Aug. 11, 2025
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ITG SUBJECT: WATER FOR PHARMACEUTICAL USE
PURPOSE
This ITG will cover the different types of water used in the manufacture of drug products.
THE 8 TYPES OF WATER ARE:
The USP designation means that the water is the subject of an official monograph in the current US PHARMACOPEIA with various specifications for each type. The latter 4 waters are "finished" products that are packaged and labeled as such and need not be of concern during an inspection outside of plants which actually produce these products.
The USP purified water and the USP WFI on the other hand are components or "ingredient materials" as they are termed by the USP, intended to be used in the production of drug products.
But what about potable water as a component? Is it required to undergo routine sampling and testing before use in production? According to the preamble to the Current Good Manufacturing Practice regulations (CGMPs), no acceptance testing is required for potable water unless it is obtained from sources that do not control water quality to Environmental Protection Agency (EPA) standards. It is important to know that potable water may not be used to prepare USP dosage form drug products or for laboratory reagents to test solutions. However, potable water may be used to manufacture drug substances (also known as bulk drugs or bulk pharmaceutical chemicals).
During your inspection, determine the source of the water used for wet granulations or for any aqueous liquid preparations as well as for the laboratory. It should be of USP purified water quality both chemically and microbiologically.
Is non-potable water a concern during drug inspections? It may be present in a plant in the boiler feed water, cooling water for the air conditioning or the fire-sprinkler systems. Look carefully for any cross-connections to the potable water supply. Non-potable water supply lines should be clearly marked as such, especially when adjacent to potable water supply connections.
WATER PRODUCTION SOURCES
The USP defines acceptable means of producing the various types of component waters. USP WFI may be made only by distillation or reverse osmosis.
Potable water is obtained primarily from municipal water systems but may also be drawn from wells, rivers, or ponds.
SOURCES OF WATER CONTAMINATION
Piping system defects may cause contamination of clean incoming water. Because of this possibility, point-of-use sampling is indicated, that is, drawing the water sample after it has passed through the piping system.
Microbial contamination of oral liquid and topical drug products continues to be a significant problem, and is usually rooted in the use of contaminated water. Because of the potential health risks involved with the use of contaminated water, particular attention should be paid to deionized (DI) water systems, especially at small, less sophisticated manufacturers.
To minimize this contamination, the USP notes that water systems for pharmaceutical manufacturing should have "corrective facilities." By this they mean access to the system for sanitization or introduction of steam, chlorinators, storage at elevated temperatures, filtration, etc. Inquire about these during your inspection.
Seasonal variations in temperature and growth of flora may also cause fluctuations in microbial content of source water. Monitoring should be frequent enough to cover these variations.
IN-PLANT WATER TREATMENT SYSTEMS
Sand bed filters with or without chlorination equipment are common in larger plants. However, these may be centrally located and the water piped to the pharmaceutical manufacturing site. The operations of these systems should be validated along with any subsequent treatment.
If storage tanks are used, determine the capacity, the rate of use, the frequency of flushing and sanitizing the internal surfaces.
While depth or membrane type filters are often used in water systems, final filtration as the sole treatment for water purification is generally not acceptable. However, filtration could be acceptable, for example, when used for reducing microbial/particulate loads in potable water used as an ingredient in chemical manufacturing where water need not be sterile.
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Chlorination of potable water is an effective treatment if minimum levels of 0.2mg/liter of free chlorine are attained. Be aware however, that any carbon or charcoal filters in the system will remove this protective chlorine and thus eliminate any inhibitory effect on microbial growth after this point.
USP WFI is usually produced in a continuously circulating system maintained at an elevated temperature. The high temperature, maintained uniformly throughout the system by constant circulation, prevents significant microbial growth. A temperature of 80^oC is commonly used and is acceptable. Somewhat lower temperatures may also be acceptable, provided the firm has adequate data to demonstrate that a lower temperature works as intended. If WFI is held at ambient temperature rather than recirculation at elevated temperature, it must be dumped or diverted to non-WFI use 24 hours after being produced.
GENERAL COMMENT
Although there are no absolute microbial standards for water (other than water intended to be sterile), the CGMP regulations require that appropriate specifications be established and monitored. The specification must take into account the intended use of the water; i.e., water used to formulate a product should contain no organisms capable of growing in the product. Action or alert limits must be based upon validation data and must be set low enough to signal significant changes from normal operating conditions.
REFERENCES
FDA Current Good Manufacturing Practice regulations, Federal Register, Vol.43, No. 190 - Sept. 29, , I. General Comments and Subpart C, para. 211.48.
Water Programs, Environmental Protection Agency, National Interim Primary Drinking Water Regulations, Dec. 16, , 40 Code of Federal Regulations, Part 141, para. 141.14 and 141.21.
United States Pharmacopeia XXI, Water for Pharmaceutical Purposes, section and Official Monographs-various types of water, .
FDA LETTER TO THE PHARMACEUTICAL INDUSTRY Re: Validation and Control of Deionized Water Systems, - Daniel L. Michels, Bureau of Drugs, Aug. .
FDA Inspection Technical Guide, Number 36, Reverse Osmosis, Oct. .
FDA Inspection Technical Guide, Number 40, Bacterial Endotoxins/Pyrogens, March .
Protection of Water Treatment Systems series, PMA Deionized Water Committee, PHARMACEUTICAL TECHNOLOGY - May, Sept. and Oct., ; Sept. , and Nov. .
Parenteral Drug Association, Design Concepts for the Validation of a Water for Injection System, Technical Report No. 4, .
Monitoring and Validation of High Purity Water Systems with the LAL test for pyrogens, T.J. Novistsky, Pharmaceutical Engineering, March-April, .
The pharmaceutical industry utilizes purified water as one of the main ingredients for processing, formulating, and manufacturing pharmaceuticals and other active ingredients. Water can be used to reconstitute products, aid in synthesis, as a cleaning agent, and for the production of finished products. The USP monographs explain the various water grades used for pharmaceutical production and acceptable methods to produce each. In general, water can be separated into two types: bulk waters and packaged waters. Bulk waters are commonly produced on the site where they will be used. Packaged waters are produced, packaged, and sterilized to prolong product shelf life and preserve their microbial qualities. Depending on the specific pharmaceutical use case, different water grades are required.
Purified Water is a grade of pharmaceutical water used as an excipient in the production of non-parenteral preparation for pharmacology including tests and analyses.
Purified pharmaceutical water system(uk,es,vi)s typically include two stages that treat the facility’s feed water, which must always meet the local regulatory requirements for potable water quality. Pretreatment is the initial stage, which modifies the water quality to reduce target contaminant groups that can damage or otherwise interfere with the performance of downstream unit treatment processes. At a minimum, these contaminant groups typically include suspended solids, hardness, and other scale forming minerals, and disinfectants such as chlorine and chloramine. Some systems include more advanced pretreatment to address other contaminants such as biological and organic foulants, and overall total dissolved solids (TDS).
The second stage is the final treatment, sometimes called preparation, which further treats the pretreated water to meet the final purified water quality requirements. Most modern systems include at least one pass of reverse osmosis to reduce all contaminant groups except gasses (e.g. inorganic, organic, and biological) followed by a polishing step, such as Electrodeionization (EDI) or other deionization processes, to further reduce conductivity below the target limit before storage. Additional post-treatment technologies can also be included depending on the requirements of each individual application, such as UV, submicron filtration, and ultrafiltration.
Since their inception in , MECO’s MASTERpak™ systems are based on a proven hot water sanitizable system design with a robust feature set and proven performance to assure reliable ambient generation of both purified water and Water for Injection that meets or exceeds the requirements of the major global pharmacopeia (USP, Ph. Eur., and JP). The hot water sanitization capabilities assure superior performance for microbial purity, and the systems are highly configurable to meet the unique needs of each individual project. The MASTERpak™ and MASTERpak™ ULTRA systems offer a wide range of configurations including 1- or 2-pass reverse osmosis, MWCO ultrafiltration, UV, and other features commonly requested in Purified Water system design.
Pharmaceutical-grade Purified Water can be achieved through various methods to reach the required levels based on pharmacopeia requirements. MECO offers the broadest base of solutions for purified water in the industry. With over 90 years experience in the business, our team can support you every step of the way from design, installation, and service. To learn more about how MECO’s Purified Water solutions, contact our MECO team.
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