Current good manufacturing practice (CGMP) regulations require that laboratory apparatus be calibrated at suitable intervals in accordance with an established written program of scheduled procedures (21 CFR 211.160(b)(4) and 211.68). The enhanced mechanical calibration procedure recommended can be used as an alternative to the current Apparatus Suitability procedure for USP Dissolution Apparatus 1 and 2 described in USP General Chapter711 Dissolution. The Chapter 711, Apparatus Suitability procedure requires that the dissolution apparatus assembly meet certain MC tolerances and that a performance verification test (PVT) be performed with specified USP Reference Standard (RS) tablets; however, the mechanical calibration tolerances specified in USP 711 for the dissolution apparatus assembly are not as comprehensive or as stringent as those in the enhanced MC procedures recommended in this document.
There are several different sources of variation within Apparatus 1 and 2 that can be minimized by employing an enhanced mechanical calibration MC procedure.
The use of an enhanced mechanical calibration procedure to satisfy the CGMP calibration requirement (§ 211.160(b)(4)) was endorsed by US FDA on October 25, 2005 , after it was found that a gauge repeatability and reproducibility study showing that a significant amount of the observed variability in the dissolution test data was attributable to centering differences among the six dissolution vessels vessel-to-vessel variability can be minimized by assuring that mechanical variables are controlled and by performing dissolved gas measurements to provide assurance of adequate deaeration of dissolution media before test samples are introduced
Studies also indicate that using dissolution Apparatus 1 and 2 also identified several variables that contributed to the overall variation of the observed dissolution test results.Also sole reliance upon reference standard tablets to evaluate the performance of USP Dissolution Apparatus 1 and 2 does not provide assurance that the apparatus is adequately calibrated as required by CGMP regulations in cfr 211.160(b)(4). Enhanced mechanical calibration MC is advantageous, enabling a dissolution apparatus operator to minimize the significant sources of measurement system variation identified in the recently published studies.
In 2007 USP revised its General Chapter 711 Dissolution as follows:
(1) removed the term calibrator tablets and replaced it with reference standard tablets to describe its Prednisone Tablets and Salicylic Acid Tablets and
(2) retitled the 711 “Apparatus Suitability Test, Apparatus 1 and 2” to “Performance Verification Test, Apparatus 1 and 2.” In explaining these changes to Chapter 711 USP stated that “USP’s RS tablets are not calibrator tablets – they are used in performance verification – and USP will no longer use the term calibrator to describe them.
Subsequently, USP announced its intention as of December 1, 2009, to discontinue use of its Salicylic Acid Tablets RS (reference standard) in the Performance Verification Test for Dissolution Apparatus 1 and 2 in 711 (but it will retain its Prednisone Tablets RS)
In October 2007, USP posted to its Web site a toolkit to provide laboratories with an MC procedure, aligning with mechanical tolerances in 711 for the dissolution apparatus assemblies.9 However, neither the mechanical tolerances specified in USP 711 nor the MC procedure described in the USP toolkit are as comprehensive or as stringent as those in the enhanced MC procedure recommended.
It is recommend that an appropriately enhanced procedure for MC can be applied to USP Dissolution Apparatus 1 and 2 as an alternative procedure to meet CGMP calibration requirements (CFR 211.160(b)(4)) . The calibration procedure should specify the frequency at which each calibration step is to be performed. Calibration schedules should take into account the potential for variation in each parameter known to be critical.
Appropriately enhanced mechanical calibration (MC) procedure
Mechanical Qualification of Dissolution Apparatus 1 and 2
This procedure describes the MC tolerances to set up and maintain dissolution apparatus. Alternative methods of mechanical calibration can also be used to set up and maintain dissolution equipment so that mechanical variables that could significantly affect the accuracy and precision of test results are adequately controlled.
Calibration procedures that rely solely on tests using reference standard tablets are generally not recommended, since they do not provide assurance that the apparatus is adequately calibrated, nor provide a reliable basis upon which to make precise tolerance adjustments to the dissolution apparatus. Calibration procedures that rely solely on tests using reference standard tablets are generally not recommended, since they do not provide assurance that the apparatus is adequately calibrated, nor provide a reliable basis upon which to make precise tolerance adjustments to the dissolution apparatus.
Either the Apparatus Suitability procedure in 711 or an appropriately enhanced MC method executed according to a written procedure will satisfy the CGMP requirement for calibration of laboratory apparatus and mechanical equipment for manufacturing, as set forth in CFR 211.160(b)(4) and 211.68, respectively. For an approved drug product, the use of an alternative enhanced MC procedure instead of a performance verification test (e.g., USP 711 PVT) can be reported as a minor change in the applicant’s next annual report, consistent with 21 CFR 314.70(d)(2)(vii).
In addition to performing enhanced MC or the Apparatus Suitability procedure, manufacturers also should take appropriate measures to control the following recognized sources of significant variability in dissolution testing.
1. Dissolved gases – Sometimes dissolved gases can cause bubbles to form around a dosage form undergoing testing, which can affect the results of a dissolution test. To eliminate this source of variability, the dissolution medium is degassed or deaerated. The USP degassing procedure (vacuum filtration at 41°C, then cooling to 37°C before use) can be time-consuming, so some laboratories use an alternative technique such as vacuum degassing with agitation at ambient temperature. Prednisone tablets are sometimes used as a reference standard to qualify the performance of these alternative degassing techniques. One should use a total dissolved gas pressure meter to accurately measure the amount of total dissolved gas in the medium degassing to less than 60 percent saturation of total dissolved gases at room temperature.
2. Vibration – There should be no significant vibration in the dissolution apparatus or medium. Some sources of vibration to guard against during apparatus installation and routine set up are:
* the surrounding environment (HVAC, nearby equipment or operations)
* the dissolution unit itself or one of its components
* an external water bath circulating heater
3. Vessel dimensions – Vessel symmetry and other dimensional attributes may affect dissolution performance. Vessels should conform to USP 711 criteria for dimensions and tolerances and should be examined routinely for any irregular shape or defects.
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