence time distribution,” she says. Hence, the “right” excipient choices have to be made from the start of developing a formulation on a continuous process.
That can be a challenge for OSD formulations because powders of various particle sizes and densities must be meter-fed into the system at the correct ratios and then make their way through the production path, notes Becca Putans, an associate chemist from DuPont. “Materials that have a poor flowability or high cohesive properties pose a risk of accumulating in corners, causing blockages, downtime for cleaning, and non-uniform dosage forms,” she says.
Any excipient chosen also needs to demonstrate a non-segregation potential for the final blend. “Since the materials move continuously together through the unit operations, the mixture must stay at the correct ratio, otherwise the resulting dosage forms will not have a uniform distribution of the active ingredient,” Putans adds. Therefore, excipients with higher flowability, optimized density, morphology, and moisture content, low batch-to-batch variability, and compactability are preferred.
The physical behavior of an excipient when under shear stress is a major determining factor in its suitability for continuous processing, adds Carpanzano. “Excipients that perform well in continuous manufacturing can be easily fed into the process at a uniform rate, promote blending with the active ingredient and other excipients, maintain flow and do not break down or compact in the mixing phase, and can be compacted into tablets or filled into capsules after blending,” he concludes.
Many direct compression excipients have been designed for use in a continuous tableting operation, according to Putans. The particle size and morphology have been tailored to provide a high level of flowability while retaining compactability. “These materials are designed to flow through a continuous manufacturing process with little build-up, while maintaining content uniformity and good final dosage consistency,” she observes.
In some cases, a pre-blending strategy is adopted to improve flowability, such as with fumed silica when used as a glidant, according to Karry. “Fumed silica has a low density of 0.03 g/mL, which presents challenges when trying to individually dispense via loss-in-weight feeders. “To overcome this issue, formulators pre-blend the glidant with another excipient to ensure accurate feeding and good flow properties of the blend. Undoubtedly, pre-blending with silica is not ideal—especially in a continuous manufacturing setting—but it is a proven strategy for improving powder flowability,” she says.
“Improving flow properties with excipients is a proven strategy, but for troublesome low-density and/or poor water-soluble APIs, additional unit operations have also been adopted to continuous platforms,” adds Karry. Twin-screw granulation or hot-melt extrusion excipients intended for preprocessing of these APIs should have wide operating temperature ranges and resist degradation, discoloration, or drastic changes in viscosity, according to Dreibelbis.
Binder selection is also critical for continuous granulation processes for uptake of granulation liquid and quick drying to produce robust granules. Less hydrophilic grades of common binders exist to facilitate faster moisture removal from the resulting granules, which ultimately reduces cost and improves throughput, he adds.
Compared to batch processes, electrostatics (measured as static charge) is a critical piece of the puzzle for both APIs and excipients. “When a material bridge occurs due to electrostatics,” Karry explains, “material is likely not being fed through the conveying screw elements, and thus, there is no registry of weight change over time. This absent change triggers a control reaction (since feeders have Level 1 control) that involves increasing the screw speed to ‘try’ to dispense more material. Since the material is stuck on the hopper, no material is fed and the result is a subpotent (for the case of API) or superpotent (if the case is for filler) blend. The blend amount produced during this time will depend on the total mass flowrate of the process, the mean residence time, the alarm limits, and the controller dead-time.”
The problem, Karry adds, is that few options exist for accurately measuring this attribute and electrostatic properties depend on the humidity, temperature, and contact material. It is therefore important when evaluating performance to replicate the manufacturing conditions.
van Haandel notes it is unlikely that a powder will bridge due to electrostatic behavior in a hopper/feeder, but due to the combination of wall friction and hopper/feeder flow mostly caused by powder consolidation and/or incorrect powder flow in relationship to the opening diameter.
In a continuous process, ingredients need to be fed in at an appropriate rate and at the correct ratio. When there are many different ingredients, it can be challenging and costly to have feeders dedicated to each individual component. To reduce the number of feeders that must be aligned, co-processed excipients offer an effective solution, and also reduce the number of variables and opportunities for variability in a process, according to van Haandel.
“A single high-functionality co-processed excipient can accomplish the same task using only one feeder, thus enhancing finished product performance while keeping variability to a minimum,” Carpanzano agrees. A typical coprocessed excipient has a filler, a binder, and a disintegrant as part of its structure, as well as a low concentration of glidant to ensure excellent flow, according to Karry. “In addition to eliminating the need for multiple feeders, the use of such co-processed excipients simplifies the control architecture and control strategy for continuous processes,” she notes. There is also less chance of segregation of the components during mixing, according to Carpanzano.
In fact, Zeleznik asserts that multifunctional excipients are an essential part of a successful, robust formulation and process. “While not new, co-processed excipients offer the increased, multifunctional performance needed for continuous operations,” he says. DuPont, BASF, DFE Pharma, and JRS Pharma all offer advanced co-processed excipients with the flexibility and enhanced multifunctionality ideal for use in continuous production of OSD formulations. “Modifications to existing excipients, such as particle engineering, and advances in excipient performance through co-processing have accelerated the development of continuous processing, and specifically, continuous manufacture of directly compressed tablets,” Zeleznik concludes.
Consistent performance of excipients is essential for continuous manufacturing. So is a constant feed in and out of a continuous process to ensure traceability and control of all critical process parameters. “Because excipients have inherent variation, it is important to understand the implications of this variation on continuous processes and thereby final products,” states van Haandel.
Therefore, simplification of a formulation combined with the use of very consistent excipients is important. DFE Pharma is applying fundamental and mechanistic analyses to gain an understanding of the impact of potential excipient variation on continuous manufacturing processes and the performance of final products. Using this knowledge in formulation development is essential for successful implementation, according to van Haandel. “Formulations should be designed in such a way that they can cope with the variation proven in historical data and analyzed using multivariate statistics,” she states.
Specifically, DFE Pharma is applying multivariate analysis on all physical/chemical parameters to gain that needed better understanding of historical product variation and is offering stretch batches, or batches showing high multivariate variation to ensure they are representative of the historical product variation (five years of manufacturing-based data), to enable formulators to efficiently test the impact of this variation on their formulations.
DuPont is also analyzing critical excipient attributes, providing historical (four to five years) manufacturing data to establish inherent excipient variability, and performing comprehensive multivariate analysis on many grades to understand the variability within batches and at different manufacturing sites, according to Dreibelbis.
Karry adds that research centers and companies alike have developed excipient libraries that serve as input to mechanistic models that predict the impact of raw material property changes on feeding accuracy, hold-up mass, mean residence time, and downstream drug product concentration. These models are verified with tracer experiments that seek to measure the change in concentration as a function of time and total mass flowrate.
Unfortunately, according to Karry, the selection of these tracers is not a trivial task, because formulators need to consider the strengths of their spectroscopic signals (near-infrared or Raman, typically), and their bulk properties, as their addition into the blend should not affect the bulk flowing properties that one intends to study. “Such a perfect tracer does not currently exist,” she says.
Another important issue that needs to be addressed, according to Karry, is cleaning. “Taking apart, cleaning, and correctly reassembling every component of a continuous manufacturing line is basically a work of art,” she stresses. “Companies that have implemented continuous manufacturing processes agree that this task requires much more attention than with batch processes and that it has an impact on the supply chain because turnover times are greatly increased,” Karry says.
Modular equipment that can be easily cleaned in place has advantages, but piping, mixers, and contact parts still need to be disassembled for proper cleaning and reassembled prior to starting the next campaign. “An integrated line can have hundreds of parts, so the question we must ask ourselves is ‘Why disassemble?’,” Karry poses. With the right excipient, she envisions a ‘flushing’ type of cleaning process based on electrostatics. “The adequate balance of charges would pull everything in its path, and a non-contact hand-held spectroscopic device could be used for measuring the ‘cleanliness’ of the surface,” explains Karry.
While formulation and process challenges for continuous manufacturing are being addressed through advances in excipient technologies such as particle engineering and co-processing, a regulatory gap continues with novel excipient acceptance, according to Zeleznik. “New or novel excipients are often avoided due to the perceived risk associated with using a new excipient even when a novel excipient’s performance could expedite drug product development and enhance continuous manufacturing processes,” he says.
There might be some changes coming, however. FDA is now considering a pilot program for novel excipient assessment (1). “Should this program be formalized and novel excipients have an acceptance pathway, it could do much to advance continuous manufacture growth going forward,” Zeleznik believes.
1. FDA, “Novel Excipient Review Program Proposal; Request for Information and Comments,” Federal Register 84 FR 66669-66671.
Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology.
Vol. 44, No. 8
When referring to this article, please cite it as C. Challener, “Key Ingredients Needed to Drive the Success of Continuous Manufacturing,” Pharmaceutical Technology 44 (8) 2020.