HVAC Master Validation Plan

Validation Plan
For
HVAC
(Heating, Ventilation and Air Conditioning)
System in Sterile Area

(XXX pharmaceutical manufacturing Company)
Effective Date:
Validation Plan for HVAC System in Sterile Area
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
VALIDATION PLAN APPROVAL

Written by
Name
Signature
Date
: Validation Engineer
:
:
:
Reviewed and Approved By: Validation Manager

Name
:
Signature
:
Date
:
Reviewed and Approved By: Engineering Manager
Name
:
Signature
:
Date
:
Reviewed and Approved By: Production Manager
Name
:
Signature
:
Date
:
Reviewed and Approved By: Quality Control Manager
Name
:
Signature
:
Date
:
Reviewed and Approved By: Quality Assurance Manager
Name
:
Signature
:
Date
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Approved By: Quality Unit Manager
Name
:
Signature
:
Date
:
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TABLE OF CONTENTS
Sl #
Titles
Page Numbers
1.
Purpose
2.
Objective
3.
Scope
4.
Quality standards
5.
System boundaries
6.
Area Description (Sterile Area)
7.
Requirement for Materials and Equipment
8.
System Description
10
9.
Responsibilities
12
10.
Training Requirements
13
11.
Aseptic systems impact/Criticality Assessment
14
12.
Validation Approach
15
13.
Installation Qualification
18
14.
Operational Qualification
28
15.
Performance Qualification
38
16.
Planning and Cost
46
17.
Discrepancy/ Justification And Corrective Action
46
18.
Validation
46
19.
Modification/ Change Control During Qualification
46
20.
Re-qualification
47
21.
References and Related Records
47
22.
Definitions
48
23.
Glossary
48
24.
History
50
25.
Attachments
51
26.
System Qualification Statement And Qualification Summary
51
27.
Control of qualification protocol format
51
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Introduction: Pharmaceutical rules and specifications are often contains very precise but
also generally formulated requirements of air conditioning technology, such as temperature,
humidity and ventilation of premises should be adequate. This generally formulated
requirement is partially substantiated in the supplementary guidelines of the EU GMP
Guideline for the manufacture of sterile products.
Two basic types are distinguished by the terms of Room Ventilation Technology and
Process Air Conditioning Technology. Both types are found and required in the
pharmaceutical manufacturing sites. The essential task of a ventilation system is to
guarantee that the desired room conditions, such as temperature, humidity and cleanliness.
In contrast, the process air systems must guarantee the required process parameters.
General:
The HVAC system plays an important role in product, personnel, environment, instrument
and machine protection. This can be presented as clean environment, removal of hazard
contaminant and provide a suitable temperature and humidity control within acceptable noise
level by providing clean environment.
HVAC utility is designed to control the level of viable and non-viable particulate exposure that
a drug or medicinal device might receive in addition to regulating temperature and relative
humidity conditions. HVAC utility is qualified to demonstrate operating conditions of the area.
The areas serviced by the HVAC utility are classified based on viable and non-viable
particulate levels during static operating conditions and dynamic operating conditions.
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1.
Purpose: The purpose of validation plan is to schedule the tasks to demonstrate the
plan on HVAC system in Sterile Area. This plan will define who will be responsible to
initiate, execute, review and approve each task assigned, how the data/document will be
generated and what the entire validation package will be compiled and collected. This
validation plan is being written in compliance with validation master plan (VMP).
2.
Objective: The objective of this Validation plan is to demonstrate and document that all
components, control systems and processes functionality associated with the HVAC
system that appropriates in accordance with current Good Manufacturing Practices
(cGMP) regulatory aspect for sterile area.
2.1 HVAC is designed to control the level of viable and non-viable particulate exposure
that a drug receives in addition to regulating temperature and relative humidity
conditions.
3.
Scope: This validation plan is limited to HVAC system in sterile area designed for
aseptic filling process in XXX Company, which is located in facility no. YYYYYYY.
4.
Quality standards: The HVAC system must supply quality air which should be in
compliance to all standards according to:
4.1 AS/NZS ISO 14644.1:2002: Clean room and associated controlled environments,
part 1: classification and air cleanliness.
part 2: specification for testing and monitoring to prove continued compliance with
ISO 14644.1.
part 4: design, construction and start up.
4.4 ISO EN 14644.5:2004: Clean room and associated controlled environments, part 5:
clean room operations
4.5 PIC/S Guideline to GMP for medicinal product
4.6 ISPE Baseline guide volume 3, sterile manufacturing facility
4.7 AS 1386.31989 Cleanrooms and clean workstation part 1&3
4.8 EU GMP Guide, Volume IV GMP for medicinal products section 3 premises and
equipment
4.9 21CFR part 11 Subpart C building and facility and subpart D
4.10 United stat Pharmacopeia USP 32
4.11 European Pharmacopeia Ph Eur 7th Edition
4.12 ISO/IEC 17025 General requirements for the competence and testing of calibration
and testing laboratories
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5.
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System boundaries: The physical boundaries are defined as follows:

5.1 Source of air handling units (AHUs) and air conditioning units (ACUs) including
other forms of air pretreatment (e.g., heating/cooling, dehumidification/
humidification), Attachment No.2 Diagram for Sterile Area.
5.1.1
AHUs require externally supplied heating and cooling sources such as

steam, hot water, or chilled water.
5.1.2
ACUs are self-contained with respect to heating and cooling, and generally
employ a refrigeration-based heat pump. They may be reversible and both
heat and cool the supply airflow.
5.1.3
AHUs, ACUs, and associated ductwork, which supply air to critical and
controlled areas/rooms, are included, while AHUs, ACUs, and related
ductwork, which supply non-GMP; uncontrolled areas (e.g., offices,
cafeterias) are not included.
5.2 Supply air and return air ductwork up to, but not including, grills inside rooms or
areas.
5.3 Support utility interfaces (e.g., electrical connections at disconnect points) for
heating/cooling water supplies, etc.
6.
Area Description (Sterile Area)

6.1 This area is defined to use only sterile oriented products for manufacturing. The
aseptic process involves the handling of sterile components until they are sealed in
their final containers.
6.2 Aseptic area is designed, constructed and engineered to comply with pharmaceutical
compliance standards and to prevent microbial contamination.
6.3 The clean room for the aseptic area is classified according to the required
characteristics of the environment. The in-operation and at rest states should be
defined for each clean room or suites as mentioned in the below-mentioned grade:
6.3.1. Grade A: The local zone for high-risk operations includes aseptic filling
zone, stopper bowls, open vials and making aseptic connections. This zone
is equipped with laminar flow systems with homogenous air speed in a
range of 0.36 to 0.54m/s.
6.3.2. Grade B: This is the background environment for grade A zone.
6.3.3. Grade C: Clean areas for carrying out less critical stages in the
manufacture of sterile products.
6.3.4. Grade D: This area is unclassified, as it is meant for capping gowning room
and black/grey change room.
6.3.5. The airborne particulate classification for these grades are given in the
following table:
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At Rest (b)
Grade
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In Operation (b)
Maximum permitted number of particles/m3 equal to or above (a)

0.5m (d)
5m
0.5m (d)
5m
3,520
20
3,500
20
B (c)
3,520
29
350,000
2900
C (c)
352,000
2,900
3,520,000
29,000
D (c)
3,520,000
29,000
Not Defined (f)
Not Defined (f)
a. Particle measurement based on the use of a discrete airborne particle

counter to measure the concentration of particles at designated sizes equal
to or greater than the threshold stated. A continuous measurement system
should be used for monitoring the concentration of particles in the grade A
zone, and is recommended for the surrounding grade B areas also. For
routine testing the total samples volume should not be less than 1 m3 for
grade A and B areas and preferably also in grade C areas.
b. The particulate conditions given in the table for the at rest state should be
achieved after a short Clean up period of 15-20 minutes (guidance value) in
an unmanned state after completion of operations. The particulate conditions
for grade A in operation given in the table should be maintained in the zone
immediately surrounding the product whenever the product or open container
is exposed to the environment. It is accepted that it may not always be
possible to demonstrate conformity with particulate standards at the point of
fill or when filling is in progress, due to the generation of particles or droplets
from the product itself.
c. In order to reach the B, C an D air grades, the number of air changes should
be related to the size of the room and the equipment and personnel present
in the room. The air system should be provided with appropriate terminal
filters such as HEPA for grades A, B and C.
d. The guidance given for the maximum permitted number of particles in the at
rest and in operation conditions correspond approximately to the
cleanliness classes in the EN/ISO 14644-1 at a particle size of 0.5m.
e. These areas are expected to be completely free from particles of size greater
than or equal to 5m.
f. The requirements and limits are depending on the nature of the operations
carried out.
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6.4 The area is designed also in accordance to following US FDA classification.

Class Name
Particle Size
3
ISO Class
U.S. FS 209E
ISO, m
FS 209E, ft.3
Class 1
35.2
Class 10
352
10
Class 100
3520
100
Class 1000
35,200
1000
Class 10,000
352,000
10,000
Class 100,000
3,520,000
100,000
Adapted from the Federal Standard no. 209E, General Services Administration, Washington DC,
20407 (September 11, 1992) and also [4644-1:1999 Clean rooms and associated controlled
environments-part 1: Classification of air cleanliness. For example, 3520 particles of 0.5m per m3
or larger (ISO class 5) is equivalent to 1000 particles per ft3 (class 100) (1m3 = 34.314ft3).
6.5 Cleanliness Phase

Cleanliness grade A
(FS 209 E class 100 at rest) ISO 5
US class 100 in operation
SI M* 3.5
Cleanliness grade B
(FS 209 E class 100 at rest) ISO 5
US class 10.000 in operation
SI M* 5.5
(FS 209 E class 10 000 at rest) ISO

7
US class 100.000 in operation
SI M* 6.5
Cleanliness grade D
(FS 209 E class 100 000 at rest)
ISO 8
US class: not classified
The local zone for operations with a high level of risk, for
example in the filling area, assembly of the filling apparatus
(pump, filter, etc.), aseptic connections (equipment, tubes,
couplings) under laminar airflow of 0.45 m/s 20%.
Microbiological limit <1 CFU/m3
In the case of faults, controlled, brief intervention by
personnel from cleanliness grade B is permitted.
The presence of appropriately dressed personnel is
permitted.
Turbulent airflow is permitted.
Microbiological limit 10 CFU/m3 (action limit)
permitted.
Microbiological limit 100 CFU/m3 (action limit)
permitted.
Microbiological limit 200 CFU/m3 (action limit
SI M represents the classification on the basis of 0.5m particles
Limits for the microbial contamination of surfaces in these cleanliness grades are generally
tested with purchased nutrition agar contact plates with a diameter of 55 mm (corresponds to
a surface area of 23.75 cm2). Therefore need to consider the specifications per cm2 and
include them in standard operating procedures (SOPs). To be on the safe side, you can
comply with the required limit for a contact area of > 23.75 cm2. Normally, specifications are
provided per plate with a diameter of 55mm or per 25 cm2
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6.6 Types of HEPA filter used in sterile area

Grade Description
Type
Efficiency
Cleanliness grade A
H14
99.995 %
Cleanliness grade B
H14
99.995 %
Cleanliness grade C
H13
99.95 %
Cleanliness grade D
H11
95.00 %
Grade
Recommended
limits
for
microbial
(EU-GMP-Guideline, Annex 1, USP 30)
settle plates
contact plates
air sample
(diam. 90mm)
(diam. 55m)
cfu/m3
cfu/4 hours
cfu/plate
contamination
glove print
(5 fingers)
cfu/glove
<1
<3
<1
<1
3
<1
3 glove
5 clothes
10
<20
5
5
10 floor
5
10 Gloves
20 clothes
100
<100
50
25
200
100
50
For absolutely necessary interventions in cleanliness grade A, the hands covered by the
gloves should be disinfected to ensure that the limit of <1 CFU/5 fingertips is not reached.
However, since individual values of 1 and >1 cannot be excluded (<1 is an average value), in
this case, the average value of the last ten quality controls should be used. This average
value must be <1 CFU/5 fingertips (measure limit value/action limit). In the presence of
correct personnel behavior and operational cycle, a bioburden on the finger tips of >3 CFU/5
fingertips is extremely rare. If operating procedures are not adhered to, the values are
considerably higher, i.e., a value of 2 CFU/5 fingertips can be an indication of systematic
failures and should be regarded as a warning sign. The alert limit could therefore be
determined at 2 CFU/5 fingertips.
7.
Requirement for Materials and Equipment

7.1 Materials required are all the items, which will be routinely used to test air
quality for particulates and microbial counts, the manual operations, humidity,
airflow, make-up air etc. etc.
7.2 Following list of devices must be calibrated before they are used during the
qualification plan. SOPs for each test method, the operation and calibrations of
these equipment used, the data to be recorded and the criteria for acceptance
must be prepared and approved before beginning the qualification plan.
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7.2.1 Micro-manometer
7.2.2 Differential Pressure Gauge.
7.2.3 Thermal Anemometer
7.2.4 Vane-type Anemometer
7.2.5 Multi-parameter ventilation meter
7.2.6 Air Capture hood
7.2.7 Thermo hygrometer
7.2.8 Indoor Air Quality Meter
7.2.9 Compulsion Analyzer
7.2.10 Air Velocity Transducer
7.2.11 Micro-Ohmmeter with airflow hood
7.2.12 Particle Counter
7.2.13 Microbiological Air Sampler and Media Plates
7.2.14 Charts for the time, temperature and pressure recording.
7.2.15 Aerosol generator
7.2.16 Photometer
8.
System Description: HVAC system is fully integrated air conditioning and filtration
system that consists of Air Handling Unit (AHU), fans, filters, and ductwork, heating and
cooling system, gauges and control system. The details of components are described in
attachment no. 1.
8.1 Air Handling Unit: AHU is constructed in a horizontal modular, located within the
plant roof area.
8.1.1. Weather Louver: To prevent insect, eaves, dirt and rain from entering.
8.1.2. Separator: Providing primary filtration for the fresh air with steady pressure
drop.
8.1.3. Pre-filter: Filtration of the fresh air and have resistance to the standard of
EUROVENT 3 and 7 respectively.
8.1.4. Mixing/Exhaust Plenums: Fitted with parallel blade dampers which
operation is extended via drive spindles that is suitable for hand adjustment
and lockable.
8.1.5. Electric Heating Coil: To heat the air to the proper temperature. (Fitted
with over heat cutout that is of auto-reset type.)
8.1.6. Cooling Unit/dehumidifier: To cool the air to the required temperature or
to remove moisture from the air.
8.1.7. Humidifier: To bring the air to the proper humidity, if too low.
8.1.8. Secondary Filters: To eliminate particles of pre-determined dimensions
and/or microorganisms according to the user requirement specification.
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8.1.9. Fan: The fan is multivane backward curved centrifugal, to suite the
volume/pressure characteristics required with double inlet, double width
impeller.
8.1.10. Air Cooled Chillers: The chiller has two refrigerant circuits allowing for
close control of the chilled water circuit serving the Air Handling Unit cooler
battery and service void fan unit under a wide range of cooling loads.
8.1.11. Ductwork: All of the supply and general extract ductwork is installed and
manufactured from galvanized mild steel in accordance with HVAC
specification DW142 low-pressure classification. (Ductwork must be kept
clean during manufacturing and installation and it must be performed in
accordance with HVAC DW/TM2 intermediate level).
8.1.12. Terminal Filter: The final filtration within the Cephalosporin suite must be
with 99.999% efficient HEPA filters.
8.1.13. Pressure Indication: This continuously monitors the pressures of each
room, the air handling unit filters pressure drop, the return air filter pressure
drop and typical supply HEPA filter pressure drop, this being one of the
filters in the filling room.
8.1.14. Gas fumigation system: The air handling system is controlled by
sequence timers which are adjustable, to allow for the air handling system to
be shut down on commencement of fumigation together with the closing of
the airtight dampers in the main supply and return ducts.
8.1.14.1. The fumigation sockets are energized for an appropriate period then
de-energized for a further contact or kill period-stipulated time that
mentioned in the XXX SOP. Once the kill period timer has elapsed, the
air handling systems are automatically re-started with warnings lamps
illuminated indicating that the plant is in degas mode. On completion
of the pre-set degas period, the HVAC for sterile systems continue to
run and degas lights will switch off automatically.
8.2 Room Classification
Room ID
Room Description
Rooms Classification at
rest conditions.
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Responsibilities
The responsibility of the following individuals and departments as defined with reference to
validation master plan VMP001\R0
9.1 Responsibility of XXX Management:
9.1.1. Review and approve of this validation plan (VP), validation protocol, reports,
requirement specification, planning, project management and final validation
plan summary report approval.
9.1.2. Control of plan recourses, cost, activity and continuous monitoring the
process
9.1.3. Monitoring the corrective and preventive action, as well to ensure from
completeness for each stage before transfer to the next stage.
9.1.4. Support and approval from quality assurance to ensure the complete
compliance of GMP rules and regulations.
9.2 Responsibility of Vendor includes:
9.2.1. Supply of all manuals, drawings, maintenance procedures, data, spare
parts list, etc...
9.2.2. Equipment Installation and training.
9.3 Responsibilities of Validation Department
9.3.1. Auditing VP implementation.
9.3.2. Writing of VP and protocols.
9.3.3. Providing appropriate personnel to conduct the validation activity.
9.3.4. Execution of validation activity with vendor.
9.3.5. To review and approve the final validation summary report after ensuring
that the records are in order.
9.3.6. To ensure that all other related departments follow the approved validation
plan and protocols.
9.4 Responsibilities of Engineering Department
9.4.1. Reviewing and approving the VP and protocols.
9.4.2. To provide the required supporting utilities as per the standard tests
procedure and report the results
9.4.3. Initial receipt and inspection of the HVAC System.
9.4.4. Training of Engineering personnel
9.4.5. Ensuring that the HVAC (FAC001) system is ready for conducting the
qualification at different consecutive stages.
9.4.6. Providing technical support by trained and qualified engineering personnel
during the execution of VP.
9.4.7. Developing and finalizing the HVAC (FAC001) operation, cleaning and
preventive maintenance standard operating procedure (SOP).
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9.4.8. Reviewing and approving the VP, protocols and summary reports.
9.5 Responsibilities of production Department (System Owner)
9.5.1. Reviewing and approving of VP, protocols and reports.
9.5.2. Coordination and conformation with Engineering Department that the facility
is ready for conducting the validation plan at different stages.
9.5.3. Providing trained and qualified production personnel to insure from
completeness of validation plan to be able to initiate the related SOP for
related to production activity.
9.5.4. Reviewing and approving the VP, protocols and summery reports .
9.6 Responsibilities of Quality Control Department
9.6.1. Reviewing and approving the VP, protocols and summery reports
9.6.2. Provide qualified and trained personnel to execute the related validation
activity and generate and reporting the related records according to the
approved procedures and protocols.
9.7 Responsibilities of Quality Assurance Department
9.7.1. Reviewing and approving the VP, protocols and summery reports. after
ensuring that all the records are in order
9.7.2. Ensuring that all other related departments follow up the approved VP and
protocols.
9.7.3. Assuring compliance with all regulations and XXX requirements
10. Training Requirements: Training plan must be generated, approved and executed to
identify what kind of trainings are required and when will it be executed by whom, and
when and what course of material and records where will be maintained.
The responsibility of Vendor for the training needs should be identified before execution
of any activity, and the training record shall indicate where, when, what, and whom to
perform the training with reference to the material used in training.
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11. Aseptic systems impact/Criticality Assessment: HVAC system, supporting

systems\component criticality with reference to the system boundaries are summarize
below:
11.1 Systems impact assessment
Systems
Reasons (Rational)
Classifications
Environmental
Monitoring System
This process control system has

direct impact on the quality of
the product.
Direct Impact
Electrical Heating
System
Supports direct impact system

(HVAC).
Indirect Impact
GEP and
Commissioning.
Chilled Water System
Supports direct impact system

(HVAC).
Indirect Impact
GEP and
Commissioning.
Aseptic HVAC System
Quality of the air has direct

impact on the product.
Direct Impact
Requirements
Full qualification is
required.
Full qualification is
required.
11.2 Component Criticality Assessment:

Components
Criticality
Pressure Sensors
(Differential)
Critical
component
HEPA Filters
Critical
component
Temperature
Relative/Humidity
Sensors
Critical
component
Reasons (Rational)
1. Data output from pressure
sensors are recorded in the
batch record.
2. Failure
of
the
differential
pressure has direct impact on
product quality (Contamination).
1. Failure of this component will
have a direct impact on the
product.
2. The component used to create a
critical status of the system.
3. The normal operation of the
component has an effect on the
product quality.
1. Failure of this component will
have a direct impact on the
product
2. Data output from pressure
sensors are recorded in the
batch record.
3. The normal operation of the
component have an effect on the
product quality
Requirements.
Calibration (Internal
+external).
Filter testing
Calibration (Internal
+external).
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11.3 GMP Critical Parameters

Parameters
Criticality
Reasons (Rational)
Requirements.
Room classification (Viable

and non-viable)
GMP Critical
parameter
GMP requirement
Initially and on Continuous

basis (monitoring) at rest &
in operation.
Room Temperature
GMP Critical
parameter
GMP requirement
Continuous monitoring
Relative humidity
GMP Critical
parameter
GMP requirement
Aseptic
Filling
Differential Pressure
GMP Critical
parameter
GMP requirement
Rates Rooms air changes
GMP Critical
parameter
GMP requirement
Airflow Paths
GMP Critical
parameter
GMP requirement
for
12. Validation Approach

12.1 Validation approach will be used as a prospective validation with reference to
validation master plan (VMP/500/R0). The approach will be conducted in sequence
of IQ OQ PQ.
12.2 V-Model Showing relationship between different stages
12.2.1
User Requirement Specification: This document shall be generated and

approved to describe regarding the requirement of HVAC needs and
intended to perform and all essential requirements. The owner usually
develops it. This document links to the performance qualification
document which tests for each of the requirements.
12.2.2
Functional Requirement Specification: This document shall be generated

to describe the detailed function of HVAC system. The supplier usually
develops it. This document is linked to the operation qualification
document which testes for each function.
12.2.3
Design Specification: This document shall be generated and approved to

support construction installation such as detailed process descriptions,
narratives and diagrams, system architecture drawing, piping and
instrumentation diagrams (P&IDs), control wiring diagrams, power
distribution and grounding diagrams, panel layout drawings, hardware
and software design specification, bill of materials, other documents
required for installation, operations and maintenance.
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12.2.4
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The validation cycle includes the following testing specifications:

12.2.4.1
Design Qualification
12.2.4.2
Factory Acceptance Test
12.2.4.3
Site Acceptance Test
12.2.4.4
Commissioning
12.2.4.5
12.2.4.6
Operation Qualification and
12.2.4.7
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V Model Diagram
User Requirement
Specification (URS)
(i.e. What ?)
Functional Design
(i.e. How as Schematic?)
PQ Test Plan
IQ Test Plan
(Inc. FAT)
(PQ)
Operational Qualification
(OQ)
Design Development
Detail Design
(i.e. What)
IQ Test Plan
(Inc. PDI)
(IQ)
Impact Assessment
Implementation
The requirements defined in the three design phases are found in figure mentioned above,
starting with the conceptual design (where the basic user requirements are set), functional
design and detail design. This is followed by the build (implementation) phase and finally the
testing phases, which can be found at the right side of the diagram. IQ then corresponds to
detail design, OQ to functional design and PQ to basic design. The system impact
assessment is normally performed in the basic design phase and the component criticality
assessment at the detail design phase.
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13. Installation Qualification

The objective for installation qualification (IQ) is to demonstrate that the HVAC system
(Model No. 000) in sterile area is in conformance to the URS and manufacture literature. The
information must be documented that the equipment meets specification.
Installation qualification (IQ) protocol No IQP\VD\01\R00 shall be generated; the following
qualification tests will be included in the IQ protocol and protocol must be prepared according
to SOP-VD-010.
The proper installation of the system components must be in accordance to the URS and
manufacturers recommendation and the workmanship standard that are set in the
engineering specification.
i.
To provide the elements that will verify the following for all new components of the
HVAC system that have been installed:
i.1 Components are included with their approved design and engineering specification.
i.2 Ensure that they are properly served by the required utilities, such as electric
power, chilled water, pure steam plant, compressed air and such.
i.3 Ensure that components are installed at the specified locations.
i.4 All critical measuring instruments and gauges are calibrated against traceable
primary instrument.
i.5 Operation manuals and spare parts lists must be available to assure the proper and
continuous operations systems.
i.6 Ensure that they are properly reflected in as-built systems.
ii.
The following documents must be provided:

ii.1 Purchase orders for major components.
ii.2 Factory Acceptance Test Report (FAT).
ii.3 Copy of User Requirement Specification (URS).
iii.
Installation Qualification (IQ) Tests:

iii.1 The following qualifications for IQ are listed as plan: Successful execution of
the activities will certify the performance for HVAC system.
iii.1.1. High Efficiency Particulate Air (HEPA) audit:
iii.1.1.1. HVAC Systems for critical and controlled areas (see below)
employ HEPA filters to remove particles, which are suspended
in the supply air stream before it enters the area. The
concentration of particles in such areas is under regulatory
control (limits are tabulated under the point no. 6.3.5).
iii.1.1.2. In order to reliably remove particles before they can enter
critical or controlled areas and possibly may contaminate
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product, the HEPA filters must be integral (i.e., must be leak

free).
iii.1.1.3. An Audit of all HEPA Filter Integrity Testing Documentation for
each HEPA filter installed must be conducted.
This
documentation must be reviewed to verify that each HEPA filter
installed has passed integrity testing (post installation testing).
iii.1.1.4. The information to be reviewed that includes the availability of
the following:
iii.1.1.4.1. Procedure(s) for HEPA filter integrity testing and
repair (SOP # SOP-ENGU-006).
iii.1.1.4.2. Calibration Certificates for instruments used in filter
integrity testing.
iii.1.1.4.3. Documentation of serial numbers/locations of filters.
iii.1.1.4.4. Documentation of testing medium used.
iii.1.1.4.5. Repair and retesting report.
iii.1.1.4.5.1.
Surface area of repairs.
iii.1.1.4.5.2.
Velocity of air.
iii.1.1.4.6. Documentation of upstream concentration of testing

solution.
iii.1.1.4.7. Documentation of grid location of repairs.
iii.1.1.5. Critical and Controlled Areas
iii.1.1.5.1. Critical Areas: A critical area is the area where
sterilized dosage forms, containers and closures are
exposed to the environment.
iii.1.1.5.2. Controlled Areas: A controlled area is the area
where drug/device product, in-process materials,
and container/closures with microbial contamination
concerns are prepared. This includes areas where
products are compounded, and where components,
in-process materials, drug products and drug
product contact surfaces of equipment, containers,
and closures are exposed to the environment. This
environment should be of a high microbial and
particulate quality in order to minimize the level of
particulate contaminants in the final product and to
control the microbiological content (bioburden).
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iii.1.2. Verification of Approved or As-Built (on site) Drawings HVAC:

iii.1.2.1. Process and Instrumentation Drawings (P&IDs) are used to
graphically represent mechanical process, piping, and ductwork
systems.
iii.1.2.2. Drawings are created during the design phase of a project and
once approved, serve as a portion of the specification used to
build or create the system.
iii.1.2.3. Once built, the approved or as-built drawings serve as one of
the most important means of documenting on paper pertaining
what the system is and what it consists of.
iii.1.2.4. Modifications made to the system during installation and after
installation require subsequent modification of the drawings to
keep them up-to-date.
iii.1.2.5. Because of their importance to the documentation of the
system, approved as-built P&IDs should be verified to ensure
that they are accurately represent the installed system.
iii.1.2.6. Components that have an affect on the process such as control
valves and other instrumentation should also be verified.
iii.1.2.7. The items noted should be verified for proper installation,
location, and orientation in the process flow when compared
with the approved or as-built P&ID.
iii.1.2.8. Typical Components in an HVAC system P & ID are given as
follows:
iii.1.2.8.1. Air Handling Units:
iii.1.2.8.1.1. Manufacturer
iii.1.2.8.1.2. Model Number
iii.1.2.8.1.3. Serial Number
iii.1.2.8.1.4. Fan HP
iii.1.2.8.1.5. Electrical components
iii.1.2.8.1.6. Supply fan installed.
iii.1.2.8.1.7. Cooling coil
iii.1.2.8.1.8. Condensate collection pan
iii.1.2.8.2. Air handling heating section components
iii.1.2.8.2.1. Control valve type, Model number,
serial number
iii.1.2.8.2.2. Steam Coil
iii.1.2.8.3. Air handling humidification section components.
iii.1.2.8.3.1. Humidifier, manufacturer, model.
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iii.1.2.8.3.2. Pure steam connection.

iii.1.2.8.3.3. Control valve, type, model number,
serial number.
iii.1.2.8.4. Air Handler filtration section components
iii.1.2.8.4.1. Pre-filters (Usually 95%
efficient cartridges filter).
ASHRAE
iii.1.2.8.4.2. Final filters (usually high-efficiency or

HEPA filters).
iii.1.2.8.5. Air handler electrical, pneumatic, or electronic
control devices.
iii.1.2.8.5.1. Type
iii.1.2.8.5.2. Location
iii.1.2.8.5.3. Range and accuracy
iii.1.2.8.5.4. Manufacturer
iii.1.2.8.5.5. ID Number
iii.1.2.8.6. Air distribution network components, ductwork, noise
attenuators, dampers
iii.1.2.8.6.1. The checklist must be prepared based
on the final approved engineering
specification. Observation must be
made on the changes or modification
after issuance of specification, which
would be considered as deviations from
the original design.
iii.1.2.8.6.2. Cleaning inspection report must be
provided.
iii.1.2.8.7. Verify the actual equipment
iii.1.2.8.7.1. ID number for all the valves must be
allotted.
iii.1.2.8.7.2. Installed
versus
specifications.
iii.1.2.8.7.3. Properly reflected
drawings.
the
in
reference
the
as-built
iii.1.2.8.8. Filters and terminal filter housings:

iii.1.2.8.8.1. Specification must be provided that to
be used as reference(s), include
authorized change orders.
iii.1.2.8.8.2. Verify that the specified terminal filters
have been installed versus the
reference specification.
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iii.1.2.8.8.3. List must be provided for terminal filter

locations and actual serial numbers.
iii.1.2.8.9. Chilled and hot water distribution systems
iii.1.2.8.9.1. Specification reference must be
provided including authorized change
orders.
iii.1.2.8.9.2. Verification must be made that the
actual equipment has been installed
versus the reference specifications.
iii.1.2.8.10. Controls
iii.1.2.8.10.1. A detailed description of the operation
of automatic control system must be
provided.
iii.1.2.8.10.2. Verification must be made for installed
controls
against
the
approved
specifications.
iii.1.2.8.10.3. Verification must be made for control
wiring and tubing that to be installed in
accordance with approved drawings.
iii.1.2.8.10.4. Point-to-point verification must be
made to confirm the correct installation
and identification of field control
devices, wiring and tubing.
iii.1.2.8.11. Drawings:
iii.1.2.8.11.1. Equipment drawings
iii.1.2.8.11.2. Ventilators Curves
iii.1.2.8.11.3. Layout drawings.
iii.1.2.8.11.4. Sectional Drawings.
iii.1.2.8.11.5. Detailed Drawings.
iii.1.2.8.11.6. Circuit Diagrams
iii.1.2.8.11.7. Spare Parts
iii.1.2.8.11.8. Maintenance Instructions (inspections
and servicing).
If discrepancies observed between the installed system and the approved or as-built P&IDs,
document the discrepancies by highlighting the approved as-built P&IDs to reflect the
installed system. The verified approved as-built P&IDs should be attached to the executed
IQ Protocol.
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iii.1.3. Verification of Major Component Installation

iii.1.3.1. Major components are those components for which a failure
could result in a process or quality-related failure. The major
components of the system should be verified and to be installed
in accordance with URS and purchase order.
iii.1.3.2. Systems often include components of lesser importance. If
failure or substitution of such components would not result in
process or quality-related failures, such components would not
be included in the Verification of Major Component Installation.
iii.1.3.3. The following major components must be verified.
iii.1.3.3.1. AHUs and ACUs
iii.1.3.3.1.1. Rooms Name covered by HVAC.
iii.1.3.3.1.2. AHU Serial No.
iii.1.3.3.1.3. Class.
iii.1.3.3.1.4. Height.
iii.1.3.3.1.5. ST. Pressure.
iii.1.3.3.1.6. Temperature.
iii.1.3.3.1.7. Humidity (RH %).
iii.1.3.3.1.8. Process exhaust (cfm).
iii.1.3.3.1.9. Pressure exhaust.
iii.1.3.3.1.10. Supply airflow.
iii.1.3.3.1.11. RM Ave velocity Air changes AC\HR
+20%.
iii.1.3.3.2. Humidifiers.
iii.1.3.3.3. De-humidifiers.
iii.1.3.3.4. HEPA/ULPA and pre/final filters.
iii.1.3.3.5. Blowers/fans.
iii.1.3.3.6. Dampers.
iii.1.3.3.7. Variable Air Volume Boxes.
iii.1.3.3.8. Coils (heating/cooling).
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iii.1.4. Verification of Support Utilities Installation

iii.1.4.1. Utilities that are required for the continued operation of the
system are considered support utilities. Without them, the
system would not operate properly; therefore they must be
verified.
iii.1.4.2. Support utilities should be verified and to be connected to the
system in accordance with available documentation. Critical
support utility installation parameters (i.e., pressure, flow,
temperature, voltage, etc.) should be verified.
iii.1.4.3. For HVAC Systems, support utilities to be verified should
include the following:
iii.1.4.3.1. Electrical power: Verify that the power delivered to
integral components of the system is installed in
accordance with URS. This may include AC drives,
DC drives, programmable logic controllers (PLCs),
and computers in addition to power to AHUs and
ACUs.
This may include public utility-supplied
power,
generators,
back-up
batteries,
uninterruptable power supplies (UPSs), switching DC
power supplies, and automatic switching systems.
iii.1.4.3.1.1. Verify the source of electrical power,
equipment using the electricity, voltage
(VAC or VDC), and amperage. Identify
all circuit protection coordination
devices (fuse/breaker) by tag name,
location, and rating.
iii.1.4.3.2. Steam: Clean steam is supplied by a distillation unit
that does not use boiler additives and supplied with
water meeting USP Purified Water requirements and
is usually delivered to the point-of-use through
stainless steel piping.
iii.1.4.3.3. Clean steam is used when the steam will come in
contact with product or product contact surfaces. In
HVAC systems it is injected into the dehumidified air
to re-humidify the air to the required level.
iii.1.4.3.3.1. Verify the following and record the
temperature and pressure of the steam.
Identify the instrumentation tag name(s)
for temperature and pressure, the
emergency shut-off valve tag name,
and its location.
iii.1.4.3.3.1.1. Source of steam.
iii.1.4.3.3.1.2. Equipment utilizing the steam
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iii.1.4.3.3.1.3. Pipe material of construction

iii.1.4.3.3.1.4. Pipe size and connection to
equipment.
iii.1.4.3.4. Compressed air (instrument and control air): Verify
the following and record the air pressure and identify
the pressure gauge tag name, emergency shut-off
valve tag name, and location. Indicate whether the
compressed air is instrument air, service air, oil free,
moisture free, or oil and moisture free. Compressed
air contacting product must be oil and moisture free.
iii.1.4.3.4.1. Source of compressed air.
iii.1.4.3.4.2. Equipment utilizing the compressed air.
iii.1.4.3.4.3. Pipe/tube material of construction.
iii.1.4.3.4.4. Pipe/tube size
equipment.
and
connection
to
iii.1.4.3.5. Hot/cold water (for heat exchange).

iii.1.4.3.6. Chilled water and glycol (for heat exchange).
iii.1.4.3.7. Supply of Hot or Chilled Water and Glycol: Verify the
source of the utility, pipe/tube size, and equipment
connection size.
Record the pressure and, if
pertinent, the temperature of the utility. Identify the
instrumentation tag names. Indicate the location and
tag name of all emergency shut-off valves.
iii.1.5. Verification of Critical Instrument Installation: Instruments which are
used to make operational decisions for the HVAC System, or which
provide data that is recorded as part of production or maintenance
records are considered to be critical instruments. Critical instruments
should be verified and to be installed in accordance with URS. Critical
instrumentation for a HVAC system must include:
iii.1.5.1. Pressure gauges [including differential pressure (P) gauges].
iii.1.5.2. Pressure sensor/transmitter/display systems (including P).
iii.1.5.3. Thermometers.
iii.1.5.4. Temperature sensor/transmitter/display systems.
iii.1.5.5. Relative humidity (RH) sensor/transmitter/display systems.
iii.1.5.6. Flow meters (air and liquid).
iii.1.5.7. Dataloggers/Recorders.
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iii.1.6. Verification
of
receipt
of
all
required
system
documentation/manuals: All systems documents and instrument
manuals must be in accordance to checklist mentioned in URS.
iii.1.7. General System Inspection
iii.1.7.1. Although not considered a test, a general inspection of the
installed HVAC System should be conducted and documented
on the checklist included for this purpose in the IQ Protocol.
Perform a walk-around of the system. If problems in any of the
following categories are observed, notify the responsible
personnel:
iii.1.7.1.1. General cleanliness - AHUs and ACUs.
iii.1.7.1.2. Disconnected/improperly connected ductwork.
iii.1.7.1.3. Disconnected wiring/pneumatic lines.
iii.1.7.1.4. Defective/missing filters.
iii.1.7.1.5. Damaged HEPA/ULPA filter protective grids.
iii.1.7.1.6. Improperly seated filters.
iii.1.8. Review all calibration certificates received.
iii.1.8.1. The list of critical instruments and control panel document must
be provided to ensure that they have been identified and
calibrated in accordance with an approved procedure.
iii.1.9. Standard Operation Procedure Verification:
iii.1.9.1. Each SOP must be current and approved for use on the
systems involved. They must represent the methods to be used
in the operation of the system.
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Acceptance Criteria Test for Installation Qualification
Test
Acceptance Criteria
Audit of High Efficiency

Particulates Air (HEPA) filter
Integrity Test
Critical Area
Controlled area
The HEPA filters must pass the filter integrity test in accordance to
the USP/EP Standards
Verification of approved or asbuild (on site) HVAC system

drawings.
HVAC system Diagrams or drawings must be in accordance to the

approved design.
Verification of major component

installation.
Major Components or Lesser importance components must be in

accordance to the checklist provided during URS.
Verification of support utilities

installation.
All utilities stipulated in the approved design should not deviate

during support utilities installation.
Verification of critical instrument

installation.
All critical or non-critical instruments must be in current state of

calibration.
Verification of receipt of all

required system
documentation/manuals.
All systems documents and instrument manuals must be in

accordance to checklist mentioned in URS. (Calibration manuals
and calibration certificates for critical parts).
General system inspection
ii)
iii)
iv)
v)
vi)
vii)
The AHUs must be clean.

The ductwork is properly connected.
Pneumatic lines are properly connected
No defective or missing filters.
No damaged HEPA filter protective girds.
Filters are properly seated
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14. Operational Qualification

The OQ is to verify that the specified components of the HVAC system operates as specified
and are in agreement with the acceptance criteria and critical systems.
The HVAC system components described in the final design and specifications or authorized
changes to the design or specification needs to be qualified to demonstrate their adequate
operation. In general, the Operation Qualification scope is to test the individual components
of the system such as air-handling unit, ductwork, blowers and others.
Operational Qualification (OQ) protocol No OQP\VD\01\R00 shall be generated; the following
qualification tests will be included in the OQ protocol and protocol must be prepared
according to SOP-VD-011.
The final performance (i.e. performance qualification) of the system in terms of environmental
quality, such as temperature, humidity airborne cleanliness (viable and non-viable), can be
assessed only under dynamic conditions whether real or simulated and when the other
components of the environmental control system are in place.
Prerequisites: The following list of actions must be completed prior to the beginning of
execution of operation qualification protocol, with reference to the validation master
plan:
Installation qualification must be completed.
All critical punch-list items from IQ must have been resolved and completed.
All related SOPs for operation and maintenance of HVAC must have been
approved.
Training in pertinent SOPs for operation of HVAC & sterile area facility must
be completed and documented from all concern departments and persons.
The following qualification activities for the OQ must be performed. Successful qualification
execution of the activities listed will satisfy the OQ effort for HVAC system.
i.
Verification Of Critical Instrument Calibration.

i.1 Instrument that are used to operational decisions for the HVAC system or which
provide data that is recorded as part of production or maintenance records, are
considered to be as critical instruments. Critical instruments should be verified to be
in a current state of calibration. Critical instrument for HVAC system may include:
i.1.1. Pressure gauges (including differential pressure (P) gauges).
i.1.2. Pressure sensor/transmitter/display systems (including P).
i.1.3. Thermometers.
i.1.4. Temperature sensor/transmitter/display systems.
i.1.5. Relative humidity (RH) sensor/transmitter/display systems.
i.1.6. Flow meters (air and liquid)
i.1.7. Data loggers/Recorders.
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ii. Operational Procedure Compliance Test.

ii.1 A final draft or higher standard operating procedure (SOP) for the operation of the
equipment comprising the HVAC system should be verified to be available.
(Examples of the SOPs that will be needed):
ii.1.1. SOP # XXX -001
ii.1.2. SOP
: Operation and Maintenance of the Air Handing Unit
#XXX -002 : Calibration Procedure of Temperature Probe
ii.1.3. SOP # XXX -003 : Calibration Procedure of Humidity Probe

ii.1.4. SOP # XXX -004 : Calibration Procedure of Static Pressure Probe
ii.2 Personnel operating the system or its individual components during OQ execution
should be verified and to have been trained to the referenced SOP(s).
ii.3 SOP availability and operator training should be documented in the protocol test data
sheets for this section.
ii.4 Scrutiny of SOP and training of personnel is essentially required in order to assure
the availability of written operating procedures that can be verified to complete and
accurate, or can be highlighted to make them changes during normal function
and/or cycle testing and which can be finalized and approved prior to Performance
Qualification (PQ) execution.
ii.5 Operational procedure ensures that the outcome of the individual OQ tests are not
distorted by operating the system in a manner that differs significantly from the
intended methodology during standard operation.
iii. HVAC start-up and shutdown operation test.

iii.1 To test the start-up and shutdown sequence of the air handling units are as
controlled by the controlled system.
iii.2 The testing procedure is designed as a function of the control system. The protocol
should outline the sequence to be followed and the devices that intervene in the
system.
iii.3 Start-up and shutdown sequence must be recorded, which may provide additional
comments or description or unexpected test results.
iii.4 The air-handling unit start-up and shutdown sequence must operates in accordance
with the design specifications and accordance to the predetermined limit
accordance to URS.
iv. Loss of Utility Test.
iv.1 HVAC system response to the loss of support utilities should be investigated.
iv.2 Response to the loss of electrical power must be tested in all cases, which should
include retention of critical data as well as equipment/system response.
iv.3 Equipment/System responses to the loss of other utilities should be documented to
ensure that proper protection is provided in the equipment/system design.
iv.4 Loss of electrical power must not result in loss of critical parameters data.
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iv.5 Equipment/system behavior upon loss or upon resumption of a given utility must be
in accordance with available documentation.
iv.6 HVAC systems utility may supply multiple areas; it is very critical that execution will
not interfere with other ongoing operations. Support utilities for HVAC systems
include:
iv.6.1. Electrical Power
iv.6.2. Clean Steam
iv.6.3. Compressed Air
iv.6.4. Hot/Cold water (for heat exchange)
iv.6.5. Chilled water and glycol (for heat exchange)
v. Airflow velocities and patterns

v.1 In a unidirectional airflow area, usually over a sterile product filling lines, it is
important that the air flowing through the critical area has a velocity which is
sufficient to produce unidirectional flow and to sweep particulate matter away from
the process.
v.2 Airflow velocity should be determined for each HEPA filter, as the average of multiple
measures taken at various locations across a plane parallel to and not more than
6inches from filter face.
vi. Clean Room HEPA Filter leak test.

vi.1 HEPA filters shall be replaced after five or ten years, as applicable, from the date of
original certification at a DOE filter test facility, if the manufacturing date is not
available. HEPA filter systems are designed and installed so the system can be
quantitatively leak tested.
vi.2 The injection port and sampling ports must be of sufficient size (nominal inch in
diameter) for the insertion of the output line from the aerosol generator or
photometer probe.
vi.3 Filter leak test should be performed according to the test procedure as per ISO
14644 which will confirm the filter media and filter seal integrity.
vii. Audit of Air Balance reports.
vii.1 Airflow from AHU to each individual supply air location within the area must be
adjusted to within specified tolerances of design flow. This is necessary to achieve
proper airflow patterns within the area serviced by the system.
vii.2 Air change in the room must be not less than 20air changes per hour.
vii.3 The return airflow to the AHU must also be adjusted in order to produce the
specified pressure differential between individual areas served by the system and
adjacent areas.
vii.4 The air balance reports should be reviewed for the following:
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vii.4.1. SOP for Availability of air balancing procedures.

vii.4.2. Conformance of post-balanced airflow to design.
vii.4.3. Availability of calibration certificate for instruments used during balancing.
vii.4.4. Conformance of static pressures throughout the system to design.
vii.4.5. Room air changes rates.
vii.4.6. Room/area differential pressures.
vii.4.7. Test technician qualifications.
viii. Air pattern Test (Airflow visualization)
viii.1 It is important (Unidirectional flow area) that air flows through the critical area in a
smooth pattern without disturbances or eddies which would prevent particulate
matter from being swept out of the area by the airflow or cause less clean air to be
brought into the cleaner area.
viii.2 Air pattern testing shall be conducted in critical rooms/areas to demonstrate airflow
patterns from HEPA through areas/levels of product exposure.
viii.3 Air pattern testing shall also be designed to verify airflows from high-pressure areas
(clean) towards lower pressure areas (less clean).
viii.4 All air patterns shall be verified by visually observing airflow with smoke sticks,
vapor generators, or other suitable means.
viii.5 Air pattern testing must be recorded via videotaping.
viii.6 Airflow pattern testing should be done in both static and dynamic conditions.
viii.7 Influence of personnel on the airflow pattern during normal operations (sterile filling
machine set-up, aseptic connection of sterile transfer lines and interventions)
should be included in the studies.
viii.8 An audit may be performed if the documentation for air pattern testing is available
and complete. If the documentation is found not satisfactory then the test
procedure must be performed.
ix. Temperature and Relative Humidity Monitoring

ix.1 Temperature and relative humidity (RH) within the rooms/areas served by the HVAC
system is controlled for personnel comfort and process interactions (i.e. too low an
RH contributes to static formation; too high may hinder drying steps).
ix.2 Temperature and RH testing should be performed to verify the ability of the HVAC
system to control and maintain these parameters in all rooms and areas.
ix.3 Temperature and relative humidity measurements shall be taken in each of the
rooms or areas with the environment in an at-rest condition and operational
conditions.
ix.4 The temperature and RH measurements shall be collected in each room or area over
a twenty-four (24) hour period using independent calibrated measuring devices.
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ix.5 Measurement must be taken in the four corners and the approximate center of each
room or area at a height of approximately 3feet from the floor.
ix.6 Measurement must be performed at least once in each of three consecutive eighthour time periods.
ix.7 Control system temperature and RH readings should be recorded for each room
simultaneously with taking the independent measurements.
ix.8 Available control system temperature and RH archives for the test period should be
attached to the protocol.
ix.9 Outside temperature and humidity should also be measured and recorded once for
each set of measurements.
ix.10 An audit may be performed if the documentation for Temperature and Relative
humidity monitoring is available and complete. If documentation is found not be
satisfactory then the Test procedure must be performed.
x. Clean room pressurization test (also differential pressures)

x.1 To maintain air quality in critical and controlled areas, it is important that any airflow
that occurs between adjacent areas, which have different classification levels, must
be from the cleaner area to the less clean area (i.e. from a class 5 area to a class 8
area). This is accomplished by maintaining the air pressure in the cleaner area at a
slightly higher level than an air pressure in the less clean area.
x.2 Airflow direction (i.e. in some solid dosage facilities) is designed to create conditions
that contain product and minimize cross contamination. This is accomplished by
maintaining the air pressure in a common area at a slightly higher or lower level
than the air pressure in the adjacent areas of different classifications or cleanliness
level (same classification).
x.3 Differential pressure/airflow directional testing shall be conducted to verify the ability
of the HVAC system to maintain plant pressurization (positive and negative)
between adjacent areas as per the design specifications. This monitoring should be
performed routinely and action level should be established in the monitoring
program.
x.4 Differential pressure readings/measurements should be recorded using existing,
(calibrated) installed system instrumentation. In the absence of such
instrumentation, an independent calibrated P gauge or inclined manometer with an
appropriate range may be used. The recording of differential pressure
measurements shall be conducted once a day for three (3) days in order to
demonstrate stability.
x.5 An audit may be performed if the documentation for the Differential Air Pressure and
Direction Test is available and complete. If documentation is found not satisfactory
then the Test procedure must be performed.
x.6 P between any room and the main corridor must be within the tabulated defined
range, which ensures that the P between two adjacent rooms, which have
same/different classification levels, is not less than 12.5pa. The supply and return
air volumes should conform with the range specified. Pressure differential between
rooms should be maintained as indicated in the specifications
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xi. Clean room non-viable particulate count test

xi.1 The non-viable particulate test shall be performed to verify the effectiveness of the
environmental filters in minimizing and in effectively removing non-viable
particulates from critical and controlled areas, which may be present.
xi.2 Non-viable particulate samples shall be taken in each room or area in at-rest
conditions.
xi.3 Non-viable particulate samples shall be taken using an independent calibrated
particle sampler and recording instrument.
xi.4 Each sample location within the room/area shall be sampled to determine the count
of particulates. The number of sample locations must be determined based on the
floor area according to ISO standard 14644-1 (Annex B Point no. B.4 Sampling)
and the area classification.
xi.5 Limits are as defined in table, Airborne Particulate Classification (under point no.
6.3.5 in this report)
xii. Clean room viable particulate count test
xii.1 The viable particulate test shall be performed to monitor the viable particulates,
which may be present in critical and controlled areas, and to determine the
microbial quality of the air being supplied to each room or area.
xii.2 Viable particulate samples must be taken in each room in normal operating
conditions (machinery in use and normal complement of operators present).
xii.3 Sampling must be performed for duration sufficient to sample each room during
normal production.
xii.4 Each room must be sampled a minimum of once per shift per day, when the room is
in production (operational condition).
xii.5 Testing should be performed over a time period of seventy-two (72) hours
concurrent with the temperature, relative humidity and differential pressure
monitoring testing.
xii.6 In the event of no production in a room, a minimum of one (1) sample shall be taken
for each location daily.
xii.7 Each room must have not less than two (2) sample locations.
xii.8 As defined in tablet: Recommended limits for microbiological monitoring of clean
areas during operation (under point no. 6.7 in this report).
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xiii. Control, Alarms and Interlocks.

xiii.1 Alarms
xiii.1.1. HVAC systems frequently incorporate safety features such as smoke alarms
or noxious fume alarms.
xiii.1.2. HVAC systems frequently include alarms for items such as room
pressurization, temperature and relative humidity, which could, if out of
specification (OOS), potentially have an adverse effect on product quality.
xiii.1.3. Safety system features should be tested in order to ensure personnel and
system safety.
xiii.1.4. Critical alarms should be tested for proper operation to ensure that they are
functional and will provide warning before any system, product quality, or
personnel safety is compromised.
xiii.1.5. HVAC system alarms are listed below:
xiii.1.5.1. Smoke detector operation.
xiii.1.5.2. Plenum pressure alarms
xiii.1.5.3. Room door interlocks
xiii.1.5.4. Filter P alarms.
xiii.1.5.5. Room pressure/P alarms
xiii.1.5.6. Temperature alarms
xiii.1.5.7. Humidity alarms.
xiii.2 Interlocking:
xiii.2.1. Interlocks may be mechanical or part of the electrical/mechanical control
system.
xiii.2.2. Some interlocks are not associated with loops and may serve to either act
as preventive measures (turn the pump off before the tank is empty
preventing pump cavitation) or to initiate an activity (an exhaust fan
automatically starts when the supply fan is started).
xiii.2.3. Interlock testing may be performed as part of normal sequence of operation
testing or as a separate activity.
xiii.2.4. Like sequence testing, interlock testing involves the forcing either through
simulation or through expected operating conditions of inputs and verifying
that the interlock action operations as specified.
xiii.2.5. Door interlocking (X door is opened when Y door is closed, similarly, Y door
is opened when X door is closed) system creates to keep the area intact
and prevent from the contamination.
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xiv. Power Fail and Recovery test.

xiv.1 Verification must be performed that control system can maintain the components of
the air-handling unit within the specified range after the power failure (within
15minutes).
xiv.2 Testing operation objective for air handling pneumatic, electric or electronic control
system during a power fail and recovery cycle.
xiv.3 Testing procedure must be designed as a function of the system tested. Because
the power fail and recovery test is a major system test greatly exercised to prevent
damage to personnel or equipment.
xiv.4 The test should be designed in accordance with HVAC and controls design
engineers. Therefore, the following must be concluded:
xiv.4.1. Proceed to simulate the failure.
xiv.4.2. Bring the system to complete stop.
xiv.4.3. Wait for the required time before restart to prevent mechanical or electrical
(overcharge) damage to the system.
xiv.5 After completion of the foregoing three steps, restart the system.
xiv.6 Recording of the time that it takes for the system to reestablish the approved
conditions.
xiv.7 Record the monitored environmental parameters (air volume, pressure differential,
temperature, humidity).
xiv.8 The data must be compared that had already been acceptable for the environment
tested.
xiv.9 Particular attention must be given to pressure differentials as the best indicator of
the system capability to regain control.
xiv.10 Schedule of tests to be performed on regular basis to continuing compliance of
system.
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Acceptance Criteria Test for Operational Qualification

Test
Acceptance Criteria
Verification of Critical
Instrument Calibration
All critical instruments must be in the state of calibration.
Operational procedure
compliance test
All the operational procedure must comply with Functional Requirement

Specification.
HVAC Start-up and

Shutdown Operation Test
The air-handling unit start-up and shutdown sequence must operates in

accordance with the design specifications and accordance to URS.
Loss of utility test
Loss of utility test must not interfere with other ongoing operations.
Airflow Velocities and

pattern
The airflow velocity in a unidirectional airflow device should not exceed the
limit set in the design criteria. The highest and lowest reading should not be
more than 15-20% from the unit average velocity.
HEPA Filter Leak Test
Audit of air balance

reports/Air volume test
Air pattern test (Air Flow

Visualization
1. Filter media integrity test should pass according to ISO 14644

2. filter seal integrity test should pass according to ISO 14644
1-The room air change must be not less than 20air changes per hour.
2-Air balance report should include all the data within the
acceptance criteria
1-Air should flow in a parallel stream to prevent the flow of the outside air into
the critical environment.
2-Air pattern testing should verify airflows from high-pressure areas (clean)
towards lower pressure areas (less clean).
Temperature
Audit/Monitoring
(22.0 3.0) C for all controlled rooms.
Relative humidity
Audit/Monitoring
(30 - 65) RH% for all controlled rooms.
Differential air pressure

test
pre-determined
1-P between any room and the main corridor must be within the tabulated
defined range, which ensures that the P between two adjacent rooms, which
have same/different classification levels, is not less than 12.5pa. The supply
and return air volumes should conform with the range specified. Pressure
differential between rooms should be maintained as indicated in the
specifications.
2-Absence of cross-contamination (measurement of pressure difference).
Non-viable particulates
As defined in table, Airborne Particulate Classification (under point no. 6.3.5 in

this report)
Viable Particulates Test
As defined in tablet: Recommended limits for microbiological monitoring of

clean areas during operation (under point no. 6.7 in this report).
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Alarm test and Interlock

Test
Power-fail and Recovery

test
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1-All alarms systems and interlock must comply with Functional Requirement
Specification.
2-Door interlocking testing should pass for all doors in sterile area to insure
there will be no contamination between each individual area
The controlled environment should recover to the original setup after loss of
power ( within 15minuts)
Recommended interval for the following test parameters:

Test Parameter
Maximum
Time interval
Objective
Test Procedure and Key aspects
Filter leakage
Verify filter integrity
12 months
Filter media and filter seal integrity
Containment leakage
Verify absence of crosscontamination
12 months
Airflow directional
differential.
6 months
Dust particle counts to be carried out

and results printouts produced.
Number of readings and positions of
tests to be in accordance with ISO14644-1 Annex B.
12 months
Log of pressure differential readings

to be produced or critical plants
should be logged daily, preferably
continuously. A 15Pa pressure
differential between different zones
is recommended. In accordance with
ISO 14644-d Annex B5.
12 months
Airflow readings for supply air and

return air grills to be measured and
air change rates to be calculated. In
accordance with ISO 14644-3 Annex
B13
Particle count test
Air Pressure Difference
Verifies Cleanliness
Absence of crosscontamination
and
pressure
Airflow Volume
Verify air change rates
Airflow Velocity
Verify
unidirectional
airflow and or containment
condition.
12 months
Air velocities for containment

systems and unidirectional flow
protection systems to be measured.
In accordance with ISO 14644-3
Annex B4
Recovery (time)
Verify clean-up time
12 months
Time taken maximum 15 minutes.
Airflow visualization
Verify required
patterns
12 month
Airflow
direction,
evidence.
airflow
documented
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15. Performance Qualification

Performance Qualification is outlined below represents the quality testing performed
in the OQ (i.e. viable) but expands the scope to include testing under dynamic
conditions. The final and real challenge for the environment control system and HVAC
system is represented by the process that must be executed within the areas it is
serving. Upon determination of the new approved conditions, if needed, changes to the
system are to be executed and revalidated before proceeding to the performance
qualification.
Performance Qualification (PQ) protocol No PQP\VD\01\R00 shall be generated; the
following qualification tests will be included in the PQ protocol and protocol must be
prepared according to SOP-VD-012.
This section describes the various types of monitoring that would be performed to
adequately qualify the operating environment for processing.
i.
Performance Qualification must be performed on the facility in three different

stages that are
i.1 As-built (No equipment, no personnel).
i.2 At-rest (equipment but no operations and no personnel)
i.3 Operational (With personnel, equipment operations)
Consistent results must be obtained which should be within specified limits for
20consecutive working days for each of the three stages (as built, at rest and
operation).
ii.
Verification of Performance Qualification prerequisites

ii.1 The success of the system to control the level of viable and non-viable
particulate levels as well as its ability to regulate temperature and relative
humidity conditions depends not only on the system performance, but on
outside factors such as personnel training, room sanitization, and system
maintenance.
ii.2 Method for sanitization procedures, supporting utilities and personnel should
be qualified/trained before the initiation of the PQ as well as procedures for
sampling, operation and maintenance should be in place.
ii.3 By having these prerequisites completed before the HVAC system PQ and
environmental monitoring program, the success for PQ is greatly extended and
it is much easier to isolate attributable causes in the event of PQ failure.
ii.4 The prerequisites for the HVAC system PQ can be summarized below:
ii.4.1. HVAC: IQ and OQ complete.
ii.4.2. Utilities: IQ, OQ, PQ and including SOPs for compressed air and
steam.
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ii.4.3. Personnel: SOPs and training documentation for equipment operation,

room sanitization gowning and environment monitoring. Training in
pertinent SOPs for HVAC & sterile area facility & all related operation
and maintenance machines are completed and documented from all
concern departments and persons
ii.4.4. Standard Operating System (SOP) must be development and approved
before performance qualification (PQ) tests are executed for following:
a. Environmental Monitoring.
b. System Operation
c. System Maintenance.
ii.5 All critical punch-list items from IQ and OQ must be cleared and resolved.
iii.
Temperature Humidity Control Test - Dynamic Condition

iii.1 To demonstrate the ability of the HVAC system to control temperature and
humidity during operating conditions. This test must be executed while the
process or operation are simulated or executed.
iii.2 The Temperature-humidity control test provides verification of temperature and
humidity under dynamic conditions, as well as indicating that the system is
capable of maintaining the design conditions. It also provides a good basis for
determination of the general status of the system, for its malfunction can be
used as diagnostic of the inadequate operation of the HVAC.
iii.3 Seasonal conditions of temperature and humidity may vary with the system
design and the amount of external non-conditioned air supplied to the airhandling units serving the controlled environment. Sporadically, seasonal
variations can be simulated during validation conditions.
iv.
Differential Air Pressure and Direction Test Dynamic Conditions

iv.1 In order to maintain air quality in critical and controlled areas, it is important
that any airflow that occurs between adjacent areas which have different
classification levels must be from the cleaner area to the less clean area (i.e.,
from a Class 5 area to a Class 7area). This is accomplished by maintaining
the air pressure in the cleaner area at a slightly higher level than the air
pressure in the less clean area.
iv.2
In s solid dosage facilities, airflow direction is designed to create

conditions that contain product and minimize cross contamination. This is
accomplished by maintaining the air pressure in the common area at a slightly
higher level than the air pressure in the processing area.
iv.3 US guidelines require a differential pressure of 0.05 water column between

rooms of different air cleanliness. EU guidelines require a differential pressure
10-15 Pascals.
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iv.4 Differential Pressure/Airflow Directional Testing shall be conducted to verify

the ability of the HVAC System to maintain plant pressurization positive
between adjacent areas while in a normal operating condition (machinery in
use and normal complement of operators present). This monitoring should be
performed routinely and action levels should be established in the monitoring
program per the requirements of ISO standard 14644-1 and 2.
iv.5 Differential pressure readings/measurements should be recorded using
existing, (calibrated) installed system instrumentation. In the absence of such
instrumentation, an independent calibrated dP gauge or inclined manometer
with an appropriate range may be used. The recording of differential pressure
measurements shall be conducted once a day for three (20) working days in
order to demonstrate stability.
v.
Air Cleanliness Test

v.1 Air Cleanliness test must be performed in order to determine that the complete
as-built, operational facility meets the air cleanliness requirements specified in
the user requirement specification.
v.2 Airborne concentrations are measured with white light, laser, or condensation
nuclei particle counters.
v.3 Air cleanliness classification for controlled environments must be based on the
concentration of particles of a specific size per unit of volume.
v.4 Sampling location and sample size must be set cautiously.
v.5 A sample should be taken at the fill point at a distance not exceeding 30cm
(1ft3) from the point of exposure and a sample volume of 1ft3.
v.6 The table demonstrates the limit and range of air quality for every parameters
that are performed in accordance with standard establishment
Parameters
Limit/Range
Reference
TSI Instrument
Temperature
22 3C
ASHRAE standard 551992
Q-Trak Plus
IAQ-Calc
TH-Calc
VelociCalc Plus
Relative humidity
30% to 65%
ASHRAE Standard 551992
Q-Trak Plus
IAQ-Calc
Air movement
80ft/s or 0.25m/s
WHO
VelocioCalc
VelociCalc Plus
VelociaCeck
DP-Calc
AccuBalance
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Ventilation (fresh
air)
Ventilation (CO2)
Particles
concentration in
cleaned HVAC
systems
vi.
1.0
Validation
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ASHRAE Standard 621999
Q-Trak Plus
IAQ-Calc
TH-Calc
About 700ppm over outdoor ASHRAE Standard 62ambient

1999
InspectAir
Q-Trak Plus
IAQ-Calc
15 to 60 cfm/persons
minimum depending on
type of space
1.0g/100cm2
NADCA 1992-01
n.a
n.a
Ultrafine particles
Carbon Monoxide
Version No.:
8 hr. TWA
50 ppm
35 ppm
9 ppm
9 ppm
9 ppm (peak)
25 ppm
9 ppm
1 hr TWA
35 ppm
35 ppm
26 ppm
OSHA
NIOSH
EPA
ASHRAE
ACGIH
WHO
p-Trak
DustTrak
SidePak
P-Trak
Q-Trak Plus
IAQ-Calc
CA-CAlc
Airborne Bioburden Test

vi.1 The scope of this test is to determine if all the components of this system are
capable of performing in accordance with the process functional requirements
for airborne bioburden.
vi.2 The achieving of predetermined levels of microbial contamination in aseptic
processing and supporting environments is a primary goal of the
environmental control system.
vi.3 Suitable neutralizers should be added to avoid inadequate interaction with
disinfectant agents employed in the environments.
vi.4 Organisms found in samples obtained from critical environments should be
quantified and identified.
vi.5 Organisms found in other less critical environments should be quantified and
identified also, in order to establish the prevalent flora in the environment.
vi.6 Selection of sampling sites is critical and special attention should be given to
areas near personnel. As well as areas of transfer and connection to less
critical environments.
vi.7 The sampling during validation must be extensive because the collection of
microorganisms in such a clean environment is extremely difficult.
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vi.8 Tests are performed to show that the air quality meets the specifications for
particulates, temperature, humidity, microbial counts, lighting levels, etc. for
the specification and classification of each room.
vii. Surface Bioburden Test
vii.1 The final evaluation of cleaning and disinfection must be performed in order to
determine the bioburden content on the surface either in the facility or on
particular equipment and device.
vii.2 The use of adequate cleaning and disinfection to achieve a level of quality
environmental.
vii.3 As part of validation task, it is essential to determine that the effectiveness of
this procedure is reflected at the rest of environment is being qualified.
vii.4 Evaluation of the surface bioburden test in pre-cleaning condition must be
performed.
vii.5 Testing after the cleaning and disinfection in a repetitive approach, this must
ensure to establish of these methods to perform such activity.
vii.6 Limits for surface bioburden test must be as follows:
vii.6.1. The limit for critical environment must be not more
1CFU/12.9cm2 or 2 in2 (FDA Aseptic Processing guidelines).
vii.6.2. Similarly, other environments
environments: 5/12.9 cm2 or 2in2.
that
are
adjacent
to
than
critical
vii.6.3. For controlled environments: 20/12.9cm2 or 2in2.
viii. Non-Viable Particulate Testing (Critical and Controlled Rooms/Areas Only)

Dynamic Conditions
viii.1 Non-viable Particulate Testing shall be performed to verify the effectiveness
of the Environmental Filters in minimizing and in effectively removing nonviable particulates, which may be present in critical and controlled areas.
viii.2 Testing shall be performed in accordance with the current U.S. FDA
Guideline to Aseptic Processing and ISO Standard 14644-1
viii.3 Non-viable particulate samples shall be taken in each room or area in a
normal operating condition (machinery in use and normal complement of
operators present).
viii.4 Non-viable particulate samples shall be taken using an independent
calibrated particle sampler and recording instrument, or may be taken using a
qualified Particulate Counting System (PCS), if available.
viii.5 Each sample location within the room/area shall be sampled to determine the
count of particulates. The number of sample locations shall be determined
based on the floor area and the area classification.
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viii.6 Limits:
Controlled Areas: The EU guidelines require these areas to be Class C.
Air in controlled areas is generally of acceptable particulate
quality if it has a per-cubic-meter particle count of not more than
3,520,000 in a size range of 0.5 micron and larger (Class 8) when
measured in the vicinity of the exposed articles during periods of
activity. There is also a requirement to have less than 29,000
particles/m3 of 5.0 m and larger in the in operation state. To
meet EU requirements both 0.5 and 5.0 m particle sizes must be
counted.
Critical Areas:
The EU guideline requires these areas to be Class A

(corresponding to US Class 5 unidirectional flow), with the
background of Class B. Air in the immediate proximity of exposed
sterilized containers/closures and filling/closing operations is of
acceptable particulate quality when it has a per-cubic-meter
particle count of no more than 3,520 in a size range of 0.5 micron
and larger (corresponds to US Class 5) when measured not more
than one foot away from the work site, and upstream of the
airflow, during filling/closing operations. It is accepted that
sometimes conformity with particle counts may not be met at
point of fill due to generation of particles or droplets from the
product itself. Class B under dynamic conditions is of acceptable
particulate quality when it has a per-cubic-meter particle count of
no more than 352,000 of 0.5 micron and larger. The 5.0 m limits
are 20 particles/m3 for Grade A and 2,900 particles/m3 for Grade
B in operation.
ix.
Viable Particulates Test (Critical and Controlled Rooms/Areas Only)

Dynamic Conditions
ix.1 The Viable Particulates Test shall be performed to monitor the viable
particulates, which may be present in critical and controlled areas, and to
determine the microbial quality of the air being supplied to each room or area.
ix.2 Viable particulate samples shall be taken in each room in a normal operating
condition (machinery in use and normal complement of operators present).
ix.3 Sampling shall be conducted in accordance with the companys procedures.
Sampling shall be performed for duration sufficient to sample each room
during normal production.
ix.4 Each room shall be sampled a minimum of two (2) times per day, when the
room is in production (operational condition).
ix.5 Testing should be performed over a time period of 20 consecutive days
concurrent with the temperature, relative humidity, and differential pressure
monitoring testing. In the event of no production in a room, a minimum of one
(1) sample shall be taken for each location daily.
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ix.6 Each room shall have no less than two (2) sample locations.
EU guidelines require a maximum average viable organism
Controlled Areas:
3
count of 100/M (2.8/Ft3).
Critical Areas: EU guidelines a maximum average viable organism count of <
1.0/m3 (0.03/Ft3), with a background maximum average viable organism count of
/m3 (0.14/Ft3).
For testing to EU standards the average of the last 10 samples taken from a
sampling site should be compared to the values given above.
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Acceptance Criteria Test for Performance Qualification

Test
Acceptance Criteria
Verification of
prerequisites
All actions must be performed before starting execution of performance

qualification activities.
1. The specified temperature range must not be more than 22 3C.
Temperature Humidity
Control test
Differential
Air
Pressure
and
Direction Test
Dynamic Conditions
2. The specified relative humidity range must not be more than 30-65% in
aseptic processing areas. Unless otherwise specified by the process
requirements.
1-P between any room and the main corridor must be within the tabulated
defined range, which ensures that the P between two adjacent rooms, which
have same/different classification levels, is not less than 12.5pa. The supply and
return air volumes should conform with the range specified. Pressure differential
between rooms should be maintained as indicated in the specifications.
2-Absence of cross-contamination (measurement of pressure difference).
1. Critical Environment: The particle concentration under dynamic conditions
should not be more than 3.5 particles of 0.5m and larger per cubic meter
(100particles of 0.5m and larger per cubic feet).
Air Cleanliness Test
2. Other Environments: Typically a tenfold gradient must be used from critical to

less critical environments (ex. 1,000 for environment adjacent to critical
environment 10,000 for those adjacent to it.)
1. Critical Environments: Not more than 1CFU/m3 or 0.03 CFU/ft3.
Airborne Bioburden Test
2. Typical for other environments: Adjacent to critical environment 5/m3 or

0.15/ft3.
3. Controlled Environments: 87/m3 or 2.5/ft3.
1. Critical Environments: Not more than 1 CFU/12.9 cm2 or 2in2.
Surface Bioburden Test
2. Typical for other environments: adjacent to critical environments: 5/12.9 cm2

or 2in2.
3. Controlled Environments: 20/12.9cm2 or 2in2.
Non-Viable
Particulate
Testing
(Critical
and
Controlled Rooms/Areas
Only)
Dynamic
Conditions
As defined in table, Airborne Particulate Classification (under point no. 6.3.5 in

this report)
Viable Particulates Test

(Critical and Controlled
Rooms/Areas Only)
Dynamic Conditions
As defined in tablet: Recommended limits for microbiological monitoring of clean

areas during operation (under point no. 6.7 in this report).
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16. Planning and Cost: All planning and cost schedule is performed in Microsoft Project
(Windows based) 2003 software. The total cost of this HVAC validation plan project is
USD. 38,000/-.
16.1 The reports are attached for immediate reference (Attachment no. 05).
17. Discrepancy/ Justification And Corrective Action
17.1 If deviations are observed while performing the qualification tests, generate
deviation report as outlined in attachment no. 03/R0. Generate deviation
report individually for each test that failed to meet the acceptance criteria.
17.2 If deviations are acceptable, write justification(s) for acceptance and impact of
the function and complete the deviation report.
18. Validation Plan Report

18.1 Prepare a validation plan report as outlined in attachment no. 04/R0. The
validation plan report should include date study initiated, date completed,
observations made, problems encountered, and completeness of information
collected, summary of deviation report, sample data if appropriate, other
information relevant to the study, and conclusions on the validity of the
qualification.
18.2 After completion of the report in all aspects submit the report to QA for review
and approval.
19. Modification/ Change Control During Qualification: For Direct Impact systems,
certain changes may affect qualification plans, tests, or documentation. Changes should
be assessed for potential impact and communicated to appropriate team members.
Agreement should be obtained from the approval signatories before implementation of
the change as per SOP-XXX-: Change Control. An assessment will be made before any
modification or change to the system to determine if revalidation is required or not
required. The QA should review and input into changes when one or more of the
following conditions occur.
19.1 The change alters the impact assessment (i.e. it causes a formerly Indirect
Impact system to now be a Direct Impact, system or vice-versa.)
19.2 There is a fundamental Change in the design concept.
19.3 There is a change in the User Requirements Brief or Requirement
Specifications.
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20. Re-qualification: Re-qualification can be performed as the result of an event-based or

time based assessment as defined in the Validation Master Plan (VMP), in both cases of
time or event based circumstances; the system owner, Quality Assurance, Engineering
and Validation Departments will be responsible for assessing the level of the revalidation
requirement. Normally the requalification for IQ,OQ and PQ can be summarized below:
20.1 IQ Requalification
20.1.1. Modification in the HVAC system
20.1.2. Replacement of major component
20.1.3. Relocation of any component of the HVAC system
20.2 OQ & PQ Requalification
20.2.1. Modification in the HVAC system
20.2.2. Replacement of major component
20.2.3. Relocation of any component of the HVAC system
20.2.4. Annual re qualification
20.2.5. Any contamination problem
21. References and Related Records

21.1 ISO standard 14644-1 (Annex B Point no. B.4 Sampling) Clean rooms and
associated controlled environments
21.2 Validation Master Plan-VMP
21.3 User requirement specification
21.4 Supplier drawing and specification
21.5 Commissioning and Qualification (ISPE/Volume 5)
21.6 WHO Guide for GMP requirements-Part 2 Validation.
21.7 Qualification of HVAC Lab compliance www.labcompliance.com.
21.8 Validation of Pharmaceutical Processes, Second Edition.
21.9 United States Pharmacopoeia 32.
21.10 American society of heating, refrigerating and air conditioning engineers.
21.11 XXX Validation guideline for HVAC.
21.12 WHO validation guideline for HVAC for non sterile product.
21.13 Institute of Environmental sciences (IES). Federal Standard 209E. Airborne
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Particulate cleanliness classes in clean rooms and clean zones.
22. Definitions: Definitions of terms and abbreviations relating to this validation plan which
are given below:
Abbreviation
Expansion
HVAC
Heating ,ventilation and air conditioning
IQ
OQ
Performance qualification
PQ
SOP
Facility
FAC
CC
Standard Operating Procedure
Change Control
Good Manufacturing Practice
GMP
QA
Quality Assurance
QC
Quality Control
VMP
Validation Master Plan
ACUs
Air Handling Units
XXX
XXX Pharmaceutical Manufacturing Company
US FDA
United State Food & Drug Administration
USP
United State Pharmacopoeia
CFU
Colony Forming Unit
SA
Sterile Area
VP
Validation Plan
GEP
Good Engineering Practice
FAT
Factory Acceptance Test
HEPA
High Efficiency Particulate Air
PI&Ds
Piping and instrument Diagrams
23. Glossary
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23.1 Acceptance criteria: Numerical limits, ranges, or other suitable measures for
acceptance of test results.
23.2 Action level (in clean rooms): An established microbial or airborne particle level
that, when exceeded, should trigger appropriate investigation and corrective action
based on the investigation.
23.3 Alert limits (Environmental Monitoring): Established microbial or particulate levels
giving early warning of potential drift from normal operating conditions which are
not necessarily grounds for definitive corrective action but which require follow-up
investigation.
23.4 Alert limits (media fill): Established levels or numbers of positive media filled units,
the cause of which should be investigated, but which are not necessarily grounds
for definitive corrective action.
23.5 Aseptic filling: Operation whereby the product is sterilised separately, then filled
and packaged using sterilised containers and closures in critical processing zones.
23.6 Aseptic processing facility: A building, or segregated segment of it, containing
cleanrooms in which air supply, materials, and equipment are regulated to control
microbial and particle contamination.
23.7 Aseptic processing room: A room in which one or more aseptic activities or
processes are performed.
23.8 Aseptic manufacturing area: The classified part of a facility that includes the aseptic
processing room and ancillary cleanrooms.
23.9 Change control: A formal system by which qualified representatives of appropriate
disciplines review proposed or actual changes that might affect a validated status
of facilities, systems, equipment or processes. The intent is to determine the need
for action that would ensure that the system is maintained in a validated state
23.10 Clean area: An area with defined environmental control of particulate and
microbial contamination, constructed and used in such a way as to reduce the
introduction, generation and retention of contaminants within the area
23.11 Cleaning Validation: Cleaning validation is documented evidence that an
approved cleaning procedure will provide equipment, which is suitable for
processing medicinal products.
23.12 Cleanroom: A room designed, maintained, and controlled to prevent particle and
microbiological contamination of drug products. Such a room is assigned and
reproducibly meets an appropriate air cleanliness classification.
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23.13 Controlled area: An area constructed and operated in such a manner that some
attempt is made to control the introduction of potential contamination (an air supply
approximating to grade D may be appropriate), and the consequences of
accidental release of living organisms. The level of control exercised should reflect
the nature of the organism employed in the process. At a minimum, the area
should be maintained at a pressure negative to the immediate external
environment and allow for the efficient removal of small quantities of airborne
contaminants.
23.14 Installation Qualification (IQ): The documented verification that the facilities,
systems and equipment, as installed or modified, comply with the approved design
and the manufacturer's recommendations
23.15 Laminar flow: An airflow moving in a single direction and in parallel layers at
constant velocity from the beginning to the end of a straight line vector.
23.16 Media fills: Method of evaluating an aseptic process using a microbial growth
medium. (Media fills are understood to be synonymous to simulated product fills,
broth trials, broth fills etc.).
23.17 Operational Qualification (OQ): The documented verification that the facilities,
systems and equipment, as installed or modified, perform as intended throughout
the anticipated operating ranges.
23.18 Performance Qualification (PQ): The documented verification that the facilities,
systems and equipment, as connected together, can perform effectively and
reproducibly, based on the approved process method and product specification.
23.19 Pre-determined acceptance criteria: The criteria assigned, before undertaking
testing, to allow evaluation of test results to demonstrate compliance with a test
phase of delivery requirement
23.20 Unidirectional flow: An airflow moving in a single direction, in a robust and uniform
manner, and at sufficient speed to reproducibly sweep particles away from the
critical processing or testing area.
23.21 Validation master plan: A document providing information on the company's
validation work programme. It should define details of and timescales for the
validation work to be performed. Responsibilities relating to the plan should be
stated.
23.22 Validation protocol: A written plan stating how validation will be conducted and
defining acceptance criteria. For example, the protocol for a manufacturing process
identifies processing equipment, critical process parameters/operating ranges,
product characteristics, sampling, test data to be collected, number of validation
runs, and acceptable test results.
23.23 Validation report: Document reporting the validation activities, the validation data
and the conclusions drawn.
24. History: First Issue
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25. Attachments
27.1 Attachment No. 01/R0 : HVAC System Diagram
27.2 Attachment No. 02/R0 : Sterile Area Diagram.
27.3 Attachment No. 03/R0 : Discrepancies and corresponding report.
27.4 Attachment No. 04/R0 : Qualification Report.
27.5 Attachment No. 05/R0 : Microsoft Project Reports for HVAC Validation plan.
27.6 Attachment No. 06/R0 : List of Discrepancy (ies).
27.7 Attachment No. 07/R0 : Qualification Notes.
27.8 Attachment No. 08/R0 : Installation Qualification Template.
27.9 Attachment No. 09/R0 : Operational Qualification Template.
27.10 Attachment No. 10/R0 : Performance Qualification Template.
27.11 Attachment No. 11/R0 : Signature Identification.
26. System Qualification Statement And Qualification Summary
26.1 After conclusion of all the verifications, tests and challenges indicated and
after complying with the approved specifications and parameters, the system
can be considered validated.
26.2 A final report or summary must be prepared for every section and for the
overall protocol. Deviations should be noted and explained if approved; the
rationale should be included in the final protocol summaries.
26.3 The documents should be verified for completeness, accuracy and
compliance with cGMP requirements before its final approval.
26.4 Validation of the environmental control system should serve as a basis for not
only approval and commissioning of all the components of the system, but also
to establish the basis for routine monitoring.
27. Control of qualification protocol format
27.1 IQ, OQ and PQ validation protocols will be performed in accordance to attachment
no. 08, 09 and 10.
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Validation Plan

System in Sterile Area

Validation Plan for HVAC System in Sterile Area

VALIDATION PLAN APPROVAL

Reviewed and Approved By: Validation Manager

Validation Plan for HVAC System in Sterile Area

Area Description (Sterile Area)

Requirement for Materials and Equipment

Aseptic systems impact/Criticality Assessment

Planning and Cost

Discrepancy/ Justification And Corrective Action

Modification/ Change Control During Qualification

References and Related Records

System Qualification Statement And Qualification Summary

Control of qualification protocol format

Validation Plan for HVAC System in Sterile Area

Validation Plan for HVAC System in Sterile Area

Validation Plan for HVAC System in Sterile Area

System boundaries: The physical boundaries are defined as follows:

AHUs require externally supplied heating and cooling sources such as

Area Description (Sterile Area)

Validation Plan for HVAC System in Sterile Area

Maximum permitted number of particles/m3 equal to or above (a)

Not Defined (f)

Not Defined (f)

a. Particle measurement based on the use of a discrete airborne particle

Validation Plan for HVAC System in Sterile Area

6.4 The area is designed also in accordance to following US FDA classification.

6.5 Cleanliness Phase

(FS 209 E class 10 000 at rest) ISO

SI M represents the classification on the basis of 0.5m particles

Validation Plan for HVAC System in Sterile Area

6.6 Types of HEPA filter used in sterile area

Requirement for Materials and Equipment

Validation Plan for HVAC System in Sterile Area

Validation Plan for HVAC System in Sterile Area

Validation Plan for HVAC System in Sterile Area

Validation Plan for HVAC System in Sterile Area

Validation Plan for HVAC System in Sterile Area

11. Aseptic systems impact/Criticality Assessment: HVAC system, supporting

This process control system has

Supports direct impact system

Chilled Water System

Supports direct impact system

Aseptic HVAC System

Quality of the air has direct

11.2 Component Criticality Assessment:

Validation Plan for HVAC System in Sterile Area

11.3 GMP Critical Parameters

Room classification (Viable

Initially and on Continuous

Rates Rooms air changes

12. Validation Approach

User Requirement Specification: This document shall be generated and

Functional Requirement Specification: This document shall be generated

Design Specification: This document shall be generated and approved to

Validation Plan for HVAC System in Sterile Area

The validation cycle includes the following testing specifications:

Factory Acceptance Test

Site Acceptance Test

Operation Qualification and

Validation Plan for HVAC System in Sterile Area

Validation Plan for HVAC System in Sterile Area

13. Installation Qualification