Content Uniformity: Separation and quantitation of sources of dose variation

Abstract

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.     

Detection of Discordant Content Uniformity Observations and Compendial Compliance

Abstract

A discordant observation is a data point whose value is drastically different from that of the rest of the members in the data set. In the context of content uniformity experiments, however, a discordant observation arises in two ways: (i) when the value of an observation is markedly distant from that of the other data points even though it is within the required compendial range, and (ii) when the value of an observation is outside the permissible compendial range. Several statistical tests for detecting one or more discordant observations are presented. Since discordancy distorts the symmetricity of the data, several tests of symmetricity are provided. Tests for detection of group discordancy induced by discordant samples are also included. The compendial requirements are explained in statistical terms. The impact of discordant observations on compendial compliance requirements is assessed. The statistical basis of the construction of compendial limits as well as the assumptions implicit in the construction is elaborated. The results of the statistical analysis of three content uniformity studies are appropriately interpreted.     

Detection of Discordant Content Uniformity Observations and Compendial Compliance

A discordant observation is a data point whose value is drastically different from that of the rest of the members in the data set. In the context of content uniformity experiments, however, a discordant observation arises in two ways: (i) when the value of an observation is markedly distant from that of the other data points even though it is within the required compendial range, and (ii) when the value of an observation is outside the permissible compendial range. Several statistical tests for detecting one or more discordant observations are presented. Since discordancy distorts the symmetricity of the data, several tests of symmetricity are provided. Tests for detection of group discordancy induced by discordant samples are also included. The compendial requirements are explained in statistical terms. The impact of discordant observations on compendial compliance requirements is assessed. The statistical basis of the construction of compendial limits as well as the assumptions implicit in the construction is elaborated. The results of the statistical analysis of three content uniformity studies are appropriately interpreted.     

Content Uniformity of a Low Dose Pharmaceutical Product

ABSTRACT

Optimum homogeneity and physical stability for a Roche compound (RO) low dose formulations (0,125 and 0.250 mg Tablets i.e. 0.07 to 0.14% w/w drug load, respectively) were achieved. Direct compression powder formulations were prepared by mixing the active drug substance with Starch 1500 (ST) to form an active pre-mix. Other ingredients were added subsequently. The final powder mix was subjected to a vibration of 4 Hz frequency using a specially designed segregation unit and content uniformity was assessed for these formulations. ST was considered superior to both lactose anhydrous and Avicel PH 102 in preparing homogeneous and physically stable mixes. Production-size batches of the product were successfully manufactured (Mean Drug content = 98 100%, RSV = 2%).     

Blending Validation and Content Uniformity of Low-Content,Noncohesive Powder Blends

Abstract

Blending validation has become mandatory, partly through good manufacturing practice (GMP), partly through a court action (the Barr decision) in 1993. Although feasibly carried out with existing technology, there are situations where the methodology for sampling causes a suspected bias in the figures, and one such case is where the drug content (expressed as fraction in the following) is low. In particular, this dilemma is predominant where the blended materials are not cohesive. Possible explanations for this are voiced, as are suggestions on how to proceed rationally in such cases.     

Blending Validation and Content Uniformity of Low-Content, Noncohesive Powder Blends

Blending validation has become mandatory, partly through good manufacturing practice (GMP), partly through a court action (the Barr decision) in 1993. Although feasibly carried out with existing technology, there are situations where the methodology for sampling causes a suspected bias in the figures, and one such case is where the drug content (expressed as fraction in the following) is low. In particular, this dilemma is predominant where the blended materials are not cohesive. Possible explanations for this are voiced, as are suggestions on how to proceed rationally in such cases.     

Exact Power Function of Compendial Test Requirements for Content Uniformity

The exact distributions associated with the current compendial test requirements are generated by resorting to the well known Computer Intensive Algorithm method to establish the exact percentage point (limit) for RSD, corresponding to each selected cut-off probability level (confidence level) for each of the four possible experimental outcomes based on the USP-NF test requirements. A table is constructed to present the two-dimensional power function. The similarities between these tabular values and the current compendial RSD limits for 10 and 30 dosage units are extremely remarkable.

Minor differences exist, however. It is suggested that both the theoretical as well as the numerical approaches should be carried out to arrive at a comprehensive solution.     

Exact Power Function of Compendial Test Requirements for Content Uniformity

Abstract

The exact distributions associated with the current compendial test requirements are generated by resorting to the well known Computer Intensive Algorithm method to establish the exact percentage point (limit) for RSD, corresponding to each selected cut-off probability level (confidence level) for each of the four possible experimental outcomes based on the USP-NF test requirements. A table is constructed to present the two-dimensional power function. The similarities between these tabular values and the current compendial RSD limits for 10 and 30 dosage units are extremely remarkable.

Minor differences exist, however. It is suggested that both the theoretical as well as the numerical approaches should be carried out to arrive at a comprehensive solution.     

Analysis of Content Uniformity Data of Tablets with two Active Ingredients

A method based on scatter plots of content uniformity data of tablets containing two active ingredients was utilized to gauge the degree of segregation in the finished product. The difference of semi-axes of the tolerance ellipse imposed on the content uniformity data and the covariance of data were found to be useful in estimating degree of segregation. Direct compression formula of a specific case was found to have slightly more segregation than a wet granulated product.     

Separation and quantitation of short-chain coenzyme A's in biological samples by capillary electrophoresis

Because of the importance of coenzyme A's (CoA's or CoASH) in many metabolic processes and the biosynthesis of some carbohydrates and lipids, many methods have been developed to separate and determine their levels in various tissues for metabolism studies, including enzymatic assays, paper chromatography, and high-performance liquid chromatography (HPLC). However, inadequate separation of coexisting CoA's in biological samples was often encountered due to the similarity of their structures. In this paper, we demonstrated for the first time the separation and quantitation of 12 different CoA's by using capillary electrophoresis with UV detection at 254 nm. All 12 CoA's (CoASH, HMG CoA, methylmalonyl CoA, succinyl CoA, methylcrotonyl CoA, isobutyryl CoA, oxidized CoA, acetyl CoA, crotonoyl CoA, n-propzoyl CoA, acetoacetyl CoA, malonyl CoA) were completely separated at -30 kV in a 100 mM NaH2PO4 running buffer containing 0.1% beta-cyclodextrin at pH 6.0. The total separation time was less than 30 min. The signal response was linear over 2 orders of magnitudes (from 1 to 100 nmol), and the detection limits were in the picomole range. The effects of pH, buffer concentration, additives, and operation voltages on sensitivity and resolution were also discussed. This technique, described here, is much more sensitive, faster, and simpler than the published HPLC methods and can potentially be used for mechanistic study in biological systems involving CoA metabolism.     

Studies Relating to the Content Uniformity Cif Ethinylo-Estradiol Tablets 10 Ug: Effect of Particle Size of Ethinyloestradiol

Ethinyloestradiol is formulated in minute amounts, e. g. 10 μg per tablet of 50 mg weight. Experiments to relate the shape of the distribution curve and the extent of homogeneity to the particle size of ethinyloestradiol were performed.

Results showed that on comparison of values of C_R (the coefficient of variation for a random mix), with C_P and C_t (the coefficients of variation for powder mix and tablets respectively), for the batches containing the large particle size fractions of drug the values are as predicted by random mixing theory. As the particle size of the drug is decreased, the values of C_P and C_t also decrease in accordance with random mixing theory until a critical particle size d_c′ is reached. For batches containing drug particles of size less than d_c′ then both C_P and C_t increase with decreasing particle size. This change is associated with a change to a positively skewed distribution because of the cohesive properties of fine powders and their tendency to form agglomerates which remain undispersed in the excipients. Above d_C′ the rate limiting step in powder mixing is randomisation and below it the rate limiting step in achieving the required homogeneity is the breaking down of the drug agglomerates. In addition to its effects on the magnitude of C_P and C_t, the particle size of ethinyloestradiol has a marked influence on the shape of the distribution curve.     

An Evaluation of a Unit-Dose Compacting Sample Thief and a Discussion of Content Uniformity Testing and Blending Validation Issues

Abstract

The ability of the unit-dose compacting sample thief to provide quantitative, precise, and reproducible sampling of powder blends has been demonstrated in Jive cases. The thief enables the pharmaceutical researcher to comply with Food and Drug Administration guidelines for unit-dose sampling of powders and granulations. Some issues regarding blending validation and content uniformity testing have been addressed.     

Effect of Granulating Method on Content Uniformity and Other Physical Properties of Granules and their Corresponding Tablets. II

Various properties of dexamethasone and sulfadiazine granules and tablets prepared by microgranulation, slugging, wet granulation and direct compression were compared.

The dexamethasone tablets showed comparable disintegration rates by all methods. The sulfadiazine tablets prepared by slugging did not meet the USP XIX limit, whereas those by microgranulating were satisfactory.

It was found that granule-homogeneity was not only dependent on the particle size and distribution, but also dependent on the granulating method. For either drug, the microgranulating procedure gave the best weight and content uniformity.     

Optimal coordinate sensor placements for estimating mean and variance components of variation sources

In-process optical coordinate measuring machines offer the potential to diagnose the sources of the variations that are responsible for product quality defects. Such a sensor system can thus help manufacturers to improve product quality and reduce process downtime. The effective use of sensor data in the diagnosis of the sources of variations depends on the optimal design of the sensor system, which is often also called the problem of sensor placement. This paper addresses coordinate sensor placement for the diagnosis of dimensional variation sources in assembly processes. Sensitivity indices for the detection of the process mean and variance components are defined as the design criteria and are derived in terms of process layout and sensor deployment information. Exchange algorithms, originally developed for optimal experimental design, are revised and then used to maximize the detection sensitivity. A sort-and-cut procedure is proposed, which is able to significantly improve the algorithm efficiency of the current exchange routine. The resulting optimal sensor layout and its implications are illustrated in the specific context of a panel assembly process.     

The annual effective dose from natural sources of ionising radiation in Canada

A review and analysis of published information combined with the results of recent gamma ray surveys were used to determine the annual effective dose to Canadians from natural sources of radiation. The dose due to external radiation was determined from ground gamma ray surveys carried out in the cities of Toronto, Ottawa, Montreal and Winnipeg and was calculated to be 219 microSv. A compilation of airborne gamma ray data from Canada and the United States shows that there are large variations in external radiation with the highest annual outdoor level of 1424 microSv being found in northern Canada. The annual effective inhalation dose of 926 microSv from 222Rn and 220Rn was calculated from approximately 14,000 measurements across Canada. This value includes a contribution of 128 microSv from 222Rn in the outdoor air together with 6 microSv from long-lived uranium and thorium series radionuclides in dust particles. Based on published information, the annual effective dose due to internal radioactivity is 306 microSv. A program developed by the Federal Aviation Administration was used to calculate a population-weighted annual effective dose from cosmic radiation of 318 microSv. The total population-weighted average annual effective dose to Canadians from all sources of natural background radiation was calculated to be 1769 microSv but varies significantly from city to city, largely due to differences in the inhalation dose from 222Rn.     

Characterization of the sources of variation affecting near-infrared spectroscopy using chemometric methods

A rapid assessment of product quality can often be made using a combination of near-infrared spectroscopy (NIR) and multivariate calibration. The robustness of such a method is determined by the sensitivity of the multivariate calibration model to variations in the spectral data. An approach is described that uses a combination of experimental design methodology and principal component analysis to identify the main sources of variation in the spectra and to estimate their influence on the quantitative predictions. This is accomplished by comparing variations in a set of measured, replicate spectra to spectra with simulated variations. The approach was applied to the hydroxyl number determination of polyols by NIR spectroscopy and partial least-squares calibration. The results indicated that the most significant sources of variation were due to a variable cell path length and a variable curved background. Correction for these errors resulted in a 58% reduction in the standard deviation of the hydroxyl number predictions, indicating that a substantial improvement in the method precision is possible.     

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.