Improving a Pharmaceutical Water System based on a Risk Analysis Approach - Pharmaceutical Technology

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Improving a Pharmaceutical Water System based on a Risk Analysis Approach
In this study, fault tree analysis applied to a water pretreatment and purification installation exposed cause-and-effect complex interrelations in possible fault events.

Pharmaceutical Technology

At the softener's battery outlet, good water hardness levels were achieved (<5 ppm calcium carbonate). At the RO system, water product conductivity values were <1.7 μS/cm, (see Figure 5). In this case, ionic removal gained in effectiveness compared with daily operation before performing any changes.

TOC levels from pretreatment to the RO system were reduced compared with those from a previous study in which levels of approximately 2000 ppb of carbon were detected. This result indicated that replacing the carbon–SILEX mixed bed by the new free-chlorine removal system was beneficial. At the same time, organic matter removal at the RO system was effective, as shown in Figure 6, where TOC values in water product were below 300 ppb.

Free-chlorine in water was kept over 0.2 ppm, even though it is consumed as a consequence of oxidative action on organic and microbiological matter through different pretreatment stages (see Figure 7). Free-chlorine removal mainly based on sodium meta-bisulfite dosage showed an almost total effectiveness. Outlet free-chlorine values were nearly undetectable, therefore membranes' deterioration risk was reduced to a minimum.

As a result of ensuring adequate free-chlorine levels throughout pretreatment stages and reducing stagnant zones by replacing mixed beds, good bioburden and endotoxin content control was achieved, with very low values within prearranged limits (see Figure 8). This result also facilitates a more viable work of the RO system and reduces biofilm formation hazard on membranes.

As a result of WPP process qualification, the study demonstrated that changes made to the installation and its operation ensure better performance as well as a water product obtained with water for injection quality according to USP and highly purified water quality according to EP.


Applying a risk analysis approach on a WPP process disclosed installation design and operational insufficiencies. A model obtained from the fault tree analysis method became a useful qualitative tool, revealing cause-and-effect complex interrelations between various fault events likely to arise. A model obtained from the failure modes and effects analysis method consolidated information from fault tree analysis and facilitated the establishment of priorities quantitatively on actions to be taken to correct or mitigate those failure modes according to their criticality. Such actions were directed to keep good care of reverse osmosis membranes and a safer reverse osmosis purification process.

Performance qualification carried out during 15 days demonstrated that, after prescribed modifications on the installation and its operation were made, functioning was improved from a chemical and microbiological point of view throughout the process stages, thereby ensuring a water product of pharmaceutical quality. However, risk-threat levels to which the system is subjected do not make it fully reliable. Therefore, the authors recommend that the continued use of water product obtained from this process be limited to washing operations and other technological applications as required. Its direct use in parenteral formulation shall be analyzed cautiously and only in a force majeure case.


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