Pharmacy Courses

Root Cause Investigation for Pharmaceutical Water Systems (PWS)

In their 21CFR guidance, the FDA emphasize the importance of corrective and preventative action (CAPA) for any deviations potentially impacting product quality.

Regulatory authorities expect manufacturers to investigate deviations take corrective action, put in place interventions to prevent recurrence of the deviation and to assess the effectiveness of those interventions. 

Without adequate root cause investigation, the success of those interventions is questionable. However, TOC or conductivity contamination events can be transient in nature. 

For example, a water system that is experiencing gradual biofilm build up may experience TOC excursions in the distribution loop just after sanitization cycles as biofilm sloughs off the inside of the pipework.

This excursion can quickly disappear by being diluted as the water passes into the large quantity of water in the storage tank, or by being oxidized and broken down by UV lamps connected to the distribution network put in place to discourage microbial build-up.

This transient nature makes root-cause investigations difficult as it is not easy to get a sample of the excursion as there is not enough time to do so.

The use of the terms Purified Water (PW) and Water For Injection (WFI) implies that these waters meet the quality expectations defined by the pharmacopoeias. There are four critical quality attributes that define PW and WFI:

  • Microbial colony forming units (CFU) – potentially harmful bacteria that might cause infection and illness in patients
  • Conductivity – inorganic contaminants that are not meant to be present and could cause illness in patients
  • Total organic carbon (TOC) – organic material that may encourage microbial growth in water systems
  • Endotoxins – pyrogenic substance found in the cell wall of gram-negative bacteria that can cause a fever if injected into patients

Currently only conductivity and TOC can be measured on-line in real time. Both the CFU and endotoxin tests are laboratory-based tests.

As PW or WFI contamination events can be transient in nature, TOC analyzers that can capture a sample of the contaminated water can provide valuable assistance in root-cause investigations.

Data on changes to the oxidation profiles from the TOC analyzer can be a useful indicator of potential changes to water organic chemistry, providing an early warning of potential deterioration in RO membranes.

At the same time, avoiding false high or low TOC results through robust analyzer design can help reduce wasted time in un-needed root-cause investigations and avoiding the ‘no fault found’ results that the regulators do not like.

Resource Person: Barbara Pirola

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