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..
Sep 02, 2006
Volume 30, Issue 9

As the pace of product development accelerates, the approach to dissolution-method development must advance beyond a manual method and an assay. A natural progression of the method-development process must include the transfer of the manual method onto automated instrumentation.

Validating the automated method is the primary challenge when transferring from the manual method. A dissolution scientist must understand the potential effects from filtration, system interference, carry-over, cleaning parameters, and media replacement. Automated dissolution instrumentation can help generate good manufacturing practice (GMP) data only when validated testing parameters can negate these influences, so the dissolution scientist can be confident that results do not differ between the manual and the automated methods. In addition, all laboratory equipment used to support or generate GMP data about automated instrumentation must follow an instrument "chain of compliance." Proper documentation must exist that proves each piece of equipment has been properly qualified and calibrated for its intended use.

Product development life cycle

Tips for validating automated dissolution parameters
The level of automated dissolution-method validation depends upon a product's phase of development. For early-phase products, minimal validation is required to screen the initial batches. Typically, filtration parameters must be established first to ensure that no amount of active pharmaceutical ingredient (API) is lost with filtration. The initial filtration parameters could be established manually and then transferred to the automated instrument. Next, automated dissolution-profile testing is completed to screen several different dissolution media. Profile sampling could be performed at 10, 20, 30, 45, and 60 min and the results compared. Selecting the various dissolution media that are used in the evaluation depends upon the solubility and stability of the API in each media. This process allows a dissolution chemist to determine quickly the media having the potential to provide the most discriminating dissolution performance for the product. Once these initial parameters have been established, a dissolution chemist can use the automated instrumentation to quickly screen early formulations and help formulators direct their future formulation efforts.

As the life cycle of the product progresses, automated dissolution-method parameters must be validated if the generated data have the potential to be included in any type of GMP submission. At this phase of development, a dissolution chemist should have substantial experience performing both manual and automated dissolutions on a product. This experience can be useful to select automated dissolution method parameters, which should be able to generate results equivalent to those of manual dissolution tests.

Ensuring instrument qualification
Because the manual test is considered the "official" dissolution test, side-by-side dissolution-profile testing should be conducted manually and with automation. Results could be compared at 10, 20, 30, 45, 60, and infinity minutes. At the infinity time point, a final sample is taken after the dissolution has progressed with a stirring apparatus speed of 250 rpm for an additional 30 min after the Q time point. The chosen acceptance criteria for the comparison between the two methods should reflect and compensate for both nonvariable and highly variable drug products. The results generated at the earlier time points are the most significant because they have the highest potential for variation between the manual and automated methods. If comparable results are obtained between the two methods at the earlier time points, a dissolution chemist is more likely to be assured that accurate data are obtained at all time points of the automated dissolution-profile testing. At later time points, the percent drug released typically approaches 100%; therefore, not as much variation between the two tests would be expected at these later time points. Acceptance criteria must be established for results generated at the earlier time points (<85% dissolved) and the later time points (>85% dissolved) with tighter acceptance criteria established at the later time points.

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