Drawn from the proposals as published for comment. USP can revise a proposal after comment, so confirm each one against the official text. Impact ratings are this site's judgement of where inspection attention will fall.
<1231> §3Guidance chapterHigh
Ozone below the detection limit before use
Where ozone is used to sanitise, it must be reduced to below the detection limit before the water is used.
Ozone is the usual sanitant for ambient Purified Water loops and is common on cold WFI loops. "We switch on the UV lamp" is not evidence. What is wanted is a measured residual at the points of use after each sanitisation, by a method sensitive enough that "below detection" means something, recorded before the loop is released back to production.
<1231> §5.1.3Guidance chapterMedium
Additives get a risk assessment
Any substance added to the water or its system — sanitisers, pH adjusters, anti-scalants — and their by-products are assessed for use, reduction and detection.
Most sites can list what they add. Fewer can show how they know it has gone before the water is used, and at what level they would detect it if it had not. Each additive needs those two answers in writing.
<1231> §6Guidance chapterHigh
Online measurement preferred; grab samples must represent use
Online TOC and conductivity are preferred to offline testing. An offline sample must represent the water as it is actually used.
The quiet finding here is the sampling valve. If production draws water through a hose after a two-minute flush, and QC samples from a clean port after thirty seconds, the sample describes a water nobody uses. Sample the way the water is used, or show why the difference does not matter.
<1231> §7.1Guidance chapterLow
Conductivity: offline tests may start at Stage 2
For offline analysis, the Stage 1 step of the conductivity test may be omitted.
A sample carried to a laboratory absorbs carbon dioxide from the air on the way, which is exactly what Stage 1 cannot forgive. Starting at Stage 2 for offline work recognises that. Update the SOP so analysts are not repeating a stage the chapter no longer expects.
<1231> §7.1Guidance chapterLow
TOC: target limit response is not the limit
The difference between the "target limit response" and the actual TOC limit is clarified, with emphasis on official USP reference standards for system suitability.
A common laboratory confusion, and one that turns up in investigations: a result compared against the wrong figure. Check that your SOP and your analyser configuration use the same term the same way.
<1231> §7.2Guidance chapterHigh
Sterile waters: nominal container volume, and packaging in the TOC result
"Nominal container volume" is defined as the volume the container is designed to hold, whatever the actual fill. Volatile organics from packaging that contribute to TOC are addressed, with extractables identified, quantified and evaluated for toxicity during development.
The sterile water monographs set different limits for small and large containers, so which volume counts decides which limit applies. And in a plastic container, part of the TOC result may be the container, not the water. Both need to be settled in development, not discovered in a stability out-of-specification.
<1231> §7.5 — newGuidance chapterHigh
Nitrosamines in water
A new section asks for a risk-based assessment of nitrosamine formation and contamination in the water system, and a suitable control strategy.
Nitrosamine assessments have mostly stopped at the drug substance and the excipients. Water was rarely in scope. Yet the pathways are known from drinking-water chemistry — chloramine disinfection of municipal supplies is a recognised route to NDMA, anion exchange resins carry amine groups, and nitrite can arrive in feed water. In an oral liquid, water can be most of the product.
Monographs + <86>Monograph — bindingMedium
Recombinant reagents allowed for the endotoxin test
Bacterial Endotoxins Test Using Recombinant Reagents <86> is added as an alternative to <85> in the monographs for Water for Injection, Water for Hemodialysis, Pure Steam, Sterile Water for Injection, Sterile Water for Inhalation, Sterile Water for Irrigation and Bacteriostatic Water for Injection.
An option, not an obligation: <85> remains. The limits do not change. If you adopt <86>, you verify it for your water — supplier validation data plus your own suitability tests — and regulators may ask for comparative data against <85>. For a site filing in the United States, treat the switch as a change to an approved test method, with whatever notification that requires.
