PURIFIED WATER kFOR PHARMACEUTICAL USE
Water is widely used as a raw material, ingredient, and solvent in the processing, formulation, and manufacture of pharmaceutical products, active pharmaceutical ingredients (APIs) and intermediates, compendial articles, and analytical reagents. This review discusses, primarily from a microbiological aspect, the review and evaluation of high purity water systems that are used for the manufacture of drug products and drug substances. It also includes a review of the design of the various types of systems and some of the problems that have been associated with these systems. As with other guides, it is not all-inclusive, but provides background and guidance for the review and evaluation of high purity water systems. The main objective of this review was to provide guidance to the industry on the pharmaceutical use of different grades of water in the manufacture of active pharmaceutical ingredients and medicinal products for human and veterinary use. This guidance is not intended to cover situations where, for example, medicinal products are prepared extemporaneously or where preparations are reconstituted or diluted with water prior to use by pharmacist (eg. Oral antibiotic mixtures) or in the case of veterinary products by the user (eg. Sheep dips).
Water is the one of the major commodities used by the pharmaceutical industry. It may present as an excipient, or used for reconstitution of products, during synthesis, during production of finished product, or as a cleaning agent for rinsing vessels, equipment and primary packing materials etc. There are many different grades of water used for pharmaceutical purposes. Several are described in USP monographs that specify uses, acceptable methods of preparation, and quality attributes. These waters can be divided into two general types: bulk waters, which are typically produced on site where they are used; and packaged waters, which are produced, packaged, and sterilized to preserve microbial quality throughout their packaged shelf life. There are several specialized types of packaged waters, differing in their designated applications, packaging limitations, and other quality attributes. Different grades of water quality are required depending on the different pharmaceutical uses. Control of quality of water, in particular, the microbiological quality, is a major concern and the pharmaceutical industry devotes considerable resource to the development and maintenance of water purification systems .
There are also other types of water for which there are no monographs. These are all bulk waters, with names given for descriptive purposes only. Many of these waters are used in specific analytical methods. These nonmonographed waters may not necessarily adhere strictly to the stated or implied modes of preparation or attributes. Waters produced by other means or controlled by other test attributes may equally satisfy the intended uses for these waters. It is the user’s responsibility to ensure that such waters, even if produced and controlled exactly as stated, be suitable for their intended use. Wherever the term “water” is used within this compendium without other descriptive adjectives or clauses, the intent is that water of no less purity than Purified Water be used.
a. Purified Water is used as an excipient in the production of nonparenteral preparations and in other pharmaceutical applications, such as cleaning of certain equipment and nonparenteral product-contact components. Unless otherwise specified, Purified Wateris also to be used for all tests and assays for which water is indicated. Purified Watermust meet the requirements for ionic and organic chemical purity and must be protected from microbial contamination. The minimal quality of source or feed water for the production of Purified Wateris Drinking Water. This source water may be purified using unit operations that include deionization, distillation, ion exchange, reverse osmosis, filtration, or other suitable purification procedures. Purified water systems must be validated to reliably and consistently produce and distribute water of acceptable chemical and microbiological quality. Purified water systems that function under ambient conditions are particularly susceptible to the establishment of tenacious biofilms of microorganisms, which can be the source of undesirable levels of viable microorganisms or endotoxins in the effluent water.
b. Water for Injection is used as an excipient in the production of parenteral and other preparations where product endotoxin content must be controlled, and in other pharmaceutical applications, such as cleaning of certain equipment and parenteral product-contact components. The minimum quality of source or feed water for the generation ofWater for Injectionis Drinking Water as defined by the U.S. EPA, EU, Japan, or the WHO. This source water may be pre-treated to render it suitable for subsequent distillation (or whatever other validated process is used according to the monograph). The finished water must meet all of the chemical requirements for Purified Wateras well as an additional bacterial endotoxin specification. Since endotoxins are produced by the kinds of microorganisms that are prone to inhabit water, the equipment and procedures used by the system to purify, store, and distribute Water for Injectionmust be designed to minimize or prevent microbial contamination as well as remove incoming endotoxins from the starting water. Water for Injectionsystems must be validated to reliably and consistently produce and distribute this quality of water.
c. Water for Hemodialysis is used for hemodialysis applications, primarily the dilution of hemodialysis concentrate solutions. It is produced and used on-site and is made from EPA Drinking Water which has been further purified to reduce chemical and microbiological components. It may be packaged and stored in unreactive containers that preclude bacterial entry. The term “unreactive containers” implies that the container, especially its water contact surfaces, are not changed in any way by the water, such as by leaching of container-related compounds into the water or by any chemical reaction or corrosion caused by the water. The water contains no added antimicrobials and is not intended for injection.
d. Pure Steam is also sometimes referred to as “clean steam”. It is used where the steam or its condensate would directly contact official articles or article-contact surfaces such as during their preparation, sterilization, or cleaning where no subsequent processing step is used to remove any codeposited impurity residues.
e. Sterile Purified Water is Purified Water, packaged and rendered sterile. It is used in the preparation of nonparenteral compendial dosage forms or in analytical applications requiring Purified Waterwhere access to a validated Purified Watersystem is not practical, where only a relatively small quantity is needed, where sterile Purified Wateris required, or where bulk packaged Purified Wateris not suitably microbiologically controlled.
f. Sterile Water for Injection is Water for Injection packaged and rendered sterile. It is used for extemporaneous prescription compounding and as a sterile diluent for parenteral products. It may also be used for other applications where bulk WaterforInjectionor PurifiedWateris indicated but where assess to a validated water system is either not practical or where only a relatively small quantity is needed. SterileWaterforInjectionis packaged in single-dose containers not larger than 1 L in size.
g. Bacteriostatic Water for Injection is sterile Water for Injection to which has been added one or more suitable antimicrobial preservatives. It is intended to be used as a diluent in the preparation of parenteral products, most typically for multi-dose products that require repeated content withdrawals. It may be packaged in single-dose or multiple-dose containers not larger than 30 mL.
h. Sterile Water for Irrigation is Water for Injection packaged and sterilized in single-dose containers of larger than 1 L in size that allows rapid delivery of its contents. It need not meet the requirement under small-volume injections. It may also be used in other applications which do not have particulate matter specifications, where bulk Water for Injectionor Purified Wateris indicated but where access to a validated water system is not practical, or where somewhat larger quantities than are provided as Sterile Water for Injectionare needed.
i. Sterile Water for Inhalation is Water for Injection that is packaged and rendered sterile and is intended for use in inhalators and in the preparation of inhalation solutions. It carries a less stringent specification for bacterial endotoxins than Sterile Water for Injection, and therefore, is not suitable for parenteral applications.