Pharmaceutical grade water is the most commonly used ingredient in sterile pharmaceutical manufacturing and acceptable water purity is critical to producing quality final drug product. Water for Injection (WFI) is water that is purified by distillation or a purification process that is equivalent or superior to distillation in the removal of chemicals and microorganisms. Pharmaceutical manufacturers are moving from laboratory to on-line analysis for real time water release. Real-time release can greatly improve efficiencies and cost while allowing for increased quality assurance awareness. Real-time release of pharmaceutical waters increases system understanding, decreases QC testing, reduces batch risk and improves process controls.
Real-time testing results are based on the following testing (time requirements listed parenthetically):
- On-line Total Organic Carbon (TOC)
- Electrical Conductivity (less than 5 minutes total time required)
- Rapid Bacterial Endotoxin Testing (less than 25 minutes required)
- Total Aerobic Count
Relying on laboratory grab samples obtained from points of use within the water system is inefficient and less reliable than using on-line TOC analyzers located at critical locations within the water distribution loop. On-line TOC analysis at a critical point in the distribution loop such as the return point in the loop prior to return into the storage tank will provide meaningful real time data and allow for collection of continuous measurements.
Grab samples are easily contaminated through the sampling process and exposure to the environment and do not always represent the “true” quality of the water generated. This however does not infer that routine monitoring of points of use should cease altogether, but rather that routine monitoring data supports the use of on-line monitoring of the chemical attributes of the water system to support real time release.
The placement and connection of the on-line TOC instrument to the water system should be based on a risk assessment. The on-line TOC measurement location shall represent the quality of the sample as measured at the points-of-use (POU). Typical placement of the instrumentation should be at a connection point in the distribution loop after the POU, before the return to the distribution storage tank, and before any purification processes on the return line. Additional on-line TOC instruments may be placed at other locations as necessary based on risk assessment.
Real-time release is supported by the Process Analytical Technology (PAT) initiative issued by the FDA. The FDA’s Process Analytical Technology (PAT) Initiative is a system for designing, analyzing and controlling manufacturing with a goal of both understanding and controlling the manufacturing process.