主题：【资料】WATER FOR PHARMACEUTICAL PURPOSES

SOURCE OR FEED WATER CONSIDERATIONS
To ensure adherence to certain minimal chemical and microbiological quality standards, water used in the production of drug substances or as source or feed water for the preparation of the various types of purified waters must meet the requirements of the National Primary Drinking Water Regulations (NPDWR) (40 CFR 141) issued by the U.S. Environmental Protection Agency (EPA) or the drinking water regulations of the European Union or Japan, or the WHO drinking water guidelines. Limits on the types and quantities of certain organic and inorganic contaminants ensure that the water will contain only small, safe quantities of potentially objectionable chemical species. Therefore, water pretreatment systems will only be challenged to remove small quantities of these potentially difficult-to-remove chemicals. Also, control of objectionable chemical contaminants at the source-water stage eliminates the need to specifically test for some of them (e.g., trihalomethanes and heavy metals) after the water has been further purified.
Microbiological requirements of drinking water ensure the absence of coliforms, which, if determined to be of fecal origin, may indicate the potential presence of other potentially pathogenic microorganisms and viruses of fecal origin. Meeting these microbiological requirements does not rule out the presence of other microorganisms, which could be considered undesirable if found in a drug substance or formulated product.
To accomplish microbial control, Municipal Water Authorities add disinfectants to drinking water. Chlorine-containing and other oxidizing substances have been used for many decades for this purpose and have generally been considered to be relatively innocuous to humans. However, these oxidants can interact with naturally occurring organic matter to produce disinfection by-products (DBPs), such as trihalomethanes (THMs, including chloroform, bromodichloromethane, and dibromochloromethane) and haloacetic acids (HAAs, including dichloroacetic acid and trichloroacetic acid). The levels of DBPs produced vary with the level and type of disinfectant used and the levels and types of organic materials found in the water, which can vary seasonally.
Because high levels of DBPs are considered a health hazard in drinking water, Drinking Water Regulations mandate their control to generally accepted nonhazardous levels. However, depending on the unit operations used for further water purification, a small fraction of the DBPs in the starting water may carry over to the finished water. Therefore, the importance of having minimal levels of DBPs in the starting water, while achieving effective disinfection, is important.
DBP levels in drinking water can be minimized by using disinfectants such as ozone, chloramines, or chlorine dioxide. Like chlorine, their oxidative properties are sufficient to damage some pretreatment unit operations and must be removed early in the pretreatment process. The complete removal of some of these disinfectants can be problematic. For example, chloramines may degrade during the disinfection process or during pretreatment removal, thereby releasing ammonia, which in turn can carry over to the finished water. Pretreatment unit operations must be designed and operated to adequately remove the disinfectant, drinking water DBPs, and objectionable disinfectant degradants. A serious problem can occur if unit operations designed to remove chlorine were, without warning, challenged with chloramine-containing drinking water from a municipality that had been mandated to cease use of chlorine disinfection to comply with ever tightening EPA Drinking Water THM specifications. The dechlorination process might incompletely remove the chloramine, which could irreparably damage downstream unit operations, but also the release of ammonia during this process might carry through pretreatment and prevent the finished water from passing compendial conductivity specifications. The purification process must be reassessed if the drinking water disinfectant is changed, emphasizing the need for a good working relationship between the pharmaceutical water manufacturer and the drinking water provider.

TYPES OF WATER
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.
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. The associated text may not specify or imply certain quality attributes or modes of preparation. 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 compendia without other descriptive adjectives or clauses, the intent is that water of no less purity than Purified Water be used.
What follows is a brief description of the various types of pharmaceutical waters and their significant uses or attributes. Figure 1 may also be helpful in understanding some of the various types of waters.

Figure 1. Water for pharmaceutical purposes.
Bulk Monographed Waters and Steam

The following waters are typically produced in large volume by a multiple-unit operation water system and distributed by a piping system for use at the same site. These particular pharmaceutical waters must meet the quality attributes as specified in the related monographs.
Purified Water— Purified Water (see USP monograph) 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 Water is also to be used for all tests and assays for which water is indicated (see General Notices and Requirements). Purified Water is also referenced throughout the USP–NF. Regardless of the font and letter case used in its spelling, water complying with the Purified Water monograph is intended. Purified Water must 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 Water is 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. These systems require frequent sanitization and microbiological monitoring to ensure water of appropriate microbiological quality at the points of use.
The Purified Water monograph also allows bulk packaging for commercial use elsewhere. When this is done, the required specifications are those of the packaged water Sterile Purified Water, except for Sterility and Labeling. There is a potential for microbial contamination and other quality changes of this bulk packaged nonsterile water to occur. Therefore, this form of Purified Water should be prepared and stored in such a fashion that limits microbial growth and/or simply used in a timely fashion before microbial proliferation renders it unsuitable for its intended use. Also depending on the material used for packaging, there could be extractable compounds leaching into the water from the packaging. Though this article may meet its required chemical attributes, such extractables may render the water an inappropriate choice for some applications. It is the user's responsibilitiy to assure fitness for use of this packaged article when used in manufacturing, clinical, or analytical applications where the pure bulk form of the water is indicated.
Water for Injection— Water for Injection (see USP monograph) 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 of Water for Injection is 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 Water as 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 Injection must be designed to minimize or prevent microbial contamination as well as remove incoming endotoxins from the starting water. Water for Injection systems must be validated to reliably and consistently produce and distribute this quality of water.
The Water for Injection monograph also allows it to be packed in bulk for commercial use. Required specifications include the test for Bacterial endotoxins, and those of the packaged water Sterile Purified Water, except for Labeling. Bulk packaged Water for Injection is required to be sterile, thus eliminating microbial contamination quality changes. However, packaging extractables may render this water an inappropriate choice for some applications. It is the user's responsibility to ensure fitness for use of this packaged article when used in manufacturing, clinical, or analytical applications where the purer bulk form of the water is indicated.

Water for Hemodialysis— Water for Hemodialysis (see USP monograph) 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. Its attributes include specifications for Water conductivity, Total organic carbon (or oxidizable substances), Microbial limits, and Bacterial endotoxins. The water conductivity and total organic carbon attributes are identical to those established for Purified Water and Water for Injection; however, instead of total organic carbon, the organic content may alternatively be measured by the test for Oxidizable substances. The Microbial limits attribute for this water is unique among the “bulk” water monographs, but is justified on the basis of this water's specific application that has microbial content requirements related to its safe use. The Bacterial endotoxins attribute is likewise established at a level related to its safe use.
Pure Steam— Pure Steam (see USP monograph) 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. These Pure Steam applications include but are not limited to porous load sterilization processes, to product or cleaning solutions heated by direct steam injection, or in humidification of processes where steam injection is used to control the humidity inside processing vessels where the official articles or their in-process forms are exposed. The primary intent of using this quality of steam is to ensure that official articles or article-contact surfaces exposed to it are not contaminated by residues within the steam.
Pure Steam is prepared from suitably pretreated source water analogously to either the pretreatment used for Purified Water or Water for Injection. The water is vaporized with suitable mist elimination, and distributed under pressure. The sources of undesirable contaminants within Pure Steam could arise from entrained source water droplets, anti-corrosion steam additives, or residues from the steam production and distribution system itself. The attributes in the Pure Steam monograph should detect most of the contaminants that could arise from these sources. If the official article exposed to potential Pure Steam residues is intended for parenteral use or other applications where the pyrogenic content must be controlled, the Pure Steam must additionally meet the specification for Bacterial Endotoxins  85 .
These purity attributes are measured on the condensate of the article, rather than the article itself. This, of course, imparts great importance to the cleanliness of the Pure Steam condensate generation and collection process because it must not adversely impact the quality of the resulting condensed fluid.
Other steam attributes not detailed in the monograph, in particular, the presence of even small quantities of noncondensable gases or the existence of a superheated or dry state, may also be important for applications such as sterilization. The large release of energy (latent heat of condensation) as water changes from the gaseous to the liquid state is the key to steam's sterilization efficacy and its efficiency, in general, as a heat transfer agent. If this phase change (condensation) is not allowed to happen because the steam is extremely hot and in a persistent super heated, dry state, then its usefulness could be seriously compromised. Noncondensable gases in steam tend to stratify or collect in certain areas of a steam sterilization chamber or its load. These surfaces would thereby be at least partially insulated from the steam condensation phenomenon, preventing them from experiencing the full energy of the sterilizing conditions. Therefore, control of these kinds of steam attributes, in addition to its chemical purity, may also be important for certain Pure Steam applications. However, because these additional attributes are use-specific, they are not mentioned in the Pure Steam monograph.
Note that less pure “plant steam” may be used for steam sterilization of nonproduct contact nonporous loads, for general cleaning of nonproduct contact equipment, as a nonproduct contact heat exchange medium, and in all compatible applications involved in bulk pharmaceutical chemical and API manufacture.

Packaged Monographed Waters
The following monographed waters are packaged forms of either Purified Water or Water for Injection that have been sterilized to preserve their microbiological properties. These waters may have specific intended uses as indicated by their names and may also have restrictions on packaging configurations related to those uses. In general, these packaged waters may be used in lieu of the bulk form of water from which they were derived. However, the user should take into consideration that the packaging and sterilization processes used for the articles may leach materials from the packaging material into the water over its shelf life, rendering it less pure than the original water placed into the package. The chemical attributes of these waters are still defined primarily by the wet chemistry methods and specifications similar to those formerly used for the bulk pharmaceutical waters prior to their replacement with water conductivity and total organic carbon (TOC). It is the user's responsibility to ensure fitness for use of this article when used in manufacturing, clinical, or analytical applications where the purer bulk form of the water is indicated.
Sterile Purified Water— Sterile Purified Water (see USP monograph) is Purified Water, packaged and rendered sterile. It is used in the preparation of nonparenteral compendial dosage forms or in analytical applications requiring Purified Water where access to a validated Purified Water system is not practical, where only a relatively small quantity is needed, where sterile Purified Water is required, or where bulk packaged Purified Water is not suitably microbiologically controlled.
Sterile Water for Injection— Sterile Water for Injection (see USP monograph) 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 Water for Injection or Purified Water is indicated but where assess to a validated water system is either not practical or where only a relatively small quantity is needed. Sterile Water for Injection is packaged in single-dose containers not larger than 1 L in size.
Bacteriostatic Water for Injection— Bacteriostatic Water for Injection (see USP monograph) 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.
Sterile Water for Irrigation— Sterile Water for Irrigation (see USP monograph) 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 in the general test chapter Particulate Matter in Injections  788 . It may also be used in other applications which do not have particulate matter specifications, where bulk Water for Injection or Purified Water is indicated but where access to a validated water system is not practical, or where somewhat larger quantities than are provided as Sterile Water for Injection are needed.
Sterile Water for Inhalation— Sterile Water for Inhalation (see USP monograph) 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.
Nonmonographed Manufacturing Waters
In addition to the bulk monographed waters described above, nonmonographed waters can also be used in pharmaceutical processing steps such as cleaning, synthetic steps, or a starting material for further purification. The following is a description of several of these nonmonographed waters as cited in various locations within this compendia.
Drinking Water— This type of water can be referred to as Potable Water (meaning drinkable or fit to drink), National Primary Drinking Water, Primary Drinking Water, or National Drinking Water. Except where a singular drinking water specification is stated (such as the NPDWR [U.S. Environmental Protection Agency's National Primary Drinking Water Regulations as cited in 40 CFR Part 141]), this water must comply with the quality attributes of either the NPDWR, or the drinking water regulations of the European Union or Japan, or the WHO Drinking Water Guidelines. It may be derived from a variety of sources including a public water utility, a private water supply (e.g., a well), or a combination of these sources. Drinking Water may be used in the early stages of cleaning pharmaceutical manufacturing equipment and product-contact components. Drinking Water is also the minimum quality of water that should be used for the preparation of official substances and other bulk pharmaceutical ingredients. Where compatible with the processes, the allowed contaminant levels in Drinking Water are generally considered safe for use for official substances and other drug substances. Where required by the processing of the materials to achieve their required final purity, higher qualities of water may be needed for these manufacturing steps, perhaps even as pure as Water for Injection or Purified Water. Such higher purity waters, however, might require only selected attributes to be of higher purity than Drinking Water (see Figure 2 below). Drinking Water is the prescribed source or feed water for the production of bulk monographed pharmaceutical waters. The use of Drinking Water specifications establishes a reasonable set of maximum allowable levels of chemical and microbiological contaminants with which a water purification system will be challenged. As seasonal variations in the quality attributes of the Drinking Water supply can occur, due consideration to its synthetic and cleaning uses must be given. The processing steps in the production of pharmaceutical waters must be designed to accommodate this variability.

谢谢分享，美国药典的定义比较科学。

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因为太多了