Evaluating Functional Equivalency as a Lyophilization Cycle Transfer Tool - Pharmaceutical Technology

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Evaluating Functional Equivalency as a Lyophilization Cycle Transfer Tool
The authors describe a comprehensive methodology for establishing functional equivalence among various lyophilizers.

Pharmaceutical Technology
Volume 33, Issue 9, pp. 54-70


Table III: Weight-loss data during sublimation from each tray containing mannitol solutions (kg).
Comparability of relevant technical characteristics of the lyophilizer units. An overview of the relevant technical characteristics of the lyophilizers (see Table I) includes only equipment parameters that are generally regarded as having the greatest influence on the course of a lyophilization cycle. The parameters that are most critical to maintain a desired lyophilization profile are the shelf temperature, the condenser temperature (higher temperatures in response to greater condensation rates of ice), the chamber pressure, the duration of various stages, and the control–monitoring systems. Table I shows that all of the critical hardware and the process control–monitor mechanisms between the lyophilization units are comparable. Similarity suggests that the independent programmable-cycle parameters (shelf temperature, chamber pressure, and duration of various steps) will be executed identically in these units. Therefore, the resultant lyophilization cycles will be equivalent as long as the process conditions do not over-burden the system's capabilities.

Table IV: Comparison of sublimation rate studies: weight loss irrespective of the locations of trays.
The temperatures of the shelf inlet–outlet, the condenser inlet–outlet, and of products are monitored by identical resistance temperature devices and are routinely calibrated. Similarly, the chamber and condenser pressures are monitored and controlled by manometer diaphragm-based gauges. These absolute gauges ensure that the pressure registered is a true pressure without any artifacts that may arise because of the composition of gases, as in the case of Pirani-type gauges. The chamber pressure is maintained within a narrow range (20 mTorr) with dry sterile nitrogen or air by modulation of a proportional solenoid valve. This control mechanism ensures very tight control of desired chamber pressure. Similarity of these lyophilizer units in this regard (i.e., monitoring and controlling of chamber pressure) is an important factor in ensuring their equivalency.

Table V: Comparison of sublimation rate studies: weight loss according to the locations of trays.
Comparison of sublimation rate studies using mannitol solution. Sublimation rate studies using mannitol solutions as a model system were conducted to confirm the similarity suggested by the general capabilities of the units. Table III shows the weight-loss data during the sublimation phase. The differences in drying rates between trays or vials at various positions in the lyophilizer unit are expected to be greatest during the early parts of the drying process and tend to diminish as the cycle proceeds to completion. This difference exists because as the drying proceeds and a considerable cake width starts accumulating at the top of the cake structure, resistance from the dried cake, peripheral drying because of glass walls on the sides, and secondary drying processes start contributing to the overall rates and these effects may not be consistent in all the vials during the intermediate stage. At the end of the cycle, following an extended period of primary and secondary drying, the residual moisture levels reduce to very low levels and a constant value is obtained in all the locations of the chamber.

Figure 2: Lyophilizer performance (full load): chamber pressure, shelf temperature, mean product temperature, and condenser temperature for FD-103, FD-104, and FD-105 (A420FT, B420FT, and C220FT units are FD-103, FD-104, and FD-105, respectively). (FIGURE IS COURTESY OF THE AUTHOR)
To detect differences in drying rates, it was necessary to terminate the lyophilization cycle after initial primary drying stage of the process (i.e., approximately first 40–50% of the sublimation stage), when the differences were expected. Based on the average loss of 1.75 kg of water per tray, the amount of total water lost during this process would be 45% of the total amount that could be removed during the entire process. This result allowed comparison of trays or vials having different amounts of moisture remaining during initial primary drying.


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