This document discusses the validation of critical utility systems used in pharmaceutical manufacturing facilities. It covers the validation of HVAC systems, water systems, steam systems, compressed air systems, and nitrogen gas systems. For each system, it provides an overview and discusses the user requirements, design qualification, installation qualification, operational qualification, and performance qualification protocols. The validation aims to ensure these utility systems meet quality standards and specifications to support the manufacturing of safe and effective pharmaceutical products.

1. • PRESENTD BY :-
• PATIL PRANJAY SADASHIV.
• FIRST YEAR M.PHARM.
• DEPARTMENT OF QUALITY ASSURANCE.
H. R. Patel Institute of Pharmaceutical Education
and Research, Shirpur

2. Content:
1 • Validation of HVAC
2 • Validation of water system
3 • Validation of pure steam system
4 • Validation of compressed air
5 • Validation of nitrogen gas
6 • Reference

3. Validation Of Utility System
 The use of critical utility systems in the pharmaceutical
industry is very important to final product quality.
 Critical utilities found in pharmaceutical, medical device,
and biotechnology production facilities usually support
various equipment and processes.
 These utilities must meet both quantitative and qualitative
specifications.
 The critical utilities that been used:
1. Water systems
2. Clean steam system
3. Heating Ventilation and Air Conditioning (HVAC)
systems
4. Process gases

4. Why is Utility System Quality
Important in Pharmaceuticals?
 All pharmaceutical manufacturing facilities need
to adhere strictly to FDA-approved regulations.
 CGMP requirements can be useful in ensuring the
efficacy, quality and safety of product,

5. VALIDATION OF HVAC
SYSTEM
 Heating, ventilation and air conditioning system are used in the
pharmaceutical plant to prevent contamination and to provide
comfortable working conditioning.
 Environmental parameter like conc. of airborne nonviable and
viable particulate matter, chemical and gaseous material can affect
the quality of finished product.
 The product quality can also be affected although to a lesser extent
by vibration, lighting and other radiation.
 Ambient air may have different contaminant the most common
being the dust. Dust can be roughly classify by size:
a) Coarse dust(particle size 50-500µ)
b) Fine dust(particle size 1-50µ)
c) Ultra fine dust (particle size 0.5-1.0µ)

6.  https://www.youtube.com/watch?v=ScVBPAitibQ
 https://www.youtube.com/watch?v=DaCmHEjz6p4
(AHU system)
 https://www.youtube.com/watch?v=uWwVsFqNFp4
(AHU system)

7. HVAC Control and monitoring
system
 The validation team should prepare a validation protocol first. The
protocol should include DQ, IQ, OQ, & PQ.
User required specification
1. Room name.
2. Pressure gradient.
3. Temperature, Relative humidity.
4. Filter to be used.
5. Machine horse power.
6. Minimum air changes per hour.
7. Class of air to be maintained.
8. Room dimension in meters

8. DQ protocol
 Scope: to demonstrate that functional requirement have been incorporate
into the HVAC design specification and equipement selection.
 Objective: the element will provide for the verification of the
conformance of the selected components design specification with their
intended operational and performance specification.
 Responsibility: the element define the responsibility.
 System Description: this element give description of the system specify:
1) Class of cleanliness
2) Category of product to be manufactured
3) Room design criteria
4) Design and guideline for equipement and material selection
5) Reference to regulatory requirement
6) Testing and qualification requirement

9. IQ protocol:
 Scope: to verify that all component of HVAC system have
been installed in accordance with their approved design and
engineering specification.
 Responsibility: name and designation of person responsible
for approving and executive of the protocol
 Manufacturing equipment and workmanship verification:
this element should provide an inventory of the equipment
installed vis-a-vis approved specification. It should also
provide the means to verify the proper installation of system.

10. Cont….
 Calibration verification: under this element a list of
instrument which require calibration should be prepared and
calibration should be carried out calibration certificate should
form a part of the documentation.
 SOP verification: under this element a list of SOP and
manual should be prepared.
 Utilities connection verification: under this element
utilities connection supporting HVAC system should be
verified to ensure that the same have been installed properly
and are in accordance with specification and drawing.
 Change parts and replacement parts verification: under
this element a list of replacement and change part should be
prepared.

11. Cont…..
 Maintenance procedure verification: under this element it should
be ensure that a maintenance program exist as recommended by
the manufacturer.
 Lubricant verification: under this element it should be ensure that
only approved lubricant have been used and these do not come in
contact with supply air.
 As built drawing listing & verification: many time there are
difference between original drawing and as built drawing . As built
drawing is the drawing which has been physically verified through
inspection, signed and dated by the person performing inspection

12. OQ protocol
 Objective: to verify that given component of HVAC system
operate as specified and are in agreement with acceptance
criteria fixed for the system parameter.
 Responsibility: names and designation of person who are
responsible for approval and execution of protocol.
 System description: under this element a brief description of
how the system operates and sequence of control should be
given.

13. Cont..
 Instrumental calibration: under this element it should be verified that all the
instrumentation specified have been installed and are in calibrated system.
 Testing equipment calibration verification: certain instrument might be
required to verify operation of the system.
 SOP verification: under this element verification of all SOP required operation
system should be verified. If SOP is under draft stage, it should be finalized.
 OQ test: these include a series of tests designed to prove proper operation of
HVAC system;
1) Air system balancing
2) HEPA filter integrity system
3) Pressure differential stress test.
4) Airflow velocity and uniformity system

14. PQ protocol
 The PQ protocol is similar to OQ protocol. In the PQ the
HVAC system is assessed for its performance with in the area
it serving.
 Data is collecting under static conditions as well as under
dynamic condition by stimulating the process or actually
carrying the process.
 The test that may be carried out during the PQ include;
1. Temperature-humidity control test.
2. Air cleanliness test.
3. Airborne bio-burden test.
4. Surface bio-burden test.

15. PQ include various test:
1. Air system balancing and pressure differential test:
2. Air volume for non-unidirectional airflow terminal airflow
filter test:
3. HEPA filter integrity system(DOP test):
4. Pressure differential stress test:
5. Start up and shut down test:
6. Control and monitoring device test

16. Cont….
7. Power fail and recovery test:
8. Airflow velocity:
9. Airflow parallelism test:
10. Temperature-humidity test:
11. Air cleanliness test:
12. Air borne bio-burden test:
13. Surface bio-burden test:

17. Validation of water system
 The Indian GMP text state that:
There shall be validated system for treatment for water drawn from
own or any other source to render it potable in accordance with
standard specified by the Bureau of Indian standard or local
municipality.
 Grade of water:
1. Drinking water
2. Purified water
3. water for injection.
 water purification method:
1) Reverse osmosis
2) Chlorination
3) Distillation

18.  https://www.youtube.com/watch?v=axY_1SSKKcY
 https://www.youtube.com/watch?v=uARhWaQ8SMA
 https://www.youtube.com/watch?v=4FjQxkIdFDU

19. User required specification
 The first step in designing a water system is to define
the system’s intended use.
 Type of water
 Source of water
 Grade of water
 Flow of water
 Conductivity.
 Temperature
 Purification method.

20. IQ PROTOCOL:
 A careful check is made to ensure piece of the equipment
ordered has been received and is according to the system
design.
 It will be the beneficial to make a check before the equipment
is shipped by the vendor.
 At this stage issue related to support system like instrument
calibration system, prevention & maintenance procedure and
operation sop are addressed.
 IQ also involved the following activities:
1. Review of steel passivation
2. Verification of material of instrumentation
3. Absence of leaks
4. Review of documentation

21. OQ protocol:
 OQ verifies the capability of the processing until that they perform
satisfactory within the operation limit.
 The focus of the OQ is to define the critical item and practices e.g.
alarm conditions for utilities such as low stem pressure, differential
pressure limit, conductivity limit.
 calibration need are assesed and calibration are carried out.
 Documented procedure are also developed fir the maintainance,
adjustments, monitoring and control of the equipement involved.
 Limites within which the plant will operate should be specified.
 The OQ protocol provide a functional testing of the system
component.

23. PQ protocol:
Phase 1:
 During the phase a test period of 2-4 weeks should be spent
monitoring the system. The system should operate contineously
without failure or performance deviation. T include;
1. Sampling of the incoming feed water daily to verify its quality.
2. Sampling after each step in psurification process daily.
3. Finalization of operating ranges.
4. Verification of provisional alert.
5. Finalization of operation, sanitization, cleaning and maintainance
procedure.
6. Testing of water for each microbiological and chemical testing as
per plan.

24. Cont….
Phase 2:
 After complition of phase1 a further period of 2-4 week should be spent on
monitoring the water system. the sampling system might remain the same as in
the phase1.
 This approach should demonstrate the following:
1. The water system operate consistency.
2. The water system produce and delivared constantly the require quality of
water in require quality.
Phase 3:
 Usually run of 1 year after the succesfull complition of phase 2. water can be
used for manufacturing purpose during the phase.
 The phase has the following objective:
1. To demonstrate reliable performing in long run .
2. To evaluate seasonal variation in feed water.
3. To reduce sample location.

25. VALIDATION STEAM
SYSTEM
 There are 2 type of steam system in pharmaceutical industry.
 The system which is called house steam. Consist of steam
generator and distribustion system made up of iron or steel.
 The second type of system called as clean steam estabilished when
steam is used for directly treating the product or product contact
surface.
 Distribution line in both plant and clean steam are insulted to
reduce heat and to provide safety.
 Approach of steam system validation include the following step:
1. Make a process diagram and identify major step.
2. Define major equipment process.
3. Carry out IQ & OQ.
4. Carry out PQ

26.  https://www.youtube.com/watch?v=GMo6A1n1ztE

27. IQ protocol:
 Clean steam generator:
1. Conform the checklist according to purchase
specification
2. Connect the generator to the required utilities.
3. Tighten flanges or other fiting clean generator
chemically and passivate generator after installation.
4. Carry out pressure testing and result record.
5. Check and calibrate all critical process intrument. If
calibration of any instrument can not be done by internal
staff, engage an external agency.

28. Distribuion system:
1. Conform that material of construction of distribution system is as per the
specification of the company.
2. Compare the design drawing and the as built drawing and make note of
modification carried out in the design drawing at the time of construction.
3. Clean the distribution system efoe start up and record it.
4. Carry out the pressure test and record the result.

29. OQ protocol:
 Test all the point of the system for adequate supply of the
steam under maximum load or other production conditions. If
there is limitation of use of only a few use point at time these
conditions should be tested as worst case condition.
 Quality of steam should be tested ay all the use point.
 Use point should be tested to find out that excess condensate
is not present under operation condition
 If it is found excess condensate is present, it should be
removed by additional traps or other suitable means.

30. PQ protocol
 The PQ consist of the required testing specified in protocol.
 A typical protocol would include several test under defined load
conditions.
 testing consist of conditioning steam at various use point and subject
condensate to testing for WFI.

31. Validation for compressed air
 Two types of compressed sir system used in the
pharmaceutical industry.
 One conventional oil lubricated compressor for operating
instrument and machinery where no contact with product
or environment, where product is being manufactured is
involved.
 Second is an oil free air system used in clean room areas.
As an illustration only oil free compressed air system will
be taken up for discussion.
 Typically oil free compressed air system consist of an oil
fee compressor, dry drum storage tanker and distribution
system.

32.  http://www.gmptech.net/watersystem.php

33.  https://www.youtube.com/watch?v=2KKCwfvqoNs
 https://www.youtube.com/watch?v=bGoWii2L7bE

34. IQ protocol:
 Oil free compressor:
Check
specification
on purchase
order
Verify that no
oil or other
lubricant used
in the
compressor
Check that all
required utility
requirement
have been met
check whether
start up
procedure were
performed and
document
All critical
instrument
have been
calibrated

35.  Compressed air storage tank
Conform
whether the
material of
construction
is as per
specification
Check
capacity of
the tank
against the
purchase
specification
Carry out
pressure
holder test
Examine
cleaning
procedure
Check all
pressure rate
for tank
against
purchase
specification
Calibrate all
critical
specification
Distribution system
Conform
material of
construction
Compare the
drawing of system
with as built
drawing to show
whether any
modification
Pressure test
Examine
cleaning
procedure

36. OQ protocol:
 Check all the use point for the test mentioned below and
record their result:
1. Identity
2. Nonviable particle count
3. Microbial count
 Check several worst case location for purity
 Test all instrumenats and alarm for their operation status
 Test the compressor output for hydrocarbon

37. PQ protocol
 PQ consist of completing the documentation for various step mentioned above
and repairing operation testing as specified in the validation protocol.
 The operation test should be repeated over several days.
 PQ can be considered as validation.

38. Validation for nitrogen gas
OQ PROTOCOL:
 A) storage tank:
1. Check storage tank for comforance to the purchase specification.
2. Check whether the material of construction conform to the
purchase specification.
3. Conduct pressure hold test.
4. Document all pressure rate for tank as well as component against
the purchase specification.
5. Calibrate all pressure gauge and sensors, both monitoring &
controlled

39.  B) Distribution system:
1. Confirm the material of construction and design parameter
specified by the company.
2. Compaire the design drawing of the system
3. Pressure test the system & document to conform its
integrity.
4. Examine the cleaning procedure.

40. PQ PROTOCOL
 PQ consist of completing the documentation from the various above
mentioned step and repeating the testing specified in the validation
protocol.
 As stated earlier, in case of equipment and system,PQ can be considered
as validation.

41.  https://www.youtube.com/watch?v=qmQvqfMBVAA

42. REFERENCES:
 “Validation in pharmaceutical industry” P.P. Sharma,
second edition, published in 2007 Delhi, page no-169
to 233
 http://pharmaceuticalvalidation.blogspot.in/2010/01/util
ity-qualification.html
 http://www.gmptech.net/watersystem.php
 https://www.pharmamanufacturing.com/articles/2017/m
onitoring-plant-utilities-for-operational-excellence/
 http://www.rscal.com/utility-system-qualification-
pharmaceutical-industry/