Water-Intrusion Test Integration - Pharmaceutical Technology

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Water-Intrusion Test Integration
The authors describe the operational qualification of test accuracy with regard to temperature drift using a thermal-compensation algorithm on several freeze dryers.

Pharmaceutical Technology
pp. 64-70

Integrating WIT into a freeze dryer from the design phase

The integration of WIT into a freeze dryer makes the integrity test a fully integrated process step, thus eliminating the need for any additional effort for manual or semiautomatic filling of the filter housing with test water. The test can be performed before and after the freeze drying cycle.

Figure 1: Simplified piping and instrumentation diagram of the freeze dryer including set-up for water intrusion test.
The integration consists of the following steps:
  • Implementing the required hardware (e.g., water tank, piping, valves, temperature sensors, and pressure sensor) next to the filter to be tested (see Figure 1).
Programming the software of the freeze dryer with the necessary algorithms and valve sequences as required.

Figure 2: Water filling phase of filter housing for predefined volume and overflow valve to generate known gas net volume.
WIT may be integrated into existing freeze dryers, but the effort of requalification is substantial because of the significant software and hardware modifications required.The water used for the integrity test can be directly supplied from a water for injection (WFI) line or generated by condensing steam. A cooling system, including a control loop, ensures that the test water temperature is within specification, and a system to homogenize the water avoids thermal stratification. Once the water has been generated and stabilized in terms of temperature, the filter housing can be cooled down and refilled for test.

Figure 3: Stabilization phase and compaction of predefined volume after closing of overflow valve.
A headspace volume, validated by weighing, on top of the filter housing allows for the highest accuracy. This technique is important because the final compacted headspace gas volume after filling is calculated based on the ratio between the actual atmospheric pressure and the actual test pressure (see Figures 2 and 3). The value of the compacted headspace gas volume is also corrected for any temperature drift during the stabilization phase.

When the system has been stabilized for 10 min and the pressure, temperature, and intrusion rate are constant, the filling valve at the bottom of the housing is closed. The water intrusion value is then calculated from the measured pressure drop and the compacted headspace gas volume derived from the ideal gas equation as follows (see also Figure 4):

Figure 4: Expansion of compacted gas volume due to water intrusion.
where WIT is water intrusion value in ml/min, Δp is pressure drop, V comp is compacted headspace gas volume, p ref is reference pressure of 1000 mbar (regardless of atmospheric pressure), and t is test time (10 min).

Temperature influence on the test value during the measurement phase

Temperature variations of the headspace can lead to significant errors in the determination of WIT. A temperature drift of as little as 1 C can lead to an error of 24%. The following calculation is derived from the perfect gas law (pV = nRT):

where p T1 is absolute pressure before the temperature change (typical test pressure is 3500 mbar), V T1 is volume before the temperature change, T 1 is temperature in Kelvin before the temperature change, p T2 is absolute pressure after the temperature change, V T2 is equal to V T1, and T 2 is temperature in Kelvin after the temperature change.

Because V T1 = V T2 when the intrusion rate is zero, then the following equation can be used:

Thus pressure variation (Δp T ) can be calculated according to the following equation:

where Δp T is pressure variation due to temperature drift during the measurement phase. Therefore, a 1 C temperature drift inside the net volume at an absolute test pressure of 3500 mbar, generates a pressure variation of 12 mbar.

The typical pressure drop for a WIT is 50 mbar in 10 min. The influence of one degree of temperature drift inside the headspace volume is then estimated by the following equation:


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