Water Systems in Pharmaceutical Processing

Water for Biopharmaceutical processing Water : One of the most important raw materials :  used as a basic ingredient - Cell culture media, buffers, solvent in extraction and purification, solvent in preparation of liquid form and freeze-dried products - used for ancillary processes : cleaning - ~ 30,000 liters of water: - in production of 1 kg of a recombinant biopharmaceutical produced in a microbial system  Generation of water of suitable purity: - Is central to successful operation of any facility

Water for Biopharmaceutical processing 2 Utility water is insufficient because it contains: Salts, organic matter, particles, and microorganisms that pollute or even destroy products and processes. Water for the pharmaceutical industry must be of high quality and at the same time meet the regulatory requirements of the pharmacopeia governing the water treatment equipment. Softened and de-mineralized water is used in many processes to ensure uniform water quality of the end product and to facilitate the final validation.

Purified water Prepared from potable water source Meet pharmacopoeia specification for chemical and microbial purity Protected from recontamination Protected from microbial proliferation

Purified Water cont. Two levels of water quality : Purified water and WFI - Outlined in international pharmacopeias Use of purified water: Solvent in the manufacture of aqueous-based oral products - e.g., cough mixtures Primary cleaning of some process equipment/clean room floors Generation of steam in the facilities, autoclaves Cell culture media Water for injection (WFI) Highest purity Extensive use in biopharmaceutical manufacturing

Potable water Water that has been boiled, filtered, cleaned, or treated to meet the standards for drinking water meaning that it is reasonably clear of contaminants and harmful bacteria. Thereby, making the water safe for drinking and cooking.

Non-Potable water Non-potable water is raw water from ground wells springs, rivers or lakes that is not treated at all It is not safe to drink non-potable water as it could contain unknown contaminants. Non-potable water may taste normal but it can carry health risks

Generation of Purified water and WFI Generated from potable water Potential impurities in potable water: Multi-step purification steps for purified water and WFI: Monitoring of each step: continuous measurement of the resistivity of the water Example: Deionization: anion/cation exchangers Filters to remove microorganisms: 0.22 µm, 0,45 µm Reverse osmosis (RO) membrane : Semi-permeable membrane (permeable to the solvent, water, but impermeable to solute, i.e., contaminants)

Osmosis Osmosis is a special case of diffusion in which the molecules are water and the concentration gradient occurs across a semipermeable membrane. The semipermeable membrane allows the passage of water, but not ions (e.g., Na+, Ca2+, Cl-) or larger molecules (e.g., glucose, urea, bacteria). Diffusion and osmosis are thermodynamically favorable and will continue until equilibrium is reached. Osmosis can be slowed, stopped, or even reversed if sufficient pressure is applied to the membrane from the 'concentrated' side of the membrane.

Reverse Osmosis Basics Osmosis is a natural phenomenon that provides water to all animal and vegetable cells to support life Water moves from a high concentration of water (less sugar/salt dissolved in it) to a low concentration of water (more salt/sugar dissolved in it) across a semi-permeable membrane This means that water can cross a selectively permeable membrane from a dilute solution (less dissolved in it) to a concentrated solution (more dissolved in it)

Reverse Osmosis Reverse osmosis occurs when the water is moved across the membrane against the concentration gradient, from higher concentration to lower concentration. To illustrate, imagine a semipermeable membrane with fresh water on one side and a concentrated aqueous solution on the other side. If normal osmosis takes place, the fresh water will cross the membrane to dilute the concentrated solution. In reverse osmosis, pressure is exerted on the side with the concentrated solution to force the water molecules across the membrane to the fresh water side.

Reverse Osmosis

Reverse Osmosis continued. Reverse Osmosis Membrane:    The Reverse Osmosis Membrane is the heart of the system. The most commonly used is a spiral wound Two options: the CTA (cellulose tri-acetate), which is chlorine tolerant, the TFC/TFM (thin film composite/material), not chlorine tolerant. Post filter (s): After the water leaves the RO storage tank, but before going to the RO faucet, the product water goes through the post filter (s). The post filter(s) is generally carbon (either in granular or carbon block form). Any remaining tastes and odors are removed from the product water by post filtration.

RO Advantages Friendly to the environment, Do not produce or use any harmful chemicals during the process. Require a minimal amount of power. Taste of the purified water is a distinct advantage. Reverse osmosis removes dissolved minerals and other contaminants that cause water to smell unpleasant, taste poorly and take on unusual colors Removal of dissolved minerals, metals and other particles benefits plumbing systems. There is nothing in the water to corrode pipes or collect as sediment

Disadvantages Reverse osmosis treatments require an enormous amount of water. Such systems typically return as little as 5 to 15 percent of the water pushed through the system, which means it also takes a long time to properly treat the water. This amount of wastewater can burden home septic systems. Water entering the reverse osmosis system should also be free of bacteria. While reverse osmosis systems do remove nearly all microorganisms the risk of contamination through tiny leaks or deteriorating parts prevents reverse osmosis systems from being used to remove bacteria

Reverse osmosis applications Sea Water Desalination Pharmaceutical Water Purification Bottled Water Production Waste Water Recycling Car washes ‘Spot Free’ rinse Medical Device Manufacturing Rural Water purification Brackish Well Water Desalination Laboratory Water Purification Food Products and Cosmetic Products Industrial Water Purification

Demineralisation All natural waters contain, in various concentrations, dissolved salts which dissociate in water to form charged ions. Positively charged ions are called cations; Negatively charged ions are called anions. Ionic impurities can seriously affect the reliability and operating efficiency of a boiler or process system. Overheating caused by the build-up of scale or deposits formed by these impurities can lead to: catastrophic tube failures, costly production losses, and unscheduled downtime. Hardness ions, such as calcium and magnesium, must be removed from the water supply before it can be used as boiler feed water. For high-pressure boiler feed water systems and many process systems, nearly complete removal of all ions, including carbon dioxide and silica, is required. Ion exchange systems are used for efficient removal of dissolved ions from water.

Water system requirements Monitoring of water sources Chemical and microbiological Endotoxin level (where relevant) Monitoring of system performance, storage and distribution systems Records of results, and action taken Validated sanitization procedure followed on a routine basis

Highly Purified Water (HPW) Prepared from potable water source Prepared by combination of methods Reverse osmosis (RO), Ultrafiltration (UF) Deionization (DI)

Water For Pharmaceutical Use (WPU) Suitable materials include: Stainless steel (Low carbon Grade) Polypropylene (PP) Polyvinylidenedifluoride (PVDF) Perfluoroalkoxy (PFA)

Bio-contamination control techniques Periodic sanitization with hot water Periodic sanitization with super-heated hot water or clean steam Reliable Monitoring temperature during cycle Routine chemical sanitization Removal of sanitizing agent before use of water important

Pipes and Pumps hygienic couplings welded pipes hygienic pumps hygienic sampling points acceptable floor no leaks

WPU Documentation to review: Qualification protocols and reports Water: Documentation to review: Qualification protocols and reports Change control request (where applicable) Requalification (where applicable) QC and microbiology laboratory: SOP for sampling Procedures and records

WPU cont. Sampling There must be a sampling procedure Sample integrity must be assured Sampler training Sample point Sample size

WPU: Water Testing Review method verification Chemical testing Microbiological testing Test method Types of media used Incubation time and temperature Objectionable organisms Must set specifications