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


Carry-over. If it has been determined that system interference is not a factor for the product, the elimination of carry-over must be validated for an automated dissolution testing system. Carry-over of an API may occur between sampling time points during dissolution-profile testing and between batches during multiple batch runs. To determine whether carry-over exists between sampling time points, perform a sampling sequence using solutions equivalent to 100% of the highest dosage form and a blank solution. The solutions must be sampled according to the already established automated filtration and sampling procedures. The sequence of the sampling should be as follows: 100% solution, blank, 100% solution.

The API in the blank solution should not exceed 1.0%, and the result for the second 100% sampled solution must be equivalent to 99.0–101.0% of the result of the first 100% sampled solution. If results exceed these acceptance criteria, increased sampling flush volumes, filter changes between time points, different filters, or any combination of these three parameters may need to be altered to obtain acceptable results.

Potential drug product carry-over between batches must be validated and eliminated if possible. This process allows the automated testing system to be used to its fullest potential so that multiple batches can be tested in a single run. The validation can be conducted by performing dissolution tests with the highest dosage strength batch followed immediately with a blank batch (no dosage forms). The API in the blank batch must not exceed an average of 1.0% for six vessels. The samples should be taken and compared at the infinity time point when results are expected to approach 100% API released. Cleaning parameters may need to be increased if results exceed this acceptance criterion.

Cleaning parameters. It is important to clean the automated dissolution-testing system between batches of a single run and between product changes. Clean the dissolution vessels, stirring shafts, sampling needles, and the entire length of all sampling lines. Potential problems may occur, especially between product changes, if a surfactant was used previously. Results from future batches may be inaccurately high if surfactant remains in the system from a previous run.

Adequate cleaning procedures must be validated to ensure no carry-over occurs between batches of a single run or after product changes. Validation of the cleaning parameters may be determined at the same time as the carry-over between batches experiments. If the carry-over results between batches exceed the acceptance criteria, increased cleaning parameters may solve the problem. The amount of dissolution media or hot water flushed through the lines at the end of a dissolution test may be set at the maximum allowable volume for that particular automated dissolution-testing system. In addition, the highest number of vessel washes and the volume of dissolution media or hot water used for the vessel washes may be set at the maximum allowable volume for that particular automated system. If even the most extensive cleaning parameters do not prevent an acceptable level of carry-over from an API, a dissolution chemist may decide that the dissolution procedure for this particular product is not "automatable."

Media replacement. A media-replacement process between time points for off-line sample collection should be validated with an automated dissolution-testing system. The media-replacement option corrects for sampling loss. This option allows a dissolution chemist to replace fresh media into each dissolution vessel after each sampled time point. The replacement media may be the primary dissolution media or a secondary media, typically used to affect the pH of the media already present in the dissolution vessel. The secondary media may be used for enteric-coated products that require a media pH change.


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