Blend Uniformity Research Articles

Opportunities for Process Control and Quality Assurance Using Online NIR Analysis to a Continuous Wet Granulation Tableting Line

This paper investigates the application of online near-infrared measurements as a means to measure blend uniformity in a continuous tableting line. Underlying all the monitoring and control methods is the ability to measure key tablet properties online at a rate suitable for control purposes. The use of NIR to determine any deviations in blend uniformity is demonstrated by interpreting the relevant spectral signature allowing quantitative information to be acquired for process monitoring and quality assurance. In addition to demonstrating the functionality of the NIR probe, the practical issues arising in the application are discussed. The composition of the blend was measured using an NIR probe over a range of concentrations and the results were calculated comparing sub unit dose scale of scrutiny of small populations. This was compared with predicted product quality for whole tablets over the whole production period. This technique has demonstrated how data collected online can be used to successfully predict the quality of the whole production run for the purposes of real-time product quality assurance.

Blending quality of co-air-textured yarn: Optimization parameters of Kevlar/polypropylene applicable for thermoplastic composites

Nowadays, hybrid yarns, which consist of at least one-component thermoplastic fibers, are used in thermoplastic textile composites. The uniformity of the fibers in hybrid yarns is a key factor that directly influences the composite properties. Accordingly, one of the main aims of the present research was to optimize the air texturing parameters to achieve the uniform blending of Kevlar/polypropylene fibers. To evaluate the blending uniformity of yarns, the radial, lateral and angular distribution of fibers, based on the position of the pixels of the constituent fibers, was evaluated using the image processing data of yarn cross sections. According to this method, the production parameters, namely, blend ratio, delivery speed, feed rate and air pressure, were optimized simultaneously via the response surface method to obtain the blending uniformity of the fibers. The uniform blending distribution could be achieved by a higher blend ratio of Kevlar/PP (1:6), a lower production speed (300 m/min), a higher feed rate (500 m/min), and a higher air pressure (10 bar). Eventually, it was confirmed that there was a good correlation between the blending quality of the real samples and the predicted quality of the response surface method model.

Process analytical technology for continuous manufacturing tableting processing: A case study

The use of Near Infrared Spectroscopy (NIRS) as a fast and non-destructive technique was employed for the control and monitoring of the tableting step during a continuous manufacturing process.Two NIRS methods were optimized in order to in-line control the blend uniformity in the tablet feed frame and the API concentration of freshly pressed tablets prior the ejection. The novelty of this work first lies in the acquisition speed of NIR spectra reaching up to 70,000 tablets/h. Partial Least Square (PLS) regression was used as chemometric tool for the computation that resulted in excellent predictive calibration results. A coefficient of correlation (r) value of 0.99 was obtained for both probes. The root mean square error of calibration (RMSEC) and the root mean square error of prediction (RMSEP) were respectively 1.8% and 1.8% for active content in the tablet feeder and 2.2% and 2.3% for the tablet content. In addition, calibration performance and robustness of the methods were evaluated. Moreover several qualitative methods were proposed to monitor the tableting process in different stages of development (single wavelength, Principal Component Analysis, and Independent Component Analysis). In early phase development, the requirement/quality of the input material is not established yet; hence the use of a qualitative approach allows to confirm the suitability of the PAT methodology for in-process material monitoring & control. Later, the qualitative approach constitutes the foundation for the quantitative approach when input materials are fixed and larger production size occurs. The proposed strategy is a performant PAT tool for continuous manufacturing and a step forward to real time release.

Additive manufacturing of prototype elements with process interfaces for continuously operating manufacturing lines

Rapid prototyping based on in silico design and 3D printing enables fast customization of complex geometries to multiple needs. This study utilizes, additive manufacturing for rapid prototyping of elements for continuously operating mixing geometries including interfaces with process analytical technology (PAT) tools, to show that 3D printing can be used for prototyping of both parts of production line and PAT interfacing solution. An additional setup was designed for measuring the dynamic calibration samples for a semi-quantitative near infrared (NIR) spectroscopic model. The powder was filled in a small calibration chamber and in-line NIR spectra of calibration samples were collected from moving material while mimicking the powder flow dynamics in a typical continuous mixer. This dynamic powder mixing system was compared with a static powder calibration model where the NIR probe was placed at different positions on a static sample. Principal component analysis (PCA) revealed that the 3D printed device with dynamic measurement of the NIR spectra had more potential for quantitative analysis. With the prototype continuous mixer, two differently placed process interfaces for NIR spectroscopic monitoring of the powder mixing were evaluated. With this approach, the importance of positioning the process analytical tools to assess the blend uniformity could be demonstrated. It was also observed that with the longer mixing geometry, a better mixing result was achieved due to a larger hold up volume and increased residence time.

Mixing of low-dose cohesive drug and overcoming of pre-blending step using a new gentle-wing high-shear mixer granulator

The objective of this study was to examine the influence of drug amount and mixing time on the homogeneity and content uniformity of a low-dose drug formulation during the dry mixing step using a new gentle-wing high-shear mixer. Moreover, the study investigated the influence of drug incorporation mode on the content uniformity of tablets manufactured by different methods. Albuterol sulfate was selected as a model drug and was blended with the other excipients at two different levels, 1% w/w and 5% w/w at impeller speed of 300 rpm and chopper speed of 3000 rpm for 30 min. Utilizing a 1 ml unit side-sampling thief probe, triplicate samples were taken from nine different positions in the mixer bowl at selected time points. Two methods were used for manufacturing of tablets, direct compression and wet granulation. The produced tablets were sampled at the beginning, middle, and end of the compression cycle. An analysis of variance analysis indicated the significant effect (p < .05) of drug amount on the content uniformity of the powder blend and the corresponding tablets. For 1% w/w and 5% w/w formulations, incorporation of the drug in the granulating fluid provided tablets with excellent content uniformity and very low relative standard deviation (∼0.61%) during the whole tableting cycle compared to direct compression and granulation method with dry incorporation mode of the drug. Overall, gentle-wing mixer is a good candidate for mixing of low-dose cohesive drug and provides tablets with acceptable content uniformity with no need for pre-blending step.

Cross-sectional analysis of impregnated excipient particles by energy dispersive X-ray spectroscopy

Impregnation of active pharmaceutical ingredients (APIs) onto porous excipients has numerous benefits for solid dosage formulations. Previous work has successfully demonstrated the manufacturing of pharmaceuticals using fluidized bed (FB) impregnation of APIs onto porous carriers and discussed its advantages (such as easy to implement, improvement of blend uniformity and dissolution kinetics, and stabilization of amorphous APIs). This study aims to develop methods for analysis of the spatial distribution of the impregnated API inside the porous excipient. An understanding of the spatial distribution of the API can be important if one wants to achieve high drug loadings. In addition, the spatial distribution of the API can impact its dissolution rate. The impregnation profile is analyzed using energy dispersive X-ray spectroscopy (EDS). Two formulations are investigated using Fenofibrate and Acetaminophen (model APIs), impregnated onto Neusilin (porous excipient). Several methods are presented for particle embedding and cutting in order to produce cross-sections for analysis. Embedding with carbon-based resins/adhesives produces cross-sections with high quality but the resins contaminate the sample with carbon and reduce the detection of trace elements. Manually cutting particles immobilized on carbon tape or inorganic-based adhesives produces cross-sections with a higher degree of roughness but improves the detection of trace elements and reduces/eliminates carbon contamination in the sample, allowing for API detection by its carbon footprint. EDS analytical results showed that for both Fenofibrate and Acetaminophen formulations examined in this work, the API profile is highly uniform (detected by both carbon and characteristic trace elements).

Modeling and simulation of continuous powder blending applied to a continuous direct compression process

Continuous manufacturing techniques are increasingly being adopted in the pharmaceutical industry and powder blending is a key operation for solid-dosage tablets. A modeling methodology involving axial and radial tanks-in-series flowsheet models is developed to describe the residence time distribution (RTD) and blend uniformity of a commercial powder blending system. Process data for a six-component formulation processed in a continuous direct compression line (GEA Pharma Systems) is used to test the methodology. Impulse tests were used to generate experimental RTDs which are used along with parameter estimation to determine the number of axial tanks in the flowsheet. The weighted residual from the parameter estimation was less than the χ2 value at a 95% confidence indicating a good fit between the model and measured data. In-silico impulse tests showed the tanks-in-series modeling methodology could successfully describe the RTD behavior of the blenders along with blend uniformity through the use of radial tanks. The simulation output for both impulse weight percentage and blend uniformity were within the experimentally observed variance.

A Science and Risk-Based Pragmatic Methodology for Blend and Content Uniformity Assessment.

This paper describes a pragmatic approach that can be applied in assessing powder blend and unit dosage uniformity of solid dose products at Process Design, Process Performance Qualification, and Continued/Ongoing Process Verification stages of the Process Validation lifecycle. The statistically based sampling, testing, and assessment plan was developed due to the withdrawal of the FDA draft guidance for industry "Powder Blends and Finished Dosage Units-Stratified In-Process Dosage Unit Sampling and Assessment." This paper compares the proposed Grouped Area Variance Estimate (GAVE) method with an alternate approach outlining the practicality and statistical rationalization using traditional sampling and analytical methods. The approach is designed to fit solid dose processes assuring high statistical confidence in both powder blend uniformity and dosage unit uniformity during all three stages of the lifecycle complying with ASTM standards as recommended by the US FDA.

Development of a continuous direct compression platform for low-dose drug products

In this work a continuous direct compression process was developed for a low-dosed drug product. Each unit operation of the GEA CDC-50 system was thoroughly investigated. This paper aimed to tackle the macroscopic and microscopic blend uniformity challenges inherently associated with continuous direct compression of cohesive and agglomerated APIs formulated at low dose. Density, compressibility and flow were identified as key material properties at the feeding stage. The screw speed coupled with powder flow regulated the gravimetric feeding performance. The impact of process and design variables was elucidated at the blending stage. The impeller configuration (number and pattern of radial mixing blades) and speed were key variables to steer the residence time distribution at the blending stage. An impeller configuration with distributed radial mixing blades could sufficiently filter the steady state feeding variability at low mixer speed, but exerted limited strain and shear on the blend. Hence micro-agglomerates persisted through the blending process and occasionally resulted in super potent tablets. Therefore, a new configuration was evaluated with more radial mixing blades centered on the impeller. This configuration resulted in a long mixing time at high tip speed which induced a maximized strain and shear. Consequently, excellent uniformity of the blend and tablets at macroscopic and microscopic level was achieved. Besides, this impeller improved robustness towards feeding disturbances, changes in process settings and variable blend properties. Next, it was demonstrated that the lubrication step requires critical attention during the design of the equipment, formulation and process. This study provided abundant evidence that an optimized continuous direct compression process allows direct compression of challenging low-dose drug products.

Effects of Process and Design Parameters on Granule Size Distribution in a Continuous High Shear Granulation Process

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.

Macro-Raman spectroscopy for bulk composition and homogeneity analysis of multi-component pharmaceutical powders

A new macro-Raman system equipped with a motorized translational sample stage and low-frequency shift capabilities was developed for bulk composition and homogeneity analysis of multi-component pharmaceutical powders. Different sampling methods including single spot and scanning measurement were compared. It was found that increasing sample volumes significantly improved the precision of quantitative composition analysis, especially for poorly mixed powders. The multi-pass cavity of the macro-Raman system increased effective sample volumes by 20 times from the sample volume defined by the collection optics, i.e., from 0.02μL to about 0.4μL. A stochastic model simulating the random sampling process of polydisperse microparticles was used to predict the sampling errors for a specific sample volume. Comparison of fluticasone propionate mass fractions of the commercial products Flixotide® 250 and Seretide® 500 simulated for different sampling volumes with experimentally measured compositions verified that the effective sample volume of a single point macro-Raman measurement in the multi-pass cavity of this instrument was between 0.3μL and 0.5μL. The macro-Raman system was also successfully used for blend uniformity analysis. It was concluded that demixing occurred in the binary mixture of l-leucine and d-mannitol from the observation that the sampling errors indicated by the standard deviations of measured leucine mass fractions increased during mixing, and the standard deviation values were all larger than the theoretical lower limit determined by the simulation. Since sample volume was shown to have a significant impact on measured homogeneity characteristics, it was concluded that powder homogeneity analysis results, i.e., the mean of individual test results and absolute and relative standard deviations, must be presented together with the effective sample volumes of the applied testing techniques for any measurement of powder homogeneity to be fully meaningful.

Improving blend content uniformity via dry particle coating of micronized drug powders

Content uniformity of low dose blends with fine active pharmaceutical ingredients (API) is adversely impacted due to API agglomeration caused by high powder cohesion. Dry coating using high-intensity vibratory mixing is employed to reduce API cohesion and granular Bond number as well as agglomeration as predicted by contact models, hence improve blend content uniformity (CU). Micronized acetaminophen (mAPAP) (~10μm), a model API, was dry coated with nano-silica R972P (20nm), and mixed with Avicel 102. The amount of silica was varied from 0 to 2.74wt%, corresponding to theoretical surface area coverage (SAC) from 0 to 100% respectively. Bulk density, unconfined yield strength, and dispersive surface energy results indicated dry coating with 0.27 to 1.0wt% silica was adequate for API property enhancement; further corroborated by improved CU for 5wt% API blends. Excellent CU was achieved for 3, 5 and 10wt% API loaded blends, where 30min of mixing was found to be acceptable for all three. The CU with dry coated mAPAP was significantly lower and within the acceptable range as compared to control blends without silica, as well as those with silica added during blending. Sieving of mAPAP illustrated the reduction in mAPAP agglomeration, necessary for improved CU after dry coating, corroborating model based predictions. Compared to theoretical predictions, actual CU was higher unless API agglomerate size distribution obtained via sieving was taken into account. Overall, cohesion reduction by dry coating is shown as a promising approach for improving content uniformity of cohesive API blends.

Continuous direct compression as manufacturing platform for sustained release tablets

This study presents a framework for process and product development on a continuous direct compression manufacturing platform. A challenging sustained release formulation with high content of a poorly flowing low density drug was selected. Two HPMC grades were evaluated as matrix former: standard Methocel CR and directly compressible Methocel DC2. The feeding behavior of each formulation component was investigated by deriving feed factor profiles. The maximum feed factor was used to estimate the drive command and depended strongly upon the density of the material. Furthermore, the shape of the feed factor profile allowed definition of a customized refill regime for each material. Inline NIRs was used to estimate the residence time distribution (RTD) in the mixer and monitor blend uniformity. Tablet content and weight variability were determined as additional measures of mixing performance. For Methocel CR, the best axial mixing (i.e. feeder fluctuation dampening) was achieved when an impeller with high number of radial mixing blades operated at low speed. However, the variability in tablet weight and content uniformity deteriorated under this condition. One can therefore conclude that balancing axial mixing with tablet quality is critical for Methocel CR. However, reformulating with the direct compressible Methocel DC2 as matrix former improved tablet quality vastly. Furthermore, both process and product were significantly more robust to changes in process and design variables. This observation underpins the importance of flowability during continuous blending and die-filling. At the compaction stage, blends with Methocel CR showed better tabletability driven by a higher compressibility as the smaller CR particles have a higher bonding area. However, tablets of similar strength were achieved using Methocel DC2 by targeting equal porosity. Compaction pressure impacted tablet properties and dissolution. Hence controlling thickness during continuous manufacturing of sustained release tablets was crucial to ensure reproducible dissolution.

ATR/FT-IR and NIR Auto-correlation Spectroscopic Analysis of Powder Blending Uniformity of Low-content Magnesium Stearate and Potato Starch.

Here, we report on near-infrared and ATR/FT-IR spectroscopic measurements of magnesium stearate and potato starch powder blends. In the pharmaceutical and food industries, magnesium stearate is commonly used as a supplement in powder blends or granules for the purpose of lubrication and to minimize aggregation and adherence. However, excessive blending of magnesium stearate (MgSt) may lead to unwanted effects, and more particularly during the manufacturing of products. Upon blending, the IR bands due to both CH symmetric and anti-symmetric stretching modes decreased and displayed a frequency shift to higher wavenumber as the blending duration increased. The NIR and the auto-correlation spectra were collected during the duration of blending in real-time. The auto-correlation spectra indicated the disaggregation of starch particles and a following effect of excessive blending. We suggest that the disaggregation of starch and the following process can be monitored by NIR and the auto-correlation spectra.

Evaluation of Granulated Lactose as a Carrier for Dry Powder Inhaler Formulations 2: Effect of Drugs and Drug Loading

Previously, granulated lactose carriers were shown to improve uniformity and aerosolization of a low-dose model drug. In the present study, the blending uniformity and aerosol dispersion performance were assessed for 2 model drugs salbutamol sulfate (SS) and rifampicin (RIF), blended at high loadings (10% or 30% drug) with granulated lactose carriers. The model drug powders differed in particle size distribution, morphology, density, and surface energies. Content uniformity of RIF blends was better than that of SS. Aerosolization studies showed that all blend formulations had acceptable emitted fractions (>70%). The SS blends showed low induction-port deposition (6%-10%) compared to RIF (5%-30%). This difference was greater at high flow rates. At 90 L/min, the low induction port deposition of SS blends allowed high fine particle fraction (FPF) of 73%-81%, whereas the FPF of the RIF blends was around 43%-45% with higher induction port deposition. However, SS blends exhibited strong flow rate–dependent performance. Increasing the flow rate from 30 L/min to 90 L/min increased SS FPF from approximately 20% to 80%. Conversely, RIF blends were flow rate and drug loading independent. It was concluded that the aerosolization of high drug–loaded dry powder inhaler formulations using granulated lactose, particularly flow rate dependency, varies with active pharmaceutical ingredient properties.

At-line determination of pharmaceuticals small molecule's blending end point using chemometric modeling combined with Fourier transform near infrared spectroscopy

This article summarizes the development and validation of a Fourier transform near infrared spectroscopy (FT-NIR) method for the rapid at-line prediction of active pharmaceutical ingredient (API) in a powder blend to optimize small molecule formulations. The method was used to determine the blend uniformity end-point for a pharmaceutical solid dosage formulation containing a range of API concentrations. A set of calibration spectra from samples with concentrations ranging from 1% to 15% of API (w/w) were collected at-line from 4000 to 12,500cm−1. The ability of the FT-NIR method to predict API concentration in the blend samples was validated against a reference high performance liquid chromatography (HPLC) method. The prediction efficiency of four different types of multivariate data modeling methods such as partial least-squares 1 (PLS1), partial least-squares 2 (PLS2), principal component regression (PCR) and artificial neural network (ANN), were compared using relevant multivariate figures of merit. The prediction ability of the regression models were cross validated against results generated with the reference HPLC method. PLS1 and ANN showed excellent and superior prediction abilities when compared to PLS2 and PCR. Based upon these results and because of its decreased complexity compared to ANN, PLS1 was selected as the best chemometric method to predict blend uniformity at-line. The FT-NIR measurement and the associated chemometric analysis were implemented in the production environment for rapid at-line determination of the end-point of the small molecule blending operation.

Near infrared analysis of blending homogeneity of Chinese medicine formula particles based on moving window F test method

Blending uniformity is essential to ensure the homogeneity of Chinese medicine formula particles within each batch. This study was based on the blending process of ebony spray dried powder and dextrin(the proportion of dextrin was 10%),in which the analysis of near infrared (NIR) diffuse reflectance spectra was collected from six different sampling points in combination with moving window F test method in order to assess the blending uniformity of the blending process.The method was validated by the changes of citric acid content determined by the HPLC. The results of moving window F test method showed that the ebony spray dried powder and dextrin was homogeneous during 200-300 r and was segregated during 300-400 r. An advantage of this method is that the threshold value is defined statistically, not empirically and thus does not suffer from threshold ambiguities in common with the moving block standard deviatiun (MBSD). And this method could be employed to monitor other blending process of Chinese medicine powders on line.

Blend uniformity evaluation during continuous mixing in a twin screw granulator by in-line NIR using a moving F-test

This study focuses on the twin screw granulator of a continuous from-powder-to-tablet production line. Whereas powder dosing into the granulation unit is possible from a container of preblended material, a truly continuous process uses several feeders (each one dosing an individual ingredient) and relies on a continuous blending step prior to granulation.The aim of the current study was to investigate the in-line blending capacity of this twin screw granulator, equipped with conveying elements only. The feasibility of in-line NIR (SentroPAT, Sentronic GmbH, Dresden, Germany) spectroscopy for evaluating the blend uniformity of powders after the granulator was tested.Anhydrous theophylline was used as a tracer molecule and was blended with lactose monohydrate. Theophylline and lactose were both fed from a different feeder into the twin screw granulator barrel. Both homogeneous mixtures and mixing experiments with induced errors were investigated. The in-line spectroscopic analyses showed that the twin screw granulator is a useful tool for in-line blending in different conditions.The blend homogeneity was evaluated by means of a novel statistical method being the moving F-test method in which the variance between two blocks of collected NIR spectra is evaluated. The α- and β-error of the moving F-test are controlled by using the appropriate block size of spectra. The moving F-test method showed to be an appropriate calibration and maintenance free method for blend homogeneity evaluation during continuous mixing.

Dry powder formulation from fruits of Physalis peruviana L. standardized extract with hypoglycemic activity

The aims of this study were to develop a dry powder formulation from standardized extract of fruits of Physalis peruviana L., for oral administration, and to choose the best drying process for retaining the hypoglycemic activity, applying a factorial type experimental design. The development of a pharmaceutical formulation from an herbal extract has technological complications arising from inappropriate pharmaceutical characteristics related to its extract nature as a multicomponent system. P. peruviana extract showed the following technology difficulties: high hygroscopicity (which affects its flow, blend uniformity and stability), reduced flow properties (poor, non-uniform flow), high cohesivity, and low compressibility. To solve these problems, physical state changes of the extract (e.g. by absorption processes in a substrate) could contribute to improving its physical properties. The selection of excipients for use in the formulation was based on a compatibility study with binary solid mixtures (extract and each excipient) analyzed trough HPLC, and additionally, applying a factorial statistical experimental design to choose the best absorbent for the extract and the best drying method, evaluating like response variables: particle size, bulk and tap densities, angle of repose and hygroscopicity. Finally, a hypoglycemic assay was conducted in mice, using the best formulation. According to the compatibility study, the following excipients may be considered promising for use in a possible solid formulation from the ethanolic extract of fruits of P. peruviana: Disintegrants, absorbents and diluents: microcrystalline cellulose and corn starch; binder: polyvinylpyrrolidone. From the extract and the excipients selected as absorbents and binder (microcrystalline cellulose PH 101, 102, 200, corn starch and polyvinylpyrrolidone), different granules were produced, which were dried by two methods. The factorial experimental design showed that microcrystalline cellulose PH 102 and corn starch were the best absorbents, and that drying in a fluidized bed was the best method, offering advantages in terms of physicochemical properties such as particle size, density, voluminosity, flowability and hygroscopicity, compared to the initial extract and to the other formulations. The hypoglycemic assay showed that the activity of the extract remained after its transformation to a solid state. The results suggest that the dry powder formulation obtained from the ethanolic extract of fruits of P. peruviana may be of use as a future phytotherapeutic product, or a more stable intermediate herbal product than the extract, as an adjuvant in the treatment of diabetes.

Scientific rationale for sampling regimen and acceptance criteria of blend uniformity based on Monte Carlo simulation

This study proposes an alternative sampling regimen (number of sampling points, number of samples from each sampling point) and setting of the acceptance criteria for blend uniformity based on a statistical rationale. Currently, the sampling regimen and the acceptance criteria for the blend uniformity test of powder blends are determined according to the withdrawn guidance for industry by the Food and Drug Administration (FDA) and the proposal of the International Society for Pharmaceutical Engineering (ISPE)-sponsored Blend Uniformity and Content Uniformity (BUCU) Group to substitute the withdrawn guidance. However, both approaches lack scientific rationale in their publications. Herein this study addresses the scientific background based on the simulations utilizing the Monte Carlo method, in order to provide a scientific rationale for the sampling regimen and acceptance criteria. False positive probability, defined as the probability of failure to meet the minimum necessary requirement in future samples even when the tested sample satisfies the acceptance criteria in fact were used to evaluate the adequacy of the sampling regimen and acceptance criteria. This study aims at stimulating the discussion about blend uniformity that may ensure a higher quality of pharmaceutical products finally.