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Pharmaceutical Water Categories - USP Guidelines

The following chapters of the United States Pharmacopeia (USP) provide guidelines and specifications for water used in the pharmaceutical industry:

  1. General Chapter <1231>: Water for Pharmaceutical Purposes: This chapter provides general information and guidelines for the different types of water used in pharmaceutical applications, including Purified Water, Water for Injection, Sterile Water for Injection, and Sterile Purified Water. It covers the quality attributes, testing requirements, and control strategies for water systems.

  2. General Chapter <645>: Water for Pharmaceutical Purposes - Microbial Attributes: This chapter specifically addresses the microbial attributes of water used in pharmaceutical applications. It provides guidelines for testing methods, acceptance criteria for microbial counts, and measures to control and monitor microbial contamination in water systems.

  3. General Chapter <85>: Bacterial Endotoxins Test: This chapter focuses on the testing and control of bacterial endotoxins (pyrogens) in pharmaceutical products and water. It describes the methods for endotoxin testing, including the Limulus Amebocyte Lysate (LAL) test, and establishes limits and criteria for endotoxin levels.

These chapters, along with other relevant chapters in the USP, provide comprehensive guidance on the quality and control of water used in the pharmaceutical industry. It is important for pharmaceutical manufacturers to refer to these chapters and follow the specified requirements to ensure compliance with regulatory standards and maintain the safety and efficacy of pharmaceutical products.

The following categories of water are defined for use in the pharmaceutical industry:

  1. Purified Water (PW): Purified Water is used for non-sterile pharmaceutical preparations, such as oral solutions, topical products, and some manufacturing processes. It should meet the specifications outlined in the USP for chemical and microbial quality.

Purified Water, as defined by the United States Pharmacopeia (USP) in Chapter <1231> Water for Pharmaceutical Purposes, should meet certain chemical quality requirements. The USP specifies the following limits for chemical impurities in Purified Water:

  • Total Organic Carbon (TOC): The USP sets a limit of not more than 500 parts per billion (ppb) for TOC in Purified Water.
  • Conductivity: The USP specifies a maximum limit of 1.3 microsiemens per centimeter (µS/cm) at 25 degrees Celsius for the conductivity of Purified Water.
  • Heavy Metals: Purified Water should be free from heavy metals such as lead, arsenic, cadmium, mercury, and other toxic metals. The specific limits for heavy metals may vary depending on the regulatory jurisdiction and the intended use of the water.
  • Oxidizable Substances: The USP requires that Purified Water should not contain oxidizable substances that may interfere with the intended use or stability of the pharmaceutical products.

The pH specification for Purified Water, as per the United States Pharmacopeia (USP) in Chapter <1231> Water for Pharmaceutical Purposes, is not explicitly defined. The USP does not provide a specific pH range or limit for Purified Water. Instead, the USP emphasizes that Purified Water should be free from substances that may cause it to be unsuitable for its intended use. The pH of Purified Water can vary depending on the water source, purification processes, and storage conditions. However, it is generally expected that Purified Water should have a neutral pH, close to 7.0. This is because a neutral pH is considered to be compatible with most pharmaceutical formulations and applications.

The specific microbial limits for Purified Water, as defined by the United States Pharmacopeia (USP) in Chapter <1231> Water for Pharmaceutical Purposes, depend on the type and intended use of the water. The USP provides the following microbial limits for Purified Water:

  • Total Viable Aerobic Count (TVC): The USP specifies that the TVC of Purified Water should not exceed 100 colony-forming units (CFU) per milliliter.
  • Total Combined Molds and Yeasts Count: The USP sets a limit of 10 CFU per milliliter for the total combined molds and yeasts count in Purified Water.
  • Absence of Specified Microorganisms: Purified Water should be free from specified objectionable microorganisms, such as Escherichia coli, Salmonella species, Pseudomonas aeruginosa, Staphylococcus aureus, and other pathogenic or indicator organisms. The absence of these specified microorganisms should be demonstrated by appropriate testing methods.
  1. Water for Injection (WFI): Water for Injection is used as a vehicle for the preparation of parenteral products, such as injectable drugs and intravenous solutions. It must meet additional quality standards compared to Purified Water, including stricter limits for microbial contaminants and endotoxins.

The United States Pharmacopeia (USP) has specific specifications for Water for Injection (WFI) in Chapter <1231> Water for Pharmaceutical Purposes. The USP defines the following specifications for WFI:

  • Conductivity: The maximum conductivity of WFI should not exceed 1.3 µS/cm at 20°C. This requirement ensures that WFI has a low level of dissolved impurities.
  • Total Organic Carbon (TOC): The maximum allowable limit for TOC in WFI is 0.5 mg/L. This ensures that WFI has a low level of organic impurities.
  • Bacterial Endotoxins: The maximum allowable limit for bacterial endotoxins in WFI is 0.25 EU/mL. This ensures that WFI is free from pyrogens that can cause adverse reactions.
  • Microbial Limits: The USP specifies that WFI should comply with the microbial limits outlined in Chapter <61> Microbial Enumeration Tests. According to this chapter, the total viable aerobic microbial count should not exceed 10 colony-forming units (CFU) per 100 mL of WFI.

It's important to note that these specifications are specific to the USP and may vary in different regulatory regions. It's advisable to consult the applicable regulatory standards and guidelines in your region for precise specifications for WFI.

  1. Sterile Water for Injection (SWFI): Sterile Water for Injection is WFI that has been sterilized and is intended for direct administration as a sterile solvent or diluent for parenteral products.

The United States Pharmacopeia (USP) provides specific requirements for Sterile Water for Injection (SWFI) in Chapter <1231> Water for Pharmaceutical Purposes. The characteristics of SWFI defined in the USP include:

  • Sterility: SWFI must be sterile, meaning it is free from viable microorganisms. It should comply with the requirements specified in Chapter <71> Sterility Tests.
  • Particulate Matter: SWFI should be essentially free from visible particulate matter. The limits for particulate matter are specified in Chapter <788> Particulate Matter in Injections for Large Volume Parenterals.
  • Bacterial Endotoxins: The USP sets a maximum limit for bacterial endotoxins in SWFI. The limit is typically expressed in endotoxin units per milliliter (EU/mL) and should comply with the requirements outlined in Chapter <85> Bacterial Endotoxins Test. SWFI is often required to meet the same endotoxin limits as other injectable products, which is typically specified as not exceeding 0.25 endotoxin units per milliliter (EU/mL).
  • Chemical Impurities: SWFI should meet the requirements for chemical impurities as specified in the USP. This includes limits for substances such as heavy metals, residual solvents, and specific impurities that may be present.
  • pH: While the USP does not provide a specific pH requirement for SWFI, it is generally expected to be within the range of 5.0 to 7.0.
  1. Sterile Purified Water (SPW): Sterile Purified Water is used for various pharmaceutical applications, including the preparation of sterile products, rinsing of equipment, and compounding of sterile formulations. It must meet the requirements for sterility and microbial limits. The USP does not have a specific monograph for "Sterile Purified Water" (SPW). However, it does have monographs for "Sterile Water for Injection" (SWFI) and "Purified Water," each with their own specific requirements.