Blend Uniformity Research Articles

Particle parameters of microwave-expanded cut stems and their influences on slim cigarette quality

Gray correlation and regression analyses were used to study the influences of microwave-expanded cut stem with different particle sizes on the physical properties and mixing homogeneity of cut tobacco blends. The effects on the levels of smoke components, such as the seven harmful components in smoke, and sensory quality of the mainstream cigarette smoke were also evaluated when the blends were made into slim cigarettes. The experimental results were as follows. 1) The contribution index of sliced width (X1) and shredded width (X2) was approximately the same for filling capacity; this was true for the proportion of long strands, small strands, the blending uniformity and smoke hazard index (H). However, for the amount of mainstream smoke released, the contribution index of X1 was slightly larger than X2. 2) When the sum of sliced and shredded width was≤0.6 mm, the dust contents of the cigarettes and tobacco, as well as the loss from the cigarette end, were high and did not meet the product quality requirements. 3) Cigarette draw resistance initially increased then decreased and the RSDs increased with the changes in the cut parameters. 4) When the sum of sliced and shredded width exceeded 0.9 mm, the degree of mixed uniformity of microwave-expanded cut stems significantly decreased. 5) The amount of tar, nicotine, and CO released initially increased and then decreased with the increased cut-stem width, peaked at 0.9 mm. 6) With increasing cut-stem width, cigarette's sensory quality decreased and the smoke hazard index initially increased then decreased. Generally, the total cut stem width should preferably range from 0.7 mm to 0.8 mm and X1 equals or slightly bigger than X2.

Abstracts from The Aerosol Society Drug Delivery to the Lungs 26 Edinburgh International Conference Centre Edinburgh, Scotland, UK December 9-11, 2015.

Abstracts from The Aerosol Society Drug Delivery to the Lungs 26 Edinburgh International Conference Centre Edinburgh, Scotland, UK December 9-11, 2015.

Continuous feeding of low-dose APIs via periodic micro dosing

Precise and effective feeding of small powder quantities remains a challenge in many fields, including pharmaceutical development and production. This paper demonstrates that a simple feeding principle can be applied to accomplish stable micro feeding (<100mg/s) and describes a gravimetric powder feeding system with a vibratory sieve mounted on a chute. Feeding was induced via vertical vibrations that can be adjusted within a broad range of frequencies and amplitudes. The feeding system was studied using different frequencies, amplitudes, sieves and powder properties. Feeding was characterized by means of a dynamic scale and high-speed camera recordings. The feeding system provided effective powder feeding even in a range of 1–2mg/s. It was shown that powder properties require special attention when the vibratory sieve-chute system operates at higher feed rates (or feeding times >30min), i.e., feeding at a higher throughput.A combination of discrete element method (DEM) simulations and compartment population balance model (PBM) was used to incorporate the proposed micro feed system into a continuous powder mixer (Gerike GCM250; Gerike Holding LTD., Regensdorf, Switzerland). It illustrates how oscillating feeding rates (the latter is a characteristic of the studied micro feeding system) affect the content uniformity of low dose blends, i.e., powder mixtures with a relatively low fraction of active pharmaceutical ingredient.

A Rational Analysis of Uniformity Risk for Agglomerated Drug Substance Using NIR Chemical Imaging.

Early risk detection and quick diagnosis of manufacturing challenges are necessary to support the accelerated development pace of drug product in the current competitive environment. Analytical tools, such as near-infrared (NIR) chemical imaging (CI), can be employed for alerting drug substance uniformity risks in intermediates and the final product of solid dosage forms. In this particular study, the ability to characterize the behavior of agglomerated drug substance throughout process development was enabled by NIR CI to identify uniformity risks with small sample sizes and short turnaround time. Using NIR chemical imaging, the drug substance distribution and cluster size in all intermediates were visualized throughout the drug product process. NIR CI enabled rapid identification of the key unit operations that produced the greatest reduction in cluster size for enhanced distribution of the drug substance. The comil acted as a high shear mixing step to disperse soft lumps prior to roller compaction. Shear forces or pressure during roller compaction was sufficient to break down and disperse the agglomerates further. Ultimately, the process was robust against a range of drug substance input properties such that the uniformity of the final blend was consistently achieved and the agglomerated drug substance had no risks to the drug product process.

Nano-confinement of acetaminophen into porous mannitol through adsorption method

A new formulation has been developed successfully, which includes production of highly-porous mannitol particles with high surface areas through the spray drying of mannitol solutions containing ethanol-soluble sugar or food-grade acids as templating agents. The resultant porous particles after ethanol washing have been transferred to ethanol solutions containing the drug component. The results of this study showed that deposition of acetaminophen in the pore-space of highly-porous mannitol resulted in better blending uniformity of drug dosage, as well as a fast drug release rate due to nano-confinement of drugs into porous excipients. Within the first 5 min of the experiment 80% of the drug was released for the drug-loaded samples. Low variability for the drug content was found for the finished products, even for low-dose drug products with around 4% relative standard deviation or less. The drug content of porous mannitol with a surface area and pore volume of 6.1 ± 0.1 m2 g−1 and 0.037 ± 0.003 ml/g, respectively, significantly increased from 0.62 ± 0.03 wt% to 21.7 ± 0.8 wt% when the concentration of acetaminophen was increased from 0.01 M to 0.5 M.

Analysis of the Main Methods of Monitoring the Blending of Natural and Chemical Fibers

A classification is presented for well-known methods and equipment used to evaluate the composition and uniformity of blends of natural and chemical fibers. A visual method, a photometric method, and a method based on differences between the physicochemical properties of the components being blended are analyzed. Aspects of the use of these methods are also discussed.

Adequacy and verifiability of pharmaceutical mixtures and dose units by variographic analysis (Theory of Sampling) – A call for a regulatory paradigm shift

In spite of intense efforts in the last 20 years, the current state of affairs regarding evaluation of adequacy of pharmaceutical mixing is at an impressive standstill, characterized by two draft guidances, one withdrawn, and the other never approved. We here analyze the regulatory, scientific and technological situation and suggest a radical, but logical approach calling for a paradigm shift regarding sampling of pharmaceutical blends. In synergy with QbD/PAT efforts, blend uniformity testing should only be performed with properly designed sampling that can guarantee representativity—in contrast to the current deficient thief sampling. This is necessary for suitable in-process specifications and dosage units meeting desired specifications. The present exposé shows how process sampling based on the Theory of Sampling (TOS) constitutes a new asset for regulatory compliance, providing procedures that suppress hitherto adverse sampling errors. We identify that the optimal sampling location is after emptying the blender, guaranteeing complete characterisation of the residual heterogeneity. TOS includes variographic analysis that decomposes the effective total sampling and analysis error (TSE+TAE) from the variability of the manufacturing process itself. This approach provides reliable in-process characterization allowing independent approval or rejection by the Quality Control unit. The science-based sampling principles presented here will facilitate full control of blending processes, including whether post-blending segregation influences the material stream that reaches the tabletting feed-frame.

On-line monitoring of blend uniformity in continuous drug product manufacturing process—The impact of powder flow rate and the choice of spectrometer: Dispersive vs. FT

One of the commonly acknowledged issues in continuous manufacturing of drug products is how to provide a representative sampling on flowing powder to assure its blend uniformity. An investigation was conducted to improve understanding on the impact of powder flow rate under different continuous manufacturing conditions and the impact of optical parameters (such as resolution, co-adds, and integration time) on NIR spectral quality with respect to a dispersive and a Fourier transform instrument. A partial least squares (PLS)-based spectral pretreatment was found useful to tackle the impact of different flow rates on NIR spectral signals. Multivariate figures of merit (FOM) were used to evaluate performances across different instruments and optical settings and discover the advantageous selectivity and sensitivity on the Fourier transform than the dispersive instrument regardless of the use of co-adds.

Assessment of powder blend uniformity: Comparison of real-time NIR blend monitoring with stratified sampling in combination with HPLC and at-line NIR Chemical Imaging

Scope of the study was (1) to develop a lean quantitative calibration for real-time near-infrared (NIR) blend monitoring, which meets the requirements in early development of pharmaceutical products and (2) to compare the prediction performance of this approach with the results obtained from stratified sampling using a sample thief in combination with off-line high pressure liquid chromatography (HPLC) and at-line near-infrared chemical imaging (NIRCI). Tablets were manufactured from powder blends and analyzed with NIRCI and HPLC to verify the real-time results. The model formulation contained 25% w/w naproxen as a cohesive active pharmaceutical ingredient (API), microcrystalline cellulose and croscarmellose sodium as cohesive excipients and free-flowing mannitol. Five in-line NIR calibration approaches, all using the spectra from the end of the blending process as reference for PLS modeling, were compared in terms of selectivity, precision, prediction accuracy and robustness. High selectivity could be achieved with a “reduced” approach i.e. API and time saving approach (35% reduction of API amount) based on six concentration levels of the API with three levels realized by three independent powder blends and the additional levels obtained by simply increasing the API concentration in these blends. Accuracy and robustness were further improved by combining this calibration set with a second independent data set comprising different excipient concentrations and reflecting different environmental conditions. The combined calibration model was used to monitor the blending process of independent batches. For this model formulation the target concentration of the API could be achieved within 3min indicating a short blending time. The in-line NIR approach was verified by stratified sampling HPLC and NIRCI results. All three methods revealed comparable results regarding blend end point determination. Differences in both mean API concentration and RSD values could be attributed to differences in effective sample size and thief sampling errors. This conclusion was supported by HPLC and NIRCI analysis of tablets manufactured from powder blends after different blending times. In summary, the study clearly demonstrates the ability to develop efficient and robust quantitative calibrations for real-time NIR powder blend monitoring with a reduced set of powder blends while avoiding any bias caused by physical sampling.

Differential scanning calorimetric characterization of pharmaceutical powder blend uniformity in a laboratory-scale V-blender

Testing of powder blend uniformity is one of the important steps during formulation development and routine commercial production of pharmaceutical products. Pharmaceutical industries heavily rely on chemical analysis by UV or HPLC for the same. However, the chemical methods are time consuming, need a few grams of powder sample, and they are not green in nature. The objective of this research is to explore the use of DSC as an alternative of UV analysis to assess the powder blend uniformity of a binary mixture of metformin hydrochloride and HPMC (5:95 w/w) at 50% and 60% occupancy of a laboratory-scale V-blender. Samples were withdrawn at 5, 10, 15, and 20min intervals each of the top, middle, and bottom positions of the blender. Samples from all three locations at all time-points were found to have similar concentrations by both methods with the maximum RSD below 26%. Percent of metformin HCl recovery from the powder mixture after 20min was comparable to the DSC method (2.68±0.22% and 2.29±0.14% at 50% and 60% occupancy, respectively) and UV method (2.66±1.10% and 2.60±0.32% at 50% and 60% occupancy levels, respectively). DSC, after a careful evaluation of drug and excipient specific interaction, can be considered as an alternative of pharmacopoeial spectrophotometric or chromatographic methods for powder blend uniformity assessment at various stages of pharmaceutical product development and its commercial production.

An efficient, maintenance free and approved method for spectroscopic control and monitoring of blend uniformity: The moving F-test

Dry powder mixing is a wide spread Unit Operation in the Pharmaceutical industry. With the advent of in-line Near Infrared (NIR) Spectroscopy and Quality by Design principles, application of Process Analytical Technology to monitor Blend Uniformity (BU) is taking a more prominent role. Yet routine use of NIR for monitoring, let alone control of blending processes is not common in the industry, despite the improved process understanding and (cost) efficiency that it may offer. Method maintenance, robustness and translation to regulatory requirements have been important barriers to implement the method. This paper presents a qualitative NIR-BU method offering a convenient and compliant approach to apply BU control for routine operation and process understanding, without extensive calibration and method maintenance requirements. The method employs a moving F-test to detect the steady state of measured spectral variances and the endpoint of mixing. The fundamentals and performance characteristics of the method are first presented, followed by a description of the link to regulatory BU criteria, the method sensitivity and practical considerations. Applications in upscaling, tech transfer and commercial production are described, along with evaluation of the method performance by comparison with results from quantitative calibration models. A full application, in which end-point detection via the F-test controls the blending process of a low dose product, was successfully filed in Europe and Australia, implemented in commercial production and routinely used for about five years and more than 100 batches.

Formulation Development and Evaluation of Gabapentin Controlled Release Tablets

The objective of the present study was to develop a pharmaceutically equivalent, stable, robust, cost effective and quality improved formulation of Gabapentin controlled release tablets by using different grades of controlled release polymer. The design of dosage form was performed by choosing Hydroxypropyl Methyl Cellulose (HPMC K100MCR), Hydroxypropyl Methyl Cellulose (HPMC K15MCR), Microcrystalline Cellulose (MCC) and Di-calcium phosphate polymers as matrix builders. The drug-polymer compatibility studies were performed. Blend Uniformity was studied and accordingly the flowability was optimized for the powder blend. Tablets were prepared by direct compression with free flowing powder. The network formed by HPMC, MCC and DCP had been coupled satisfactorily with the controlled resistance, in vitro release and FT-IR. Mean dissolution time was also reported to compare various dissolution profiles. The formula was finalized by comparing the in vitro dissolution with that of the innovator SR and IR tablets. Optimized formulation of Gabapentin was formulated using 23% HPMC K100MCR and 10% of DCP. In vitro drug release profile was examined 98.69% within 12h. The releases of the formulation were fitting to Hixson Crowell model suggesting controlled zero order release from the formulation. The results suggested that direct compression is a suitable method to formulate controlled release Gabapentin tablets and it can perform therapeutically better than conventional immediate release dosage form.

Development of a NIR-based blend uniformity method for a drug product containing multiple structurally similar actives by using the quality by design principles

The aim of this study is to develop an at-line near infrared (NIR) method for the rapid and simultaneous determination of four structurally similar active pharmaceutical ingredients (APIs) in powder blends intended for the manufacturing of tablets. Two of the four APIs in the formula are present in relatively small amounts, one at 0.95% and the other at 0.57%. Such small amounts in addition to the similarity in structures add significant complexity to the blend uniformity analysis. The NIR method is developed using spectra from six laboratory-created calibration samples augmented by a small set of spectra from a large-scale blending sample. Applying the quality by design (QbD) principles, the calibration design included concentration variations of the four APIs and a main excipient, microcrystalline cellulose. A bench-top FT-NIR instrument was used to acquire the spectra. The obtained NIR spectra were analyzed by applying principal component analysis (PCA) before calibration model development. Score patterns from the PCA were analyzed to reveal relationship between latent variables and concentration variations of the APIs. In calibration model development, both PLS-1 and PLS-2 models were created and evaluated for their effectiveness in predicting API concentrations in the blending samples. The final NIR method shows satisfactory specificity and accuracy.

Effect of material properties and design parameters on the final blend uniformity using experimental and simulation results

One of the most important operations in the food, chemical, and pharmaceutical industries is powder mixing. In the pharmaceutical industry this operation is currently performed mainly in batch mode. However, the Food and Drug Administration (FDA), using the Process Analytical Technology (PAT) initiative, has been working on the promotion of the application of continuous processes in the pharmaceutical industry. The main goal of this study was to understand the powder phenomena inside the mixer and monitor mixing uniformity using experiments and simulations by Discrete Elements Methods (DEM). The experimental results showed highest relative standard deviation (RSD) using the lowest active pharmaceutical ingredient (API) concentration (2.5%), and after using image analysis part of this effect was attributed to the position of the feed inlet. The two experiments with the highest RSD (50 and 70 RPM) were replicated using a new feeding position (25°). The RSD values for the new feeding position demonstrated an improvement in mixing uniformity. The new feed position was studied in more detail using DEM by performing a simulations set that included simulations at two mixer speeds (50 and 70 RPM), three concentrations (2.5%, 10.5%, and 50%), and two different material properties (with and without cohesion). Values of hold-up, velocity profile, mean residence time (MRT), and mixing uniformity were compared for both feed positions. Also the blend uniformities inside the tumble, at each tumble exit, and at the final exit of the system were compared. The results show a positive effect of the angle in the uniformity inside the mixer, in the exit points, and at the exit of the system. Additionally, a relationship between RSD and concentration was found.

Exploring mixing uniformity of a pharmaceutical blend in a high shear mixture granulator using enthalpy values obtained from DSC

Assessing mixing uniformity of a powder blend in pharmaceutical formulation of a low dose potent drug is a very critical step, failing which the entire formulation needs to be reworked from the beginning. Thermal analytical methods like differential Scanning calorimetry [DSC] are rapid method requiring very lesser sample for quantification. In this project we have made use of enthalpy values obtained from DSC for estimation of mixing uniformity in powder blend mixed using high shear mixture granulator. Influence of various parameters like melting behavior of drug and excipients, bulk density of excipients and mixing time on the results of enthalpy values was also evaluated. The results from DSC analysis were further confirmed using HPLC analysis and a correlation was proposed between the two analytical methods. It was observed that at lower levels of drug i.e. 0.5%, 1% and 2%, the relative standard deviation values obtained using DSC were higher than that using HPLC but at concentration above 5% of drug, the results of DSC and HPLC were quite similar. It was concluded that DSC could reliably predict the uniformity of powder blend where drug loading was above 5%, however results accuracy was somewhat less below this level.

Process–structure relationship of carbon/ polyphenylene sulfide commingled hybrid yarns used for thermoplastic composites

Commingling is a prospective manufacturing process for the production of hybrid yarn in which a reinforcement material and a thermoplastic matrix in the form of filaments are mixed to form continuous filament yarn. In this work, hybrid two-component carbon/ polyphenylene sulfide (PPS) yarns designed for high-performance thermoplastic composites were developed. Experiments were carried out to investigate the manufacturing process of commingled yarn and quantify the homogeneity of distribution of carbon and PPS fibers in cross section of commingled hybrid yarns. The effect of process parameters in commingling including degree of overfeeding, production speed, and air pressure on the filament distribution in the cross section of commingled hybrid yarns was investigated. The results show that process parameters play a large part in improving blend uniformity and filament distribution in hybrid commingled yarns. A correlation between the observed homogeneity and the process parameters was established.

Assessment of Blend and Content Uniformity. Technical Discussion of Sampling Plans and Application of ASTM E2709/E2810

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.

Recommendations for the Assessment of Blend and Content Uniformity: Modifications to Withdrawn FDA Draft Stratified Sampling Guidance

The following paper describes the International Society for Pharmaceutical Engineering (ISPE)-sponsored Blend Uniformity and Content Uniformity Group’s proposed modifications to the withdrawn FDA draft guidance document for industry “Powder Blends and Finished Dosage Units—Stratified In-Process Dosage Unit Sampling and Assessment.” The modifications targeted FDA’s primary concerns that led to the withdrawal of the draft guidance document, which were insufficient blend uniformity testing and that a one-time passing of the criteria stated in USP General Chapter Uniformity of Dosage Units testing lacks confidence to ensure the content uniformity of a batch. The Group’s approach discusses when triplicate blend samples should be analyzed and the importance of performing variance component analysis on the data to identify root causes of non-uniformity. The Group recommends the use of statistically based approaches, acceptance criteria, and sampling plans for assessing content uniformity for batch release that provide increased confidence that future samples drawn from the batch will comply with USP . Alternative statistical approaches, sampling plans, and acceptance criteria, including modern analytical method (e.g., process analytical technology (PAT)) sampling plans, may be substituted for those mentioned in this paper, with justification. This approach also links blend and content uniformity testing to the three stages of the life cycle process validation approach. A framework for the assessment of blend and content uniformity that provides greater assurance of passing USP is presented.

Blend uniformity and powder phenomena inside the continuous tumble mixer using DEM simulations

Powder mixing is an essential operation in pharmaceutical, food, and petrochemical industries. Pharmaceutical companies have been working in the implementation of continuous processes as an alternative to the batch process using the food and drug administration process analytical technology initiative. The main goal was to understand the mixing phenomena inside the continuous tumble mixer and monitor blend uniformity using discrete element method. Results demonstrated that the main mixing mechanism is convection similar to the common tumbling mixers. This mechanism is driven by the bulk flow of the particles, due to the mixer rotation. The simulations' results, demonstrated that the cohesion reduces the concentration variability due to the higher holdup, particle interactions, and mean residence time. The blend uniformity at the exit of the system was measured and a relationship between relative standard distribution, cohesion, and the collision frequency was found. © 2014 American Institute of Chemical Engineers AIChE J, 61: 792–801, 2015

Quality-by-design III: application of near-infrared spectroscopy to monitor roller compaction in-process and product quality attributes of immediate release tablets.

The objective of this study is to use near-infrared spectroscopy (NIRS) coupled with multivariate chemometric models to monitor granule and tablet quality attributes in the formulation development and manufacturing of ciprofloxacin hydrochloride (CIP) immediate release tablets. Critical roller compaction process parameters, compression force (CFt), and formulation variables identified from our earlier studies were evaluated in more detail. Multivariate principal component analysis (PCA) and partial least square (PLS) models were developed during the development stage and used as a control tool to predict the quality of granules and tablets. Validated models were used to monitor and control batches manufactured at different sites to assess their robustness to change. The results showed that roll pressure (RP) and CFt played a critical role in the quality of the granules and the finished product within the range tested. Replacing binder source did not statistically influence the quality attributes of the granules and tablets. However, lubricant type has significantly impacted the granule size. Blend uniformity, crushing force, disintegration time during the manufacturing was predicted using validated PLS regression models with acceptable standard error of prediction (SEP) values, whereas the models resulted in higher SEP for batches obtained from different manufacturing site. From this study, we were able to identify critical factors which could impact the quality attributes of the CIP IR tablets. In summary, we demonstrated the ability of near-infrared spectroscopy coupled with chemometrics as a powerful tool to monitor critical quality attributes (CQA) identified during formulation development.