The USP has revised the General Chapter <1231> on Pharmaceutical Water

In the Pharmacopoeial Forum PF 51(4), the USP has published the draft revision of chapter <1231> “Water for Pharmaceutical Purposes”.

In Section 2 (Source Water Considerations) of Chapter <1231>, a cross-reference to Subsection 3.3 (Drinking Water) is corrected. In Section 3 (Waters Used for Pharmaceutical Manufacturing and Testing Purposes), it is clarified that ozone used for sanitization must be reduced to a level below the detection limit before the pharmaceutical water is used. Insufficiently removed ozone can have a negative impact on the product and/or material of the water system. A value for the limit is not specified.

Section 5.1.3 (Additives) adds that a risk-based assessment is required to evaluate the use, reduction and detection of added substances.

According to Section 6 (Sampling), online measurement of total organic carbon (TOC) according to <643> and water conductivity according to <645> offers advantages over offline testing and is expressly recommended. If online measurement is not used, it should be ensured that the water samples are representative of the water actually used.

Section 7.1 (Chemical Tests for Bulk Waters) clarifies that the conductivity test may be started directly with step 2 for offline analysis - step 1 can be omitted in this case - a simplification in everyday laboratory work. In addition, the difference between the frequently used “target limit response” and the actual limit value for TOC is explained, as is the need to use official USP reference standards.

Section 7.2.1 (Conductivity for Sterile Waters) contains a cross-reference to section 7.2.2 (Total Organic Carbon for Sterile Waters) to explain the term “nominal container volume”. In section 7.2.2, this term is then defined as the volume that a container should hold according to the specification, regardless of the actual filling volume. Reference is also made to the problem of volatile organic components from packaging materials (of sterile, packaged water), which can increase the TOC value. USP chapters 661, 1663 and 1664 are listed in this regard.

A new section, 7.5 (Nitrosamines), will be added to address the low risk of nitrosamine contamination. It is emphasized that suitable water treatment processes can remove nitrosamines and their possible precursors. However, according to the USP, this cannot be guaranteed, so a suitable control strategy should be defined and a risk-based assessment should be carried out if appropriate.

The revised Chapter 1231 draft is available for free on the Pharmacopoeial Forum website. Registration is required but free of charge. The comment period ends on September 30, 2025.