PQ and Monitoring of Water

Systems
Dawn Tavalsky
Deputy Director
Cleaning Validation

Water in the Pharmaceutical World

Critical component in the
manufacture of any drug product:
Raw
material
R
i l
Process ingredient
Cleaning agent

High likelihood to be source of

contamination:
All life needs water
Mi b can grow with
ith littl
ti t
Microbes
little nutrient
encouragement, as long as there is
water

Where to turn for Validation Guidance?

USP <1231> Water for Pharmaceutical
Purposes
FDA Guide to Inspection of High Purity
Water Systems
Parenteral Drug Association Technical
Report No. 4 titled, "Design Concepts for the
Validation of a Water for Injection System."
ISPE Good practice guide Commissioning
and qualification of pharmaceutical water
and steam systems
40CFR141 Total Coliform Rule
Standard Methods for the Examination of
Water and Waste Water
US FDA 483 Observations, Warning Letters,
Recalls

USP <1231> Water for Pharmaceutical

Purposes

Validation of Water Systems

A typical program involves intensive daily sampling and
testing of major process points for at least one month after
operational
ti
l criteria
it i h
have b
been established
t bli h d ffor each
h unit
it
operation, point of use, and sampling point

USP Pharmacopeial Forum Vol. 30 (5) p1773

Validation of Water Systems

IQ
OQ
PQ
PQ is executed by intensively monitoring the system over a
period of 1 year and is typically structured into 3 phases
phases. Before
starting the PQ, the operational ranges and sanitizing cycles must
be fixed based on the results of the OQ and then verified in the
subsequent PQ.

Validation of Water Systems

Sample Sites During PQ
Raw water and water immediately after the production system
must be tested.
tested
Sampling points after critical stages of production for qualification
purposes must be considered, based on the system configuration
and risk assessment. To prove effectiveness, samples are
typically taken after carbon filters, deionizers, and before and
after UV units.
Well water must be tested and comply with drinking water
regulation
The Points of Use must be sampled
Any additional System Monitoring Sites must be sampled

Validation of Water Systems

Performance Qualification Phase 1
PQ Phase 1 is intended to demonstrate that the system operates
p
g ranges
g and delivers water of the
within p
predetermined operating
required quality.
PQ Phase 1 usually lasts over a time period of 2 weeks to 4
weeks with daily sampling (representing worst case usage
condition) for 10 to 20 working days at every monitoring point.
Samples must be tested for the required microbiological and
physicochemical parameters.
All additional online-recording of TOC and Conductivity must
be assessed in the respective validation report.

Water produced during this period must not be used for regular
production purposes.
The formal provisional release of the water system must be
performed after the review and assessment of all available
results obtained during this phase.
8

Validation of Water Systems

Performance Qualification Phase 2
The second phase is intended to demonstrate that the system
consistently operates within predetermined operating ranges and
delivers water of the required quality, when it runs in accordance
with the SOPs with consumptions representing production usage.
The sampling is performed daily in the same manner as in PQ
Phase 1 for another period of 2 to 4 weeks with daily sampling
for at least 10 to 20 working days at every monitoring point.

Water produced during PQ Phase 2 may be used for regular

p
p
p
production p
purposes,
provided that PQ Phase 1 was assessed
and documented by QO to be successful and authorized for use.
If critical operating parameters (e.g. sanitization conditions)
need to be changed during phases 1 and 2, consideration
must be given to their possible repetition.

Validation of Water Systems

Performance Qualification Phase 3
The PQ Phase 3 demonstrates that the water system, which is
operating in accordance with the SOPs over a long period of time
(at least 44 to 48 weeks), will consistently produce water of the
required quality.
Microbiological sampling is performed (working) daily at a
minimum of one monitoring point, with all monitoring points
tested at least weekly.
Physicochemical sampling is performed at least weekly from a
selected monitoring point representing the whole system (e.g.
the return to the tank).
The PQ of the water system is completed, when data for a full
year are obtained.

10

Validation of Water Systems

The validation of WFI systems must follow the approach as given in the table above. For PW
and HPW Systems the approach shown above is highly recommended but may be adapted
according to site usage and risk analysis assessment particularly in terms of sampling point
frequencies.

11

ISPE Guide with Respect to WFI

Phase 1 and 2 (the first month)
For the first month of sampling you test every point every
day

Phase 3 (for the rest of the first year)

"For WFI systems, the FDA Guide recommends sampling
daily from a minimum of one point of use, with all points of
use tested weekly."

After Phase 3
No formal frequency recommendation, But, the agency
would be looking for testing similar to Phase 3 unless you
had a very good record and justification to reduce the
sampling.

12

Developing the Sampling Scheme

Begin with end in mind
There is no one size
fits all
all

Each situation is unique

Taylor the analytical
techniques to the final
use of the water in the
manufacturing process

13

Microbial Water Validation Considerations

Most waterborne contaminants are Gram negative bacteria.
We want quantification and qualification.
Exogenous
contamination:
E
t i ti
ffaulty
lt air
i vents,
t faulty
f lt seals,
l
human interaction
Endogenous contamination: colonization in resins, carbon
beds, filter membranes, dead legs.
Biofilm formation: microbes adaptation to survival in low
nutrient environment.
Sampling captures planktonic organisms shed from
biofilm upstream.

14

Sampling Considerations
How do I develop a sampling scheme that minimizes
risk without overdoing it?
First know the regulations/site policies
Second Evaluate the time and cost involved with
additional sampling
Third Weigh the risk of getting a failing sample
You HAVE to be a little strategic!!

15

Review Printed Time Estimation Sheet

Note: It takes more time than

you might
y
g think when you
y
add up all of the
minutes

16

Example List of Sample Sites

17

Example Sample Scheme

18

Example Sample Scheme

19

Example Sample Scheme

20

10

Sampling Instruction Considerations

Proper sampling equipment
Document training of samplers
Fl hi ?
Flushing?
Do not spray alcohol prior to sampling
Transfer hose?
Refrigerate after 30 minutes, test within 24 hours
OOS? Not always the labs fault.

21

Sampling Instruction Considerations

Include specific details on how to sample photos are
also often very helpful

22

11

Example List of Sample Containers

23

Example List of Sample Equipment

24

12

Example Sample Instructions

25

Example Sample Instructions

26

13

Example Testing Specifications

27

Heavy Metals?
USP justifies:
NPDWR specs are very tight
Contemporary water system
construction materials do not leach heavy metals
No failures in previous tests

Washington Post Article:1

Questions veracity of local water authority tests
Old infrastructure in old distribution systems leach lead

European Pharmaceopeia:
Retains heavy metal requirement

Instrumentation
AA or ICP allows for higher sensitivity.

Should at least document absence during

commissioning.

28

14

How long should microbial monitoring continue?

A water purification system is dynamic and changing

I
Internal
l ffactors:
Aging resin
Aging filters
Aging UV lights
Maintenance
Leaks
Dead legs
Biofilm formation
Production shifts

29

How long should microbial monitoring continue?

Seasonal Variations
Water
quality
with
W
li changes
h
i h seasons
Affected by temperature
Drought, flood

Wisconsin Cryptosporidium outbreak 1993:

50 people died
4000 people hospitalized
403 000 people became ill
403,000
Ineffective filtration failed to remove oocysts
Turbid feed water slows disinfection

30

15

What is a biofilm?
Unwanted adhesion of bacteria or other organisms onto
surfaces of solution handling systems
N t necessarily
Not
il uniform
if
in
i space & time
ti
May contain significant amounts of inorganic materials held
together by the polymeric matrix
(Charackis & Marshall, Biofilms, 1990)

31

Biofilms

32

16

Biofilms

33

Biofilms

34

17

Biofilms

35

Biofilms

36

18