Very clean water...

Cleanrooms in the pharmaceutical and healthcare sectors are normally supplied with water that meets the standards set out in the various pharmacopoeias for Water for Injection. The Fourth Edition of the European Pharmacopoeia (Ph Eur), published in January 2002, introduced a new grade of water which may make this a thing of the past. Highly Purified Water (HPW) is intended for use in the preparation of medical products where water of high biological purity is required but where Water for Injection (WFI) is not specified. The water quality specifications for Highly Purified Water and for Water for Injection 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 (DI) which offer considerable cost savings. Following the lead of the United States Pharmacopoeia (USP) the water quality for Highly Purified Water is specified in terms of conductivity for the measurement of inorganic purity, and Total Organic Carbon (TOC) as a measure of organic purity. This means that on-line instrumentation can be used to monitor water quality in production facilities, providing immediate verification of compliance to the organic and inorganic specifications. The maximum values for Highly Purified Water are a conductivity of 1.1µS/cm (20°C) and a TOC of 500µg/l, both of which are relatively easy to achieve and measure. The biological specifications are a total viable bacteria count of 10cfu/100ml and an endotoxin content 0.25EU/ml and these are much more difficult to achieve and measure. In particular bacteria measurements are very labour intensive and results take days to process. This means that plant design is critical to ensure consistent performance if costly product spoilage is to be avoided.

Point of use The specified water quality has to be met at the point of use. Producing water of this quality is relatively easy providing good engineering and hygienic design standards are followed, but maintaining the quality for any length of time is rather more difficult. This is because in any water treatment system operating at ambient temperature there will always be a degree of regrowth of bacteria in time and consequent generation of endotoxin following sanitisation. In addition, atmospheric carbon dioxide is invariably drawn into the storage tank, and this can increase the conductivity above the specified limit. The best solution to this is to ensure that the water quality at the point of production is considerably better than that specified at point of use, and the most usual key purification processes used 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 100ppb, with the CEDI reducing the conductivity of the product water to below 0.2_S/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. So a traditional RO/CEDI system would comfortably achieve the conductivity and TOC standards, but would require very frequent sanitisation to meet the bacteria and endotoxin parts of the Highly Purified specification and, in practice, would inevitably fall outside of the specification from time to time.

Get into hot water Conventional RO/CEDI systems rely on chemicals for sanitisation and while these procedures are effective, they are labour 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. Hot water sanitisation is a more effective process than chemical methods since it is more penetrating and does not rely on contact to achieve good bacterial inactivation. ELGA Process Water had a long track record in pharmaceutical water treatment systems and set its development engineers the task of developing a standardised "packaged" system. This would not only meet the Highly Purified Water specification and be simple in design and operation but also be capable of hot water sanitisation, completely eliminating the need for sanitising chemicals. The result was Orion Plus.

The treatment process The process route finally selected for the package is shown schematically in Figure 1. The first step is softening 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 so as to protect the RO and CEDI membranes from oxidative damage. The softened water is filtered to 5 micron using conventional cartridge filters, to remove particles which could foul the RO membrane elements, before entering a stainless steel break tank. This tank serves several functions. It enables product water to be recirculated during periods of low demand as well as housing the sanitisation 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 sanitisable low pressure membrane elements in pharmaceutical standard 316L stainless steel housings and the level of pre-treatment ensures high recovery (usually around 80%) with minimum fouling problems. Hot water sanitisable reverse osmosis systems are well established, but the need for a hot water sanitisable 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 sanitisation. After a good deal of testing, the design team settled on 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. It is vital that seal integrity is not compromised at sanitisation temperature, so a plate and frame stack design was preferred over the lower cost spiral wound type, and 'thick cell' technology was adopted because of its proven superiority at removing weak anions like silicate and bicarbonate. Careful hydraulic design of the stack was essential to ensure that there were no 'dead areas' and that all areas of the module reach sanitisation temperature. The process includes a final ultrafiltration (UF) stage to remove bacteria and endotoxins. 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 more efficient process. However, experience disproves this, and a number of studies have shown that UF removes endotoxins more efficiently and consistently than RO. In fact Japanese studies found the performance of hot water sanitisable polysulphone membranes to be so reliable that, in 1988, the official monograph on Water for Injection in the 11th Edition of the Japanese Pharmacopoeia allowed the use of ultrafiltration as well as RO and distillation.

Sanitisation The Fourth Edition of the European Pharmacopoeia states that "correct operation and maintenance of the [Highly Purified Water] system is essential". The United States FDA Code Federal Requirement, 21 CFR 820, affirms that "Equipment shall be cleaned, maintained, and sanitised 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 sanitisation is automated and carried out regularly to maintain low bacteria counts. The procedure can be timed to take place overnight or at weekends to minimise downtime and disruption to production and a full validation document showing temperatures achieved and sanitisation time can be printed out for GAMP compliance.

Packaged system All the equipment, including pre-treatment, is pre-assembled on a skid to provide a self contained water purification package. Standardised engineering means that Design Qualification is a formality and the package is pre-validated at works so that the time required for Installation and Operational Qualification is also minimised, which means that Orion Plus can be installed and commissioned in a fraction of the time that is required for conventional systems.