CLEAN-IN-PLACE EDI ENDOTOXINS EP HIGHLY PURIFIED WATER HYDROGEN PEROXIDE ION EXCHANGE MEMBRANES PERACETIC ACID PHARMACEUTICALS REVERSE OSMOSIS STEAM TOC ULTRAFILTRATION USP WFI

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Abstract

Ultrafiltration is seldom used as a compendial water systems unit operation in the United States. The current edition of the European Pharmacopeia Monographs for Highly Purified Water and Water for Injection indicates that an acceptable method of production may include ultrafiltration (UF). Ultrafiltration can be a valuable technique, particularly when employed downstream of reverse osmosis (RO) and electrodeionization (EDI), in production of United States Pharmacopeia/European Pharmacopeia (USP/EP) Water for Injection (WFI) and EP Highly Purified Water. “Case Histories” discussing the use of UF in compendial water systems, coupled with RO and/or ion exchange (IX) indicate that properly designed, operated, and maintained systems can provide ‘… a purification process that is equivalent to distillation”.

Introductory Discussion

Prior to the development and acceptance of RO, Purified Water systems, feedwater systems to multiple effect distillation units, and feedwater systems to Pure Steam generators employed IX, coupled with UF. Quite often, the UF systems were positioned downstream of polishing mixed-bed deionization systems. As compendial water system design evolved to include RO, the use of UF significantly decreased as the “tighter” RO membranes provided bacteria, bacterial endotoxin, and organic removal that was seemingly superior to UF. State-of-the-art RO systems frequently use EDI “ion polishing” and final 0.1- or 0.2-micron (µm) membrane filtration. However, the recently revised EP Water for Injection production technique states:

“Reverse Osmosis, which may be single-pass or double-pass, coupled with other appropriate techniques such as electro-deionisation, ultrafiltration, or nanofiltration, is suitable.  Notice should be given to the supervisory authority of the manufacturer before implementation.”

The production method also requires correct operation, monitoring, and maintenance of the system, validated procedures, “in-process” monitoring of the electrical conductivity, and regular monitoring of total organic carbon (TOC) and microbial contamination.

UF membranes consist of a synthetic membrane material such as polysulfone. They do not directly remove ionic material or lighter molecular weight organic material. These membranes generally employ a pore size of 0.001 to 0.05 µm (with molecular weight cut-off of 10,000 to 100,000 Daltons) to effectively remove bacteria, bacterial endotoxins, colloids, and heavy molecular weight organic material. In water purification systems using IX resin for ion removal, UF may decrease conductivity by removing ions existing in a complex with organic/colloidal material. Further, UF will provide a 4- to 5-log reduction in bacterial endotoxins in water with a conductivity < 0.1 to 1.0 microsiemens per centimeter at 25°C, since bacterial endotoxins will undergo aggregation in relatively low conductivity water, increasing molecular weight and size.

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