Sterility guaranteed

G. Eickermann

High-purity water designated as VE water, E water, D water, WFI (water for injection) or aqua purificata (AP) has to be produced by means of the appropriate processes in accordance with the quality requirements specified by DAB 10 and USP 23. The following parameters have to be clarified for basic arrangements regarding the treatment, storage and distribution of high-purity water:

• daily requirement/requirement per shift,

• amount extracted during a defined time period per point of use,

• temperature on exit from the point of use,

• pressure requirement at the point of use,

• simultaneity factor for all points of use,

• layout plan and storey plan with details of the points of use in numbered form.

This information constitutes the basis for planning the storage and distribution configuration.

In practice two different procedures are available for storage and distribution of high-purity water:

• cold storage and distribution with integrated ozonization,

• hot storage and distribution.

The purpose of the other requisite procedures, such as sanitizing measures and heating and cooling systems at the consumers’ points of use, is disinfection and ensuring that the specific extraction temperature is maintained.

The basic prerequisite for implementation of the concept of “cold storage and distribution with integrated ozonization” is extraction at ambient temperature at the consumers’ points of use.

The required sterility of this system is ensured by the use of ozone. Part of the high-purity water system is continuously treated with minimal amounts of ozone (2 to 8 g/h depending on the volume and circulation rate), so that the entire system remains aseptic. Nevertheless, in order to ensure the complete absence of ozone at the points of use, a UV sterilizer is integrated upstream of the first such point. All residual ozone in the high-purity water is removed here. Measuring devices are used control the amount of the added ozone upstream of the UV sterilizer as well as the quality of the ozone-free, high-purity water.

Since the effectiveness of the added ozone is dependent on the water temperature in the distribution system, the capacity of the circulating pump should be adjusted in accordance with the extraction cycles by means of a frequency regulator and/or an FDA-approved cooler with a double tube sheet for temperature limitation (max. 25 °C ) installed in the distributor system. If a pump regulation system is used, care should be taken to ensure that a full turbulent flow is always maintained in the return section to the storage tank, in conformity with FDA requirements.

With “hot storage and distribution”, on the other hand, a temperature of at least 65 °C is maintained during storage and distribution. The storage temperature must be set at least 65 °C, because this is when the pasteuriza-tion effect takes place. Practice has shown, however, that the higher the storage temperature, the lower the probability of any contamination of the system.

The high-purity water is returned to the storage tank via a special, spherical spray head. This ensures that the empty, upper tank compartment is constantly hot-rinsed, so that no pockets of contamination can form there. In addition, all the tank supports are designed in accordance with the loose flange technique and with no clearance on an aseptically sealed dome cover.

The storage temperature is constantly maintained as specified, and thermal stratification simultaneously prevented, by means of a separate circulation system installed on the storage tank and an FDA-approved heater with a double tube sheet. The distribution loop is driven by a separate circulating pump in accordance with the hydraulic calculation data. It is possible to maintain the extraction temperature required by the specific extraction conditions within this distribution loop independently of the storage temperature, whereby the extraction temperature may be lower than the storage temperature. Sub-loops of the kind described below are used in this case.

The whole system is sanitized during non-production periods by raising the distribu-tion temperature to the sanitizing temperature. The required loop temperature can then be reached again before production is resumed, either by a time control or by a cooler installed in the distribution system. The conditions prevalent in the distribution system during production (extraction) and sanitizing are monitored and recorded at quality-relevant measuring points.

The purpose of sanitization is to subject the storage and/or distribution system to a process of cyclic, precautionary disinfection. Thermal, chemical and physical methods of disinfection are used.

Thermal disinfection is subdivided into hot-water sterilization up to 95 °C, water-pressure sterilization ( > 95 °C) and steam sterilization (at least 121 °C) by means of high-purity steam.

Hot-water sterilization can be carried out with the installed plant technology, in which case the option of water-pressure steriliza-tion and steam sterilization must be taken into consideration in advance when planning the plant. It is necessary to ensure, among other things, that the storage tank is designed as a pressure tank. In addition, the necessary temperature compensation and the associated special mounting fixtures have to be taken into account.

In the case of chemical disinfection, there are various possibilities using ozone, hydrogen peroxide or peracetic acid. If hydrogen peroxide or peracetic acid are used, it is essential to note that when rinsing out after disinfection it is extremely difficult to detect evidence of any residues for the purposes of the validation qualification.

Physical disinfection in the form of UV sterilization does not take place at regular intervals in practice, but – if used at all – is rather permanently employed as an additional safety measure.

Practice has shown that, on account of the investment costs and the consequential operating costs, the preferred methods are chemical disinfection by means of ozone and thermal disinfection with hot water, of which the latter is the most frequently used system.

The quality-relevant measuring and sampling points are extremely important when setting up these distribution loops. The measuring points are fixed by agreement between the project engineer and the operator of the high-purity water system.

The following quality-relevant parameters have proved to be the most important in practice pharmaceutical requirements:

• TIRA for temperature recording and monitoring,

• FQRCA for recording, monitoring and regulating the speed of the circulating pump for the relevant loop for maintenance of hydraulic conditions,

• QRSA (conductance) for recording, monitoring and closure of the extraction valve when the quality value is reached (max. 1.3 m S),

• QIRS (TOC) for recording the total organic carbon in ppb and for closure of points of use at the latest when 500 ppb is reached.

The above-mentioned quality-relevant measuring points are always used in the return section of the distribution loop, though also upstream of the pressure resistance to the storage tank. To keep costs as low as possible, only a single evaluation device need be used for TOC measurements in a system with several distributor loops. Up to five measuring samplers, connected to this central evaluation device, then extract the samples cyclically in each of the loops by means of controlled extraction valves.

The basic rule for determining the test points for the defined parameters is that one sampling valve per loop should be installed at the outlet of the storage tank and in the return section at the inlet of the storage tank. If there are still critical components and units in the distribution loop itself, sampling valves must also be installed for monitoring at these points.

In accordance with the sampling plan, the manually operated extraction points may also be designated as sampling points. In the case of pneumatically operated extraction points, the corresponding manually operated sampling valves must always be positioned such that these extraction points can be sampled for evaluation. A sampling point can take the form of a suitable aseptic valve of bellows or diaphragm design, or alternatively of a sampling membrane in which the sample is taken by means of a hollow or injection needle. The bellows-type aseptic valve technology increasingly used in this connection is especially advantageous for high-purity water systems which must be kept constantly mobile, since its functions are monitored by means of visual inspections (leakage) and sampling can take place directly in the product flow (no clearance space). The high level of availability and the durability of the bellows ensure economical operation. The cost of using diaphragm valves is much higher, on the other hand, on account of the necessary prophylactic replacement of the diaphragms.

The following can be defined as general data for distributing a capacity of 6 m3/h and an exit conductance of 0.2 (S/cm; the specified storage volume is 16 m3 and the storage temperature 70 °C (6 5°C). N2 superposition and CO2 absorption are not used. Distribution inside the eight buildings is by means of five loops operating independently of one another. The basic daily requirement in this case amounts to about 80 m3. The conductance return is 0.4 m S/cm (with a limit value of 1.3 m S/cm), while the TOC return amounts to about 20 ppb (limit value: 500 ppb). The Table shows the corresponding general data.

When the high-purity water is treated and fed in, the aqua purificata is conveyed as required from the electrodeionization unit – the final treatment stage – through a central feeder channel to the storage tank. If there is no contrary requirement regarding the treatment facility, this feeder channel is constantly rinsed by a bypass connection of the storage-tank circulating system.

The filling cycle takes place whenever the tank is approximately 50% full. It is important to determine the correct filling level and cycle, in order to avoid temperature fluctuations and thermal stratification in the storage tank.

The volume of the storage tank is adjusted to the capacity of the treatment facility, depending on the daily output at the points of use. In order to ensure that the treatment facility remains within an economical performance range, the outputs of the points of use are allocated simultaneity factors. These factors are usually between 0.4 and 0.6, whereby the production areas most prone to failure are to be given priority.

The storage volume is circulated and heated by means of a separate circulation system. The temperature in the storage tank is maintained at a differential temperature of 6 5 °C within a temperature window.

The storage tank is designed as a pressure-free storage system. Excess pressure and overflow protection are ensured by an aseptic rupture disk with a signal contact disk. The rupture disk works in two directions for overpressure and underpressure. A sterile filter is used for ventilation.

One or more distributor loops have been provided on the basis of operating requirements at the points of use, according to the avai-lable space and the distances concerned. The individual loops should be configured so that they can be installed at a reasonable cost in line with the hydraulic requirements. If possible, the distributor loops should never be subjected to any major deviations from the required temperature. Divergent temperature requirements over small areas can then be covered by sub-loops for cooling or heating at the appropriate points of use.

With regard to distribution at the points of use, the loops should if possible be connected to them from above. This will allow the extraction valves to be used simultaneously as drain valves. If the point of use is fed from below, then an additional drainage point must be provided for each feed loop.

The assessment of this project shows that even with comparatively large storage volumes – in this case 16 m3 – it is possible to ensure optimum planning of the plant with respect to sterility. It has also proved possible to optimize the compliance with FDA requirements by significantly reducing the number of manual welded seams, with a rate of 6% for a total 4391 welded seams and a pipe length of 4,050 m. In addition, the percentage of endoscoped welded seams was increased to 12% (normal 5%), in spite of the extremely difficult space conditions and the fact that various parts of the plant are relatively inaccessible.

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Further information cpp-203