Pharmaceutical Water: Standards and Uses

• Water is essential in the pharmaceutical industry for various purposes, including raw material, ingredient, solvent in processing, formulation, manufacturing, and drug extraction.
• Water serves as an analytical reagent and solvent for reagent preparation in quality control.
• It is also used for cleaning glassware and instruments during lab work and pharmaceutical production.
• Water used for pharmaceutical purposes must adhere to specific standards set by the United States Pharmacopeia (USP) or European Pharmacopeia (EP).
• High water purity is crucial in the pharmaceutical industry.
• Contaminated water can compromise the safety and effectiveness of the final drug product.
• Regular water quality control is crucial to ensure manufacturing standards and safety.
• Water types for pharmaceutical purposes are classified according to USP and EP standards.
• USP classifies water as Purified Water (PW) and Water for Injection (WFI).
• EP classifies water as Purified Water (PW), Highly Purified Water (HPW), and Water for Injection (WFI).
• PW, HPW, and WFI have specific uses, preparation methods, and quality attributes that must be met.
• Water for Injection (WFI), includes Sterile Water for Injection, Bacteriostatic Sterile Water for Injection, Sterile Water for Irrigation, and Sterile Water for Inhalation.
• Sterile Water for Injection is Water for Injection packaged and rendered sterile, used as a sterile diluent for parenteral products in containers of 1 L or less.
• Bacteriostatic Sterile Water for Injection is sterile Water for Injection with antimicrobial preservatives, used for diluting parenteral products, typically in multi-dose products in containers of 30 mL or less.
• Sterile Water for Irrigation is Water for Injection packaged and sterilized in containers larger than 1 L, allowing for rapid delivery.
• Sterile Water for Inhalation is Water for Injection packaged and rendered sterile, intended for use in inhalators and the preparation of inhalation solutions.

Purified Water Treatment Process

• Purified water is utilized as an excipient in non-parenteral preparations, reagent preparation, and cleaning equipment before, during, and after preparation.
• Purified water is used in oral liquid preparations like syrups, elixirs, suspensions, and emulsions.
• Purified water is used in oral solid preparations like wet granulation and tablet coating.
• Purified water is used in topical preparations like creams, gels, lotions, ointments, ear/nose drops, and nebulizer solutions.
• Purifying water for drug and pharmaceutical product production is the process of pharmaceutical water treatment.
• Water treatment is vital as it ensures the safety and quality of finished products.
• Purified water should be prepared from a potable water source of minimum quality.
• It should meet the chemical and microbiological purity specifications of relevant pharmacopoeias.
• It should also be protected from recontamination and microbial proliferation.
• Techniques for preparing PW: Ion-Exchange, Reverse Osmosis, Deionization, Ultrafiltration, and Distillation.

Ion-Exchange

• Ion-Exchange is a common water softener, also known as Cation exchange water softener.
• Softening is primarily used as a pretreatment to reduce water hardness prior to reverse osmosis (RO).
• The key part of the process is the lon exchange resin, spherical particles 0.5 – 1.2 mm in diameter, typically of dark-yellow color.
• Ca and Mg ions are entrapped, and Na ions are exchanged into the feed water as the principle mechanism.
• When water passes through the resin bed, the beads exchange Na cations for Ca and Mg ions.
• The ion exchange resin needs to be regenerated after it is saturated with calcium and magnesium.
• A brine solution regenerates the resin by drawing sodium cations, discarding Ca and Ma cations into the sewer, and rinsing the resin bed.

Reverse Osmosis

• Reverse Osmosis (RO) is a water purification filtration process that uses a semi-permeable membrane.
• It works in contrast to the Osmosis phenomenon, where water moves from lower to higher concentration.
• To obtain purified water, feed water is forced through a semipermeable membrane under pressure, flowing from the higher to the lower concentrate side.
• It is a filtration that rejects dissolved salts (ions), submicron colloids, and microorganisms.
• Process begins with pre-filters, including sediment filters that remove larger particles such as sediment, chlorine, and organic matter.
• A high-pressure pump applies pressure to the feed water, which then passes through the semipermeable membrane.
• Only smaller molecules, like water, can pass through the membrane, while dissolved solids, suspended solids, and micro-organisms are rejected.
• Clean water, the "permeate", passes to the other side of the membrane.
• The remaining water, called "concentrate" or "brine" is at the original side.

Deionization

• Deionization removes both cationic (+) and anionic (-) ions from feed water using an ionic exchange resin bed.
• Positive and negative ions are removed and replaced by H+ and OH- attached to the resin bed.
• There are two types of resins: cation-exchange and anion-exchange resins.
• Cation-exchange resin: H+ ions get exchange with the cationic ions in the feed water such as Ca2+, Na+, K+, Mg2+.
• Anionic-exchange resin: OH- ions get exchange with the anionic ions in the feed water such as Cl-, CO(3)2-, HCO(3)2-, SO(4)3-
• All unwanted ions are replaced by H+ and OH- ions, which combine to form pure water.

Ultrafiltration

• Ultrafiltration (UF) is a membrane filtration process similar to Reverse Osmosis, using hydrostatic pressure to force water through a semi-permeable membrane.
• An ultrafiltration water system forces water through a 0.02 micron membrane.
• The UF membrane removes particles, and 3750 times smaller than human hair.

Distillation

• Distillation involves converting a liquid into vapor by heating, then re-converting the vapor back into liquid through condensation (cooling).
• Feed water is boiled to produce steam, which evaporates to the condenser, where it returns to liquid form, free of impurities.
• The first 10% to 20% of aqueous distillate contains volatile substances and must be discarded.
• Also, about 10% of of water remaining in the distillation apparatus must be discarded because decomposition of remaining solid volatile substances.
• Impurities remain in the boiler and are usually removed by dissolving them in an acid solution.
• Double still is used for increased purity.
• Types of distillation: Simple, fractional, steam, and distillation under reduced pressure.

Highly Purified Water

• Highly Purified Water, a double-pass reverse osmosis purification found only in EP.
• European specialists believe methods for obtaining PW are insufficiently reliable.
• High purity water is defined as high-quality (very low in microorganisms and endotoxins) and is for use in pharmaceutical products where a high quality of water is needed, except for parenteral products.
• A double-pass RO system uses permeate from the first RO as feed water for the second RO, yielding higher quality permeate.

Storage and Distribution System

• Water obtained for pharmaceutical use must be properly stored and distributed.
• Storage and distribution systems are designed to prevent contamination and maintain water purity.
• Including closed systems, which prevent outside impurities, regular cleaning, and sanitization of the storage and distribution systems to prevent microorganisms' growth.
• Purified water storage tanks are key components of storage and distribution systems.
• The tanks prevent leaks, spills, and contamination from the environment and are made of corrosion and erosion-resistant materials.

Specification Requirements

• The United States Pharmacopoeia (USP) specifies water grades for pharmaceutical purposes based on quality parameters.
• Parameters: microbiological assay values, contaminants, conductivity, and total organic carbon (TOC).
• Purified Water, Highly Purified water, and Water for Injection have different specification requirements.
• Ensuring the quality of water used in the pharmaceutical industry is crucial for the safety and efficacy of drugs.
• Regular testing and validation are required to ensure that the water used meets the necessary quality standards.
• Methods to ensure the quality of water: total viable counts (TVC), endotoxin testing, and conductivity testing.
• Conductivity testing measures the water's electrical conductivity to determine the presence of dissolved ions.
• Salts or high levels of dissolved ions can indicate impurities.
• "Total Organic Carbon (TOC) testing in water" measures the amount of dissolved carbon compounds.
• It indicates the amount of organic contamination, which helps assess water quality.
• Total viable counts (TVC) testing determines the number of microorganisms present in the water.
• A sample of water is incubated, and the number of colonies formed is counted and then compared against acceptable limits.
• Endotoxin testing is used to detect endotoxins (toxins released by certain bacteria when they die).
• The most common endotoxin, Limulus amoebocyte lysate (LAL), measures the level.