Design & validationof water systems.

Design of the system.

• Type of water- -Purified water -Water for injection• Product to be manufactured• Temperature of system

Water for injection.

• Distillation.• Reverse osmosis. However in the bulk pharmaceuticals and

biotechnology ultrafiltration is employed to minimize endotoxins.

Water for injection.

• Some opthalmic irrigating solution and inhalation products where there are pyrogen specification.

• Otherwise purified water.

Purified water.

• Opthalmic.• Inhalation.• Oral.• Topical.• Cosmetics.

Temperature.

• Hot (65-80 c ) systems are self-sanitizing.• Circulating water systems.• One way water systems – “dead leg”

Risk assessment or level of quality.• Parental requires very pure water with no

endotoxins.• Topical and oral products – purified water but preservatives in antacids are marginally

effective. Hence more stringent microbial limits required.• Add a microbial reduction step –

ultrafilteration.

System validation.

• Parental association technical report no.4 titled “design concept for validation of a water for injection system”

- use of an appropriate challenge. In this situation it would be undesirable to introduce micro organisms into an online system.

System validation.

• Hence reliance is placed on - periodic testing for microbial quality - installation of monitoring equipments at

specific check-points

Design qualification.

• Supply water source and specification - periodic monitoring for inorganic and

radioactive traces.• General environment – clean and tidy.• System – leak and rust free, well

maintained.

Design qualification.

• System controls – electrical panels and switches well protected.

• Access to the system restricted.• Material of construction – pipes, tanks. • Vender qualification – selection and

acceptance of specification.

Design qualification.

• Description of the system along with a print.

• Drawing showing all the equipments from water feed to point of use.

• Specifications for all the parts of system.• Sampling points and their locations.

Design qualification.

• The print should be compared to the actual systems annually to ensure its accuracy.

• To detect unreported changes.• To confirm reported changes.

Installation qualifications.

• To ensure that all the design qualification parameters are verified and confirmed during actual installation of the system.

• All the changes during installation are covered with change control system and documented.

• All SOP’s are developed and authorised.

Operational qualifications.

• To demonstrate that system will consistently produce the desired water quality when operated in conformance with SOP’s.

• The sampling and testing is performed for initial phase and for the same time period.

• Data evaluated for its specification.

Performance qualifications.

• To demonstrate the water system is operated in accordance to SOP’s over a long period of time ( 1 year ).

• Variation in quality of feed water.• Sampling and testing is performed

according to procedure and frequencies.• Daily from one point of use with all points

of use tested weekly.

Performance qualifications.

• There must be a data to support SOP’s.• There must be data demonstrating that

SOP’s are valid.• There must be a data to support that

seasonal variations in feed water do not adversely affect the operation of the system or water quality.

Performance qualifications.

• Compilation of the data with conclusions into the final report.

• Final report must be signed by the appropriate people responsible for operation and quality assurance of the water systems.

Review of validation.

• Validation performed according to schedule protocol.

• Report indicates that the system is operating in repeatable and reliable manner.

• Any non conformities indicated in the report, explained and suitably authorized.

Microbial limits. (water for injection)

• Essentially sterile.• Occasionally low level count due to

sampling error may occur.• Less than 10cfu/100ml is acceptable action

limit.• None of the limits for water are pass / fail.• All are action limits.

Microbial limits.

• When action limits are exceeded - investigate the cause of problem. - take action to correct the problem. - asses the impact on product. - document the results of investigation. - prepare action plan.

Microbial limits.

• Sampling volume 100-300 ml preferred.• Less than 100 ml unacceptable.• Monitor for both endotoxins and micro-organism.

Microbial limits ( purified water)

• Federal environmental protection agency regulation for drinking water

- 500 micro-organisms / ml.• USP action guideline – not greater than 100

organisms / ml.• Purified water used to manufacture drug

products by cold process – free of objectionable organisms.

Microbial limits.

• Objectionable organism - can cause infections. - capable of growth in drug products.• As per guide to inspection of

microbiological pharmaceutical quality control lab, the specific contaminants rather than the number is more significant.

Microbial limits.

• Organisms exist in water systems. - free floating. - attached to the walls of pipes and tanks – biofilm.• Contamination not uniformly distributed.• Pre treatment of feed water is recommended

for distillation equipment and is definitely required for RO units.

Still.

• Malfunctioning of feed water wall and level control results in droplets of feed water being carried over in the distillate.

• 50 ltr of WFI in condenser remains at the startup.

This leads to contamination.

Heat exchanger.

• Methods for preventing contamination due to leakage.

- monitoring pressure differential to ensure high pressure is always on the clean fluid by gauges.

- double tube sheet type of heat exchanger.• When not in use heat exchanger not to be

drained to avoid pinhole formation.

• Holding tank – vent filter integrity testing, readily accessible.

• Pump – static or periodically operational – accumulation of water in reservoir leads to microbial contamination.

• Piping – high polished stainless steel. - PVDF ( polyvinylidene fluoride ) requires

support, when heated tends to leak, deal legs and no threaded fittings.

Reverse osmosis.

• Cold system.• Filters are not absolute – at least two filters

be in series.• No ball valves to be used – stagnant water.• Ultrafiltration to be added.• Filters are to be used with stated purpose.

Purified water system.

• Ozone utilization – for optimum effectiveness dissolved ozone residue remains in the system.

- employee safety and use problem• 0.2 micron line filter housing provides good

environment for contamination.• UV light to be kept on continuously, glass sleeve

around the bulb must be kept clean – kills only 90% of the organisms entering the system.

Purified Water System