Dissolution Method Validation

Sinkers can significantly influence the dissolution profile of a drug. Therefore, the use of sinkers should be part of the dissolution method validation. If equivalent sinkers are identified during the sinker evaluation and validation, the equivalent sinkers should be listed in the written dissolution test procedure. When a dissolution method utilizes a dissolution sinker and is transferred to another laboratory, the receiving laboratory should duplicate the validated sinker design(s) as closely as possible. 

The validation requirements are discussed as they apply to both the sample preparation and sample analysis aspects of a dissolution method. The focus of the discussion in this chapter is on the validation considerations that are unique to a dissolution method. Validation is the assessment of the performance of a defined test method. The result of any successful validation exercise is a comprehensive set of data that will support the suitability of the test method for its intended use. To this end, execution of a validation exercise without a clearly defined plan can lead to many difficulties, including an incomplete or flawed set of validation data. Planning for the validation exercise must include the following determination of what performance characteristics to assess (i.e., strategy), how to assess each characteristic (i.e., experimental), and what minimum standard of performance is expected (i.e., criteria). The preparation of a validation protocol is highly recommended to clearly define the experiments and associated criteria. Validation of a test method must include experiments to assess both the sample preparation (i.e., sample dissolution) and the sample analysis. ICH Q2A [1] provides guidance for the validation characteristics of the dissolution test and is summarized in Table 4.1. 

Table 2.5 Experimental Domain for a Dissolution Method Validation Experiment... 

Table 2.6 Plackett-Burman (Hadamard) Design of 12 Experiments and 11 Factors for Dissolution Method Validation...

The USP Dissolution General Chapter < 711 > describes the basket (Apparatus 1) and paddle (Apparatus 2) in detail. There are certain variations in usage of the apparatus that occur in the industry and are allowed with proper validation. The literature contains a recommendation for a new USP general chapter for dissolution testing (6). In this article, guidance for method validation and selection of equipment is described. It may be a useful guide when showing equipment equivalence to compendial equipment. 

Leeson LJ. ANDA dissolution method development and validation. Dissolution Technol 1997 4(1) 5—9, 18. 

Therefore, the development and validation of a scientifically sound dissolution method requires the selection of key method parameters that provide accurate, reproducible data that are appropriate for the intended application of the methodology. It is important to note that while more extensive dissolution methodologies may be required for bioequivalency evaluations or biowaivers (i.e., multiple media, more complex dissolution media additives, and multiple sampling time points), it is also essential for the simplified, routine quality control dissolution method to discriminate batch-to-batch differences that might affect the product s in vivo performance. 

Different approaches may be used to validate the sample preparation component of the dissolution test. However, it is important to understand that the objective of validation is to demonstrate that the procedure is suitable for its intended purpose. For example, one of the strategies will demonstrate the validity of different aspects of sample preparation during method development (prior to the formal method validation exercise). As a result, the final validation experiments will confirm the work done during method development. The strategy that will be followed for the method development and validation process will depend on the culture, expertise, and strategy of the analytical laboratory. 

Rotational Speed. The rotational speed of a basket or paddle is an important consideration in the development and validation of the dissolution test. A speed of 100 rpm is commonly used with the basket apparatus and a speed of 50 rpm is used with paddles. In method validation, one needs to ensure that slight variations in rotational speed will not affect the outcome of the dissolution test. The compendial limit for variations in rotational speed is 4%, but a wider variation (e.g., 10%) may be considered in testing the robustness of the method. 

In the following pages we summarize the common deficiencies of a dissolution method which may result in problems during the validation process. The common... 

Equivalency. This test compares the results of the automated procedure with the results of the validated manual method. If accuracy of the automated procedure has been proven, it may not be necessary to perform the equivalency study. However, if the manual method does not exist, then accuracy and reproducibility data should be used to assess the suitability of the automated method. The recommended testing for content uniformity, assays, degradation and impurity methods and dissolution methods are listed in Table 5.4. 

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. 

When developing a dissolution method, the process should begin with a familiarity of the literature on method development. There are many good articles,21,22 books,9 11 and the aforementioned new USP Informational General Chapter <1092> The Dissolution Procedure Development and Validation.8 Some of the key considerations in dissolution method development are discussed below. 

There are four basic steps in the development (excluding validation) of a dissolution method for low-dose drug products (1) selection of dissolution apparatus (2) selection of a suitable analytical technique to quantify analyte release (3) selection of dissolution medium and (4) selection of dissolution apparatus operating conditions. 

The goal of solution stability for different tests can vary. For assay and degradation product test, no new degradation products (over time and above LOQ) should be formed in solution. Certain acceptance criteria (max % increase) may be set for impurities at particular levels during the solution stability study. For assay determination (assay, CU, and dissolution), the content of assay over time should not change more than 2.0%. Also, refer to Chapter 9, which discusses method validation. 

Analytical method validation should track closely to the stages of development of the method itself However, it is not realistic to expect complete and thorough validation of the method until its development cycle is complete. An exception to this would be a situation where an accepted compendial method is applied to clinical material (such as a dissolution test or release testing of a compendial component). In these cases, companies must be prepared to demonstrate that consistent acceptable results can be obtained when using the compendial method in the company s laboratory (also known as methods verification). The obvious... 

As required by regulatory authorities [1-3, 6] and International Conference on Harmonisation (ICH) guidelines [7], analytical method validation is especially important in establishing the assay methods and procedures of quantitative or semi-quantitative measurement of target substances or compounds. Among the specification items for drug products, assay, content uniformity, and dissolution are typical of those which require almost full analytical validation. The purity test, related... 

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