Co-Processed Excipients for Continuous Manufacturing of Drug Products

This article provides insights about the powder characterization in dynamic flow, bulk, and shear using a powder flow tester. Powder comparative characterization and particle engineering co-processed excipients can be more economical than conventional ingredients in continuous manufacturing of drug products. In this article, we discuss powder flow and its measurement techniques and focus on parameters to study powder flow properties using a flow function test, wall friction, a bulk density test, and friction angle evaluation of the co-processed excipient BARETab PH as an example to fulfill scientific and regulatory requirements in continuous manufacturing.

Research Background

Recent research and guidelines clarify continuous manufacturing concepts and describe scientific approaches and regulatory considerations specific to the continuous manufacturing of drug substances and drug products.1 Some research highlights and key points are outlined next.

Dongmei and co-authors described particle engineering technologies and challenges in the development of particulate delivery systems for pharmaceutical discussed.2 Faqih et al. described a new method to quantitatively measure flow characteristics of unconfined cohesive powders in a rotating drum, showing that cohesion affects flow properties and characteristics, mixing rates, and segregation tendencies in particle engineering.3 Navaneethan and co-authors worked to understand particulate systems’ behavior under different conditions of shear dynamics and powder lubrication.4 Schubert et al. identified the appropriate distribution functions for characterizing particle size distribution and flow properties.5

Teunou et al. used shear testing and measuring particle size, bulk, and particle densities of powder flow6 to evaluate how a number of powder physical properties affect powder flowability. Rohilla and co-authors evaluated the physical properties and flow properties, collected from seven fields of electrostatic precipitator hoppers of a power, using powder flow tester operating based on Jenike’s methodology.7 Berry et al. presented preliminary results from round-robin trials undertaken in a powder flow tester using the BCR limestone (CRM-116) standard test material and compared mean flow properties with published data found in the literature for the other shear testers.8

Zatloukal and co-authors discussed flow properties of nonconsolidated pharmaceutical powder excipients and co-processed excipients in combinations to estimate flow rate.9 Rios et al. discussed when the US Pharmacopeia began working toward standardizing the methods to measure powder flow with a survey and a “stimuli to the revision process” article in Pharmacopeial Forum published in 1999. Since that research, a harmonized chapter on powder flow has been released, and sophisticated analyzers have been introduced and are slowly entering pharmaceutical laboratories.10 Sutton and co-authors outlined the methods commonly used in characterizing powders, and the powder characteristics’ effects on the part properties in powder-bed fusion processes.11

Divya et al. studied orderly assessment of the flow of powders and granules using compendial and non-compendial procedure, angle of repose, tapped density, Carr’s compressibility file, bulk density, and Hausner’s ratios. Moreover, flow was described using a powder rheometer wherein delicate force transducer screens the forces created as consequence of the sample displacement.12 Nan and co-authors described particle flow behavior as a function of strain rate, such as screw conveyors, impeller mixers, and feeders. The traditional commercial instruments used for bulk powder flow characterization—shear cells—operate at low shear strain rates under dynamic conditions.13

Svarovski and co-authors illustrated design tools and techniques to measure physical properties that affect flow characteristics of bulk solids and cause problems during storage, transport, and transfer, discussing in detail the wide range of test methods used to measure the flow and properties of bulk solids powder.14 ASTM International’s “ASTM D6128-16: Standard Test Method for Shear Testing of Bulk Solids Using the Jenike Shear Tester” gives the study of apparatus and procedures for measuring the cohesive strength of bulk solids during both continuous flow and after storage at rest. It also stated that bulk solids cannot be tested, but one example may be those consisting of highly elastic particles of solid powder.15

Continuous Manufacturing

Traditional unit operations have dominated oral solid dosage (OSD) manufacturing for decades. However, there are several practical challenges to batch manufacturing in the pharmaceutical industry, such as more manufacturing steps, constraints from equipment size, time-consuming changeover, high waste generation, lesser flexibility in process flow, a larger plant footprint, reduced time for quality control, a higher risk of errors because of heavy human intervention, and increased product handling.1^, 2 To contend with these challenges, the pharmaceutical industry put more faith and study into continuous manufacturing (see Figure 1).

Figure 1: Continuous manufacturing flow diagram.

Traditional unit operations have dominated oral solid dosage (OSD) manufacturing for decades. However, there are several practical challenges to batch manufacturing in the pharmaceutical industry.

The pharmaceutical sector’s research-and-development departments constantly adjusted formulations of powder products to satisfy customer demand for improved powder flow properties, improved coating action, and more rapid dissolving of chemicals when put into solution. The classic problems with powders were first, their failure to discharge reliably from bins, hoppers and silos, and second, poor or unpredictable flow in feeders, dosing machines, packing machines. These failures caused unwanted production interruptions, sometimes leading to complete plant shutdown to correct flow restrictions and stoppages. They also led to variations in pack weight, mixture, performance, and sensory properties of powder materials products.3^, 5^, 6

To understand the application of powder flow measurements, it was useful to understand the flow patterns and flow obstructions that could occur inside the storage vessels or on a processing line.3^–5 The powder flow tester instrument evaluates flow properties using flow function tests, wall friction, bulk density tests, and friction angle evaluation.

The continuous manufacturing approach involved the continuous feeding of input materials into, the transformation of in-process materials within, and the concomitant removal of output materials from a manufacturing process. Its benefits were then evident for the pharmaceutical industry and widely advocated by the regulators through several initiatives (ICH Q13 and the latest US FDA Q13 continuous manufacturing guidance for industry). It was significantly influenced by the quality of input materials along with aspects such as process models and dynamics; process monitoring and control; equipment design; system integration; output material traceability; and diversion.1^, 3

Bulk powders inherently exhibit unpredictable flow in feeders, dosing machines, and packed machines under gravity’s pull. Powders assume a pile-like structure with some angles because of internal friction and cohesion. Therefore, at ambient conditions, powders may not change flow behavior when subjected to variable shear rates. However, if powder is put under a higher pressure—as in a hopper filled with bulk powder—it would flow less readily. This yields out-of-specification products with possibly altered performance and variable packed weights4^, 5 and leads to unwanted interruptions in the production process, including complete plant shutdown to correct flow variations. A typical oral solid formulation consists of many ingredients to improve poor micromeritics and impart different functionalities. Therefore, selecting appropriate ingredients in optimized quantities was again challenging.7

Co-processed excipients have better flowability, compaction, processability, performance, and stability (see Figure 2). The simplicity in the manufacturing process yields higher productivity at lower cost, making these excipients an ideal choice to use as ready-to-mix in direct compression formulations.

Figure 2: Typical production schematic for co-processed excipients.

The benefits of using a co-processed excipients in continuous manufacturing include dust-free handling during production; multifunctional properties such as enhanced lubrication efficiency, superior binding properties, higher surface area, and more-desired product quality attributes; increased production speed; and increased production capacity with uniform product quality.

Co-processed excipients have better flowability, compaction, processability, performance, and stability.

Materials and Methods

Materials

BARETab PH, the co-processed excipient this article evaluates, was sourced internally. Its benchmarking was done with the powder obtained by physically mixing all the constituent ingredients in the same ratio in octagonal blender. The BARETab PH ready mix was manufactured by co-processing appropriate binder and filler (microcrystalline cellulose), glidant (croscarmellose sodium), disintegrant (colloidal silicon dioxide), and lubricant (purified talc) using the spray-drying method. This ready mix’s individual constituents were weighed and mixed thoroughly using a powder blender for 10 minutes to yield a physical mix. A powder flow tester was used for characterization of powder properties such as flow and friction.

Methods

The flow function test was performed to evaluate powder arch across a hopper outlet. The powder was placed in a cylindrical cell and compacted under normal stress (S1). The mold was then carefully removed to reveal a compacted column of powder. The normal stress acted on the column of powder was gradually increased until failure occurred, and the peak normal stress was recorded by software in the powder flow tester.4^, 5 The greater the flow factor (ff) value, the more free-flowing the powder refer (see Table 1). Shear stress was applied to move the sample against a stainless-steel surface: using the maximum shear stress between the powder sample and the wall material yielded a locus for each sample at each normal stress value. The results were interpreted by the powder flow tester’s software.7

Table 1: Standard classification of powder flowability.

Results and Discussion

The friction at the wall-powder interface significantly influenced the stress distribution within processing vessels, silos, and hoppers. The higher the wall friction, the more the powder weight transferred down through the silo, vessel, and walls, rather than compacting the bulk solid pattern. The lower the friction, the more the powder self-weight transferred through the bulk solid powder materials.2 As needed, there are different softwares that can be used to analyze estimate pressures based on measurements of the bulk density, wall friction, internal friction, and diameter.

Flow Function Test

To demonstrate powder flowability, the flow function is presented graphically pattern in Figures 3A and 3B and shows behavior over the stress range of approximately 0.3 kPa to 13 kPa. This stress range was representative of what was applied to the powder in small to intermediate-sized silos. Alternatively, flowability rankings for specific stress levels could be determined by the estimated critical arch diameter and the estimated rathole diameter.

The estimated critical arch diameter (measured in meters) is the minimum silo outlet size required for reliable gravity discharge in a mass-flow vessel, calculated using the arch equation. Here, the stress value was the intercept of the flow function with an ff = 1.4 line. This was the default flow factor setting, but the user could adjust it within a 1.0–1.8 range for silo design applications. The estimated critical rathole diameter (measured in meters) is the minimum outlet diameter required to prevent the formation of a stable rathole in a core-flow vessel. Tables 2 and 3 show flowability.

Table 2: Results of flow function test.

Thus, the flow function data obtained by flow index number from 0.1–0.25 would be class as predicted easy-flowing. The flow factor/index and the bulk density values were useful in the calculations of arch dimensions and studied flow patterns. The internal friction angles and wall friction angle values were useful in the calculations of rathole dimensions of powder flow properties. The graphical data on flow function is represented in Figures 3A and 3B.

Figure 3: Flow function graphs for BARETab PH A) physical mix and B) ready mix.

Thus, the excellent density and the flow least arching and ratholing of the co-processed excipient ready mix over the physical mix of individual ingredients could be attributed to uniform density, narrow particle size distribution, and comparable morphology obtained from co-processing by spray-drying technology.

The wall friction test represents the limiting shear stress the powder could experience at a wall; hence, it measured friction between the powder and a given wall surface. The bulk density was used for assessing mass-flow hopper half-angles and gravity flow chute angles. The compressibility index measured the powder’s ability to settle, and it permitted an assessment of the relative importance of interparticulate interactions. The compressibility ratio is the ratio of final press density to the apparent density of the powder.

The wall friction angle represents the angle to which a wall surface must be inclined to make powder slip. The wall friction angle is typically in the range of 10 degrees to 45 degrees (see Table 3) and it is what determines the minimum chute angle for the gravity flow gradient. The maximum wall friction angle is displayed as a coefficient. The wall cohesion shear stress determines the “stickiness,” i.e. whether powder is likely to stick to wall surface under close to zero stress (meaning the powder built up on the walls of the chutes around the discharge/transfer point). The friction stress study data is represented in Figures 4A and 4B.

Table 3: Results of wall friction test.

Figure 4: Wall friction graphs for BARETab PH A) physical mix and B) ready mix.

Evaluation of Friction Angle

The friction angle measurements are translated into powder cohesive strength. When evaluating friction angle, angles of 30 degrees to 45 degrees signal cohesiveness, and angles of 45 degrees to 55 degrees signal very cohesive powder. For this, the free-flow powders generally had a less-than-30-degree angle. The failure loci is the line of maximum shear stresses that a powder could support before flow occurred under over consolidated normal stresses. The dependent on the consolidation level was evaluated and was signaled by flow and friction angles (see Figure 4 and Table 3). Thus, the co-processed excipient ready mix demonstrated better flow, better compressibility properties, and a lesser tendency to stick to the wall surface than the physical mix evaluated.

Conclusion

Particle engineering co-processed excipients are more versatile than conventional ingredients in continuous manufacturing of drug products. This article presented data using BARETab PH as an example to illustrate the potential uses and benefits of these excipients. However, there are many types of co-processed excipients that can be used in a continuous manufacturing process.

Acknowledgment

The authors are thankful to Ametek Brookfield Instrumentation Specialty Controlled Division for making the powder flow tester facility available for testing.

Disclaimer

ISPE does not endorse specific products. Data provided in this article are for information purposes only.