Water is a critical component used in the manufacture of pharmaceutical products, and it must meet specific quality standards in order to demonstrate that the water intended to be used for manufacture is suitable for its intended purposes.  USP <1231> on Water for Pharmaceutical Purposes provides an overview of the different water types used in manufacturing, such as purified water, water for injection, water for hemodialysis, and pure steam, including different sterile water types.

In the manufacture of parenteral drug products, Water for Injection (WFI) is of particular importance, and it must meet its USP monograph test requirements for Bacterial Endotoxins, Total Organic Carbon, and Water Conductivity.  One might consider the test for Water Conductivity as a simple test; however, the test may be challenging if it is performed offline as water will readily absorb atmospheric carbon dioxide upon exposure until an equilibria point is reached with the formation of Hydrogen (H+) and Bicarbonate (HCO3–) ions, resulting in an increased conductivity.  When Carbon Dioxide dissolves in water, it reacts to form Carbonic Acid, which dissociates to form the Hydrogen and Bicarbonate ions.  In addition, ionic contaminants in the testing environment can also impact the conductivity measurement and may be difficult to prove if the result is OOS.  Precautions should be taken to minimize container contaminants by rinsing the container with water at the time of sampling and completely filling the container to minimize the headspace and surface exposure to the atmosphere.  If the collected sample is transferred to another laboratory container for measurement (such as a beaker), then this container should also be rinsed with the sample and precautions should be taken to minimize the introduction of air into the sample while pouring the water sample into the measuring container.

The effectiveness of the offline sampling and testing controls should be assessed.  This could be achieved by comparing the conductivity results obtained by placing a handheld conductivity meter in the water stream at the point of sampling against the conductivity results obtained when the sampling and testing controls have been employed.  An alternative approach would be as follows:

  • Obtain a previously unopened reagent bottle of HPLC grade water or distilled water.
  • Place the conductivity meter probe in the bottle and measure the conductivity.
  • Collect a sample of the water in the reagent bottle by employing the appropriate sampling controls.
  • Determine the conductivity of the collected sample by employing the appropriate testing controls.

USP <645> on Water Conductivity provides guidance on performing Water Conductivity Stage testing.  The following highlights are from the general chapter:

  • The conductivity meter should be periodically calibrated for resistance (twelve months being a typical frequency) using certified precision resistors traceable to the NIST, cell constant, and temperature sensor.
  • Verification tests are to be performed for resistance and cell constant. Typically these are performed on the day of use.  It is important to note that the cell constant requirement for water conductivity testing is ± 2% of the known value rather than ± 5% of the known value, as specified in USP <644> on Conductivity for Solutions.
  • Online conductivity measurements provide real-time data and are not subject to the absorption of atmospheric carbon dioxide and environmental ionic contaminants.
  • Stage 1 testing is a non-temperature compensated measurement.
  • If Stage 1 test criteria are not met, then testing proceeds to Stage 2, where the sample is allowed to equilibrate for atmospheric carbon dioxide (less than a 0.1 µS/cm change over five minutes).
  • If Stage 2 test criteria are not met, then the testing proceeds to Stage 3, where the pH of the test sample is taken into consideration by adding an aliquot of saturated Potassium Chloride (KCl) solution (0.3 mL per 100 mL of sample) to the test sample and determining its pH.

In addition to USP <645> and USP <1231>, the USP has a general chapter on Theory and Practice of Electrical Conductivity Measurements of Solutions (USP <1644>).  I should also not forget to mention that the USP also has FAQs on Water for Pharmaceutical and Analytical Purposes, which include several questions related to Water Conductivity testing.  The three USP General Chapters and FAQs provide a wealth of information related to water conductivity testing and are an interesting read, if you haven’t read them recently.

If you have any questions about the application of USP General Chapters <645>, <1231>, and <1644> related to water conductivity testing at your firm, Lachman can help!  Please reach out to us at LCS@LachmanConsultants.com for a free consultation.