Pharmaceutical Water Systems Mason P. Waterbury Nektar Therapeutics 28 June 05

Pharmaceutical Water Systems Let’s talk about: What is High Purity Water? How do we make High Purity Water? How do we store and distribute High Purity Water? Specific challenges / solutions

Pharmaceutical Water Systems What is High Purity Water? Purified Water (PW) Sterile Purified Water (SPW) Water for Injection (WFI) Sterile Water for Injection (SWFI) Water for Irrigation Future Monographs (e.g., Water for Hemodialysis)

Pharmaceutical Water Systems What is High Purity Water? Purified Water (PW) Sterile Purified Water (SPW) Water for Injection (WFI) Sterile Water for Injection (SWFI) Water for Irrigation Future Monographs

Pharmaceutical Water Systems Purified Water USP: “. . .obtained by a suitable process” Conductivity ≤ 1.3 µS/cm @ 25º C Total Organic Carbon (TOC) ≤ 500 ppb Microbial ≤ 100 cfu/ml No endotoxin requirement EP: “. . .prepared by distillation, by ion exchange, by reverse osmosis or by any other suitable method” JP: “. . .purified by distillation, ion-exchange treatment, ultrafiltration or combination of these methods”

Pharmaceutical Water Systems Purified Water – Example System

Pharmaceutical Water Systems Water for Injection (WFI) USP: “. . .distillation or a purification process that is equivalent of superior to distillation” Conductivity ≤ 1.3 µS/cm @ 25º C Total Organic Carbon (TOC) ≤ 500 ppb Microbial ≤ 10 cfu / 100 ml Endotoxin requirement < 0.25 EU/ml EP: “. . .distillation” JP: “. . .distillation. . .or by the Reverse Osmosis Ultrafiltration of Purified Water”

Pharmaceutical Water Systems Water for Injection (WFI) Distillation Techniques Multi-Effect Still (MES) Uses Plant Steam to convert feedwater to pure steam Separators allow impurities to drop out of the pure steam Pure steam from first effect used to convert feedwater to pure steam in subsequent effects

Pharmaceutical Water Systems Water for Injection (WFI) Distillation Techniques Vapor Compression (VC) Uses plant steam to convert initial feedwater to vapor (pure steam) Pure steam is compressed, elevating temperature Compressed vapor is used to evaporate new feedwater, giving up latent heat and condensing as WFI Higher electrical demand, but lower steam demand

Pharmaceutical Water Systems High Purity Water Storage and Distribution Materials of Construction (Chemical and Heat Compatibility) Stainless Steel (316 or 316L) Teflon, EPDM, Silicone, Viton (gaskets, diaphragms) Fully Drainable (minimum slope 1/8” per foot, hygienic design of components) Minimize Dead Legs (<= 2 pipe diameters) Smooth Surfaces (Mechanical Polish vs. Electropolish) Clean joints (sanitary Tri®Clamp, automatic orbital welding) Passivate interior surfaces to form barrier between water and free iron

Pharmaceutical Water Systems Storage and Distribution – Sanitization Heat (Continuous or Periodic, >81 deg. C for >1 hour) Most popular – nothing added to system If system continuously hot, all but eliminates concerns about sanitization Can be a utility hog Ozone Gaining popularity Ozone destruction and monitoring very important Environmental concerns Chemical Must ensure that cleaning chemicals are completely removed from system Rinsing post-sanitization time and cost intensive

Pharmaceutical Water Systems Storage and Distribution – Hot vs. Cold ? Hot storage: WFI produced through distillation is often generated hot, so why not store it hot? Advantageous if there will be hot WFI distribution Cold storage: Periodic heat-up & cool-down of storage tank time- and energy-intensive Could expedite heat-up by dumping tank contents, but this is wasteful Best solution will vary depending on specific user requirements

Pharmaceutical Water Systems Hot Storage, Hot and Ambient Distribution

Pharmaceutical Water Systems Hot Storage, Hot and Ambient Distribution Cost-effective when there are many ambient use points Heat Sanitization of ambient loop by displacement of AWFI or by heating ambient loop Two loops mean increased installation labor Only one heat exchanger means all ambient users get water at same temperature, no local temperature selection

Pharmaceutical Water Systems Hot Storage, Hot Distribution with Use Point Coolers

Pharmaceutical Water Systems Hot Storage, Hot Distribution with Use Point Coolers Cost-effective when there are few ambient use points Main distribution loop is continuously hot, therefore self-sanitizing Can have locally adjustable use point temperatures Ambient point-of-use piping must be sanitized by flushing or pulsing HWFI through heat exchanger to drain Additional heat exchangers means increased capital (and maintenance) cost Some feel POU cooler piping is a dead leg, prone to microbial growth

Pharmaceutical Water Systems Hot Storage, Hot Distribution with Use Point Cooler Sub-loops

Pharmaceutical Water Systems Hot Storage, Hot Distribution with Use Point Cooler Sub-loops Cost-effective when there are few ambient use points Main distribution loop is continuously hot, therefore self-sanitizing Heat exchanger piping kept hot when not in use Can have locally adjustable use point temperatures Dead leg question replaced by “turbulent flow” question – this becomes a balancing problem Additional heat exchangers means increased capital (and maintenance) cost