Control procedures to monitor the mixing process are essential to ensure consistent and efficient production of OSDs. PAT tools such as NIR and Raman offer an alternative to sample thieves by enabling online analysis of content consistency. The most common method for assessing content uniformity in DSOs is high-performance liquid chromatography (HPLC), Andrews observes. “HPLC has the advantages of flexibility, sensitivity and ubiquity, and many analytical chemists are trained in the use of HPLC methods,” he says. “The downsides, however, are the time and resources required to prepare the samples.” Checking the homogeneity of the content sets a limit for the variance of the API in each tablet or capsule. “The intention is to ensure that OSDs do not have an unusually low or high amount of API that can occur because the powder is mixed and processed before being compressed or encapsulated,” andrews says. “The mixture causes natural fluctuations in the amount of a dosage amount.” Each unit is evaluated individually in the content equalization test, while all multiple units are processed simultaneously in one test. Therefore, this is another difference between the uniformity of the content and the dosage. In addition, another difference between content homogeneity and testing is that content homogeneity is a kind of qualitative test, while a test can be qualitative or quantitative. Uniformity of content and dosage are two types of analytical tests used to determine the quality of pharmaceutical products.
For DSOs, there needs to be an appropriate sampling strategy to verify consistency of content, Robertson points out. “The most common sampling designs proposed by the oral care team are: simple sampling, stratified sampling (dividing the lot into sections, then sampling each section) and systematic sampling (at regular intervals throughout the lot),” he says. contains methods for uniformity of weight content and variation and acceptance criteria for assessing the uniformity of dosage units. These apply to both newly registered and existing products. In addition, it is important to test the uniformity of the content to assess the uniformity of the dosage of a drug, while a test helps to characterize the main functional component of a sample. As with NIR, Raman instrumentation enables non-destructive in-line measurements of the pharmaceutical process, including mixing and uniformity measurements of tablet content. “Raman spectroscopy can be used as a PAT tool for content uniformity applications,” says Karen Esmonde-White, senior marcom specialist at Kaiser Optical Systems. “Raman`s sampling flexibility is suitable for offline measurement with a Raman microscope or sampling tray and in-process measurement with sampling probes.” She points out that in-process Raman measurements are beneficial because they allow for real-time understanding of the process without the need to collect samples for offline measurements. Answer: As a rule, the determination of the uniformity of the contents is carried out on individual dosage units using the method found in the test. For some products, a separate procedure is specified in the monograph.
If this is the case, the monograph procedure would be considered as a special procedure for uniformity of content. Theophylline Extended-Release Capsules is an example of a monograph that requires a special procedure for the homogeneity of the content. Uniformity of content is an important measure of quality for the final solid dosing product, notes Ian Robertson, spectroscopy application specialist at PerkinElmer. It ensures that a constant dose of the API is maintained between batches so that the patient receives the correct dose. Robertson points out that content consistency is especially important when tablet splitting is used. “The active ingredient should be evenly distributed throughout the tablet to ensure that when the tablet is divided in half, each half of the tablet has an equal dose,” he says. In addition, the types of goals are a significant difference between content uniformity and testing. Pharmaceutical drugs are the target of the content homogeneity test, while DNA, RNA, proteins, carbohydrates, antibodies, metal ions, pharmaceutical drugs, etc. can be the target of a test.
The main difference between content homogeneity and testing is that content homogeneity is a test in which the evaluation units are performed individually, while the test is a test in which several units are performed simultaneously. In addition, the procedure for evaluating content homogeneity tests is the same for all units. The main concept behind the revised uniformity criteria of dosage units is statistical tolerance intervals. The general idea of tolerance intervals is to use the available data to form an interval that covers a certain proportion of the distribution underlying the data. For uniformity of content, this would be the distribution of content and the intention is to form an interval on the label claim into which a certain proportion of units would fall. Technically, an interval (a, b) is a 95% tolerance interval (the “confidence”) for 90% of the distribution (the “coverage”) if 95% of these repeated sampling intervals would cover at least 90% of the distribution. Tolerance intervals can be parametric or nonparametric. Parametric intervals are based on a supposed distribution, usually the normal.
Assuming the normal distribution, bilateral tolerance intervals have the form, where the mean, S is the standard deviation, and k depends on coverage, confidence level, and sample size. (The multiplier k becomes smaller as the sample size increases, but never to 0. For example, for 95% coverage, it drops to 1.96.) This is the form of the criteria generally used in chapter . Robertson adds that NIR spectroscopy can also be used to measure the uniformity of the contents of solid dosing tablets. “The measurement can be carried out non-destructively directly on the tablet by means of reflection or transmission according to appropriate quantitative calibrations, usually against the reference values of hplc measurements,” he explains. “No sample preparation is required and measurement does not require solvents or other hazardous chemicals.” According to Robertson, one of the limitations of Raman spectroscopy for content uniformity measurements was the limited size of the laser`s points, analyzing only a small fraction of the entire tablet. “However, recent advances in laser scanning make it possible to examine the entire tablet,” he says. “Further progress has been made with Transmission Raman Spectroscopy (TRS), which measures the Raman signal transmitted through the entire tablet, measuring a much larger sample volume.” The uniformity test of dosage units (1) is used to evaluate dosage units such as tablets and capsules in terms of uniformity of contents or, where appropriate, weight variation. There is a threshold between consistency of content (for dosage units with < 25 mg or < 25%) and weight variation (for dosage units with ≥ 25 mg and ≥ 25% API; with the exception of sugar-coated tablets, which require uniformity of content).