Pharmaceutical Water: Types, Specifications, Testing Parameters, Preparation & Regulatory Guidelines (FAQs)

Pharmaceutical water isn’t just H₂O – it’s a rigorously controlled raw material that meets exacting standards to ensure drug safety and quality

Pharmaceutical water is the most widely used raw material in the pharmaceutical industry. From pharmaceutical development to equipment cleaning and laboratory use, water plays a critical role in nearly every stage of pharmaceutical manufacturing. However, not all water is created equal – pharmaceutical applications require water of exceptionally high purity to ensure the safety, efficacy, and stability of pharmaceuticals.

Pharmaceutical water must comply with strict quality standards set by international pharmacopoeias such as the United States Pharmacopoeia (USP), European Pharmacopoeia (Ph. Eur..), and World Health Organisation (WHO). Depending on its intended use, pharmaceutical water is classified into various types, including Purified Water (PW), Water for Injection (WFI), and Sterile Water, each with its own production methods, quality parameters, and regulatory requirements.

Understanding the types, uses, production techniques, and regulatory guidelines of pharmaceutical water is essential for maintaining good manufacturing practices (GMP) and ensuring patient safety

Pharmaceutical Water

Pharmaceutical water refers to water that has been purified and processed to meet specific quality standards for use in pharmaceutical manufacturing and laboratory applications. It plays a critical role because it’s often used as an ingredient, solvent, or cleaning agent in drug production, and any impurities could affect product safety, stability, or efficacy.

Related: Pharmaceutical Analysis

Types of Pharmaceutical Water

1. Purified Water (PW)
   • Used in the manufacture of non-parenteral (non-injectable) products.
   • Obtained by distillation, ion exchange, reverse osmosis, or other suitable processes.
   • Must meet standards for conductivity, total organic carbon (TOC), and microbial content.
2. Water for Injection (WFI)
   • Used in products that will be injected into the body (parenteral use).
   • Must be free from pyrogens (fever-causing substances).
   • Produced by distillation or double-pass reverse osmosis and maintained under strict microbiological control.
3. Sterile Water for Injection (SWFI)
   • WFI that has been sterilized.
   • Used when a sterile water source is required for reconstitution or dilution.
4. Sterile Water for Inhalation
   • Similar to SWFI but has less stringent particulate standards.
   • Used in respiratory therapy.
5. Sterile Water for Irrigation
   • Used for washing wounds or surgical procedures.
   • Not suitable for injection due to potential contamination risks from larger containers.
6. Bacteriostatic Water for Injection
   • Contains a preservative to prevent microbial growth.
   • Used for multi-dose vials where repeated entry is expected.

Why It’s Important

Contaminated or improperly purified water can introduce:

• Microorganisms
• Endotoxins
• Particulates
• Organic or inorganic impurities

Preparation of pharmaceutical water

The techniques used to prepare pharmaceutical water vary depending on the type of water being produced (like Purified Water vs. Water for Injection), but the goal is always to remove impurities such as ions, organic matter, particulates, microorganisms, and pyrogens.

The following techniques are used for preparation of pharmaceutical water:

1. Distillation
2. Reverse Osmosis (RO)
3. Deionisation (Ion Exchange)
4. Ultrafiltration
5. UV Irradiation
6. Microfiltration

1. Distillation

• How it works: Water is boiled to produce steam, which is then condensed back into liquid.
• What it removes: Ions, microorganisms, pyrogens, and most organic contaminants.
• Used for: Water for Injection (WFI), Sterile Water.
• Advantages: Very effective and reliable.
• Disadvantages: Energy-intensive, expensive equipment.

2. Reverse Osmosis (RO)

• How it works: Water is forced through a semi-permeable membrane that blocks dissolved salts, bacteria, and organic molecules.
• Used for: Purified Water, sometimes as a pre-treatment for WFI.
• Advantages: Highly effective for ion and organic removal.
• Disadvantages: Sensitive to membrane fouling; needs pre-treatment.

3. De-ionisation (Ion Exchange)

• How it works: Water passes through resin beds that exchange unwanted ions (like Ca²⁺, Na⁺, Cl⁻) with H⁺ and OH⁻ ions.
• Used for: Purified Water.
• Advantages: Efficient at removing ionic impurities.
• Disadvantages: Doesn’t remove microorganisms or organic materials well; resins need frequent regeneration.

4. Ultrafiltration

• How it works: Uses membranes with very small pores to remove particles, bacteria, and pyrogens.
• Used for: Polishing step in WFI systems to remove endotoxins.
• Advantages: Effective microbial barrier.
• Disadvantages: Not suitable as a standalone purification method.

5. UV Irradiation

• How it works: UV light (usually at 254 nm) disrupts microbial DNA and degrades organics.
• Used for: Controlling microbial growth and reducing Total Organic Carbon (TOC).
• Advantages: No chemicals involved.
• Disadvantages: Not a complete purification method on its own.

6. Micro-filtration

• How it works: Filters out particles and microorganisms using membranes with pore sizes of 0.1 to 0.2 microns.
• Used in: Final purification or point-of-use filters.
• Advantages: Good for bacterial removal.
• Disadvantages: Doesn’t remove dissolved solids or organics.

Typical System Combinations:

• Purified Water: Pre-treatment → RO → De-ionisation → UV → Filtration
• Water for Injection (WFI): Pretreatment → RO (optional) → Distillation → Storage & Distribution under strict conditions

Regulatory guidelines for pharmaceutical water

Regulatory guidelines for pharmaceutical water are crucial because water is a major raw material in drug manufacturing. Different pharmacopoeias and regulatory bodies like USP (United States Pharmacopoeia), EP (European Pharmacopoeia), and WHO have laid out specific quality standards and testing requirements for each type of pharmaceutical water.

The following are the key regulatory guidelines:

1. United States Pharmacopoeia (USP)

Purified Water (PW)

• USP Monograph: <1231>, <643> (Conductivity), <645> (TOC)
• Standards:
  • Conductivity: ≤1.3 µS/cm at 25°C
  • TOC: ≤500 ppb
  • Microbial Limit: NMT 100 CFU/mL (action level)
  • Non-pyrogenic but not sterile

Water for Injection (WFI)

• Produced by: Distillation or validated membrane process (e.g., double-pass RO + UF)
• Standards:
  • Conductivity: ≤1.3 µS/cm
  • TOC: ≤500 ppb
  • Microbial Limit: ≤10 CFU/100 mL (very strict)
  • Pyrogen-free (must pass LAL/endotoxin test)

2. European Pharmacopoeia (Ph. Eur.)

Purified Water

• Similar to USP, but microbial limit is <100 CFU/mL
• Bacterial endotoxins test not required

Highly Purified Water (HPW)

• Only in Ph. Eur. (not in USP)
• Alternative to WFI for non-injectable sterile products
• Must meet WFI standards for chemical and microbiological purity

Water for Injection

• Traditionally, only by distillation
• Since 2017, also allows validated membrane systems (like RO + UF), similar to the FDA

3. WHO Guidelines

• Focus on Good Manufacturing Practices (GMP) for water systems.
• Emphasizes:
  • Validation and qualification of water systems
  • Sanitary design of piping and storage
  • Online monitoring of conductivity and TOC
  • Microbiological control and regular testing

4. Good Manufacturing Practices (GMP)

• All water systems must be:
  • Qualified (design, installation, operation, and performance)
  • Validated (demonstrate reliable performance)
  • Subject to routine monitoring and preventive maintenance

Common Key Testing Parameters

Specification for Purified Water

Specification for Water For Injection

Uses of Water of Injection (WFI)

The WFI is used for preparation of:

• Injectable (parenteral) drugs
• Irrigation and ophthalmic solutions
• Final rinse for aseptic equipment

Uses of Purified Water (PW)

Purified Water is not sterile and not pyrogen-free, so it’s not used in injectables, but it plays a huge role in non-parental pharmaceutical manufacturing and cleaning processes.

1. As a Raw Material or Solvent

• In the formulation of non-sterile pharmaceutical products like:
  • Oral solutions and suspensions
  • Tablets (as granulation fluid)
  • Topical preparations (creams, gels, lotions)
  • Syrups and elixirs
• For reconstitution of non-injectable products

2. Cleaning and Rinsing

• Cleaning of:
  • Equipment
  • Containers
  • Manufacturing areas
• Final rinse for equipment used in non-sterile production

3. Laboratory and Research Use

• Used in:
  • Preparation of reagents, buffers, and culture media
  • Analytical procedures like HPLC or spectrophotometry (if further filtered)
  • Microbiology and chemistry labs (if it meets quality standards)

4. Utility Applications in Production

• Used in humidifiers, steam generators, or environmental monitoring systems in controlled areas.
• In pharma HVAC systems where purified water is needed for air washing or conditioning.

Note: Purified water is not suitable for:

• Injectable (parenteral) products
• Ophthalmic products (unless further sterilized)

Conclusion

Pharmaceutical water is a critical raw material in the production of medicinal products, playing a vital role as a solvent, ingredient, and cleaning agent. Depending on its intended use, it must meet stringent regulatory standards for purity, microbial content, and chemical composition as defined by pharmacopeias like USP, EP, and WHO.

The two most commonly used types—Purified Water (PW) and Water for Injection (WFI)—are produced using advanced purification technologies such as reverse osmosis, distillation, ultrafiltration, and deionization. Ensuring the consistent quality of pharmaceutical water through validated systems, continuous monitoring, and adherence to Good Manufacturing Practices (GMP) is essential to maintain the safety, efficacy, and quality of pharmaceutical products.

Related: HPLC Water: How to Decide fate Of HPLC Analysis

FAQs

What is the difference between distilled water and pharmaceutical-grade purified water? Is one more pure?

Distilled water has no dissolved solids or salt whereas pharmaceutical grade purified water has no pathogens (bacteria…) and no dissolved solids such as NaCl, KCl etc

References

• Guideline on the quality of water for pharmaceutical use | EMA
• USP Monograph: <1231>, <643> (Conductivity), <645> (TOC)