Manual – 042 Water Quality Standard

Samples should be collected from points of use in the same way as, or in a manner that simulates how the water is used during routine production. Where possible samples will be taken on a rotational basis to ensure that points are not always sampled on the same day.

Samples that are not taken from points of use, and which may be taken from a sample point that is exposed to the elements, may be flushed for a defined time to ensure the sample reflects the water in the system. See Appendix 1 for suggested minimum sampling frequencies.

5.2 Testing

Written, approved and validated test methods are required. Test methods as per the EP or United States Pharmacopeia (USP) are considered validated.

5.2.1 Potable Water

Testing for the full analytical requirements for Potable Water is usually outside the scope of the typical pharmaceutical laboratory. The recommended practice is to receive Analytical Reports and/or Certificates of Analysis from the municipality/supply company providing the water, together with supporting local test data. If alternative sources of water are used, e.g. borehole/well water, it may be possible to arrange for the local municipality/supply company or a contract water- testing laboratory to sample and test the water against the appropriate standard. The local site should perform a limited number of analytical monitoring tests that have been pre-established in a local procedure or standard.

5.2.2 Purified Water

The tests, methodology and specifications for Purified Water are described in the relevant Pharmacopoeias.

5.2.3 Endotoxin-Controlled Purified Water

The tests, methodology and specifications for Endotoxin-Controlled Purified Water are, as minimum, the same as for Purified Water with the addition of the Bacterial Endotoxin Test with a limit of not more than 0.25 IU/ml.

5.2.4 HPW

The tests, methodology and specifications for HPW are described in the EP.

5.2.5 WFI

The tests, methodology and specifications for WFI are described in the relevant Pharmacopoeias.

5.2.6 Pure Steam

The steam condensate should meet the appropriate quality requirements of the water used in the facility. This would normally be Purified Water or WFI as above.

5.3 Alert and Action Levels

Each site shall develop its own procedures for establishing alert and action levels for microbiological testing and action levels for analytical testing of water.

5.3.1 Alert Levels

Enough test data should be developed over a period of time (minimum 1 month) to determine the normal operating range of the water system and to enable alert levels to be defined for the process as appropriate.

Alert levels for analytical testing can be developed at the discretion of the local site.

5.3.2 Action Levels 

Action levels for the various water systems should be equivalent to the compendial limits where specified, or other non-compendial guidelines, or lower as appropriate for the system. 

The impact on product quality and the status of the water system should be assessed when an action limit is exceeded. Actions taken will be dependant on the nature of the failure(s), and may include for example, batch rejection, review of results from the particular point or others, additional testing, examination of sample points, sanitization of the system etc. 

Maximum microbiological action levels for the various water systems must be:

* Potable Water: Not more than 500 colony forming units per millilitre, i.e.≤ 500 cfu/ml (Ref: 6.1). If tighter water standards are necessary then appropriate limits for total microbial count, objectionable microorganisms and/or endotoxin content should be established

* Purified Water: Not more than 100 cfu/ml. The requirement for absence of specific microorganisms should be based on the use of the water. Ingredient water may require the absence of selected Gram-negative microorganisms based on the product formulation and use, e.g. topical application versus a liquid oral dosage form.

* Endotoxin-Controlled Purified Water: Not more than 100 cfu/ml and with an endotoxin limit, e.g. where used in the final isolation and purification of a non-sterile API intended for use in a sterile parenteral drug product, of < 0.25 IU/ml. The water should also be tested for specified organisms, (Ref: 6.2), e.g. absence of coliforms andPs. aeruginosa in a 10 ml sample. * HPW: Not more than 10 cfu/100ml and endotoxin content < 0.25 IU/ml.

* WFI: Not more than 10 cfu/100ml and endotoxin content < 0.25 IU/ml. In addition WFI systems are normally operated hot (70-800C) and therefore the isolation of Gram-negative microorganisms should be a rare event. Repeated isolation of Gram-negative microorganisms would require an investigation to determine the cause with corrective action being taken.

* Pure Steam: Normally as for Purified Water or WFI, depending on the appropriate quality requirements of the water used in the facility.

5.4 Monitoring

Suggested minimum sampling frequencies for the microbiological testing of different water types during normal operation are outlined in Appendix 1. In facilities where use of water is infrequent, different sampling frequencies may be established. This is acceptable but the frequencies should be justified to ensure that assurance of the water quality is maintained, and takes into account those periods when the water is used. For example, Class 1 user points may be classified as Class 2 during periods of extended non-use.

5.4.1 Potable Water

The analytical testing frequency of Potable Water varies based on the source. For example, the testing frequency of municipal water is often based on the size of the population being served. This information is available from the local municipality/supply company. Microbiological testing of Potable Water by the municipality will typically include information on coliform bacteria but may not include the total bacterial count. Additional in-house microbiological testing is typically performed on a monthly basis. The final frequency of testing can only be determined after the initial validation where the influences of seasonal variations have been taken into account.

5.4.2 Purified Water

Analytical testing of a validated, well-controlled Purified Water system may be performed as infrequently as once a month. However, it is becoming common to install in-line monitors, e.g. Total Organic Carbon (TOC) and Conductivity to continuously monitor the chemical purity of the water system. It may be considered appropriate to validate in-line monitors to provide assurance that the data is representative of the water as used. The exact nature of the testing is determined by the specification claimed for the water system, i.e. Purified Water USP, EP, etc.

5.4.3 Endotoxin-Controlled

Purified Water Analytical testing frequency would be as for Purified Water.

5.4.4 HPW

Analytical testing of a HPW system would typically be performed weekly. As with Purified Water and WFI systems it is now common to install in-line meters to perform TOC and Conductivity measurements.

5.4.5 WFI

Analytical testing of a WFI system would typically be performed weekly. As with Purified Water systems it is now common to install in-line meters to perform TOC and Conductivity measurements.

5.4.6 Pure Steam

Analytical testing of Pure Steam condensate would typically be performed monthly.

5.5 Storage and Distribution 

Particular care is required for the storage and distribution of water. The major concern is maintaining the microbiological quality of the water. Typically enough Potable Water is held in a buffer or break tank to provide a uniform flow and working pressure for the user point(s) and/or treatment system. 

Should it be necessary to hold larger quantities of Potable Water then an anti-microbial pre- treatment step is likely to be required. Depending on the quantity being held various options include the use of UV light, ozone addition or chlorination, although any chemical added must not exceed the Potable Water quality standards. 

Any chemicals added during pre-treatment or subsequent conversion to Purified Water or other higher quality waters must be removed as part of the purification process Purified Water and Endotoxin-Controlled Purified Water is usually held and distributed in stainless steel vessels and pipes although plastic alternatives have been successfully used. 

It is typical to make use of hygienic designs, provide re- circulating distribution systems and to provide for routine sanitization to maintain the quality of stored Purified Water. 

It is possible to add ozone to the storage tank and to remove the ozone with UV light during distribution. Periodically turning off the UV light and letting the ozonated water circulate for an appropriate time will sanities the distribution system. An alternative method with stainless steel systems is to periodically heat the Purified Water to about 80 ºC and circulate the heated water through the distribution system for an appropriate time before cooling back to ambient temperature. Steam sanitisation of systems with Pure Steam may be possible although this would normally only be used in the event of, for example, major microbiological contamination or major modifications to, e.g. WFI systems. Filtration is not recommended due to the concerns of bacterial grow through and The difficulties associated with filter maintenance, particularly for large systems. It is recommended that HPW be held and distributed in stainless steel vessels and pipe work. 

The microbiological specifications for HPW argue against trying to use plastic or other alternatives. Maintaining the microbiological quality of HPW during distribution and storage could prove to be a very demanding operation. HPW systems are likely to be cold systems and therefore the recommendation is to use either an ozone sanitization system or the periodic application of heat as for Purified Water. 

WFI is held and distributed in stainless steel tanks and distribution systems. It is typically maintained at an elevated temperature (70-80 ºC) at which temperature the system is considered to be ‘self-sanitising’. 

The WFI may be cooled for use as required by using local hygienic heat exchangers at the points of use or by cooling the distribution system periodically. Pure Steam distribution systems would normally be manufactured in stainless steel with appropriate hygienic design and surface finishes. Installation should allow for removal of non-condensable gases and condensate. Storage tanks for water, other than Potable Water, should be fitted with a 0.22 µm hydrophobic vent filter, normally located in a heated housing to avoid possible blockage of the filter with moisture. The filter quality should be tested for integrity at installation and when changed. 

Dead legs in distribution pipe-work should not be greater than six diameters of the unused pipe measured from the axis of the pipe in use.

5.6 Requirements for Water

Quality for Different Uses The quality of water used at different stages in the manufacture of APIs and pharmaceutical products should take into account the nature and intended uses of the finished product and the stage at which the water is used.

The minimum acceptable qualities of different water types that must be used during normal operations are tabulated in Appendix 2. Typical uses of water and steam are described below.

5.6.1 Potable Water

Potable Water may be used for the manufacture of API intermediates and the final isolation and purification of APIs, plus cleaning of associated equipment, unless there are specific requirements for greater chemical and/or microbiological quality, e.g. for manufacture of a non-sterile API intended for production of a sterile formulation.

It may also be used for the initial cleaning of equipment used for manufacture of non-sterile dosage forms. Potable Water that is used for non-pharmaceutical purposes, e.g. hand-washing, is not covered by this guideline.

5.6.2 Purified Water

Purified Water is used for the manufacture of certain API intermediates and APIs that are to be used to produce sterile, non-parenteral dosage forms. It is used as the ingredient water in the manufacture of non-sterile dosage forms and certain sterile formulations, and as the final rinse clean of associated containers, closures and manufacturing equipment.

It may also be used for the initial cleaning of equipment associated with the manufacture of sterile formulations. Purified Water may normally be used in laboratories to produce chemical reagents, solutions, buffers, microbiological culture media etc., although the quality required should be defined by the test method, compendial requirements, etc.

5.6.3 Endotoxin-Controlled Purified Water

Endotoxin-Controlled Purified Water would typically be used to manufacture a non-sterile API intended for use in a sterile, parenteral dosage form.

5.6.4 HPW

HPW is intended for use in the preparation of medicinal products where water of high biological quality is needed, except those where WFI is required.

5.6.5 WFI

WFI is intended as the ingredient water to be used in sterile, pyrogen free product manufacturing. It is also used as the final rinse for containers, closures and equipment used in sterile, parenteral product manufacture.

5.6.6 Pure Steam

Pure Steam is intended for use when the steam quality should not compromise the product and/or contact part quality. It would be used primarily as a sterilizing medium, but may also be used for example, for humidification and/or energy transfer duties. Pure Steam used for sterilization should be dry saturated with minimum superheat and minimum levels of non-condensable.

5.7 Validation

In common with other pharmaceutical systems, water and steam pre- treatment, generation and distribution systems that impact on product quality require validation to establish critical process parameters and their operating ranges.

A unique facet of validation of a water system is that it can take at least one year to complete all of the testing so as to encompass all of the seasonal effects on the water supply. After successful installation and operational qualification activities, an extensive period of performance testing is undertaken to complete the validation.

Typically, an initial period of one month of extensive sampling (up to each point each day) and testing throughout the pre-treatment, generation and distribution system to establish operating conditions is followed by a further month of extensive sampling/testing to demonstrate the system is under control. If the results are satisfactory the system can be released for use with the number of tests performed over the one- year period decreased to that required for routine operation. Critical process parameters should be regularly monitored to ensure compliance with the validated ranges.

Any changes to an existing system must be controlled through appropriate procedures and the requirements for assuring quality assessed accordingly. Additional sampling will be required, taken from those points affected and for a time appropriate to the change. As a guide, at least two weeks of intensive data, operating with normal procedures would be expected, with samples taken from the affected points twice per week for chemical analysis and daily for microbiological/ endotoxin analysis as appropriate.

5.8 Trending and Review

Microbiological and analytical quality data from water pre-treatment, production and distribution systems should be regularly trended and reviewed to identify problems and focus attention where corrective action is required to maintain the required water quality. 

Regular reviews of supporting information, e.g. operating performance, changes, should be performed in conjunction with the water quality data to provide assurance that the system continues to be operated in a validated state.

5.9 System Maintenance

All water systems should be subject to defined maintenance programs and schedules together with the appropriate specification/calibration of critical instruments. 

5.10 Change Control 

All modifications to the, e.g. installation, operation, control and sampling, of water systems should be subject to appropriate change control procedures.

Appendix 1 

SAMPLING FREQUENCY FOR MICROBIOLOGICAL TESTING 

The frequencies below should be considered as the minimum acceptable during normal operation. Individual sites may prefer to perform more frequent sampling and testing. This sampling frequency is based on an established, validated water system. 

Samples should be taken from points of use (e.g. where the water enters the vessel) or if not possible then from points that accurately reflect the point of use water quality. Samples should be taken from the source water and within a pre-treatment/ generation unit on a periodic basis. 

Sampling points can be classified into three groups. 

Class 1– point of use or other sampling point that provides information on the quality of water as used (e.g. it represents ingredient water) or on the quality of water in the distribution loop. 

Class 2– sampling points for water that does not have a defined compendial/suitable non-compendial quality standard, e.g. samples taken after softeners, de-chlorination units or RO units, within the pre-treatment and generation system, and/or points that may be considered less critical, e.g. water is not used directly in the product 

Class 3– points that are used for operations such as drainage, sanitization or a point that is not in operation.

POTABLE WATER

Potable water that is used as source water only (i.e. not used in production) may be tested for total aerobic count on a monthly or quarterly basis.

This data should be combined with the municipality/supply company testing data, or other data as available. Similar levels of sampling are required from appropriate points within a pre-treatment and generation system to monitor the performance of the individual stages.

Potable Water that is used in manufacturing (e.g. APIs) should be tested as defined for Purified Water, Class 1.

PURIFIED WATER & ENDOTOXIN CONTROLLED PURIFIED WATER

Class 1: at least one point is tested weekly with each point of use tested at least monthly

Class 2: quarterly.

Class 3: exception basis only, e.g. investigating results Out of Specification (OOS) and/or exceeding the Action Limit.

HPW & WFI

Class 1: at least one point each day with each point of use tested at least weekly.

Class 2: monthly

Class 3: exception basis only, e.g. investigating results Out of Specification (OOS) and/or exceeding the Action Limit.

PURE STEAM (CONDENSATE)

Class 1: at least one point, plus the supply from the Pure Steam Generator (PSG) is tested monthly.

Class 2: quarterly. Class3: exception basis only, e.g. investigating results Out of Specification (OOS) and/or exceeding the Action Limit.

Appendix 2

REQUIREMENTS FOR WATER QUALITY FOR DIFFERENT USES

The minimum qualities of water that must be used at different manufacturing stages are tabulated below.

For Manufacturing the Intermediate of an API: