Content Uniformity: Separation and quantitation of sources of dose variation

A propagation of error formula is presented which describes a mathematical relationship between uniformity of dosage units (dose variation) and the individual sources of variability. Using this propagation of error formula and a minor modification of the USP Content Uniformity test procedure, one can assign dose variation to weight variation, blend heterogeneity and assay imprecision without compromising the information required by the USP XXII. This formula separates and quantitates the sources of dose variation and defines the manner in which weight variation, blend heterogeneity and assay imprecision are propagated. By knowing how the dose variation is propagated, specific measures can be taken to improve the uniformity of dosage units.

The propagation of error formula can also be used to calculate a priori estimates of dose variation by choosing reasonable or expected variances for weight variation, blend heterogeneity and assay imprecision. Such calculations can save hours of fruitless effort which attempt to improve the content uniformity without considering how dose variation is propagated and to what extent the expected dose variation can be improved.     

Content uniformity acceptance limit for a validation batch—suppositories,transdermal systems,and inhalations

Background: The USP test for ‘Uniformity of Dosage Units’ specified by USP Chapter <905> is required of every drug product sold in the United States. Dosage-unit uniformity is determined either by weight variation or by assay of individual units. The USP acceptance criteria for content uniformity states that the relative standard deviation (RSD) of a sample of 30 units should not exceed 7.8%. Purpose: This article provides a methodology for deriving an upper acceptance limit on the RSD of dosage units from a validation batch of suppositories, transdermal systems, or inhalations such that future batches will have a 95% chance of passing the USP content uniformity RSD acceptance criterion (the RSD of 30 dosage units does not exceed 7.8%).     

Validation of Liquid Chromatographic Method of Assay for Acetaminophen,Butalbital and Caffeine in Solid Dosage Forms

Abstract

The validation of a liquid chromatographic procedure for the determination of acetaminophen, butalbital and caffeine in solid dosage forms is described. The dosage content of tablets or capsules is diluted and chromatographed on a Radialpak Cyanopropylsilane Cartridge with a mobile phase of water-acetonitrile-1M dibutylamine phosphate (90+9+1, V/V) with detection at 215 nm. The calibration curve is linear with correlation coefficients of 0.999 for each component. Recoveries of spiked excipient blend averaged 99.5% for acetaminophen, 102.5% for butalbital and 101.0% for caffeine. The method met USP requirements for system suitability with proper resolution between two adjacent peaks. The relative standard deviation (RSD) of peak response of each component (obtained by chromatographing six replicates of standard solution) is less than 2.0% and the tailing factor of each component is not greater than 1.5. The method can be used for composite, content uniformity and dissolution assay of acetaminophen, butalbital and caffeine in tablet and capsule formulations.     

A Statistical Approach to Blend Uniformity Acceptance Criteria

Abstract

Recent Food and Drug Administration (FDA) validation guidelines and comments indicate that applying finished product content uniformity specifications to blend testing is unacceptable. The scenario the FDA has presented is one in which disorder increases as the process progresses so that blend test specifications should be more restrictive (tighter) than finished product testing specifications. In other publications, it has been suggested that finished product assay limits be applied as a blend specification along with a lower relative standard deviation value than the current USP content uniformity limit (6.0%). This approach is questionable since assay results are applied to an aggregate finished product sample rather than individual doses. A method is presented in this paper for applying statistical tolerance limits (Sib) to blend data. This procedure provides a 95% confidence level that at least 90% of the values for the entire population are within the calculated limits. These statistical tolerance limits provide an acceptable criterion that is statistically tighter than the application of USP XXIII finished product content uniformity specifications. In addition, this method involves a decision process or multiple-level evaluation based on a statistical comparison of the variance and mean for the blend and finished product. In cases where the calculated STLs are unacceptable, the decision process allows for determining if the out-of-specification values from the first level of testing are due to a true blend failure or if the cause of the aberration is due to other phenomena, which could include sampling technique, thief design, and analytical testing problems.     

High-Performance Liquid Chromatographic Determination of Ibuprofen in Bulk Drug and Tablets

Abstract

A simple and rapid HPLC procedure is described for the assay of ibuprofen in bulk drug and tablets and for dosage uniformity testing. HPLC was carried out on a stainless steel octadecylsilane (5 urn) column (150 × 4.6 mm) using 25% 0.25M glacial acetic acid in acetonitrile as the mobile phase, with UV detection at 254 nm. Results obtained with this procedure compared favorably with those obtained using the USP procedures.     

Validation of the Content Uniformity Testing of USP XXI (1985) for Tablets Containing Potent Drugs

Abstract

The content uniformity of tablets containing high potency, low dosage drugs can only be successfully maintained by application of GMP at all stages of the total manufacturing process including both formulation and quality control. This requires both understanding of the pharmaceutical technology involved and appropriate designing of content uniformity test.

The USP XXI (1985) has made the content uniformity test more stringent by applying both tests by attributes and variables, In this study the test has been challenged by using 27 batches of ethinyloestradiol 10 μg tablets having different degrees of homogeneity in powder mixes and tablets.

The results indicate that the test has a weak potential in determining the content uniformity of batches prepared from cohesive drug powders and characterised by skewed distribution of drug content in tablets. It is the same drawback of the USP XX (1980) content uniformity test. This defect is due to the small sample size of 10 unit doses in the first step which is not sufficient to detect the presence of unit dosages containing high drug content in a batch of tablets hawing skewed distribution. Statistical analysis of the results using coefficient of skBwness and nonparametric Lilliefors test has shown that some batches which have passed the USP XXI (1985) content uniformity test are pharmaceutically unacceptable. This indicates the importance of incorporating within the official specifications a test which includes an examination of the type of distribution and hence, increasing sample size is required.     

Blend Uniformity and Unit Dose Sampling

Abstract

Process validation for solid dosage forms must include a component that demonstrates content uniformity of the final blend. As a result of a recent court ruling this aspect of validation has received increased attention from both industry and government. In particular, the court ruled that the appropriate sample size for content uniformity testing of the final blend in validation batches is three times the run weight of the finished product. Furthermore, recent FDA communications suggest that the uniformity of the final blend should be held to a higher standard than that of the tablet in order to provide reasonable assurance that the finished product will exhibit acceptable uniformity. The purpose of this article is to communicate some problems that our firm encountered during the validation of a lower strength of a currently marketed tablet. The validated process for the marketed product has a long history of providing tablets that exhibit acceptable content uniformity at the higher strength. Extensive data from three validation batches manufactured at each of two production sites demonstrate consistently and significantly lower drug content in the lubricated granulation than in the finished product. The variability of the granulation data as characterized by the standard deviation is, for the most part, acceptable and comparable to that of the tablets. Unfortunately, these batches fail validation when subjected to the acceptance criteria suggested in recent FDA communications. We attribute the lower assay values of the granulation to sampling bias that occurs when small volumes of powder are extracted from a large V-blender with a sampling thief. In order to circumvent this problem and avoid rejecting acceptable processes we recommend an alternative acceptance criteria in which the mean assay of the powder samples is not relevant, This criteria relies solely on the standard deviation of the blend.     

Examination of Components of Variance for A Production Scale,Low Dose Powder Blend and Resulting Tablets

Abstract

A study was performed to quantify the contributions of the different components comprising the total variance term observed following the analysis of content uniformity testing of powder blends and tablets. A full scale (400 kg) blend study was performed on a low dose tablet formulation (drug content = 0.13%). Content uniformity samples were pulled from throughout the blender using a pocket type probe thief in a manner which allowed the blend to be assessed for both homogeneity and sample to sample variability at a given location. Tablets were compressed from the batch and assayed for content uniformity. Sampling error accounted for approximately 75% of the variance observed following analysis of drug content in the powder blends. The estimated total variance for the powder blend was approximately twice that observed for tablets compressed from the mixture. The analytical contribution to the total variance term was minor. The difference between the estimated total variance terms for powder blend and tablets was attributed to the superior sampling efficiency of the tablet press versus the sample thief. The results of the study support the use of wider specifications for powder blends than the tablets compressed from the mixture.     

RSD requirement for different sample size for blend sampling

A formula for calculating the equivalent relative standard deviation (RSD) for different sample sizes other than the Office of Generic Drugs (OGD) draft guidance was derived. These critical values vary with the population RSD and the sample size and guarantee the same confidence of passing a batch similar to the OGD blend uniformity test. Simulation results showed that the normal approximations give very close results to the simulation results. An assessment of the proposed OGD blend uniformity criteria against the first-stage USP content uniformity (CU) criteria for tablets was also made.     

RSD Requirement for Different Sample Size for Blend Sampling

A formula for calculating the equivalent relative standard deviation (RSD) for different sample sizes other than the Office of Generic Drugs (OGD) draft guidance was derived. These critical values vary with the population RSD and the sample size and guarantee the same confidence of passing a batch similar to the OGD blend uniformity test. Simulation results showed that the normal approximations give very close results to the simulation results. An assessment of the proposed OGD blend uniformity criteria against the first-stage USP content uniformity (CU) criteria for tablets was also made.     

Unit Dose Sampling and Final Product Performance: An Alternative Approach

This article documents a proposed plan for validation testing for the content uniformity for final blends and finished solid oral dosage forms (SODFs). The testing logic and statistical justification of the plan are presented. The plan provides good assurance that a passing lot will perform well against the USP tablet content uniformity test. The operating characteristics of the test and the probability of needing to test for blend sampling bias are reported. A case study is presented.     

Holographic data storage using an optimized phase mask

Abstract

A method for reducing the reconstruction error and improving the spectral distribution in holographic data storage has been proposed. An optimized phase mask is introduced into the optical system. By using the phase mask, the reconstruction error and uniformity of the spectral distribution can be optimized. The relative importance between reconstruction error and uniformity can be emphasized with an adjustable weight factor. The phase mask can be designed by using amplitude-phase retrieval algorithms. Simulation results have shown the merits of the proposed method. The feasibility of optical realization is investigated briefly.     

A Statistical Approach to Blend Uniformity Acceptance Criteria

Recent Food and Drug Administration (FDA) validation guidelines and comments indicate that applying finished product content uniformity specifications to blend testing is unacceptable. The scenario the FDA has presented is one in which disorder increases as the process progresses so that blend test specifications should be more restrictive (tighter) than finished product testing specifications. In other publications, it has been suggested that finished product assay limits be applied as a blend specification along with a lower relative standard deviation value than the current USP content uniformity limit (6.0%). This approach is questionable since assay results are applied to an aggregate finished product sample rather than individual doses. A method is presented in this paper for applying statistical tolerance limits (Sib) to blend data. This procedure provides a 95% confidence level that at least 90% of the values for the entire population are within the calculated limits. These statistical tolerance limits provide an acceptable criterion that is statistically tighter than the application of USP XXIII finished product content uniformity specifications. In addition, this method involves a decision process or multiple-level evaluation based on a statistical comparison of the variance and mean for the blend and finished product. In cases where the calculated STLs are unacceptable, the decision process allows for determining if the out-of-specification values from the first level of testing are due to a true blend failure or if the cause of the aberration is due to other phenomena, which could include sampling technique, thief design, and analytical testing problems.     

Carbamazepine Modified Release Dosage Forms

Abstract

The preparation of sustained release dosage forms of Carbamazepine (anti-epileptic drug characterized by a very low water solubility and by a short half life on chronique dosing) was carried out.

These formulations were obtained in two different steps:

a) modified release granules were prepared by the loading of cross-linked sodium carboxymethylcellulose (swellable polymer), with the drug and an enteric polymer. Cellulose acetate phthalate, methacrylic acid – methacrylic acid methyl ester copolymer (usually employed as enteric coating agents) and cellulose acetate trimellitate (a new enteric polymer) were used in different weight ratios.

b) some sustained release dosage forms were prepared tabletting physical mixtures of the modified release granules with different weight ratios of hydroxypropylmethylcellulose.

In vitro dissolution tests of modified release granules in gastric fluid (USP XXI) showed a modulation of the drug release, while in intestinal fluid (USP XXI) a quick drug dissolution was observed.

In vitro dissolution tests of sustained release dosage forms, performed varying during the test, the pH of the dissolution medium, (hydrochloric acid pH 1 from 0 to 2 hours and phosphate buffer pH 6.8 from 2 to 18 hours) showed that the determining factors in the controlling release of the drug are: the type and amount of enteric polymer constituting the granules and the amount of hydroxy-propylmethylcellulose mixed with them.     

Production of an Extremly Low Dose Procaterol HCl Preparation by Fluidized-Bed Coating Method: In Vitro and In Vivo Evaluation

Abstract

A convenient and reliable method to prepare procaterol HCl oral dosage form at an extremely low dosage (25 µg/cap) is presented in this paper. Procaterol HCl was mixed with the film-forming agent hydroxypropyl methylcellulose in an aqueous solution, which was then spray-coated on sugar spheres (Nu-pareil PG 20/25) to produce procaterol HCl pellets. The IR spectra of coated and noncoated pellets indicated that procaterol HCl was coated on the sugar spheres successfully with a weight increment less than 1%. Most of the coated pellets were able to pass through an 18-mesh screen with no agglomeration. The average weights of coated pellets filled inside of capsules were monitored during the filling process. A simple liquid chromatographic method was developed and validated for the assay and uniformity test of procaterol HCl in different dosage forms. The results of assay and content uniformity test for both in-house product and a commercial product, i.e., Meptin®-mini tablet, were satisfied. The data of f₂ function and ANOVA analysis for the dissolution profiles of both procaterol HCl products suggested that they are pharmaceutical equivalent.

In an in vivo study (n = 24), a single dose of 75 µg procaterol HCl was administrated to each volunteer and the plasma concentration of procaterol was determined by a LC/MS/MS method, developed by the same authors. There were no significant differences (p > 0.05) in the data of AUC_0→16h, AUC_0→∞, C_max, and MRT for both preparations. It is confirmed that the pellets capsule produced in this study is bioequivalent with Meptin®-mini tablet.     

Validation of Liquid Chromatographic Method of Assay for Acetaminophen, Butalbital and Caffeine in Solid Dosage Forms

The validation of a liquid chromatographic procedure for the determination of acetaminophen, butalbital and caffeine in solid dosage forms is described. The dosage content of tablets or capsules is diluted and chromatographed on a Radialpak Cyanopropylsilane Cartridge with a mobile phase of water-acetonitrile-1M dibutylamine phosphate (90+9+1, V/V) with detection at 215 nm. The calibration curve is linear with correlation coefficients of 0.999 for each component. Recoveries of spiked excipient blend averaged 99.5% for acetaminophen, 102.5% for butalbital and 101.0% for caffeine. The method met USP requirements for system suitability with proper resolution between two adjacent peaks. The relative standard deviation (RSD) of peak response of each component (obtained by chromatographing six replicates of standard solution) is less than 2.0% and the tailing factor of each component is not greater than 1.5. The method can be used for composite, content uniformity and dissolution assay of acetaminophen, butalbital and caffeine in tablet and capsule formulations.     

Alternative Granulation Technique: Melt Granulation

Abstract

A melt granulation process has been investigated (1, 2) which efficiently agglomerates pharmaceutical powders for use in both immediate- and sustained-release solid dosage forms. The process utilizes materials that are effective as granulating fluids when they are in the molten state. Cooling of the agglomerated powders and the resultant solidification of the molten materials completes the granulation process. Both the molten agglomeration and cooling solidification were accomplished in a high shear Collette Gral mixer equipped with a jacketed bowl. Hence, the melt granulation process replaces the conventional granulation and drying operations which use water or alcohol solutions. The melt granulation process has been investigated using immediate- and sustained-release TAVIST® (clemastine fumarate USP) tablet formulations. The TAVIST granulations have been characterized by power consumption monitoring, measurement of the granulation particle size distribution, bulk and tapped density determinations, and loss-on-drying measurements. Scale-up of the melt granulation process for the sustained release TAVIST tablet formulation was judged successful based on a comparison of the hardness, friability, weight uniformity during compression, disintegration time, and dissolution rate data obtained at different manufacturing scales.     

Comparison of Three Dissolution Devices for Evaluating Drug Release

Abstract

The dissolution studies are usually conducted on “official” USP dissolution devices or “non-official” dissolution devices like the Rotating Bottle Apparatus. The recent introduction of the Bio-Dis® Tester exacerbates a difficult situation : no comparative dissolution studies have been done regarding the results for a drug and/or dosage form using these three different instruments. The purpose of this investigation was to evaluate and compare three dissolution devices - USP XXI Dissolution Apparatus II, Rotating Bottle Apparatus, and Bio-Dis® Tester -taking into account pertinent factors that can affect dissolution. Dissolution profiles were obtained for two drugs - theophylline and phenylpropanolamine HCI. Three dosage forms of each drug were evaluated at different agitation intensities using two different dissolution media (simulated gastric fluid and simulated intestinal fluid) on all three dissolution devices. Various advantages/limitations for each device were observed depending on the drug, dosage form, agitation speed and dissolution medium.     

Pharmaceutical Analysis of β-Methyldigoxin in Dosage Forms Using RP-HPLC

Abstract

A reversed-phase high-performance liquid chromatographic method has been developed for the assay of β-methyldigoxin in Dimekor® tablets (0.1 mg) and ampules (0.2 mg/2 mL). Quantitation of cardiac glycoside in mentioned dosage forms was carried out by the incorporation of phenacetin as an internal standard. A Varian HPLC configured with a Paltisil P10 ODS1 column was used for the separation and quantitation of β-methyldigoxin in pharmaceutical preparations. The mobile phase was acetonitrile-water 38: 62 v/v with flow rate 1.6 ml/min and UV detection was set at 220 nm. The range of linearity extended from 0.01 to 0.11 mg/mL. For the quantitative analysis of β-methyldigoxin in tablets the recovery was 100.16% and for ampules 99.50%. The excipients did not interfere with the determination of the analysed substance. The proposed method is precise and sensitive for the examination of examine the content uniformity of tablets and is in a good agreement with PH.JUG.IV (1). A spectrofluorimetric method was used for the dissolution test by the method described in USP XXII (2).     

Controlled-Release Matrix Tablets of Ketoprofen

Abstract

To obtain a prolonged-action dosage form of ketoprofen, 3 different techniques for delaying drug release from hydrophylic matrices of hydroxypropylmethylcellulose were evaluated. They were: the incorporation of glyceryl monostearate, as a release retardant; the partial coating with an impermeable covering of cellulose acetate phthalate; the pan-spray coating with a mixture of insoluble (Eudragit) and soluble (PEG 400) polymers. The in vitro release profiles of each formulation were studied using the USP basket method. Pan-spray coating with the Eudragit-PEG mixture was found to be the best technique, enabling the desired release profile to be obtained through variation of the coating thickness