HIGH PURITY WATER FOR THE PHARMACEUTICAL INDUSTRY By Mr.

Ajay Popat, Vice President Corporate Marketing, Ion Exchange (India) Ltd.

Water, the elixir of life - a term most apt to the pharmaceutical industry for which the quality of water is critical and receives high priority. Water is an essential ingredient of pharmaceutical preparations and is used primarily for manufacture of oral preparations and in injectibles and intravenous fluids, besides washing of ampoules and bottles. The process of production of pharmaceutical grade water has evolved over time, with many upgradations in quality specifications and production methods. Non-chemical processes and greater levels of automation are fast becoming the order of the day. U.S. and Europe pharmacopeia standards specify not only the quality of water to be used but also the method to produce the water. Although the Indian pharmacopeia is based on British pharmacopeia standards, several pharma companies have also started following the United States Pharmacopeia (USP) standards as the Indian pharmaceutical industry gears up to compete in a fast growing and very demanding global market. The USP classifies pharmaceutical water as Purified Water used for manufacture of oral preparations and other formulations and Water For Injection (WFI) used for injectables, parenterals, and intravenous fluids. For process requirements the current standard for USP 24 / 25 are given below .

Component
Ultrafiltration Reverse Osmosis EDI

Purified water : : : : : 5-7 < 1.25 s/cm < 500 ppb 100 cfu/ml -

STATE OF THE ART

PH Conductivity TOC Bacteria Endotoxins

Water for injection (WFI) 5-7 < 1.25 s/cm < 500 ppb 10 cfu/100 ml 0.25 Eu/ml

Pretreatment

Reverse Osmosis

Mixed bed

1970s / 1980s

Pretreatment

Cation / Anion

Mixed bed

EARLY SYSTEMS

Raw water is generally from municipal supply, rivers and/or borewells. The type of takes into account the physical and microbial nature of the water and its end use. Pretreatment methods could range from mere activated carbon filtration for municipal supply to the more elborate process of coagulation, clarification, filtration, chlorination and activated carbon treatment. Ultrafiltration (UF) is gaining increased preference over conventional pretreatment methods due to the following advantages : 4 4 4 4 4 4 Replaces multimedia filters and clarifiers Consistent water quality Smaller space requirements Improves downstream reverse osmosis (RO) performance and reduces RO equipment size Chlorine compatible; high / low pH resistant Chemical-free treatment

PURIFIED WATER
This is prepared from water of potable quality by membrane processes followed by a polishing ion exchange unit or electrodeionisation system. Membrane processes are being preferred over ion exchange because, besides reduction of ions, they aid in removal of organics and organisms. Moreover they are continous and do not require storage and handling of acids and alkalis for regeneration. Based on the inlet ionic load, requirement of single pass/ two pass RO can be decided. Sanitary fittings and joints should be considered for the RO module; the RO system can be sanitised through chemical or heat processes. Electrodeionisation (EDI) combines the well-established water purification technologies of electrodialysis, ion selective membranes and ion exchange resin deionisation. Through this revolutionary technique, dissolved salts can be removed with low energy cost and without the need for chemical regeneration. The result is high quality water of 0.08 0.05 s/cm conductivity, which can be produced continuously at substantial flow rates. Ultraviolet sterilisation of the water is done to kill all micro-organism and viruses. Sub-micron filters/UF processes are used to remove particulates, total organic carbon (TOC), endotoxins, bacteria and viruses from the purified water.

WATER FOR INJECTION (WFI)

Purified water is used for production of pyrogen-free water for injectables and intravenous fluids. To meet the additional standards of endotoxin limits, the purified water is subsequently processed by RO or distillation processes. Distillation consists of the vaporization and condensation of water. Use of distillation in pharmaceutical water purification systems is primarily for the preparation of WFI. The Japanese Pharmacoepia and more recently the US Pharmacoepia have approved UF for producing pyrogen free water and achieving endotoxin limits.

3 WATER FOR WASHING OF AMPOULES AND BOTTLES

A significant quantity of water is required for washing of glassware used in the manufacture of pharmaceuticals. The general trend is to use purified water or water treated by ultrafiltration. If water is to be stored for more than 24 hours, it must be held at a temperature of 70 C or higher. Besides the above uses, water is used to produce steam for autoclaving and other sterlisation requirements.

DISTRIBUTION OF PURIFIED WATER

The purified water from the storage tank is supplied to various user points. The storage tank should either be steam jacketed or have adequate insulation. The distribution and recirculation loop should be designed so as to refrain the growth of bacteria within the re-circulation loop and storage tank. Based on requirement, the system can either be a hot loop or a cold/ambient loop system. The water distribution system should have minimum dead zones with adequate slope in pipelines to avoid holdup and dead lags. All distribution piping should be SS 316 L with 240 grit (electropolished) surface finish.

CONTROLS AND INSTRUMENTATION

The complete water treatment plant and the distribution system can be automated, including normal service. Automation is facilitated by electronic sensors located appropriately throughout the treatment system which send relevant operational data to the systems programmable logic controller (PLC). The complete system can thus be PLC controlled and interfaced by SCADA (Supervisory Control And Data Acquistion) which continously displays on-line product water quality data with a real-time graphical display of all system operating conditions.

VALIDATION
Validation is an important activity associated with the successful operation of pharmaceutical water systems. This certification of a water system involves several levels. In part, it is an audit from a beginning point to the end point-ofuse that provides evidence and assurance that the system performs in the way it is supposed to. Validation basically allows for two things: 1) establishing and describing the water system so it cannot be changed 2) stating that 100 % of the time that the system as described will meet chemical, bacteria, and bacterial endotoxin guidelines. The chemical test can cover such quality measurements such as total organic carbon, pH, and conductivity. The documents and qualifications required for validation are Installation Qualification (IQ), Operational Qualification (OQ), Performance Qualification (PQ), Design Qualification (DQ). The design, construction, and validation (commissioning and qualification) of water and steam systems for the pharmaceutical industry represent key opportunities for manufacturers, engineering professionals, and equipment suppliers. These systems are required to meet current Good Manufacturing Practice (GMP) regulations while remaining in compliance with all other governing codes, laws, and regulations.

Disinfection Systems

Coagulant

Sand Filter

Activated Carbon Filter

Antiscalant NaHSO3 Dosing

Incoming water

UV Steriliser 185 nm

Water Softener

Ozone

Ultra Filtration

Ultra Filtration

Deionised Water Storage Tank

Rapide Demineraliser

Membrane Degassifier

Caustic addition *

To point of use

UV Sterliser Micron Cartridge Filter

RECIRCULATION

EDI Systems

Reverse Osmosis Systems (One Pass / Two Pass)

About the author: Mr Ajay Popat is Vice President - Corporate Marketing, Ion Exchange (India) Ltd. and is a director on the board of Ion Exchange Services Limited. Holding a B.Sc., L.P.R.I. (Plastics) from the Plastic & Rubber Institute, U.K. and a Masters in Marketing Management from the University of Bombay, he has more than 20 years extensive experience in marketing. With Ion Exchange India since 1994, he was earlier with Pidilite Industries Ltd. as Head of the Industrial Chemical Division and with Resins & Plastics Ltd., Division of Asian Paints. He is a member of several professional bodies such as Indian Plastics Institute, Institute of Materials, U.K., Catalyses Society of India, Metal Finishers Association of India and Indian Water Works Association. Mr Popat has travelled abroad extensively on business and has presented papers at national and international conferences and has had several papers published in reputed industry journals.

Sent to Pharma Technology June 2003