Challenge for engineersChallenge for engineers
Introduction of new grade of water

The Fourth Edition of the European Pharmacopoeia (Ph Eur), introduced in January 2002, introduces a new grade of water: “Highly Purified Water”. Producing water which complies with these specifications is relatively easy, providing good engineering and hygienic design standards are followed, but maintaining this quality for
any length of time presents more of a challenge to the water purification system designer.



By comparison with Purified Water, Highly Purified Water has enhanced conductivity, microbial and endotoxin specifications. It is intended for use in the preparation of medical products where water of high biological purity is required but Water for Injection (WFI) is not specified. The water quality specifications for Highly Purified Water and for WFI are identical, the only difference being the production method. Ph Eur Water for Injection must be produced by distillation, but Highly Purified Water can be produced by Reverse Osmosis (RO) coupled with other suitable techniques such as Ultrafiltration (UF) and/or Deionisation (Dl).
Producing water which complies with these specifications is relatively easy, providing good engineering and hygienic design standards are followed, but maintaining this quality for any length of time presents more of a challenge to the water purification system designer. This is because in any water treatment system operating at ambient temperature there will always be a degree of re-growth of bacteria and in time generation of endotoxin following sanitization. There will also, almost inevitably, be an ingress of atmospheric carbon dioxide into the storage tank and this can increase the conductivity above the specified limit. The easiest way to ensure that the conductivity of the water at point of use meets specification is by producing it to a considerably higher standard at the point of production, to allow for some degradation due to carbon dioxide absorption.

The most usual key purification processes used to produce “Purified Water” are Reverse Osmosis (RO) and Continuous Electrical Deionisation (CEDI). The RO stage serves to remove most of the inorganic, organic and bacterial contamination from the water, reducing the TOC to less than about 50 ppb with the CEDI reducing the conductivity of the RO product water to below 0.2 µS/cm. This level of treatment ensures that the point of use requirements are met even if there is some carbon dioxide and TOC pick-up during storage, providing a degree of safety that allows on-line instrumentation to be used to monitor the purified water quality. A traditional RO/CEDI system therefore would comfortably achieve the Ph Eur Purified Water specification but would require very frequent sanitization to meet the Highly Purified specification, and in practice would inevitably fall outside of the specification from time to time. Conventional RO/CEDI systems rely on chemicals for sanitization and whilst these procedures are effective, they are labor intensive and require long periods of downtime to rinse the chemicals from the system. Handling and disposal of chemicals is problematical, and there is also a risk of product contamination if the chemicals are not thoroughly rinsed from the system before it is put back into service.
In order to overcome these problems it was decided to develop a standardized “packaged” system which would not only be simple in design and operation but would also be capable of hot water sanitization, completely eliminating the need for sanitizing chemicals. Hot water sanitization is a more effective process than chemical methods since it is more penetrating and does not rely on contact to inactivate bacteria and prevent biofilms from forming. The
other key advantage of hot water sanitization is that it can be easily automated and therefore carried out weekly to maintain control over bacteria. This frequency is impractical with chemically sanitized systems due to the downtime and labor required.
Pre-treatment as first step
The first step is softening the feed water to remove hardness from the feed water, which might otherwise scale the RO membranes and CEDI module. To ensure that this is as effective as possible, two softeners are used in series, each provided with an activated carbon bed to remove free chlorine from the water to protect the RO and CEDI membranes from oxidative damage. The softened water is filtered to five micron using conventional cartridge filters, to remove particles which could foul the RO membrane elements, before entering a break tank. This tank serves several functions. It enables product water to be recirculated during periods of low demand as well as housing the sanitization heater element and providing a Cleaning in Place (CIP) facility. The pre-treated water is then pumped to the RO system, which is the heart of the treatment process, removing most of the inorganic, organic and bacterial contamination. It uses proven hot water sanitizable low pressure membrane elements in pharmaceutical standard 316L stainless steel housings and the level of pre-treatment ensures high recovery (usually at least 80%) with minimum fouling problems.
Electrodeionisation
Hot water sanitizable reverse osmosis systems are well established, but the need for a hot water sanitizable CEDI unit was more difficult to meet. CEDI relies on the use of an electrical potential difference to remove ions from solution, so plastic materials are used extensively in construction because of their insulating properties. These materials frequently soften and distort at the elevated temperatures used for sanitization, so fairly sophisticated materials from the polyphenyl sulphone and polyphenylene families, which have high yield strengths and maintain their mechanical properties at temperatures up to 85 °C, were selected. The need to ensure that seal integrity is not compromised at sanitization temperature meant that a plate and frame stack design utilizing elastomer seals was preferred over the lower cost spiral wound type which really on glues to effect a seal. “Thick cell” technology was also adopted because of its proven superiority at removing weak anions like silicate and bicarbonate.
Final ultrafiltration
To ensure that the product water complies with the Ph Eur Highly Purified Water specification it was decided to include a final Ultrafiltration (UF) stage to remove bacteria and endotoxins from the purified water on a continuous basis. Both RO and UF have been used in water purification for the removal of endotoxins, and theory would suggest that RO membranes, which have pore sizes one hundred times smaller than those of UF, would be the most efficient process for this application. Experience has disproved this however, and a number of studies have shown that UF removes endotoxins more efficiently and consistently than RO by a factor of up to log 2. Ultrafiltration systems were first used to produce Pyrogen Free Water for pharmaceutical systems in Europe during the 1980s, based on results achieved during earlier work carried out in Japan. The first systems included polysulphone hollow fiber membranes, which were chosen because of the hygienic design of the modules and the thermal tolerance of the membrane, which allowed hot water sanitization. These systems proved capable of producing endotoxin free water low in bacteria counts. Later systems incorporated steam sterilizable membranes due to industry demands. A number of these systems have been installed, however, in practice it has been established that hot water sanitization has performed equally as well as steam sterilizable systems and because they are more cost effective have gained widespread industry acceptance. The increased convenience of hot water sanitization over steam sterilization (that is it can be easily automated) has lead to hot water systems being the preferred technology for some years now. The systems proved so reliable in Japan that in 1988 the official monograph on Water for Injection in the 11th Edition of the Japanese Pharmacopoeia (JP) allowed the use of Ultrafiltration as well as RO and distillation for the production of Water for Injection (WFI).
Sanitization overnight
Of Highly Purified water systems, The Fourth Edition of the European Pharmacopoeia states that “correct operation and maintenance of the system is essential”. The FDA Code Federal Requirement, 21 CFR 820, affirms that “Equipment shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirement”. Hot water sanitization is automated and carried out regularly to maintain low bacteria counts. The procedure can be timed to take place overnight or at weekends to minimize downtime and disruption to production and a full validation document showing temperatures achieved and sanitization time can be printed out for GAMP compliance.