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

Automated off-line sampling collection differs greatly from manual sampling. Typically, larger sample volumes are removed for automated sampling, which has the potential to affect results for dissolutions with multiple time points. For each time point, a cumulative sample volume is removed. The total volume removed includes the flush volume, the tubing dead volume, the filter-deaeration volume, and the sample-collection volume. The flush volume is the volume of sample used to saturate the filter to prevent loss of the API on the filter. The tubing dead volume is the amount of sample that must fill the lines between the dissolution vessels and the sample-collection vials. The filter-deaeration volume is the amount of sample that is used to prepare the filter for filtration (used in certain automated dissolution testing systems). The sample-collection volume is the amount of sample that is collected for the off-line assay. A dissolution chemist must take into consideration the entire sample volume removed at each time point and decide whether an equivalent amount of fresh media is to be replaced into each vessel after each sampling time point. The large amounts of sample volumes removed and replaced may affect dissolution results. Potentially, large amounts of undissolved drug substance are removed for each sample, which may inaccurately lower the results of subsequent samples. Alternately, large amounts of replacement media may inaccurately dissolve the dosage form, which may affect the results of subsequent samples.

Validation is required to determine the necessity of media replacement. A dissolution chemist should perform dissolutions with and without media replacement and compare the results to manual dissolutions. The technique that produces results that more closely resemble manual results should be used in the automated dissolution test.

Instrument qualification and calibration

Equipment qualification. In addition to all of the validation work that must be completed for each product tested on the automated dissolution system, an instrument "chain of compliance" must be established and well documented for all primary, secondary, and tertiary instruments used to support GMP data generated by the automated system. Instrument qualifications and calibrations must be completed for all components on the entire automated system. These components may include the dissolution apparatus, any on-line ultraviolet or high-performance liquid chromatography instrumentation, and any ancillary equipment. The supporting equipment used to calibrate each component periodically on the automated system includes balances, weights, stopwatches, timers, thermometers, eccentricity meters, and vibration meters. Each piece of supporting equipment must maintain a documented and current calibration status. Although the company ultimately is responsible for GMP compliance when using automated instrumentation, the company may choose to follow qualification acceptance criteria established by the US Pharmacopeia, the instrument vendor, or their own company standard operating procedures (SOPs).

Initially, an installation qualification (IQ) and operation qualification (OQ) must be completed successfully and documented for each component of the automated dissolution-testing system. The customer should request from the vendor the test-script documentation that will be followed to complete initial qualifications. It is advantageous to have the compliance department review the documentation to be certain it fulfills the requirements for the instrument to be used in a GMP environment. If one chooses to have the vendor complete the IQ and OQ activities, one must be certain the company provides training documentation for their service technicians indicating that they are qualified to complete the qualification activities.

Preventive maintenance. The qualification practices do not end after the instrument is initially installed, qualified, and calibrated. Periodic preventive maintenance and calibration schedules must be established according to company SOPs. A qualified vendor is the best choice to perform the preventive-
maintenance activities for the automated instrument. These activities may include a periodic performance qualification of the instrument, which evaluates the overall performance and operation of the system. The preventive maintenance may also include the replacement of general components necessary for the continued smooth operation of the system. These components may include tubing, belts, sampling lines, lamps, and so forth. It is important to understand that the level of maintenance or repair performed on the instrument may necessitate a requalification, recalibration, or a change control. As stricter requirements are placed on the GMP environment, company SOPs should be reviewed to ensure that preventive maintenance activities do not push the instrument out of compliance.


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