Water - pure and simple

Water quality is fundamental to drug production. There are a number of processes that ensure water quality meets the standards set out by the pharmacopoeias.

A third water quality for the pharmaceutical industry besides Aqua Purificata (AP; analogous to purified water), and water for injection (WFI) has been recognised by the European Pharmacopoeia. Highly purified water (HPW) has the same physical and chemical characteristics as WFI, but is not produced by distillation. It may be used for certain production and purification processes, such as the final rinsing of vials and vessels, and for sterile preparations for eyes and nose - applications for which WFI had been used up to now. The change to HPW should allow companies to reduce their costs, as WFI, which is produced by distillation, often incurs a commensurate cost factor.

Specialist water plant company Christ has launched the Osmotron inject, which combines a double-stage reverse osmosis with its Septrosan module, an electrodeionisation (EDI) unit. It supplies HPW with a conductivity of <0.1mmho/m and a Total Organic Carbon (TOC) content of <50ppb at a rate of 500-5000l/h. The

relevant microbiological values are <5CFU/100ml and <0.06 EU/ml for endotoxins and, thus, considerably, beneath the profile required by USP24 and EP4. The plant is made of 316L stainless steel and is hot water sanitisable at 80-85°C.

Environmental Water Systems (UK) is a leader in the design and installation of cost effective water purification systems using Reverse Osmosis (RO).

RO is a membrane technique whereby water is forced under pressure through a semi-permeable membrane; the permeate is allowed to pass through the membrane while the dissolved salts in the concentrate are rejected. This process removes up to 99% of the dissolved salts. In addition, bacteria and pyrogens are also rejected. Single pass RO systems will produce water with a typical water quality of 10µS/cm, and twin pass systems will reduce this to below 1µS/cm.

EWS (UK) offers a range of plant to pharmaceutical standards with flow rates from 50l to 23m³/hr. Its RO-2200 series will provide flows from 2300- 5000l/hr. The system is compact with a small footprint, and includes a PLC control panel with a digital conductivity meter and high performance membranes. Complete systems can include EDI, UV and mixed bed exchange cylinders as options.

Waterwise Technology, based in Thame, UK, is an expert in ozonation processes for water systems. Ozone is used in water treatment primarily because of its oxidative strength, making it effective in the elimination of colour, taste and odour; the destruction of bac-teria and inactivation of viruses, and the breakdown of organic contaminants. Table 1 shows some of the benefits. Dissolved in water, ozone provides a safe and powerful disinfectant, making it suitable for CIP disinfection of process water loops and systems, biological control in cooling towers and the treatment and disinfection of water for recycling.

Ozonated water provides a powerful non-toxic disinfectant solution for wash-down and surface disinfection in a wide range of applications, including pharmaceutical process water disinfection.

Waterwise's OCS Ozonation systems are complete, skid-mounted, ready-to-install units, incorporating ozone production, injection, contact vessel and degas system. The units are fully PLC controlled with ozone monitoring to maintain close control of the ozone level in treated water and provide fully automatic operation with the minimum of operator attention.

The OCS units are designed to

operate on pressurised water lines at pressures up to 4bar. PLC control of the ozone generator allows a rapid response to changes in ozone demand, thus ensuring that the ozone level in treated water is maintained within close tolerance to the required ozone dose. Even with wide fluctuations in water flow, the company claims that close control is maintained, even under stop/start intermittent flow conditions.

As part of its ongoing developments in pure water technology, Vivendi Water Systems (VWS) has introduced two new systems. Orion is the next generation, hot water sanitisable water purification range, designed specifically for the pharma industry. The Orion is available in seven sizes from 500-5000l/h. Utilising the engineering guidelines set out by the ISPE recently, and meeting the GAMP4 guidelines, the objectives VWS set out for the Orion were:

•to meet the current USP and Ph Eur water quality standards

•to be hot water sanitisable

•to comply with the ISPE Baseline Guide engineering standards

•to be fully pre-validated

•to reduce site disruption and installation times

'ISPE says that uncertainty over the requirements for regulatory compliance has resulted in a trend towards technically advanced plants, and that this has led to increased costs and longer lead times', commented Gary Walters, market director, pharmaceuticals, VWS. 'By using the Baseline Guides as a design tool, VWS aims to halt that trend and to provide a cost-effective plant, which minimises time consuming validation requirements.'

maximum water quality

The treatment process incorporates water softeners, RO and continuous electro-deionisation (CEDI), using VWS' latest CDI-LX thick cell layered bed technology. The complete system, including the RO and EDI membrane units, is hot water sanitisable at 85°C under automatic control.

The skid-mounted, self-contained water treatment plants consist of serial softeners and microfiltration supplying a stainless steel break tank, which doubles as a sanitation and CIP vessel, feeding a treatment process of RO and EDI. The former removes at least 97% of dissolved salts, without the use of regenerant chemicals and provides filtration equivalent to a 200 mW cut off, which removes >99% of large organic molecules.

The EDI gives enhanced deionisation at lower electrical consumption rates, typically producing treated water of conductivity <0.7mS/cm and TOC <50mg/l. Bacteria counts are typically <10cfu/ml, but an option is available to meet <10cfu/100ml and endotoxins <0.2eu/ml in accordance with the latest Ph Eur highly purified water standard.

The second system, launched under its laboratory brand Elga LabWater, has incorporated a host of technologically advanced innovative features in its new Purelab Ultra, which is used for pure water quality in critical research applications.

The Purelab Ultra is available in five application-specific models:

•Purelab Ultra Genetic and Bioscience models provide high purity endotoxin-free water for life science applications

•Purelab Ultra Analytic and Ionic models give low levels of inorganic and organic contaminants to meet the needs of ultra trace applications

•Purelab Ultra Scientific produces type 1 reagent grade water for general laboratory grade applications

All Purelab Ultra systems feature precision dispensing technology with rates of 2l/min to a drop-by-drop flow, all at the touch of a button.

Achieving maximum water purity consistently throughout product or research project lifetimes is important in ensuring quality research. However, with changes in laboratory personnel, SOPs and the laboratory environment, water quality can be compromised.

To address these concerns, the Purelab Ultra includes up to 10 integrated and complementary features, which guarantee maximum process security and ensure that the quality is repeatable daily. Multi-stage process monitoring and real time TOC monitoring are combined with new features, including security data tagging and PIN coded user operation.

New process security features combine with cartridge traceability, real time printable records, a communication port and a new validation support manual to meet the specific needs of users operating within GLP and cGMP requirements.

Within pharmaceutical manufacturing, it is essential that the water used is fit for purpose and free of any contaminants. The only way to establish its suitability is to monitor the water at the intake stage and treat it accordingly. Any deviation from the specified tolerances must be corrected at once.

This demands constant watching and on-line analysis provides the benefit of real-time results, so the monitor becomes in effect a control system.

Colorimetric analysis is the usual method for determining specific analytes in process water, however, B+L Analytics is now suggesting that a single instrument combining UV and Vis Spectroscopy could be considered as an alternative approach.

The UV Spectroscopy technique involves scanning the sample using a diode array spectrometer. The spectra are stored for a range of samples, with manual reference analysis also being performed on the same samples.

This reference data is entered into a chemometrics software package that correlates the spectral response to the reference analysis by the use of multiple linear regression, partial least squares or principle component analysis to derive a calibration for the determinands to which the reference analysis refers.

This technique is widely used in near and mid infrared spectroscopy, but is in its infancy in UV spectroscopy.

Many substances respond to excitation in the UV spectrum, their excitation producing very wide spectra with varying maxima. Compounds such as nitrate respond at two wavelengths, i.e. 210 and 225nm in clean water. A study of a wastewater sample, containing nitrate will probably show that other responding organic compounds will swamp the nitrate response at these wavelengths.

Colorimetric analysis using Vis Spectroscopy is the traditional method for analysing process water, including, boiler feed water, steam condensate, cooling water, and saturated steam.

All analysis methods are specific and have been designed to tolerate any chemical interference present. They all use high quality reagents and high quality de-ionised water, especially for silica at very low levels, i.e. 0-5ppb. The detection limit of all these methods is also critical, so the whole chemistry is carefully optimised.

The reagents for these methods are generally viable for periods of up to three months, so most of the systems will be designed to store only the required amount for this period, e.g. 5l of each reagent. The systems must also include a calibration process, which is usually performed automatically on a programmable basis every 24 hours.

good continuum

The instrument is the DiaMon Resources process system. This instrument combines proven wet chemistry procedures and diode array spectroscopy to provide real-time results.

The basis of the DiaMon system is the diode array spectrometer, with a wavelength range of 200-700nm in 2nm waveband steps. This gives the system the UV (200-380nm) and visible (380-700nm) capability at a single flow cell. The light source is a flashing xenon lamp. This yields a good continuum over the whole of the UV region, the spectra from each 'flash' being collected and then averaged out to reduce the signal noise levels.

In operation, the sample and reagents are delivered to the spectrometer flow cell using peristaltic pumps, a single large pump hose for the sample and a multi-tube pump for the reagents. The reagents are mixed with the sample in the tubing connected to the heater unit and then passed on to the flow cell. The flow cell is a simple quartz glass cell with entry at the base and exit at the top.

The whole procedure is controlled by a computer and uses a series of solenoid valves to allow the flow cell to be rinsed with sample and flushed through several times before each analysis. The untreated sample is fed though the flow cell and the UV scan taken. This is used as the background colour for the visible analysis as well as the UV. The UV scan is calibrated by taking a reference UV scan of the de-ionised water at 4-hourly intervals.

This is removed from the sample scan, which has the effect of reducing the signal noise and improving the detection limit.

rapid measurement

B+L Analytics has subjected the DiaMon instrument to a wide variety of trials, the objective being to evaluate how and where the technology could be used and where it has advantages over other technologies. Much of the work has been performed in the area of detecting the organic contamination of 'clean water' and in the rapid and simple determination of BOD5 and COD in final effluent.

Quantachrome UK has introduced the Hydrosorb 1000 water vapour sorption analyser. Until now, water sorption measurements have traditionally been slow, laborious, costly and limited to small quantities of material. The company claims that the Hydrosorb 1000 overcomes these limitations by offering a fully automated, rapid measurement of adsorption and desorption water isotherms. These include surface area calculations and heats of adsorption.

The sample temperature is thermostatted in the range 12-47°C and accurate water vapour dosing is made possible by using a unique heated (100°C) manifold design. The fully integrated control system provides colour real-time status, graphical data review and reporting functions via built-in colour monitor and printer port. Data is standard ASCII format that can be uploaded into many programs for further analysis.

On-line TOC measurements that comply with USP24 and EP 2.2.44 are provided by the Manchester-based, Ionics, with the launch of its Sievers Model 400ES. The analyser, which monitors both TOC and conductivity in bulk water for injection (WFI) and purified water, can also provide the tools for 21CFR Part 11. The determination is now mandatory for WFI, and recommended for purified water in bulk.

Both raw and temperature compensated conductivity measurements are given with a conductivity range of 0.05-45mS and 1.0-2,500ppb TOC. The user can select analysis times from one to 60 minutes. The analyser features Ionics' integrated on-line sampling system (IOS), which simplifies the handling of calibration and system suitability standards.

Ionics also offers ready-made sucrose and 1,4-benzoquinone standards for the system suitability requirements set out in EP 2.2.44. These suitability requirements are in effect instrumentation control tests designed to verify the oxidation efficiency of a TOC analyser, and to establish the TOC limit of pure water used in a pharmaceutical process. The tests compare a difficult-to-oxidise compound, 1,4-benzoquinone, against an easy-to-oxidise compound, sucrose.

Pollution and Process Monitoring has also launched a range of trace level TOC analysers for the measurement to ppb levels in ultra-pure water. All instruments in the new Protoc Trace Level range offer continuous, on-line monitoring in the range 0-500ppb with a resolution of 5ppb up to 5ppm.

The new Protoc 100TL analyser offers single stream monitoring with 4-10Ma high and low alarm outputs. Typical response times are two to three minutes. The protoc 200TL offers the same features, but with the additional benefit of auto-calibration instead of manual calibration and trend graphics on a large liquid crystal display.

For multi-point on-line monitoring, the company has a new innovative Protoc Spyder TL and web system, which, it claims, offers a powerful and economic solution.