USP <921> - Water Determination

What it says

General Chapter <921> describes methodology, most commonly Karl Fischer titration, for determining water content in drug substances and products, relevant for moisture-sensitive materials where water content can affect stability, potency or physical characteristics.

Paraphrased for plain-language clarity. Always verify against the current published regulation text.

What it means in practice

• Water content testing is particularly critical for moisture-sensitive drug substances, where even small variations in water content can affect chemical stability, degradation rate or physical form, connecting directly to stability programme considerations under ICH Q1A(R2).
• Karl Fischer titration method validation must address potential interference from the specific sample matrix, since certain compounds can interfere with the titration reaction and produce inaccurate results if not properly accounted for during method development.
• Water content specifications, like other specifications, should be scientifically justified based on the specific compound's known sensitivity to moisture, rather than applying a generic limit without compound-specific rationale.

What inspectors look for

• Whether water content method validation adequately addresses potential interference from the specific drug substance or product matrix being tested.
• Whether water content specifications have a documented scientific rationale connected to the compound's actual moisture sensitivity and stability profile.
• Whether water content is monitored throughout the stability programme where moisture sensitivity is a known risk factor for the specific product.

Related regulations