Water: HPW as a low-cost alternative: Peter Wirz, Christ Water Technology Group, reviews the introduction and use of Highly Purified Water (HPW) and suggests that ultrafiltration may harmonize global pharmaceutical water standards.
[FIGURE 1 OMITTED]The possibility of producing WFI (Water for Injection) using processes to harmonize with the USA and Japan was discussed in Europe for several years. At an international meeting in Strasbourg in 1999, a motion to approve the use of membrane processes for the production was rejected because insufficient data were available. However, a new water quality, HPW, was defined as a compromise and came into force in the European Pharmacopoeia (EP) on 1 January 2002.
What is HPW?
HPW is defined as follows in the EP: "Highly Purified Water is intended for use in the preparation of medicinal products where water of high biological quality is needed, except where Water for Injection is required." In other words, HPW cannot completely replace WFI and the EP specifies that the latter may be produced only by distillation and thus excludes the considerably cheaper membrane processes. The main argument for this is the increased risk of microbial contamination in systems that are not continuously operated at high temperatures.
HPW is now intended for applications where water with a high microbial quality is needed, but WFI is not legally required. In parallel to this, the EMEA (European Agency for the Evaluation of Medicinal Products) published a Note for Guidance on Quality of Water for Pharmaceutical Use which deals with the use of the various pharmaceutical water qualities. This Note became effective on 1 June 2002 (Table I).
Which Treatment Methods are Permitted?
The EP does not define a specific method for the production of HPW. The various methods shown in the EP are intended only as suggestions. Commonly used methods, such as RO (reverse osmosis) combined with other processes such as EDI (electrodeionization) and UF (ultrafiltration), are mentioned. Only water that meets the requirements for drinking water of the local authorities may be used as the raw water for such treatment processes.
How Can HPW be Used?
The above-mentioned Note published by the EMEA describes in detail and in a user-friendly table the water qualities defined in the pharmacopoeia for the production of pharmaceutical products. This must therefore be observed when deciding where HPW may be used.
How is HPW Currently Produced?
As the chemical quality of HPW is very similar to that of PW (Purified Water), the well-known and proven treatment processes (RO and EDI) can be used for demineralization. However, the decisive process in the production of HPW is the subsequent ultrafiltration. This means that the following combinations of processes are mainly used today:
Reverse osmosis--reverse osmosis--ultrafiltration
Reverse osmosis-electrodeionization--ultrafiltration
It is assumed that the process steps of RO and electrodeionization are generally known and do not need to be described again here. Ultrafiltration, however, involves some special features require a more detailed description.
Ultrafiltration Versus Reverse Osmosis
Examination of the cut-off values of these two different membrane processes shows that the value for RO is about 100 Dalton, much lower than that for an ultrafiltration stage. Although RO membranes excel in removing micro-organisms and pyrogens, their construction (permeators and pressure tubes) has many mechanical weak points. Examples of these are the many seals and gaskets, axial movements, the macropores which frequently exist and the glued edges of the membrane packets. All of these tiny leaks, in the order of a few tenths of one per cent, can be ignored for the demineralization of water (the main task for which RO is used). For "sterile and pyrogen filtration," however, they are absolutely unacceptable. Thus, it is no surprise that express approval of RO for the production of WFI was deleted in the latest revision of the US Pharmacopoeia (USP).
[FIGURE 2 OMITTED]
[FIGURE 3 OMITTED]
Ultrafiltration
Ultrafiltration is a membrane process for the removal of particulate contamination or dissolved substances on the basis of their molecular weight or their size (sieve effect). In the biopharmaceutical industry, it is used primarily for the production of purified water, using hollow-fibre modules with polysulphone membranes have a specific cut-off of [less than or equal to]6000 Dalton (Figure 1). This is far below the size of the contamination to be removed, such as bacteria, viruses and pyrogens.
[ILLUSTRATION OMITTED]
The advantage of hollow-fibre modules results from their construction. The individual hollow fibres are cast into the housing with epoxy resin, resulting in a module with no dead spaces and excellent separation between the feed-water and filtrate sides without the need for additional gaskets. Furthermore, the integrity of the modules--particularly after thermal treatment--can be proved in-situ with the aid of a so-called pinhole test. For this, the feed-water side is pressurized with sterile air or nitrogen and the unpressurized filtrate side is inspected for gas bubbles (Figure 2). Further advantages are that such modules can be backwashed and that they offer good resistance to chemicals and high temperatures. Some modules currently available on the market can be cleaned or sanitized with hot water ([greater than or equal to]85 [degrees]C) or even with saturated steam ([greater than or equal to]121 [degrees]C).
As a result of these properties, UF modules (with a cut-off of 6000 Dalton) have been approved in the Japanese Pharmacopoeia (JP11) since the 1980s for the production of WFI. In Europe, UF systems are also being used successfully for the production of water with "WFI quality"--purified water with more stringent requirements with respect to biological and microbiological cleanliness that is now called HPW in the European Monographs. In the industrial sector, UF systems have been used for many years for the reliable production of pure water with [less than or equal to]0.06 EU/mL and [less than or equal to]1 CFU/100 mL--values which lie far below the quality requirements for WFI. This clearly shows how reliable this process is.
System Concepts
Whether a system is designed and built as a compact standalone unit or as an additional stage for an existing PW system depends primarily on the local conditions and the desired system output. Smaller systems with an output of up to about 10 [m.sup.3]/h can be constructed in the form of standard single-rack systems which combine all process stages needed for the production of HPW from drinking water, such as a water softener and stages for RO, electrodeionization and ultrafiltration (Figure 3). All of these stages are mounted on a skid and the control technology is fully wired. This makes it possible to test and pre-qualify each system in a FAT (factory acceptance test), resulting in faster production and shorter installation times, which saves time and costs.
Autonomous UF units are used primarily as additions to existing systems and in cases where high system outputs are needed . They can also be adapted more easily to meet special customer requirements. On the other hand, however, this flexibility results in higher costs and longer delivery times.
Cost Comparison
Even with a system output as low as 500 L/h UF is an extremely economical process and a reliable alternative to the classical distillation process, as Table II illustrates. Basis for the comparison:
* PW as feed water for the UF or distillation system
* System output: 2 m3/h
* Production: 11 500 m3/year (16 h/day, 360 days/year)
* Heating steam 8 bar, 30 euros/tonne
* Cooling water 15/85 [degrees]C 5 euros/m3
* Distillation with 5 columns and pre-heater
In systems with higher outputs, the cost reductions are far higher due to the low energy costs.
Summary
The current trend is towards standardized compact systems for the production of HPW. Thanks to the ultrafiltration stage, the incoming water which already complies with the requirements with respect to conductivity and TOC value--is reliably converted into water is free of germs and pyrogens. Today, the state of the art also includes thermal sanitization of the systems. Compared with distillation, these systems offer a far cheaper method of producing water in WFI quality from purified water. Once a sufficient number of reference systems have been commissioned and the experience gained from them has been published, this production method may possibly soon be approved in the EP for the production of WFI--a further step towards harmonization with other pharmacopoeia.
All photos: Christ Water Technology Group
For more information
Christ Water
Technology Group
Hauptstrasse 192
Postfach 130
CH-4147 Aesch, Switzerland
T +41 61 755 81 11
F +41 61 751 44 85
E info@christwater.com
www.christwater.com
Table I: Quality parameters for Aqua Valde Purificata.
Ph. Eur.
Parameter Unit (Bulk)
Clear, colourless,
odourless and tasteless
TOC [ppb C] [less than or equal to] 500
Conductivity (at 20
[degrees]C) [[micro]S/cm] [less than or equal to] 1.1
Nitrate ([NO.sub.3]) [ppm] [less than or equal to] 0.2
Heavy metals [ppm as Pb] [less than or equal to] 0.1
Aerobic germs [CFU /100 mL] [less than or equal to] 10
Endotoxins [EU/mL] [less than or equal to] 0.25
Table II: Comparison of the operating costs for ultrafiltration
and distillation.
Annual operating costs Ultrafiltration Distillation
Replacement of UF 5500 [euro] --
modules
Parts subject to wear 1800 [euro] 2000 [euro]
Monitoring (1h/week) 2000 [euro] --
Annual inspection 1000 [euro] 1000 [euro]
(1 day)
Electric power (approx. 3200 [euro] --
3kWh/mL)
Steam (approx. 230 -- 79,000 [euro]
kg/mL)
Cooling water (approx. -- 46,000 [euro]
800 l/mL) --
Total costs 13 500 [euro] 128,000 [euro]
Specific costs approx. approx.
1.20 [euro]/[m.sup.3] 11.15 [euro]/[m.sup.3]
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| Title Annotation: | water management |
|---|---|
| Author: | Wirz, Peter |
| Publication: | Pharma |
| Geographic Code: | 4EXSI |
| Date: | Sep 1, 2008 |
| Words: | 1571 |
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