A Compliance Perspective on Dissolution Method Validation for Immediate-Release Solid Oral Dosage Forms on Automated Instrumentation - Pharmaceutical Technology

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A Compliance Perspective on Dissolution Method Validation for Immediate-Release Solid Oral Dosage Forms on Automated Instrumentation
An automated dissolution method can be a powerful tool to test drug products at all phases of their development. With minimal automated method validation, this tool can be used early in the drug-evaluation process. And with additional validation efforts, an automated method can be extended to the testing of Phase IV stability batches. Validating an automated dissolution-test method requires an understanding of the potential effects from filtration parameters, system interference, carry-over, cleaning..


Pharmaceutical Technology


Validation of automated method parameters

It is advantageous for a dissolution chemist to validate individual automated parameters even if comparable results are obtained between the automated and manual dissolution tests. This process provides additional information about the product and the automated procedure, which may be useful as the formulation evolves. In addition, by validating individual automated parameters, a dissolution chemist can demonstrate to the US Food and Drug Administration a high level of control and understanding of the automated procedures used to evaluate the performance of the drug product. The individual automated parameters to be validated should include filtration, system interference, carry-over, cleaning parameters, and media replacement for off-line sample collection. A dissolution chemist always must be aware that the dissolution of the product itself is validated, not a particular formula. With this fact in mind, it is beneficial to conduct the validation experiments after final formulas have been determined. If future formulations change drastically, experience and scientific judgment must be used to determine the necessity of revalidation of individual automation parameters.

Filtration. Although automated filtration parameters should be established first, the filtration procedures for manual dissolutions may not always transfer exactly to the automated instrument. Incompatible or inadequate automated filtration procedures are the most likely cause for different results between the manual and automated dissolution tests. A side-by-side comparison between a manual test and an automated test is the quickest way to evaluate compatibility between the two methods. Because results typically approach 100% drug released at later time points, samples taken at the earlier time points provide the best information. At minimum, it is advantageous to test two lots of drug product at the highest and lowest dosage strengths.

Experience in performing manual dissolutions should help determine the type of experiment to be conducted. The comparison can be performed two different ways. For highly variable batches, where the result relative standard deviation is >20% at the 10-min time point or >10% at later time points, USP recommends performing an automated dissolution and collecting manual samples simultaneously during the automated sampling. To ensure that the automated sampling probe is not affecting the hydrodynamics of the dissolution, however, a dissolution scientist should first perform the automated dissolution using only manual sampling. These results could be compared with the manual dissolution. For less variable batches, USP recommends comparing the results between separate manual and automated dissolutions tests. The acceptance criteria proposed under USP "<1092> Intermediate Precision guidelines state the difference should not exceed 10% with less than 85% dissolved and the difference should not exceed 5% for remaining time points above 85% dissolved (1, 2).

System interference. After acceptable filtration parameters have been established, a dissolution chemist should determine whether system interference is affecting the results generated with the automated instrumentation. This parameter is an important variable to investigate and hopefully eliminate as a potential source of difference between the manual and automated tests.

An example of system interference is any binding of the API to tubing or sampling needles when using sampling parameters described in the automated method. Once automated sampling occurs, the API often must travel through very long lines of tubing, thus generating the potential for system interference. The test may be performed by preparing a 20% API and a 100% placebo solution. The amount of API is measured with and without the automated system. A portion of the prepared API solution is placed into each of the six dissolution vessels. Sample aliquots should be withdrawn manually and filtered simultaneously as the automated system is sampling. The difference between the two responses should not exceed 2.0%. Because system interference is more likely to be observed with a 20% API solution, the information generated from this experiment is useful when analyzing results from dissolution-profile testing. Low levels of system interference from higher API concentrations may be less likely to be noticed. If system interference is not observed with a 20% API solution, a dissolution chemist is more likely to be assured that accurate data are obtained at earlier time points of automated dissolution profile testing. Conversely, if the results between the manual and the automated dissolution tests are not equivalent, especially at the earlier time points of profile testing, it may be determined that system interference is the cause of the nonequivalent automated results. Although only the results at Q time will pass or fail a batch, system interference is an important parameter to evaluate because it demonstrates to FDA a high level of control and understanding of the automated procedures used to evaluate the performance of the drug product.


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