Uniformity Of Dosage Units Research Articles

Sample Size for Tablet Compression and Capsule Filling Events During Process Validation

During solid dosage form manufacturing, the uniformity of dosage units (UDU) is ensured by testing samples at 2 stages, that is, blend stage and tablet compression or capsule/powder filling stage. The aim of this work is to propose a sample size selection approach based on quality risk management principles for process performance qualification (PPQ) and continued process verification (CPV) stages by linking UDU to potential formulation and process risk factors. Bayes success run theorem appeared to be the most appropriate approach among various methods considered in this work for computing sample size for PPQ. The sample sizes for high-risk (reliability level of 99%), medium-risk (reliability level of 95%), and low-risk factors (reliability level of 90%) were estimated to be 299, 59, and 29, respectively. Risk-based assignment of reliability levels was supported by the fact that at low defect rate, the confidence to detect out-of-specification units would decrease which must be supplemented with an increase in sample size to enhance the confidence in estimation. Based on level of knowledge acquired during PPQ and the level of knowledge further required to comprehend process, sample size for CPV was calculated using Bayesian statistics to accomplish reduced sampling design for CPV.

Avaliação preliminar da qualidade da fluoxetina comercializada por farmácias de manipulação em Belo Horizonte/MG

In this study, fourteen samples of fluoxetine being commercialized by thirteen different establishments of the network of magistral pharmacies in the City of Belo Horizonte/MG were assessed. The sampling corresponds to 47,0% of the total 30 different units of preparation of the city, which corresponds to about 180 points of sale. Analyses for determining weight, identification, active ingredient content and uniformity of dosage units were performed by the State Foundation Ezequiel Dias (FUNED /MG) based on methodologies described by reference pharmacopoeias. Irregularities, on the labeling and the content testing, were observed in some samples. It was also investigated, through the technique of neutron activation analysis (NAA), the presence and concentrations of metals and other inorganic impurities. The results showed the presence of elements such as As, Br, Cr Co, Cr, Hf and others, that even at low concentrations, may be harmful to human health if consumed steadily for a long term.

Use of Bayesian Methods to Analyze and Visualize Content Uniformity Capability Versus United States Pharmacopeia and ASTM Standards

The purpose of this work was to develop a straightforward and robust approach to analyze and summarize the ability of content uniformity data to meet different criteria. A robust Bayesian statistical analysis methodology is presented which provides a concise and easily interpretable visual summary of the content uniformity analysis results. The visualization displays individual batch analysis results and shows whether there is high confidence that different content uniformity criteria could be met a high percentage of the time in the future. The 3 tests assessed are as follows: (a) United States Pharmacopeia Uniformity of Dosage Units <905>, (b) a specific ASTM E2810 Sampling Plan 1 criterion to potentially be used for routine release testing, and (c) another specific ASTM E2810 Sampling Plan 2 criterion to potentially be used for process validation. The approach shown here could readily be used to create similar result summaries for other potential criteria.

Dose Uniformity of Scored and Unscored Tablets: Application of the FDA Tablet Scoring Guidance for Industry.

This U.S. Food and Drug Administration (FDA) laboratory study examines the impact of tablet splitting, the effect of tablet splitters, and the presence of a tablet score on the dose uniformity of two model drugs. Whole tablets were purchased from five manufacturers for amlodipine and six for gabapentin. Two splitters were used for each drug product, and the gabapentin tablets were also split by hand. Whole and split amlodipine tablets were tested for content uniformity following the general chapter of the United States Pharmacopeia (USP) Uniformity of Dosage Units <905>, which is a requirement of the new FDA Guidance for Industry on tablet scoring. The USP weight variation method was used for gabapentin split tablets based on the recommendation of the guidance. All whole tablets met the USP acceptance criteria for the Uniformity of Dosage Units. Variation in whole tablet content ranged from 0.5 to 2.1 standard deviation (SD) of the percent label claim. Splitting the unscored amlodipine tablets resulted in a significant increase in dose variability of 6.5-25.4 SD when compared to whole tablets. Split tablets from all amlodipine drug products did not meet the USP acceptance criteria for content uniformity. Variation in the weight for gabapentin split tablets was greater than the whole tablets, ranging from 1.3 to 9.3 SD. All fully scored gabapentin products met the USP acceptance criteria for weight variation. Size, shape, and the presence or absence of a tablet score can affect the content uniformity and weight variation of amlodipine and gabapentin tablets. Tablet splitting produced higher variability. Differences in dose variability and fragmentation were observed between tablet splitters and hand splitting. These results are consistent with the FDA's concerns that tablet splitting can have an effect on the amount of drug present in a split tablet and available for absorption. Tablet splitting has become a very common practice in the United States and throughout the world. Tablets are often split to modify dose strength, make swallowing easier, and reduce cost to the consumer. To better address product quality for this widely used practice, the U.S. Food and Drug Administration (FDA) published a Guidance for Industry that addresses tablet splitting. The guidance provides testing criteria for scored tablets, which is a part of the FDA review process for drugs. The model drugs selected for this study were amlodipine and gabapentin, which have different sizes, shapes, and tablet scores. Whole and split amlodipine tablets were tested for drug content because of a concern that the low-dose strength may cause greater variability. Whole and split gabapentin tablets were tested for weight variation because of their higher dosage strength of 600 mg. All whole tablets met the acceptance criteria for the Uniformity of Dosage Units based on the guidance recommendations. When unscored amlodipine tablets were split by a splitter, all formulations did not meet the acceptance criteria. When fully scored gabapentin tablets were split by hand and by splitter, they met the acceptance criteria. The findings of this FDA study indicated physical characteristics such as size, shape, and tablet score can affect the uniformity of split tablets.

AVALIAÇÃO DA QUALIDADE DE COMPRIMIDOS REVESTIDOS DE DICLOFENACO SÓDICO DISPENSADOS PELA REDE PÚBLICA MUNICIPAL DE SÃO PAULO

O diclofenaco é o anti-inflamatório não esteroide (AINE) mais prescrito mundialmente. Comprimidos de diclofenaco sódico com revestimento gastro-resistente foram desenvolvidos com o objetivo de reduzir o risco de efeitos adversos gastrointestinais comumente associados com o uso de AINEs. O Programa Municipal de Verificação da Qualidade de Medicamentos da Secretaria Municipal da Saúde de São Paulo avalia a qualidade de comprimidos revestidos de diclofenaco sódico distribuídos pela Prefeitura. O objetivo deste trabalho foi verificar a qualidade de comprimidos de diclofenaco sódico distribuídos em unidades de saúde municipais no ano de 2013 através de ensaios físico-químicos farmacopeicos. Foram realizados os ensaios de aspecto, variação de peso, identificação e teor de diclofenaco sódico, uniformidade de doses unitárias e dissolução. O ensaio de dissolução ocorreu em duas etapas (ácida e básica), possibilitando avaliar a qualidade do revestimento no que diz respeito ao local de liberação do princípio ativo. As amostras de diclofenaco sódico analisadas apresentaram resultados satisfatórios. O monitoramento de medicamentos distribuídos pela rede pública de saúde é uma importante ação de vigilância sanitária. A avaliação da qualidade de comprimidos revestidos de diclofenaco sódico se faz relevante para garantir a eficácia e segurança do tratamento farmacológico, sobretudo por se tratar de uma forma farmacêutica de liberação modificada.

Microtomographic studies of subdivision of modified-release tablets

The uniformity of dosage units within a certain batch is ensured when each unit contains the active pharmaceutical ingredient (API) within a narrow range around the label claim.For tablets containing a score-line authorised for dose reductions, the European Pharmacopoeia (Ph. Eur.) considers that the uniformity of the tablet parts may be based on weight measurements regardless of the tablet type (immediate or modified release). This is because it is up to the regulatory authorities first to assess whether the tablet may contain a score-line for such use.X-ray microtomography was applied to assess the symmetry of 36 modified release tablets, containing 300mg of theophylline. The sum of the volume and surface area of the pellets in the subdivided tablets were compared. Simulations were carried out to identify the optimal amount of pellets in the tablet mass.The maximum difference in the API content between two subdivided halves was 165.18mg vs 133.83mg. If the amount of pellets in the tablet mass would drop below 13% on the basis of the pellet surface area, then the Ph. Eur. requirements would be exceeded. The amount of pellets in the tablet halves resulting in the greatest variability in API content was 38%.The results of this study indicate that the pellets were not distributed uniformly in the tablet mass. Thus, the uniformity of the dose in both halves of a tablet containing pellets cannot be based on the weight measurements i.e. it is necessary to develop further standards for tablet subdivision. Microtomographic methods are a very interesting alternative to expensive and time-consuming pharmacokinetic studies.

Development of an ultra high performance liquid chromatography method for determining triamcinolone acetonide in hydrogels using the design of experiments/design space strategy in combination with process capability index.

An ultra high performance liquid chromatography method was developed and validated for the quantitation of triamcinolone acetonide in an injectable ophthalmic hydrogel to determine the contribution of analytical method error in the content uniformity measurement. During the development phase, the design of experiments/design space strategy was used. For this, the free R-program was used as a commercial software alternative, a fast efficient tool for data analysis. The process capability index was used to find the permitted level of variation for each factor and to define the design space. All these aspects were analyzed and discussed under different experimental conditions by the Monte Carlo simulation method. Second, a pre-study validation procedure was performed in accordance with the International Conference on Harmonization guidelines. The validated method was applied for the determination of uniformity of dosage units and the reasons for variability (inhomogeneity and the analytical method error) were analyzed based on the overall uncertainty.

Development of a multi-layered vaginal tablet containing dapivirine, levonorgestrel and acyclovir for use as a multipurpose prevention technology

Multipurpose prevention technologies (MPTs) are preferably single dosage forms designed to simultaneously address multiple sexual and reproductive health needs, such as unintended pregnancy, HIV infection and other sexually transmitted infections (STIs). This manuscript describes the development of a range of multi-layered vaginal tablets, with both immediate and sustained release layers capable of delivering the antiretroviral drug dapivirine, the contraceptive hormone levonorgestrel, and the anti-herpes simplex virus drug acyclovir at independent release rates from a single dosage form. Depending on the design of the tablet in relation to the type (immediate or sustained release) or number of layers, the dose of each drug could be individually controlled. For example one tablet design was able to provide immediate release of all three drugs, while another tablet design was able to provide immediate release of both acyclovir and levonorgestrel, while providing sustained release of Dapivirine for up to 8h. A third tablet design was able to provide immediate release of both acyclovir and levonorgestrel, a large initial burst of Dapivirine, followed by sustained release of Dapivirine for up to 8h. All of the tablets passed the test for friability with a percent friability of less than 1%. The hardness of all tablet designs was between 115 and 153N, while their drug content met the European Pharmacopeia 2.9.40 Uniformity of Dosage units acceptance value at levels 1 and 2. Finally, the accelerated stability of all three actives was significantly enhanced in comparison with a mixed drug control.

Raman spectroscopy for the analytical quality control of low-dose break-scored tablets

Quality control of solid dosage forms involves the analysis of end products according to well-defined criteria, including the assessment of the uniformity of dosage units (UDU). However, in the case of break-scored tablets, given that tablet splitting is widespread as a means to adjust doses, the uniform distribution of the active pharmaceutical ingredient (API) in all the possible fractions of the tablet must be assessed. A general procedure to accomplish with both issues, using Raman spectroscopy, is presented. It is based on the acquisition of a collection of spectra in different regions of the tablet, that later can be selected to determine the amount of API in the potential fractions that can result after splitting. The procedure has been applied to two commercial products, Sintrom 1 and Sintrom 4, with API (acenocoumarol) mass proportion of 2% and 0.7% respectively. Partial Least Squares (PLS) calibration models were constructed for the quantification of acenocoumarol in whole tablets using HPLC as a reference analytical method. Once validated, the calibration models were used to determine the API content in the different potential fragments of the scored Sintrom 4 tablets. Fragment mass measurements were also performed to estimate the range of masses of the halves and quarters that could result after tablet splitting. The results show that Raman spectroscopy can be an alternative analytical procedure to assess the uniformity of content, both in whole tablets as in its potential fragments, and that Sintrom 4 tablets can be perfectly split in halves, but some cautions have to be taken when considering the fragmentation in quarters. A practical alternative to the use of UDU test for the assessment of tablet fragments is proposed.

High-throughput prediction of tablet weight and trimethoprim content of compound sulfamethoxazole tablets for controlling the uniformity of dosage units by NIR

This paper establishes a novel method to simultaneously predict the tablet weight (TW) and trimethoprim (TMP) content of compound sulfamethoxazole tablets (SMZCO) by near infrared (NIR) spectroscopy with partial least squares (PLS) regression for controlling the uniformity of dosage units (UODU). The NIR spectra for 257 samples were measured using the optimized parameter values and pretreated using the optimized chemometric techniques. After the outliers were ignored, two PLS models for predicting TW and TMP content were respectively established by using the selected spectral sub-ranges and the reference values. The TW model reaches the correlation coefficient of calibration (Rc) 0.9543 and the TMP content model has the Rc 0.9205. The experimental results indicate that this strategy expands the NIR application in controlling UODU, especially in the high-throughput and rapid analysis of TWs and contents of the compound pharmaceutical tablets, and may be an important complement to the common NIR on-line analytical method for pharmaceutical tablets.

Improved Acceptance Limits for ASTM Standard E2810

ASTM Standard E2810 provides a methodology for establishing confidence in passing the USP <905> Uniformity of Dosage Units (UDU) test, and provides acceptance limits for sample means and standard deviations that can be used as elements of lot release. These acceptance limits are quite conservative, however, due to both the nature and shape of an inverted triangular joint confidence region for the lot mean and standard deviation. We obtain improved (wider) acceptance limits by using a Bayesian approach that focuses on the posterior distribution of the probability of passing the USP <905> UDU test. The Bayesian approach has good sampling properties, and the improvement in acceptance limits can be considerable. For example, for sample size of 10 units and sample means between 97 and 103, the Bayesian approach results in acceptance limits for sample standard deviations that are at least 25% greater than those in E2810. The impact of the improved acceptance limits is illustrated with operating characteristic curves.

IP4 - Establishing acceptance limits for uniformity of dosage units

IP4 - Establishing acceptance limits for uniformity of dosage units

Biopharmaceutic Risk Assessment of Brand and Generic Lamotrigine Tablets.

The therapeutic equivalence of generic and brand name antiepileptic drugs has been questioned by neurologists and the epilepsy community. A potential contributor to such concerns is pharmaceutical quality. The objective was to assess the biopharmaceutic risk of brand name Lamictal 100 mg tablets and generic lamotrigine 100 mg tablets from several manufacturers. Lamotrigine was characterized in terms of the Biopharmaceutics Classification System (BCS), including aqueous solubility and Caco-2 permeability. A panel of pharmaceutical quality tests was also performed on three batches of Lamictal, three batches of Teva generic, and one batch of each of four other generics: appearance, identity, assay, impurity, uniformity of dosage units, disintegration, dissolution, friability, and loss on drying. These market surveillance results indicate that all brand name and generic lamotrigine 100 mg tablets passed all tests and showed acceptable pharmaceutical quality and low biopharmaceutic risk. Lamotrigine was classified as a BCS class IIb drug, exhibiting pH-dependent aqueous solubility and dissolution. At pH 1.2 and 4.5, lamotrigine exhibited high solubility, whereas lamotrigine exhibited low solubility at pH 6.8, including non-sink dissolution. Lamotrigine showed high Caco-2 permeability. The apparent permeability (Papp) of lamotrigine was (73.7 ± 8.7) × 10(-6) cm/s in the apical-to-basolateral (AP-BL) direction and (41.4 ± 1.6) × 10(-6) cm/s in the BL-AP direction, which were higher than metoprolol's AP-BL Papp of (21.2 ± 0.9) × 10(-6) cm/s and BL-AP Papp of (34.6 ± 4.6) × 10(-6) cm/s. Overall, lamotrigine's favorable biopharmaceutics from a drug substance perspective and favorable quality characteristics from a tablet formulation perspective suggest that multisource lamotrigine tablets exhibit a low biopharmaceutic risk.

HPLC method for simultaneous determination of salmeterol xinafoate and fluticasone propionate for the quality control of dry powder inhalation products

A simple and accurate reversed phase high-performance liquid chromatography (HPLC) method has been developed for the estimation of uniformity of dosage units, and delivered dose uniformity tests of fluticasone propionate and salmeterol xinafoate in samples obtained during the fine particle mass determination, using C8 Luna (2) 100A 100 × 4.6 mm, 5 micrometer particle size in gradient mode, with mobile phase comprising of buffer solution: 0.6% trifluoroacetic acid solution in water-tetrahydrofurane (8:2 v/v) and acetonitrile-methanol (1:1 v/v) in the ratio of 60:40 v/v. The flow rate was 1.5 mL min−1, and the detection was monitored by ultraviolet (UV) detector at 239 nm and 250 nm. Linearity was observed in the concentration range of 0.025–4.8 μg mL−1 for salmeterol xinafoate and 0.04–32.5 μg mL−1 for fluticasone propionate (R2 > 0.999). The recovery in the range from 98.2% to 102.7% and relative standard deviation (RSD) ≤ 2.2% demonstrated accuracy and high precision of the method. The quantification lim...

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.

Statistical Properties of Large Sample Tests for Dose Content Uniformity.

The European Union (EU) test for uniformity of dosage units using large sample sizes was published in European Pharmacopoeia 7.7 in 2012. There are 2 alternative tests. Option 1 is a parametric two-sided tolerance interval-based method modified with an indifference zone and counting units outside of (0.75 M, 1.25 M) (here, M is defined by sample mean, [Formula: see text], as M = 98.5% if [Formula: see text] < 98.5%, M = 101.5% if [Formula: see text] > 101.5%, and M = [Formula: see text] otherwise). Option 2 is a nonparametric counting method with an additional indifference-zone concept. The authors extended the parametric two one-sided tolerance interval-based method that was proposed for dose content uniformity testing based on 30 tablets to large sample sizes with the restriction that all operating characteristic curves of the two one-sided tolerance intervals for any given sample size intersect with the operating characteristic curve of the US Pharmacopoeia harmonized method for a sample size of 30 at the acceptance probability of 90% when the individual tablets with on-target mean are assumed to be normally distributed. This paper studies the acceptance probabilities in relation to the batch mean and batch standard deviation among the 2 EU options and the authors' proposed method. The acceptance probabilities of EU options 1 and 2 and the proposed method were compared using simulation; results revealed that both EU options 1 and 2 produce larger acceptance probabilities when the batch mean is off-target. Furthermore, for a given standard deviation, the acceptance probability of EU option 2 at a mean 102% of the label claim is larger than that at a mean of 100% of the label claim under the normality assumption.

The Posterior Probability of Passing a Compendial Standard, Part 1: Uniformity of Dosage Units

A compendial standard is a function of data generated by one or more quality testing procedures. Since the data are sampled from an underlying distribution, the probability of passing a compendial test (Pa) can be expressed as a function of the distribution's model parameters. Applying Bayesian methodology to such a function, we show how to compute the posterior distribution of Pa and other quantities of interest. We apply this methodology to the USP<905> compendial standard and illustrate the importance of considering interbatch variance. We show that the operating characteristics of this Bayesian approach depend on the underlying model parameters almost exclusively through the population Pa and use this to develop a simple univariate procedure to determine the number of batches needed for a process qualification. We note some advantages of this Bayesian approach compared to current approaches. To show the simplicity of the approach and encourage its use, example R and WinBUGS code are provided.

PAT for tableting: Inline monitoring of API and excipients via NIR spectroscopy

This paper describes the application and implementation of inline NIR spectroscopy in an industrial tablet press. The content uniformity of a powder was analyzed via a NIR probe mounted on the feed frame. A PLS model with four latent variables (R2=0.97, Q2=0.95) was developed for the Active Pharmaceutical Ingredient (API) and two main excipients (EX1, EX2), according to the mixture DoE. The RMSEP corresponded to the relative errors of 2.7% for API, 1.7% for EX1 and 2.6% for EX2, compared to the nominal formulation. Transfer of the model, from the lab to an inline setup for manufacturing was achieved using local centering. There was a good agreement between the results of inline NIR and drawn tablets analyzed via UV–Vis. Notably, NIR indicated stochastic segregation behavior of the powder toward the end of the process, which was confirmed by the UV–Vis analysis. The outcome of our work was related to the recently published Ph. Eur. chapter 2.9.47 “Demonstration of uniformity of dosage units using large sample sizes”.

Avaliação da Qualidade da Sinvastatina Comercializada por Farmácias de Manipulação em Belo Horizonte/MG

The growing expansion of the magistral sector associated with reports of deviations from quality of compounded drugs, with serious cases, has generated a series of efforts by the Health Surveillance in the search for an efficient monitoring of pharmacies and products offered to the population. Thus, the aim of this study was to evaluate the quality of preparations containing simvastatin, manipulated in some pharmacies of Belo Horizonte/MG, after reviewing the health legislation occurred in 2007, through the realization of pharmacopoeic physicochemical analyzes of determination weight, identity and content of active ingredient and uniformity of dosage units. Further, research by neutron activation analysis, the presence and concentration of inorganic impurities in the samples of simvastatin manipulated. The results expressed an index of satisfactoriness of only 30%. This fact confirms the need for fast and efficient acts by public health authorities, and improving processes used in the manipulation within the establishments, to ensure the quality of compounded drugs.

Raman spectroscopy as a complementary tool to assess the content uniformity of dosage units in break-scored warfarin tablets

Due to the side effects of overdosing, the therapeutic dose of warfarin preparations must be very strictly controlled. In order to make it easier for the patient to take the required dose, two different strategies can be followed: The medicine can be commercialized in different dosages and/or tablets can be scored in order to make them easy to split. The splitting of the tablets introduces the question of how to control that the fractions contain the desirable amount of warfarin. The regulations regarding the content uniformity of dosage unit for scored tablets have changed considerably in the last 10 years, and they are still evolving. Warfarin is commercialized under the trademark of Aldocumar in four different preparations, containing 1, 3, 5 and 10 mg sodium warfarin per tablet. All these tablets are also scored, thus suggesting the possibility of splitting. A quantitative Raman method has been developed for the determination of warfarin in tablets and in the potential fragments, taking into account the score lines on the tablet surface. This method is suggested as an auxiliary procedure to verify the uniformity of API distribution in dividable tablets. A combination of a second derivative and standard normal variate (SNV) was used as spectral pre-treatments, and partial least squares (PLS) as the regression algorithm. The relative standard deviation in API content among portions was found to be less than 5%. An HPLC procedure has been used as a reference analytical method.