Criticial Utilities Qualifcation Part II
Criticial Utilities Qualifcation Part II
Criticial Utilities Qualifcation Part II
INTRODUCTION
There are various types of water used in the Pharmaceutical Industry. In their multiple uses, such as in actual product
formulation, in processing operations, and as a final rinse of
product contact surfaces, they can truly be considered product ingredients. Purified water can be produced many different ways and with a range of designs and equipment. The use
of pharmaceutical grade water is crucial in the production of
pharmaceutical drug products. Therefore, the validation and
the routine monitoring of these systems are critical in maintaining the quality of the final product. This section of the article on critical utility systems will discuss the basic steps in
validating water systems and, once validated, in establishing
a routine monitoring program to maintain them.
Water is classified into several groups depending upon its
source, quality, treatment, or use. It is also necessary to define each classification by its minimum quality requirements, especially with regard to expected chemical and microbiological purity.
Figure
1
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Four Basic Types of Water Classification1
Level
I
II
III
IV
Water Types
Well water
Potable water
PW used for critical batch applications
Food and Drug Administration (FDA)
water for final rinse, formulation,
and WFI
Level I Water
Level I is untreated water used for utilities (fire protection, lawn sprinklers, etc.) and may be from a well or surface source.
Level II Water
Level II (potable) is drinking water, which must meet
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Figure
2
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Major Contaminants in City Water Systems
Contaminant
Total Dissolved
Solids (TDS)
Total Hardness
Total Organic
Carbon (TOC)
pH
Microbial Limits
125.74 mg/L
77.71 mg/L
10.45 ppm
9.23
500 cfu/ml
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Figure
3
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Pre-Treatment Water Specifications
Contaminant
Specification
Conductivity
Endotoxins
Microbial
pH
Total Solids
Chlorine
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Figure
4
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Purified Water Specifications
Contaminant
Specification
Conductivity
Endotoxins
Bacteria
pH
TOC
USP Specifications
No Specifications
100 cfu/ml
5.0 - 7.0
500 ppb
Water-for-Injection System
The components that comprise the WFI system include:
System Details
Distillation System
A four-effect distillation unit produces USP water for injection. The WFI storage tank level transmitters control
the operation of the still. RO/DI treated water flows into
the WFI still feed and produces WFI quality distillate.
The multi-effect still is capable of producing clean steam
for periodic clean steam sterilization of the WFI storage
and distribution systems. The distillation process will
provide a three-log reduction in endotoxin and a five-log
reduction in bacteria to meet the requirements of USP
testing results.
WFI Storage System
Water for injection is supplied to a storage vessel from
the multi-effect still. WFI quality water is maintained
within the storage system by constant recirculation of the
storage system contents at greater than 80C. A plant
steam jacket on the WFI storage vessel maintains the temperature of the WFI within the storage system. The temperature of the vessel contents is maintained above 80C.
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Figure
5
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Water-For-Injection Specifications
Contaminant
Specification
Conductivity
Endotoxins
Bacteria
pH
TOC
USP Specification
0.25 EU/ml
10 cfu/100 ml
5.0 - 7.0
500 ppb
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Deionization
Distillation
Reverse osmosis filtration
Ultra filtration
Phase 1
1. All water systems should have documentation containing a system description along with accurate
drawings. The drawings must show all equipment in
the system from water input to points of use. They
should also show all sampling points and their designations.
Phase 3
1. The third phase of validation is designed to demonstrate that, when the water system is operated in accordance with the SOPs over a long period of time, it
will consistently produce water of the desired quality.
2. Any variations in the quality of the feed water that
could affect the operation, and ultimately the water
quality, will be noticed during this phase of the validation.
3. Sampling is performed according to routine procedures and frequencies. For WFI systems, samples
should be taken daily from a minimum of one point
of use, with all points of use tested weekly.
Phase 2
The second phase of the water system validation must
demonstrate that the system will consistently produce the desired water quality when operated in conformance with the
SOPs. Sampling is performed as in the initial phase and for
the same period. At the end of this phase, the data should
demonstrate that the system would consistently produce the
desired quality of water.
Figure
6
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Microbiological and Chemical Limits
Test
Potable Water
Purified
Water-For-Injection
pH
TOC
Conductivity
Bacteria
Endotoxins
N/A
N/A
N/A
500 cfu/mL
N/A
5.0 - 7.0
500 ppb
4.7 to 5.8 m/cm
100 cfu/mL
Not specified
5.0 - 7.0
500 ppb
Current USP specifications or method
10 cfu/100 mL
0.25 EU/mL
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moving various metal contaminates that can cause oxidization of surface areas. After the passivation process is complete, it is important to ensure that no residues remain in the
system. Last of all, it is important to verify that the distribution system and the point of use valves are labeled and
tagged.
Operational Qualification
During the OQ phase it is important to test and verify the
following functions:
Flow and pressure rates
Temperature and conductivity
Sanitization or Steam-In-Place (SIP) procedures
Computer control functions
Alarms
Pumps
Major components function according to design
specifications
Filter integrity
It is imperative to verify that all instruments and devices
have been calibrated before starting the OQ. After all functions are verified, it is essential to perform preliminary testing on the system. This involves sampling the system during
a two-week period for microbial and chemical quality. It is
also important to verify the efficiency of each major component to ensure it performs according to the design specifications. For example, the carbon bed should be tested or monitored to ensure it is capable of removing chlorides to an acceptable level. By performing this step, you will be able to
determine whether the system is ready for the PQ phase of
the validation. This step will prevent the waste of financial
resources and time spent unnecessarily on a system that may
not be ready for the PQ study. All system SOPs should be developed and finalized during the OQ phase.
Performing a baseline test of the system before starting
the PQ should capture valuable information on the systems
ability to produce high quality water. It is important to qualify the microbiological and chemical test methods before
starting the Performance Qualification Study.
Performance Qualification
The PQ phase involves monitoring the system for microbial and chemical quality over a specified period of time.
Most companies perform this study for 30 to 60 consecutive
days. After 30 days, the system is shut down for 24 hours
(stagnation test). After 24 hours, testing continues for another 30 days to determine how long it takes for the system
Figure
7
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Typical Water System Validation Lifecycle
CHGS
Identify Critical Process
Parameters and Establish
Operating Ranges
CHGS
Installation
Qualification (IQ)
Operational
Qualification (OQ)
Establish Corrective
Action Response
CHGS
Prospective Phase-Confirm
Appropriateness of Critical Process
Parameter Operating Ranges
Concurrent/Retrospective Phase
- Establish reproducibility and reliability system
- Evaluate effects of seasonal changes
- Confirm appropriateness of alert and action levels
and corrective action program
Validation Maintenance
- Change Control
- Periodic Review
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Steam Sterilizers
Steam-In-Place system (water systems sanitization,
bio-reactors, freeze dryers, etc.)
Portable Jacket Tanks
Clean Steam System Construction
The components that comprise various clean steam systems are as follows:
Multi-Effect Columns
Condenser
Heat Exchanger
Construction Qualification
During the CQ phase of the validation, material certification of tubing and components should be collected. Welding logs should be inspected to ensure that the welders are
conforming to their own quality program. Certain test procedures, such as hydrostatic testing, should be witnessed and
documented. At the same time, verification that piping is
sloped to drain as specified and according to code should be
completed.
Commissioning and Startup
During the commissioning phase, all major components
are checked to ensure they function properly and all critical
operating parameters have been set and verified according to
function specifications. A final walk down of the system is
performed to verify that the system is ready for the qualification phase.
Installation Qualification
An IQ phase consists of verifying that instruments,
valves, heat exchangers, and major components are installed
as specified in the design. Another key element is the verification of critical utility support such as high quality water,
plant steam, and electrical power. The system should be inspected to verify that the drawings accurately depict the asbuilt configuration of the water system. The data on cleaning
and passivation should be reviewed. The distribution system
and point of use valves should also be labeled and tagged.
Pumps
Major components functions
Plant steam
It is critical to verify that all instruments and devices have
been calibrated before starting the OQ. After all functions are
verified, perform the crucial preliminary testing on the systems. This involves sampling the system for microbial and
chemical quality for a period of two-weeks. All system SOPs
must be developed and finalized during the OQ phase.
Testing the system before starting the performance qualification gives valuable information on the systems ability to
produce high quality clean steam. Once again, it is critical to
qualify the microbiological and chemical test methods before starting the Performance Qualification Study.
Performance Qualification
The PQ phase involves monitoring the system for microbial and chemical quality over a specific period of time.
Most companies perform this study for 30 consecutive days.
Sampling should be performed daily at each point for the duration of the PQ.
At this point, monitoring the incoming water source is
key because doing so will make it easier to detect the source
of any problems, should they occur. Since plant steam is
used to heat up the water source via a heat exchanger, it is
important to also test for hydrazine. This test will ensure that
there are no leaks from the heat exchanger that may introduce hydrazine into the clean steam system.
Acceptance Criteria
The performance qualification test period usually extends for 30 days. Clean steam condensate samples taken at
the clean steam sampling valve shall meet the criteria indicated in Figure 8.
Operational Qualification
During the OQ phase, it is important to test and verify
the following functions:
Flow and pressure rates
Temperature and conductivity
Computer control functions
Alarms
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Figure
8
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Clean Steam Condensate Criteria
Specification
TOC
Microbial
Endotoxin
Heat Exchangers
WFI Chemistry
Data Analysis
Where applicable, calculate the arithmetic mean and
identify minimum and maximum readings for each sample
port. Summarize data in tables and correlate maintenance
activities to test data where applicable. Identify microbial
organisms to species level.
At the end of the PQ test period, assemble all documentation and tabulate the results into spreadsheets that are capable of trending the data. Collect copies of all applicable
collection data forms and validation notebook pages. Once
the data has been reviewed and a final report has been written, the system is ready for the routine monitoring program.
(This completes Part II of "Design, Construction, Commission, and Qualification of Critical Utility Systems." The
final and third part of this article covering HVAC and Gas
Systems will appear in the November 2005 issue of this Journal. The first part of this article, an overview of critical utility systems, appeared in the May 2005 issue of the JVT.)
Procedure
The following is one procedure that can be used during
the intensive monitoring phase of the clean steam system:
1.
2.
3.
4.
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REFERENCES
1. Center for Drugs and Biologics, Center for Devices
and Radiographic Health, "Guideline on General Principles
of Process Validation," FDA Rockville, Maryland, 1987.
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