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.     

Construction of upper confidence limit of coefficient of variation for content uniformity

Relative standard deviation (coefficient of variation) plays an important role in meeting the current compendial requirements for content uniformity. Since the sample RSD value would vary from sample to sample in a population (batch), the scientist would need not only the sample estimate of the RSD but also its 95% two-sided upper confidence limit, for making the proper statistical inference as well as for arriving at the appropriate pharmaceutics decisions. The primary purpose of this paper is to depict the five available methods for determining the confidence limit and to discuss their relative merits and similarities in the context of a content uniformity study associated with Product-C. Suitable tables are furnished to facilitate rapid access to the desired RSD confidence limit.     

A Rebuttal to The “Reply”

At the outset a brief background from a pharmaceutics perspective is presented here. Pharmaceutical industry is one of the most tightly regulated industries. Statistics naturally plays an important role in the implementation of the compendial, regulatory and in-house requirements. The minimal requirement consists of a set of basic statistics, such as mean and standard deviation (SD), associated with each group of sample experimental data intended for submission. However, not only each statistic is individually subjected to a set of compendial, regulatory and in-house specifications, but also the individual observation is required to be within specific range for compliance (e.g. content uniformity). Hence these basic statistics are often referred to as the stand-alone sample (SAS) statistics, meaning that each statistic has to meet its own requirements. In this context, the geometric mean is indeed a SAS statistic. It is meaningful and interpretable directly from its face value. The geometric standard deviation (GSD) as derived in ref(B) is also a (SAS) statistic. It is meaningful and easily interpretable directly from its face value. It has the same sample information and the same interpretation as that of the regular SD. Sometimes, it shares essentially the same magnitude as the regular SD. Besides, it also has essentially the same magnitude as that of the jackknife GSD statistic, GSD(JK). For decades, these geometric statistics have been in practice, particulary, since the author of ref(B) was a member of the USP In-Vitro Bioavailability Testing Subcommittee (1970-1975). It has also been accepted fully and freely by the above-mentioned over-sight agencies.     

Overview of compendial standards for solid oral dosage forms

Compendial standards define acceptable articles at the time of use, in contrast to process control and product release strategies. The establishment of drug names and the setting of requirements for identity, strength, quality, purity, packaging, storage, and labeling are addressed by compendial standards. Because the solid oral dosage forms of drugs are used most frequently in drug therapy, it is crucial to examine how the attributes of these forms affect the development of quality standards. Compendial selections of tests for identity, dose uniformity, dissolution/disintegration, and limits and of assays to confirm content are surveyed in this article. Also discussed are the packaging and storage standards established by the compendia and the relationships between drug names and labeling requirements.     

Overview of compendial standards for solid oral dosage forms

Abstract

Compendial standards define acceptable articles at the time of use, in contrast to process control and product release strategies. The establishment of drug names and the setting of requirements for identity, strength, quality, purity, packaging, storage, and labeling are addressed by compendial standards. Because the solid oral dosage forms of drugs are used most frequently in drug therapy, it is crucial to examine how the attributes of these forms affect the development of quality standards. Compendial selections of tests for identity, dose uniformity, dissolution/disintegration, and limits and of assays to confirm content are surveyed in this article. Also discussed are the packaging and storage standards established by the compendia and the relationships between drug names and labeling requirements.     

Impact damage characterisation of composite laminates using a statistical approach

Detecting impact damage is an important factor in maintaining the structural integrity of aerospace composite structures. Since impacts can cause severe reductions in stiffness and strength of composite structures, there is a need to investigate the material’s stiffness and strength after an impact event. The work discussed in this paper is concerned with one overall goal, which is to determine if an impact has caused damage and then to determine the extent of that damage using only the structural responses that are acquired from low-profile surface-mounted transducers. The work presented in this paper demonstrates that responses recorded from these sensors can provide sufficient information to infer impact damage. Previous work by various authors has established that it is possible to distinguish between damaging and non-damaging impacts if the impact force time-history is available. Therefore, it is the requirement that only response data be used here that distinguishes this work from the previous studies. Following a systematic series of experiments, on the induction of impact damage in Carbon Fibre Reinforced Polymer (CFRP) laminates, a damage model was proposed from this work which can provide preliminary information on the type and extent of damages through observations made from Scanning Electron Microscopy (SEM) and X-ray radiography. The model can be used to provide a general understanding on the prediction of damage and failure progression in CFRP as a function of the number of layers and impact energies. To accommodate the results from SEM and X-ray, discussions on outlier analysis and visualisation, which emphasise the idea of discordancy from the discipline of statistics, are presented. Results from discordancy tests, for both univariate and multivariate data, can be used to clearly separate the data (non-damaging and damaging impacts as well as the separation of the type of failure modes) by a calculated threshold value. Both of these features (univariate and multivariate) can be used as damage indicators and proxies for determining the extent of damage.     

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.     

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.     

Quality assurance in pharmaceutical powder processing: Current developments

Pharmacopoeia1 requirements relating to standardization of the physical performance of oral dosage forms containing powders are usually limited to tests on the final product.

Such tests are aimed at ensuring that all tablets or capsules have the correct, nominal, drug content and that the drug is released into solution within a specified time. Whilst dissolution or disintegration test to assess drug release can only be carried out on a finished dosage form, content uniformity tests currently carried out on tablets or capsules alone could also be usefully carried out earlier on component powders at different stages during processing. The aim of developing a quality assurance procedure for quantifying the homogeneity of powders prior to tablet compaction or encapsulation would be to pin-point more precisely the part of a process where content uniformity problems arise. Secondly, a good quality assurance procedure would provide full mechanistic information about the behaviour of a given powder system, so that appropriate remedies could be applied.

Eleven different methods of testing homogeneity of powder mixes have been cited in pharmaceutically oriented literature and these will be reviewed in terms of their usefulness as routine quality assurance procedures for drug content uniformity. Of these 11 methods, 2 test methods were considered to be especially useful: one based on a flow test and the other on vibration analysis. This techniques has been validated using a complete vibration analysis and testing rig under conditions encountered during routine powder processing.

It would be desirable to see standard powder mixes tested on apparatus of the same design in different laboratories as a means of assessing the reproducibility of the proposed quality assurance method when used by different personnel.     

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.     

Quality assurance in pharmaceutical powder processing: Current developments

Abstract

Pharmacopoeia1 requirements relating to standardization of the physical performance of oral dosage forms containing powders are usually limited to tests on the final product.

Such tests are aimed at ensuring that all tablets or capsules have the correct, nominal, drug content and that the drug is released into solution within a specified time. Whilst dissolution or disintegration test to assess drug release can only be carried out on a finished dosage form, content uniformity tests currently carried out on tablets or capsules alone could also be usefully carried out earlier on component powders at different stages during processing. The aim of developing a quality assurance procedure for quantifying the homogeneity of powders prior to tablet compaction or encapsulation would be to pin-point more precisely the part of a process where content uniformity problems arise. Secondly, a good quality assurance procedure would provide full mechanistic information about the behaviour of a given powder system, so that appropriate remedies could be applied.

Eleven different methods of testing homogeneity of powder mixes have been cited in pharmaceutically oriented literature and these will be reviewed in terms of their usefulness as routine quality assurance procedures for drug content uniformity. Of these 11 methods, 2 test methods were considered to be especially useful: one based on a flow test and the other on vibration analysis. This techniques has been validated using a complete vibration analysis and testing rig under conditions encountered during routine powder processing.

It would be desirable to see standard powder mixes tested on apparatus of the same design in different laboratories as a means of assessing the reproducibility of the proposed quality assurance method when used by different personnel.     

Drug Dissolution Testing: Today and Tomorrow

This article discusses the present role of dissolution tests both in terms of current compendial requirements and the use of such tests by the pharmaceutical industry.

Insofar as future use is concerned, the suggestion is made that the compendia clearly distinguish between those monographs where dissolution tests have been shown to be of biological significance (i.e., Digoxin Tablets) and those which are simply acting as physical quality control procedures. Logically, a dissolution test should be applied to all solid dosage forms, although from a logistical point of view it might be appropriate to confine this requirement, at least initially, to those drugs having an aqueous solubility of 0.5 per cent or less.

In the future, the pharmaceutical industry should expand its use of dissolution testing both in formulation development and production control, with a view to establishing, in as many instances as possible, dissolution tests having biological significance, i.e., where reliable in vitro - in vivo correlations have been established.     

多区加热热电偶检定炉的温场研究

针对在热电偶检定过程中使用传统的检定炉用均温块所导致的控温滞后、恒温时间长、漏电及炉管弯曲等问题,研制出不用均温块温场也能满足相关规范要求的多区加热检定炉,以提高检测效率.根据JJF 1184-2007《热电偶检定炉温度场测试技术规范》对用均温块的传统单区加热检定炉与不用均温块的多区加热检定炉的温场分别进行测试;再用热...     

Pass-Fail Testing: Statistical Requirements and Interpretations

Performance standards for detector systems often include requirements for probability of detection and probability of false alarm at a specified level of statistical confidence. This paper reviews the accepted definitions of confidence level and of critical value. It describes the testing requirements for establishing either of these probabilities at a desired confidence level. These requirements are computable in terms of functions that are readily available in statistical software packages and general spreadsheet applications. The statistical interpretations of the critical values are discussed. A table is included for illustration, and a plot is presented showing the minimum required numbers of pass-fail tests. The results given here are applicable to one-sided testing of any system with performance characteristics conforming to a binomial distribution.     

Drug Dissolution Testing: Today and Tomorrow

Abstract

This article discusses the present role of dissolution tests both in terms of current compendial requirements and the use of such tests by the pharmaceutical industry.

Insofar as future use is concerned, the suggestion is made that the compendia clearly distinguish between those monographs where dissolution tests have been shown to be of biological significance (i.e., Digoxin Tablets) and those which are simply acting as physical quality control procedures. Logically, a dissolution test should be applied to all solid dosage forms, although from a logistical point of view it might be appropriate to confine this requirement, at least initially, to those drugs having an aqueous solubility of 0.5 per cent or less.

In the future, the pharmaceutical industry should expand its use of dissolution testing both in formulation development and production control, with a view to establishing, in as many instances as possible, dissolution tests having biological significance, i.e., where reliable in vitro - in vivo correlations have been established.     

Lubricants as a Formulation Factor Affecting In Vitro Properties of Double Compressed Tablets

Abstract

The effect of some lubricants and their concentrations on the in-vitro properties of aspirin tablets as a model of tablets prepared by double compression was studied. The formulated tablets were evaluated using the U.S.P XX official tests and some other selected non-official tests. These tests include: uniformity of weight, uniformity of content, disintegration, dissolution, hardness, friability and thickness. The obtained results showed that all the prepared formulae fulfilled the requirements of such tests. Talc at a concentration of 3% w/w was found to be the most suitable lubricant for the formulation of aspirin tablets. On the other hand, magnesium stearate was found to be the worst lubricant in this study.     

The Statistical Construction of a Single Standard from Several Available Standards

In the case of physical quantities for which no international standards exist, such as microwave power and microwave noise, it may be desirable to establish an international standard by combination of the data from several laboratory standards. Even if there is an international standard, it conceivably might be replaced by a new composite standard, for example the mean of several laboratory atomic-time standards. A weighted mean may be preferable. It is noted that the "best" combination of observations for estimating a theoretical mean or median value depends on the theoretical frequency distribution from which the observations are drawn. Since the theoretical distribution for observations from different laboratories would in general be unknown, two weighted means are suggested which are reasonably good for many distributions, allowing for wild observations particularly, and in which the weight of each observation depends only on its order when the observations are ordered in size. The efficiencies of these and other estimates are evaluated for each of four distributions.