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Direct compression (DC) remains the most preferred technique to produce tablets, and its effectiveness is directly influenced by raw material attributes. Therefore, the selection of specific grades of excipients to achieve desirable powder flow and compression properties is of importance. Shifting toward continuous manufacturing requires even more enhanced performance, quality, and consistency directly from the starting ingredients. Starch, as a well-known excipient with good compression characteristics in its native state, is poorly flowing and highly sensitive to lubrication. The objective of this study was to characterize the flow properties of different starch products and investigate the suitability of modified starch products for continuous manufacturing. The proposed methodology included techniques to characterize material flow properties and their feeding performance in a loss-in-weight feeder. Principal component analysis (PCA) was then applied to project material properties onto reduced dimensions and compare the flow behavior of starch products with other common excipients. A newly developed starch product, StarTab®, was characterized and compared with two other starch products in terms of their flow behavior. StarTab showed desirable flowability and packing behavior, demonstrated by shear cell and compressibility results. During feeder refill studies, StarTab exhibited a low total deviation of material fed in excess of setpoint compared with the other two starch products. Additionally, it was observed that StarTab flow behavior was not sensitive to its moisture level. StarTab showed suitable characteristics compared with other starch products making it a potential candidate to design and develop pharmaceutical continuous direct compression (PCDC) formulations.

Loss-in-weight feeders play a vital role in assuring blend and content uniformity as well as lot-to-lot powder traceability in continuous manufacturing. Irregular flow from the feeders propagates through the system, potentially resulting in out-of-specification product. Powder properties such as density, cohesion, and adhesion can cause large variability in the flow rate of ingredients from powder feeders. Feeding of active pharmaceutical ingredients (API) can be difficult because of inherently poor flow, low density, high cohesion, and adhesion. API was chosen due to known adhesion behavior inside feeders during continuous operations. The selected APIs were blended with nanosized silica, in a V-blender, to provide separation between the API particles and reducing the effect of interparticle forces. The material was characterized by standard pharmaceutical techniques to identify bulk changes between the as-received and the blended API. The coated API was then fed using a Coperion K-Tron KT-20 pharmaceutical loss-in-weight feeder. The material was dispensed onto a catch scale, recording mass versus time, and analyzed for relative standard deviation and deviation from the set point. Additionally, the mass of the remaining API in the feeder after the run ended was compared between the API and silica-blended API. Blending APIs with nanosized silica successfully improved API feeding performance despite their intrinsic highly adhesive and cohesive behavior. Both the pure and silica-blended APIs were fed using a twin screw powder feeder. When feeding unsilicated APIs, large variability in flow rate and screw speed were observed, and large amounts of material coated the inside of the hopper and screws. When the adhesive APIs were blended with nanosized silica and fed through a loss-in-weight feeder, there was significantly less adhesion to the feeder, and the material was dispensed with significant reduction in flow rate and screw speed variability. This work provides a means to increase the applicability of continuous manufacturing by enabling the practitioner to manage adverse impact of cohesive material properties on feeder performance. Blending highly adhesive API with silica reduces the adhesion of the API to the feeder hopper and screws, while also improving the deviation in mass flow rate exiting the feeder.

Powder properties, such as density and adhesion, can cause large variability in the flow rate of ingredients fed from feeders, which can propagate through the system. Knowing an ideal range of operation and correlating powder properties to process performance can result in faster optimization of performance, which saves time and money. A K-Tron KT-20 pharmaceutical loss-in-weight feeder was evaluated with multiple screw types, feed rates, and materials. The material was dispensed onto a catch scale, recording mass versus time, and analyzed for relative standard deviation and deviation from the setpoint. The materials used in this work were characterized by particle size, packing, and flow properties. Linear relationships between the feeder’s throughput capacity and material bulk density were identified for four different types of screws. Analyzing the feeder data resulted in a region where the RSD was at a minimum across a range of screw speeds. This was identified between 20–90% screw speed for coarse concave, fine concave, and coarse auger screws and 40–90% screw speed for fine auger screws. An optimal range of operation for K-Tron KT20 feeders was identified, as well as a linear correlation between material conditioned bulk density and maximum throughput for a given material and screw type. Using both the predictable maximum throughput and the optimal screw range, an optimal design space has been identified that will save development time and money.

Continuous manufacturing offers shorter processing times and increased product quality assurance, among several other advantages. This makes it an ever-growing interest among pharmaceutical companies. A suitable efficient control system is however desired for continuous pharmaceutical manufacturing to achieve a consistent predefined end product quality. In order to control product quality more accurately, the effects of input disturbances need to be proactively mitigated. Therefore, it is desired that a combined feedforward/feedback control system integrated with suitable process analytical technology (PAT) be implemented over a traditional feedback-only control system. The feedforward controller measures and takes corrective actions for disturbances proactively before they affect the process and thereby product quality. The feedback controller considers the real-time deviation of control variable from a pre-specified set point and keeps it at a minimum possible value. The deviation of a control variable from the set point could be due to both measurable and unmeasurable disturbances. In this work, a combined control strategy has been developed for a continuous twin screw wet granulation (WG) process. An integrated flowsheet model was developed and simulated in order to evaluate the effect of control loops on critical quality attributes (CQAs). Different strategies of manipulation were evaluated and the best strategy was identified. In silico study on the combined feedforward/feedback control strategy and feedback-only control strategy demonstrates that the combined loop results in diminished variability of the CQAs.

In this study, an active pharmaceutical ingredient (API) was impregnated onto a mesoporous carrier (excipient) in a fluidized bed. Impregnating APIs in porous carriers has the potential to simplify the drug substance development process and leads to the elimination of the blending and granulation unit operations. Impregnation and drying occur simultaneously in fluidized-bed impregnation, and this method precludes several challenges encountered in other impregnation methods. Furthermore, the process ensures a uniform distribution of APIs within the porous carriers. This method also allows for a variety of solvents to be used in the impregnation. Using a batch fluidized-bed dryer, impregnation of acetaminophen (APAP) onto a magnesium/aluminum metasilicate (Neusilin R) was studied. Water and methanol were used as transport solvents to impregnate different loadings (w/w) of APAP, namely, ranging from 24 to 0.1%. Uniformity tests indicated that APAP loadings of all impregnated products are close to their target loadings across carrier size classes. Tests before and after impregnation showed that there were no changes observed in the physical properties of the carrier, such as particle size, compressibility, and flow properties. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) analysis performed on the samples indicated that the low loadings APAP was present in the carrier pores in its amorphous state. At high loadings, we observed that APAP was mainly present in its amorphous state, however, some degree of crystallinity was observed. Lastly, dissolution tests on the impregnated product showed enhanced dissolution rates in acidic media, and comparable dissolution rate in de-ionized (DI) water, compared to the pure drug crystals. Our results show that the method of fluidized-bed impregnation yields a product with high uniformity and overcomes several challenges presented by traditional physical blends.

As the pharmaceutical industry increasingly adopts continuous manufacturing technology, significant attention must be paid to process analytical technology (PAT), process integration, and process control. Published information is no substitute for hands-on comprehensive training, which is critical to implementing and operating continuous pharmaceutical manufacturing systems effectively and efficiently. In this article, an intensive hands-on training course has been developed and implemented at the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS) based on 15 years of experience and several implemented systems. Here, we brought the details of the four integral components in a continuous direct compression manufacturing process: (1) unit operations, (2) PAT, (3) modeling and process controls, and (4) material characterization. Each section built-in classroom lectures with a brief overview on the theoretical aspects of each topic, followed by a hands-on session covering the classroom theory. The training program is described here in sufficient detail to enable creation of similar programs at other institutions.

Wet granulation is widely used in the pharmaceutical industry. This advantageous technology is capable of enhancing compression and powder handling, decreasing ingredient segregation, and promoting blend and content uniformity. Currently, a high level of interest exists in the continuous version of this technology, both by the US Food and Drug Administration (FDA), and by pharmaceutical manufacturers. In this paper, a continuous high shear wet granulation process was examined based on a placebo formulation comprising 70% ∂-lactose monohydrate and 30% microcrystalline cellulose (Avicel® PH101). Granulation was then carried out in a continuous high shear mixer granulator, Glatt GCG 70. The impact of two process variables (rotation speed and liquid/solid (L/S) ratio) and two design parameters (blade configuration and nozzle position) were evaluated via an I-optimal design. Multi-factor analysis of variance (ANOVA) indicated that rotation speed and L/S ratio dominated the granulation process and had the most significant effects on granule size distribution (GSD). The largest granule mass median diameter was obtained at the lowest rotation speed and highest L/S ratio. The granulation mechanism underlying this continuous process was examined using a wetting and nucleation regime map. For the cases studied here, the mechanical dispersion regime controlled the formation of granule nuclei, leading to a broad GSD and a limited growth ratio.

The FDA withdrew the draft guidance document for industry “Powder Blends and Finished Dosage Units—Stratified In-Process Dosage Unit Sampling and Assessment.” An FDA’s primary concern was a lack of confidence that the results from USP Uniformity of Dosage Units testing ensure the content uniformity of a batch. ISPE sponsored the Blend Uniformity and Content Uniformity Group (referred to as Group), which was formed in August 2013 to discuss approaches to assess blend and content uniformity. Modifications to the withdrawn draft stratified sampling guidance document are proposed by the Group for the assessment of adequacy of powder mix and content uniformity of the finished product in “Recommendations for the Assessment of Blend and Content Uniformity: Modifications to Withdrawn FDA Draft Stratified Sampling Guidance,” accepted by J Pharm Innov, 2014. Specific statistical methodologies to construct acceptance criteria were not recommended in the paper. This paper provides an example and technical discussion of a statistical approach that can be inserted into the framework described in the Group’s paper. There may be other approaches to sampling plans, statistical analysis, and acceptance criteria that are acceptable to demonstrate content uniformity. ASTM E2709, “Standard Practice for Demonstrating Capability to Comply with an Acceptance Procedure” and E2810, “Standard Practice for Demonstrating Capability to Comply with the Test for Uniformity of Dosage Units” for demonstrating dosage unit uniformity can be used to evaluate content uniformity. These standards are discussed and applied to the sampling plans given in the Group’s paper. The method can provide with a high level of confidence that samples from a lot will have a high probability of passing the USP UDU test. The methodology can be used to evaluate content uniformity data based on a sampling plan that tests either one or more than one dosage unit from each of multiple locations throughout the lot. An acceptance limit table based on sample means and standard deviations can be generated that is easy for the user to apply to content uniformity results. Operating characteristic (OC) curves for process qualification and continued process verification/routine lot release sampling plans are presented and compared along with the USP UDU OC curve. The process qualification criteria/sampling plans are shown to be “conservative” compared to the USP UDU test. A two-stage tiered plan is shown that could be used during continued process monitoring/routine release. The ASTM E2709/E2810 methodology provides acceptance criteria for several sampling plans that could be used for the assessment of content uniformity during process qualification and continued process monitoring/routine release. Passing the acceptance criteria can assure with a high level of confidence that a lot can meet the USP UDU test.

This article presents a case study of a continuous feeding strategy for five pharmaceutical components (active pharmaceutical ingredient (API), Prosolv HD90, crospovidone, magnesium stearate, and colloidal silicon dioxide), for the purpose of developing a direct compression continuous manufacturing system. Feeding options for each of these five powders were examined. Prosolv HD90 and crospovidone easily resulted in optimal feeding conditions, whereas the remaining powders in the formulation presented some challenges. The API displayed flow issues, leading to clogging of the screen with small openings. Magnesium stearate exhibited shear sensitivity; increasing shear of the powder due to hopper agitation resulted in drifting feeding performance. Colloidal silicon dioxide exhibited electrostatic issues that render most tooling options unsuitable for steady operation. All of these difficulties were resolved using the methods described in this article.

There has been increasing interest in the last few years especially within the pharmaceutical industry towards continuous powder blending. In this paper, the effects of different design and operating parameters are investigated, which include blade speed, shaft angle, weir height, fill level, blade angle, and blade width. The projection to latent structures regression is introduced to elucidate the significance of these factors on the two key indices of continuous blending performance, the local blending rate and the mean axial velocity. Shaft angle and blade speed are the two most influential factors pointing to a blending improvement strategy. The proposed strategy is examined using an experimental setup for the production of pharmaceutical powder mixtures.

In recent years, high-pressure homogenization has been used with increasing frequency to reduce the size of pharmaceutical suspensions to the micron, submicron, and nano scales with the goal of increasing the dissolution rate of the drug, and consequently, the in vivo bioavailability. As particle suspensions become smaller in size, increased concentrations of surfactants and stabilizers are required to prevent particle agglomeration. Recently, relatively high concentrations of biocompatible polymers have been used to stabilize suspensions by imparting surface-active steric stability as well as kinetic stability through an increase in suspension viscosity and/or a transition to non-Newtonian rheological properties. While the benefits of stable suspensions are known, little is known about the effect of the high polymer concentration on the actual breakup of the particles in suspension. In this work, designed experiments were used to identify the key parameters that govern the final particle size of a drug suspension following homogenization. In particular, drug loading, operating pressure, and polymer concentration were all found to be statistically significant factors in determining the resulting size of particles in suspension. In addition, it was found that an optimal polymer concentration of 2% (w/w) was required to adequately stabilize the particle suspension while simultaneously avoiding a decrease in homogenizer performance. Concentrations higher than 2% (w/w) resulted in size reduction limitations due to the increased viscosity (>10 cP) and the transition to non-Newtonian behavior.

A laser-induced breakdown spectroscopy-based analytical methodology is developed to study tablet coating variability in pharmaceutical tablets. The method quantifies the amount of coating on a tablet by assigning an average coating thickness score to it. When tested using samples with different amounts of coating, the coating thickness scores showed direct correlation to the weight gain of the tablet, hence validating the analytical method. The relative significance of the processing parameters and the components of variability were computed using statistical techniques. The sampling frequency of laser shots was found to have no significant effect. The effect of the position of the laser pulse on the tablet surface was found to be significant; however, it was determined that this effect was due to the tablet curvature, which resulted in the laser optical path to intersect the coating diagonally. The variability between batches (lots) manufactured under the same processing conditions was not significant. The largest avoidable source of variability was the tablet-to-tablet component, possibly indicating the inadequate mixing performance of the coating device.

Introduction The identification and graphical representation of process design space are critical in locating not only feasible but also optimum operating variable ranges and design configurations. In this work, the mapping of the design space of pharmaceutical processes is achieved using the ideas of process operability and flexibility under uncertainty.

Powder feeding is a fundamental unit operation in the pharmaceutical industry. For the cases in which first-principle process models are unknown, such as when new powder mixture feeding operations are being evaluated, or no longer accurately describe current operating behavior, surrogate model-based approaches can be employed in order to quantify input–output behavior. In this work, two such metamodeling techniques—kriging and response surface methods—are used to predict a loss-in-weight feeder unit’s flow variability in terms of unit flowability and feed rate. Based on a comparison of predicted with experimental values, an iteratively constructed kriging model is found to more accurately capture the feeder system behavior compared with the response surface methodology. Although feeders are used as a case study in this paper, the kriging methodology is general to address other processes where first-principle models are not available.

In this study, a quality by design approach was applied to the design and scale-up of a batch mixing process. Mixtures of acetaminophen and lactose were sampled at different mixing times using a groove sampler. Samples were subsequently analyzed using NIR reflection spectroscopy. The effects of four processing parameters on the empirical mixing rate in a bin blender were examined. Blender rotation rate (two levels), powder fill level (two levels), powder cohesion (two levels), and blender size (three levels) represent the four parameters studied. Blender geometry and blender loading method were treated as constant parameters. Statistical analysis was used to assess the impact each parameter had on the mixing rate. Blender size (p = 0.02), powder cohesion (p = 0.05), and rotation rate (p = 0.07) all significantly affected the mixing rate. The least significant parameter was the vessel fill level (p = 0.18), indicating mixing performance is not strongly affected by fill level, given the range studied.

In this paper, the development of a compartment model to simulate mixing within a continuous blender is reported. The main benefit of the method is that it can generate extensive modeling predictions in very short computational time. The model can also be used to explore the effect of sampling parameters on estimated mixing performance, a topic that has been central to pharmaceutical manufacturing for the past 15 years and that remains a central issue in the PAT initiative. However, this method requires more input than conventional particle dynamics methods. Thus, we investigate the effects of modeling parameters on mixing performance to develop general guidance needed to adapt this modeling framework to any continuous process. An experimental technique based on longitudinal sampling is used to examine the content uniformity of the blend along the continuous mixer. The model compares favorably with continuous mixing experiments, capture the effects of feeding rate variability, active product ingredient concentration, and blender processing angle, while effectively capturing and making explicit the effect of sampling parameters such as number of samples and sample size. The modeling approach provides a convenient tool for process design.

This paper communicates a methodology that uses experimental data and a new statistical method that uses a simulation to reconstruct the composition distribution of a powder blend containing drug agglomerates. The reconstructed distribution can be used subsequently to optimize sampling protocols, compute operating characteristic curves, and estimate process capability for blends containing agglomerates. A blend containing a cohesive API and an excipient is prepared in a blender. Although the API is sieved (mesh 100 μm) prior to its addition to the blender, API agglomerates are found in samples after blending. These agglomerates have either survived the mixing operation, or been created by the operation. The population of sample concentrations is used to estimate the parameters of a statistical model that combines multiple distribution functions to describe the binary mixture with the minor component partially agglomerated. The local concentration for the non-agglomerated portion of the minor component throughout the entire blend is estimated using a Gaussian distribution with parameters $ \overline{x} $ (mode) and s (standard deviation) that are typically well established. The function and the parameters that describe the population of agglomerates of the minor component are estimated using (typically sparse) experimental data. The optimization of the parameters describing the agglomerate population is performed using a simulation of the powder bed in an iterative manner. The simulated blend, built using the statistical model, is extensively examined and a distribution of RSD estimates is obtained. The iterative process for seeking the parameters that describe the agglomerate population converges when the mode of the distribution of RSD estimates matches the experimental RSD value, which is the best available estimate of the blend homogeneity. This methodology is applied to populations of samples for different binary formulations prepared in different blenders. In all cases, after iterating to adjust the parameters of the model, there is an agreement between the experimental and the simulated population of samples with a confidence of, at least, 95%. The methodology described here is an effective tool to create an accurate representation of agglomerated blends based on limited sampling results.

Continuous processing in pharmaceutical manufacturing is a relatively new approach that has generated significant attention. While it has been used for decades in other industries, showing significant advantages, the pharmaceutical industry has been slow in its adoption of continuous processing, primarily due to regulatory uncertainty. This paper aims to help address these concerns by introducing methods for batch definition, raw material traceability, and sensor frequency determination. All of the methods are based on established engineering and mathematical principles, especially the residence time distribution (RTD). This paper introduces a risk-based approach to address content uniformity challenges of continuous manufacturing. All of the detailed methods are discussed using a direct compaction manufacturing line as the main example, but the techniques can easily be applied to other continuous manufacturing methods such as wet and dry granulation, hot melt extrusion, capsule filling, etc.