Qualification of Purified Water Systems

1 Special Edition: Utilities Qualification153 There are various types of waterused in the pharmaceuticalindustry. Their usage in theactual formulation, in processingoperations, and as a final rinse of aproduct contact surface, enables themto truly be considered a product ingre-dient. Purified Water can be producedmany different ways and with variousdifferent designs and equipment. Theusage of pharmaceutical grade wateris very important in the production ofpharmaceutical drug products. There-fore, the validation and routine mon-itoring of these Systems are critical inmaintaining the quality of the finalproduct. This article discusses thebasic steps in validating various watersystems, and once they are validated,establishing a routine monitoring pro-gram to maintain them.

2 In additionvarious types of Water and their appli-cations, design, validation require-ments, steps for validating Purified Water Systems , rou-tine monitoring program, Preventative Maintenance(PM) and revalidation is classified into many different groups, de-pending on its source, quality, treatment, or use. It is alsonecessary to define each classification by the minimumquality requirements, especially with regards to chemi-cal and microbiological purity. The following is anexample of the different types of Water and their Usage in Pharmaceutical Production Water Requirements Potable: Environmental Part-iculate Aggregates (EPA) United States Pharmacopeia(USP) Purified USP Water -For-Injection(WFI)The following table lists the fourbasic Water types and IWell waterType IIPotable waterType IIIP urified Water used for crit-ical batch applicationsType IV Food and Drug Admini-stration (FDA) Water forfinal rinse and formulationWFI Type I WaterType I is untreated Water used forutilities (fire protection, lawn sprinklers, etc.)

3 , and maybe from a well or surface source. Type II WaterType II is drinking Water (potable) that must meet theEnvironmental Protection Agency (EPA) requirementsfor quality. Its source is from a private or city supply thathas a variable degree of hardness and added chlorine formicrobial control. Type III WaterType III is Purified Water , which is the most diffi- This article discusses thebasic steps invalidating various watersystems, andonce they arevalidated,establishing a routine monitoring program tomaintain them. Qualification of Purified Water SystemsDavid W. VincentValidation Technologies, Inc. Special Edition: Utilities Qualification154 David W. Vincentcult to control from a microbial standpoint, and usu-ally used for bulk batch application where there is noreasonable alternative and for non-parenteral prod-uct formulation.

4 It is sometimes used as the initialcleaning agent for some processes. Type IV WaterType IV Water is the most critical quality level. Itis commonly used in final formulation for parenteralapplicants and as final rinse Water for critical productcontact surfaces. This Water must satisfy the specifi-cations for WFI as defined by USP compendiaDesign Requirements for Water SystemsThe first step in designing a Water system is todefine what the Systems intended use will be. Once thesystem s use has been determined, it is important totest the incoming Water source. This data will be usedto determine what type Water treatment is needed. Thedesign, installation, and operation of Water systemsused to produce Purified and WFI include similarcomponents, controls, and procedures. Usually WFIsystems are designed to produce high quality Water ,and the most common methods employed are by dis-tillation and Reverse Osmosis (RO).

5 The design ofthese Systems can vary from system to system. Thefollowing description is of a typical system, whichonly contains pretreatment and WFI. The pretreatmentsystem is only used to create Water to service the WFIdistillation City WaterThe incoming source Water is usually from the citymunicipal Water treatment facility. The Water qualitymust meet their own Water quality standards (ERC-2),plus the EPA regulations on drinking Water following table is a summary of the major con-taminants found in some city Water Systems . ContaminantCity Feed Water ResultsTotal mg/lSolids (TDS)Total mg/lTotal Organic Carbon (TOC) Limits500 cfu/ml It is also important to monitor the incoming citywater flow rates or Water SystemTo maintain a high level of biological and chem-ical control, it is necessary to limit the load by pre-treating the Water source before it enters into thestill.

6 This is accomplished through several purifica-tion steps in the pretreatment sequence. The follow-ing components are typical components found in apretreatment system: Multimedia filter Duplex Water softener with brine tank, and brinefeed pump Hot Water sanitizable carbon filter skid with cir-culation pump Heat exchanger Activated carbon filter Multi-cartridge filters RO feed tank with break tankand vent filter; ROfeed pump Single pass RO unit Deionization bottles micron filter Ultraviolet (UV) sterilizer micron final filter Multimedia FilterA multi-media filter is used to remove or reduce tur-bidity, suspended solids, and sediment from the feedwater (incoming city Water ). The filtration also removesparticles with a nominal size of 10 microns or greater. Duplex Water SoftenerA duplex Water softener, brine tank, and feed pumpsystem produces a sodium cycle, that will removescaling and other trace minerals from the Water to im-prove RO operation and extend the life of the filtermembrane.

7 Carbon Filter SkidThe hot sanitizable carbon filter is used to removeorganic material and residual chlorine from the incom-ing softened Water . The carbon bed is installed in a loopthat consists of a recirculation pump, heat exchanger,and activated carbon filter. In order to minimize the riskof microbial contamination from the carbon bed, thecontents of the loop are heated to 176 F periodically tosanitize the carbon bed and associated components. Special Edition: Utilities Qualification155 David W. Vincent Break Tank SystemA 100 gallon RO feed break tank provides an airbreak and reserve capacity for the RO system. Thepump delivers feed Water through two filters, which are used to remove car-bon fines or other particulate matter from the waterbefore it passes through the RO unit.

8 Reverse Osmosis (RO)A single pass RO unit is used to remove 99% ofparticulate matter, silica, bacteria and endotoxins. Theoperation of the RO unit is continuous in order to min-imize bacterial load. When the still does not requirefeed Water , the RO unit will operate in a high recoverymode in order to minimize Water consumption. Deionization SystemThe Deionization (DI) recirculation loop pro-vides pressurized RO/DI Water to the still feed sys-tem. The Water in this system is flowing constantlythrough the DI recirculation pump, two deionizationbottles in series, an UV sterilizer, and a trap filter. UV Sterilizer and Final Filtration SystemA filter is used to decrease the biobur-den levels, and prevent resin particles from the DIbottles from being deposited onto the surface in theUV sterilizer.

9 A UV sterilizer and a finalfilter are used to decrease the bioburden levels in thewater before it enters into the still. Pretreatment Programmable Logic Controller (PLC)Some pretreatment Systems are controlled by aPLC. The PLC is monitored by a Supervisory ControlAnd Data Acquisition (SCADA) system. The SCADA system allows access to all visual and audible alarmsfor all equipment associated with the WFI system. The pretreatment system is designed to purifyincoming city Water from USP EPA drinking waterstandards to meet the following still feed Water spec-ification summarized in the table Water SpecificationsConductivity< 5 microsiemens/cmEndotoxins< 25 EU/mlMicrobial< 200 to Solids< 5 mg/lChlorineNon-detectedThe previous specifications are those of the stillmanufacturer, and are not regulatory still requirements can vary from system-to-system.

10 It also depends on the quality of the Purification SystemUsually, the components associated with purifica-tion Systems are similar to WFI Systems with the excep-tion of the method of Water production (distillationverse RO/DI) and the final quality output. The compo-nents that comprise the Purified Water system are skidmounted multimedia, Water softener, carbon filter, dualpre-filters, UV sterilizer, RO unit, bioburden reductionfilter, and storage tank. Below is a list of major compo-nents for a typical Purified Water system: Multimedia filter Duplex Water softener with brine tank, and brinefeed pump Hot Water sanitizable carbon filter skid with cir-culation pump Heat exchanger Activated carbon filter Multi-cartridge filters RO feed tank with break tank and vent filter; ROfeed pump Single pass RO unit Deionization bottles micron filter Ultraviolet sterilizer final filter Storage tank Tank vent filterPurification Water Storage SystemPurified Water is supplied to a storage vessel fromthe purification system.