Testing of Pharmaceutical Water

Chinese Pharmacopoeia (2000 edition) [1] The determination items for purified water in this edition of the pharmacopoeia include pH, chloride, sulfate, calcium salt, nitrate, nitrite, ammonia, carbon dioxide, easily oxidized substances, non-volatile matter, and heavy metals, totaling 11 items. Among them, detection methods were established for nitrate and nitrite. The limit for bacterial endotoxins in water for injection was also reduced to 0.25 EU/ml.

USP24 [2]

Previous editions of USP specified 9 physicochemical detection indicators for purified water: pH, chloride, sulfate, calcium salt, ammonia, carbon dioxide, heavy metals, easily oxidized substances, and total solids (non-volatile matter). The detection of pH was cancelled in USP24 because the pharmacopoeia committee believed that under atmospheric equilibrium conditions, if the conductivity is qualified, the pH will not be unqualified. The sensitivity of the original determination method for heavy metals was only at the mg/L level, while the limit for some metal ions in the US drinking water standard is at the μg/L level, which is much stricter than the USP regulations. Because pharmaceutical water must be produced using raw water that meets US drinking water standards, and current production processes do not introduce heavy metals into pharmaceutical water, this test has been eliminated. The most significant changes in USP 24's quality standards for pharmaceutical water are to purified water and water for injection used in on-site production. It removes all testing items and replaces them with two items: total organic carbon (TOC) and conductivity. Specifically, TOC must not exceed 0.5 mg/L, and conductivity must not exceed 1.3 μS/cm (25°C). Another difference from the Chinese Pharmacopoeia (2000 edition) is that USP 24 has microbial action limits: not exceeding 500 cfu/ml for drinking water, not exceeding 100 cfu/ml for purified water, and not exceeding 10 cfu/100ml for water for injection. According to USP 24 standards, Gram-negative bacteria must not be detected in drinking water.

Conductivity Measurement [3]: USP24 stipulates that conductivity measurement should replace the five tests for chloride, sulfate, calcium salt, ammonia, and carbon dioxide in pharmaceutical water used in on-site production. The old version of USP adopted a limited detection method for the above five items, which was inaccurate and subjective due to visual judgment. Conductivity represents the conductivity of various ions in aqueous solution and can be used to represent the total amount of various ions. It is accurate and simplifies the detection method, and can be measured online and monitored at any time. 1.2.2 TOC Measurement [4]: USP24 uses TOC measurement to replace the qualitative detection of easily oxidizable substances. In a sense, TOC detection is a macro-control item for water pollution. Various organic pollutants, microorganisms and bacterial endotoxins and other organic carbon compounds will be converted into carbon dioxide after catalysis and oxidation, which will change the conductivity of water. The conductivity data can be converted into the amount of TOC. If TOC is controlled at a low level, it means that the content of organic matter, microorganisms and bacterial endotoxins in the water is under good control. This makes it easy to understand why some advanced pharmaceutical companies consider the detection of total organic carbon as an important aspect when conducting clean validation.

Microbial Corrective Action Limit Determination [3]: USP24, in the General Chapter "Water for Pharmaceuticals," proposes controlling the microbial corrective action limit or alert level in order to detect adverse trends in a timely manner. The reason why USP24 does not specify microbial indicators in the Specific Chapter on Water for Pharmaceuticals is that in most cases, it takes at least 48 hours to obtain culture results with existing microbial technology. During this period, the sampled batch of water has already been used in the production process. If it does not meet the requirements for water for pharmaceuticals, the batch of products must be discarded, which obviously leads to waste. Therefore, the alert level and corrective action limit can be understood as the control standards for the operation of the water for pharmaceuticals system. USP 24 recommends the following methods for microbial testing in water: Drinking water: Pour plate method, minimum sample volume 1.0 ml, plate count agar, 30℃～35℃, incubation 48h～72h; Purified water: Pour plate method, minimum sample volume 1.0 ml, plate count agar, 30℃～35℃, incubation 48h～72h; Water for injection: Membrane filtration method, minimum sample volume 100 ml, plate count agar, 30℃～35℃, incubation 48h～72h.