The document outlines the design, validation, and operational qualifications of water systems used in pharmaceuticals, emphasizing the importance of high-purity water for injection and purified water in manufacturing processes. It details the requirements for system design qualifications, installation procedures, performance testing, and microbial limits to ensure product quality and compliance with regulations. Key practices include periodic monitoring for contaminants, rigorous operational protocols, and documentation of any non-conformities.

1. Design & validation
of water systems.

2. Design of the system.
• Type of water-
-Purified water
-Water for injection
• Product to be manufactured
• Temperature of system

3. Water for injection.
• Distillation.
• Reverse osmosis.
However in the bulk pharmaceuticals and
biotechnology ultrafiltration is employed to
minimize endotoxins.

4. Water for injection.
• Some opthalmic irrigating solution and
inhalation products where there are pyrogen
specification.
• Otherwise purified water.

5. Purified water.
• Opthalmic.
• Inhalation.
• Oral.
• Topical.
• Cosmetics.

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

7. 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.

8. 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.

9. System validation.
• Hence reliance is placed on
- periodic testing for microbial quality
- installation of monitoring equipments at
specific check-points

10. 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.

11. 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.

12. 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.

13. Design qualification.
• The print should be compared to the actual
systems annually to ensure its accuracy.
• To detect unreported changes.
• To confirm reported changes.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. 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.

20. 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.

21. 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.

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

23. 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.

24. 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.

25. 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.

26. 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.

27. 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.

28. • 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.

29. 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.

30. 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.

31. Purified Water SystemPurified Water System