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Transition to enhanced mechanical qualification: the template to meet regulatory requirements

By Dan Spisak
Agilent Product Manager, Dissolution Systems

To make the transition to ASTM and FDA-approved enhanced mechanical qualification (MQ) procedures from the USP Performance Verification Test (PVT), you must do much more than simply take a few additional mechanical parameter measurements with tighter tolerances. Agilent has created the following template as a guide to ensure that you have all of the details on the requirements. It is not as simple as eliminating prednisone; to ensure dissolution apparatus integrity, each of the suggested practices must be established in the transition to enhanced MQ.

1. Verification of dissolution components
   1. Measure/verify the dimensions of the vessels, baskets, and paddles upon receipt. Component measurement and/or verification of a certificate “ensure the components are appropriate for use” [1].
   2. Ensure that your Certificate of Analysis or Conformance (COA/COC) includes measurements of each serialized component with appropriately documented measuring devices for the critical parameters outlined in USP <711>. A Declaration of Manufacturing Conformity certificate, without the individual component measurements or reference to a specific serial number, will not support the FDA or ASTM MQ guidance requirements.
2. Vital dissolution standard operating procedures (SOPs)
   1. Operational checklist – establish an ongoing evaluation procedure for component integrity, to be implemented prior to and each time the dissolution apparatus is used. Include the following details:
      1. Inspect vessels, basket shafts, and paddles [2], to ensure cleanliness and proper working condition.
      2. Verify vessel temperature and monitor environment for influences of vibration.
      3. Train dissolution analysts on procedure and MQ guidance for proper compliance.
   2. Preventive maintenance schedule – develop, implement, and document the procedure based on recommendations of the dissolution apparatus manufacturer; define the frequency based on usage.
      1. Perform at 6- or 12-month intervals or based on a number of spindle hours.
      2. Verify the entire apparatus is evaluated; inspect all parts to confirm they are in proper working condition.
      3. If parts or components show compromised integrity, replace them to avoid a future performance issue.
3. Enhanced physical parameter measurements and tolerances
   1. Verify that the following measurements adhere to the tolerance guidelines. Instructions on performing these measurements can be found in the ASTM Implementation Guidance journal [2] and Agilent’s MQ implementation white paper [3].
      1. Basket/paddle depth: 25 ± 2 mm
      2. Rotational speed: within 2% or ± 2 RPM of target, whichever is larger
      3. Shaft wobble: ≤ 1.0 mm total runout
      4. Shaft verticality: ≤ 0.5° from vertical
      5. Basket wobble: ≤ 1.0 mm total runout
      6. Vessel-to-shaft centering: ≤ 1.0 mm from center line
      7. Vessel verticality: ≤ 1.0° from vertical at each point
   2. Ensure that the positions of the measurements conform to the requirements of the enhanced MQ procedures:
      1. Shaft wobble: verify paddle and basket shaft wobble measurements in addition to basket wobble.
      2. Vessel verticality: measure in two locations on the vessel wall, 90° apart.
      3. Shaft verticality: verify that each shaft is vertical at two locations 90° apart.
      4. Vessel-to-shaft centering at two positions – one near the top but below the vessel rim and one just above the bottom portion of the vessel.
4. Control of significant sources of variability
   1. Vessel quality
      1. Acquire and install quality vessels to avoid variation in dissolution results caused by vessel imperfections.
      2. For best results, use the same supplier for dissolution vessels at all active vessel locations.
      3. Review COA/COCs for minimal variability of USP tolerances. Consider molded dissolution vessels to minimize variation, where applicable.
      4. Continually monitor and document vessel condition for scratches, cracks, and residue buildup.
   2. Vibration
      1. Place apparatus in an environment free from sources of vibration. Though the USP/FDA/ICH/FIP does not offer tolerances for vibration, it may have a significant impact on dissolution test results.
      2. Obtain baseline vibration measurements and periodically check to monitor change over time, to ensure the vibration level of the environment remains suitable.
   3. Dissolved gases
      1. To eliminate variability, define, validate, and control degassing procedures for dissolution media. This task should be performed as a part of dissolution testing SOPs with any dissolved gasses that cause test interference.
      2. To avoid reaeration, gently pour media and begin the test as soon as possible after vessel filling.

For more information on proper implementation of enhanced mechanical calibration of Dissolution Apparatus 1 and 2, see Agilent white paper 5990-9866EN, as well as mechanical qualification regulations found in the special MQ edition of Agilent’s Practical Solutions publication – from Agilent’s Dissolution Exchange.

References

1. E 2503-07 Standard Practice for Qualification of Basket and Paddle Dissolution Ap­paratus, ASTM International, April 2007.
2. Implementation Guidance for American Society for Testing and Materials (ASTM) E 2503-07 “Standard Practice for Qualification of Basket and Paddle Dissolution Appara­tus,” The Open Drug Delivery Journal, Volume 4, 2010.
3. “Proper Implementation of Enhanced Mechanical Calibration of Dissolution Apparatus 1 and 2,” Boda and Crist, Agilent white paper 5990-9866EN, May 2012.

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