Content uniformity method

Methods for the quantitation of major components of bulk drug substances or APIs, including preservatives, in finished drug products are classified in Category I. Assay and content uniformity methods fall into this category. These methods demonstrate that the label claim of the drug... 

The validation of an automated content uniformity method and an automated dissolution method based on a validated manual method can adopt a similar approach where the equivalency data can support the requirements of the other studies involved. When validating an automated method that is not based on a validated manual method, only the repeatability and reproducibility can be combined to reduce the amount of analysis to be done since the equivalency study will not be executed. 

TABLE 9-7. Recovery Results for Assay and Content Uniformity Method... 

Identity is a general requirement for dosage forms. When determining specificity for identity, the assay and related substances or the content uniformity methods can be used. Assay and content uniformity methods are quantitated by external reference standard. This identity test confirms that the correct active ingredient (s) is present and is present in correct ratio if multiple variants are available. The method could also be used for post-packaging analysis. The general requirements are that the sample and standard chromatograms should correspond in retention time and normalized peak area within 10%. 

There are two types of analysis needed for cleaning verification (1) active (2) soap. Since residual amounts of active and soap are to be determined, the methods need to be very sensitive. For measuring the active, the assay or the content uniformity method can be employed (if the sensitivity of the existing method is acceptable). If the sensitivity of the current assay or content uniformity method is not acceptable, then modifications can be made to an existing method or a more sensitive test method is developed. 

The content uniformity method is similar and therefore can be transferred based... 

Two landmark articles published by H. Mark et al. and G. E. Ritchie et al. [30, 31] demonstrate how ICH Q2 principles can be applied when developing a near-infrared method. The first part of the series describes the method validation concepts as described in this section and proposes additional validation protocols. The second part focuses on the implementation of assay and content uniformity methods for solid dosage forms. Authors present at length how each criterion was validated and how they meet ICH and FDA requirements. For instance, repeatability was tested with the predictions of 13 repeats of tablets at three different concentration levels (80,100, and 120% w/w). In addition to the stated guidelines, authors used ASTM E1655-97 [12] to provide statistics analysis that is not directly provided in ICH Q2(R1). 

Such yes/no decisions are of great importance in foodstuffs control and environmental analysis. They also play an important role in pharmacy in the form of content uniformity tests. Without suitable screening methods for rapid detection of positive samples it would scarcely be possible to carry out economic doping controls and toxicological investigations or to recognize medicament abuse. 

Subcase b2 This case, called the paired f-test , is often done when two test procedures, such as methods A and B, are applied to the same samples, for instance when validating a proposed procedure with respect to the accepted one. In practicular, an official content uniformity" 5 assay might prescribe a photometric measurement (extract the active principle from a tablet... 

Since the 1993 court decision against Barr Laboratories, 5 tjjg elimination of outliers has taken on a decidedly legal aspect in the U.S. (any non-U.S. company that wishes to export pharmaceuticals or preciwsor products to the U.S. market must adhere to this decision concerning out-of-specifica-tion results, too) the relevant section states that ... An alternative means to invalidate an individual OOS result... is the (outlier test). The court placed specific restrictions on the use of this test. (1) Firms cannot frequently reject results on this basis, (2) The USP standards govern its use in specific areas, (3) The test cannot be used for chemical testing results. ... A footnote explicitly refers only to a content uniformity test, 5 but it appears that the rule must be similarly interpreted for all other forms of inherently precise physicochemical methods. For a possible interpretation, see Section 4.24. 

Atomic techniques such as atomic absorption spectrometry (AA), inductively coupled plasma-optical emission spectrometry (ICP-OES), and inductively coupled plasma-mass spectrometry (ICP-MS), have been widely used in the pharmaceutical industry for metal analysis.190-192 A content uniformity analysis of a calcium salt API tablet formulation by ICP-AES exhibited significantly improved efficiency and fast analysis time (1 min per sample) compared to an HPLC method.193... 

Since its creation around 1973, modern high-pressure liquid chromatography (HPLC) has played a dominant role in the analysis of pharmaceuticals. It is used in many different applications for example, in content uniformity assays and stability-indicating methods, for the purity profiles of drug substances, or in the analysis of drug metabolism in animals and humans. The heart of all of these assays is the HPLC column. In this chapter, we will describe the fundamental properties of HPLC columns as well as how these properties influence column performance and separation characteristics in pharmaceutical assays. 

Tablets account for more than 80% of all pharmaceutical formulations therefore, the development and implementation of NIR methods for determining APIs in intact tablets is of a high interest with a view to assuring content uniformity and quality in the end product. Blanco et al developed an innovative strategy to prepare calibration samples for NIR analysis by using laboratory-made samples obtained by mixing the API and excipients in appropriate proportions and compacting the mixture at a pressure similar to that used industrially. This way of matching laboratory and production samples affords more simple and robust NIR methods which require the use of neither HPLC nor UV-vis spectroscopy as reference rather, reference values are obtained by weighing during preparation of the samples. The PLS calibration models thus constructed exhibited a good predictive ability with various production batches.

Once the analytical method is validated for accuracy at the laboratory scale, it can be used to obtain extensive information on process performance (blend homogeneity, granulation particle size distribution, and moisture content) under various conditions (blender speed, mixing time, drying air temperature, humidity, volume, etc.). Statistical models can then be used to relate the observable variables to other performance attributes (e.g., tablet hardness, content uniformity, and dissolution) in order to determine ranges of measured values that are predictive of acceptable performance. 

Analytical Development of API and Drug Products. Early methods to support synthetic and formulation developments are often developed in the form of potency assay, impurities/related substance assay, dissolution, Karl Fischer, identity, chiral method, and content uniformity. These analytical methods are developed and validated in a fast and timely manner to support all phase II studies. 

For content uniformity, assay, and dissolution assays, a filtered aliquot is acceptable if the difference between the response of the filtered aliquot is not greater than 1.0% of the response of the reference sample. For impurities methods, the response of each impurity after filtration should be within 20% of the... 

---