Inspection of High Purity Water System

For the evaluation of high purity water systems the following need to be considered

1.1 System design

• The primary factor to be considered in the inspection of high purity water system is its design which is dependent on the product that is to be manufactured.
• Pyrogens can be a threat for parenteral products but it can be resolved by using water for injection produced by RO filtration & Distillation. The same can be applied in equipment’s & components washing as well product formulations.
• In biotechnology & pharma companies ultra-filtration is the only method for reducing endotoxins
• For some ophthalmic products water for injection is used and for most of the inhalation, ophthalmic products, cosmetics & oral products purified water is used for their formulation.
• Hot systems with a temperature of 65-80^oC are considered to be self-sanitizing.
• Another consideration in design is whether system is one way or circulating design but one way system is considered to be dead leg and water in continuous motion has low levels of contaminant
• Quality and risk should be assessed when considering design of the system.
• Various products require various quality waters like parenteral require pure water and topical & oral products require less pure water or require different quality of water

1.2 System Validation

• Validation in water systems is done by testing the microbiological quality and checking the system for its functionality so it operates continuously & properly on installing monitoring equipment at specific checkpoints
• Documentation of the validation report should include system description with print. The drawing should depict all equipment’s from water feed to its usage points within the system & also it’s sampling points with their designations.
• Taking the print is crucial as it provides an idea to the microbiologist or QC manager where to sample and also a brief idea on validation. Those systems without prints problems were encountered on their usage.
• Every year the prints should be checked in compliance with the actual system and any changes should be reported so accuracy is maintained.
• After the system is checked for its installation then phase I validation is done where procedures and frequency for cleaning & sanitation, operational parameters are developed.
• Sampling is to be done after every purification process for 2-4 weeks at every usage point.
• The sampling procedure for sampling should depict how water is drawn.
• Phase II of the validation should demonstrate that the system should produce water with desired quality in compliance with SOPs. Sampling is to be done as in phase I and the end of phase II should show results that water of desired quality is produced.
• Phase III of validation should demonstrate that water system should operate in compliance with SOPs to produce desired quality. Changes in the water quality would show an impact on operation.
• Apart from the above method of validation, another way of validation can be done if data is available supporting SOPs. First valid data should be present supporting SOPs and by following them the system should produce consistent quality and should not affect the system operation or water quality
• Finally the data should be documented with proper conclusions and signed by people responsible for operation & quality assurance of the water system.
• Problem can be encountered when there is failure of operating procedures where contamination in system can be caused by non-sterile air in the pipe after damage.
• Acceptance criteria should be considered in the validation of purity water systems

1.3 Microbial Limits

• Microbial limits are not clear for purified water. USP XXII specifies that drinking water should be in compliance with Federal Environmental Protection Agency regulations which are considered to be minimal specifications.
• CFTA has proposed specifications as to should not be more than 500 organisms per ml
• USP XXII has proposed the limit of not more than 100 organisms per ml
• According to agency policy more than 100 CFU/ml for purified water is usually not accepted
• Action limits are given to ensure that water system is under control
• Establishment of action limits depends on the purified water system, processing and usage of the finished product
• Organisms are present either as free floating forms or attached to walls of tanks or pipes in the water system. Organisms attached to walls are known as biofilms. Due to their uneven distribution in the water system sampling can’t be done as it is difficult to obtain a sample.
• USP gives the guidelines for Microbiological Attributes of non-sterile products stating that microorganisms in a non-sterile pharmaceutical product should be evaluated basing on the use & nature of the product and adverse effects caused to the user
• But still it rests in the hands of the manufacturer to evaluate the product and establish the acceptance limits.

1.4 Pumps

• Pumps may wear and tear or may be static & not continuously operated. In pumps which were operational periodically were reported to have pseudomonas contamination.

1.5 Piping

• Piping should be of highly polished stainless steel material and at times manufacturers may opt for polyvinylidene fluoride (PVDF) piping. It is said that these PVDF pipes can tolerate heat without leaching of any extractables but the problem encountered is it requires support & tends to sag & stress the fusion connection on heating resulting in leakage.
• Common problem in piping is dead legs.
• Threaded fittings are not allowed in pharmaceutical water system
• All the pipe joints should have sanitary fittings or should be butt welded
• Procedures for piping & sanitation should be reviewed & evaluated while inspection

1.6 Other considerations

• To control microbiological contamination ozone is used. It is inexpensive. To be effective dissolved ozone should be remain in the system.
• When ozone was used problems were encountered like contamination problem with species of pseudomonas & in another case recontamination occurred when ozone generator was switched off.
• Due to the problems encountered ozone was removed from water before placing it recirculating system
• Dissolved ozone was maintained at a level of 0.45 mg per liter for 5-6 hours
• Excellent results of microbiological activity were reported when a manufacturer removed all drops off of ozonated water system & disinfected them with 70% isopropyl alcohol as part of sanitization. However the results are not prioritized as sampling is done after sanitization but not after the whole process

1.5 Inspection strategy

• Manufacturers have tabulated results or printouts for purified water system and they should be reviewed periodically
• Investigation reports should be reviewed when values exceed the prescribed limits
• Until the drug is manufactured the microbiological results are not obtained so they should be reviewed with respect to the drug formulated from such water.
• Processing or releasing of a product depends on contaminant, process and usage of the product. They are evaluated on case by case basis. Investigation report should be drafted stating the reason for release or rejection
• Manufacturers should maintain records or logs for equipment such as still. They should be reviewed so that the problems with equipment & system are evaluated
• When conducting physical inspection test results, investigation reports, summary data & other relevant data should be reviewed. To demonstrate that the system is validated an accurate description & printout of the system should be present.

Purified water system, microbiological limits, validation

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