Professional Documents
Culture Documents
For
HVAC
(Heating, Ventilation and Air Conditioning)
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
: Validation Engineer
:
:
:
Page 2 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
TABLE OF CONTENTS
Sl #
Titles
Page Numbers
1.
Purpose
2.
Objective
3.
Scope
4.
Quality standards
5.
System boundaries
6.
7.
8.
System Description
10
9.
Responsibilities
12
10.
Training Requirements
13
11.
14
12.
Validation Approach
15
13.
Installation Qualification
18
14.
Operational Qualification
28
15.
Performance Qualification
38
16.
46
17.
46
18.
Validation
46
19.
46
20.
Re-qualification
47
21.
47
22.
Definitions
48
23.
Glossary
48
24.
History
50
25.
Attachments
51
26.
51
27.
51
Page 3 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
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.
Page 4 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
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.
4.2 AS/NZS ISO 14644.2:2002: Clean room and associated controlled environments,
part 2: specification for testing and monitoring to prove continued compliance with
ISO 14644.1.
4.3 AS/NZS ISO 14644.4:2002: Clean room and associated controlled environments,
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
Page 5 of 51
Effective Date:
5.
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
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.
Page 6 of 51
Effective Date:
At Rest (b)
Grade
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
In Operation (b)
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
f. The requirements and limits are depending on the nature of the operations
carried out.
Page 7 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
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).
Cleanliness grade B
(FS 209 E class 100 at rest) ISO 5
US class 10.000 in operation
SI M* 5.5
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)
The presence of appropriately dressed personnel is
permitted.
Turbulent airflow is permitted.
Microbiological limit 100 CFU/m3 (action limit)
The presence of appropriately dressed personnel is
permitted.
Turbulent airflow is permitted.
Microbiological limit 200 CFU/m3 (action limit
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
Page 8 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
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.
Page 9 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
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.
Page 10 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
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.
Page 11 of 51
Effective Date:
9.
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
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).
Page 12 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
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.
Page 13 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
Reasons (Rational)
Classifications
Environmental
Monitoring System
Direct Impact
Electrical Heating
System
Indirect Impact
GEP and
Commissioning.
Indirect Impact
GEP and
Commissioning.
Direct Impact
Requirements
Full qualification is
required.
Full qualification is
required.
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).
Page 14 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
Criticality
Reasons (Rational)
Requirements.
GMP Critical
parameter
GMP requirement
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
Continuous monitoring
GMP Critical
parameter
GMP requirement
Continuous monitoring
Airflow Paths
GMP Critical
parameter
GMP requirement
Continuous monitoring
for
Continuous monitoring
12.2.2
12.2.3
Page 15 of 51
Effective Date:
12.2.4
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
Design Qualification
12.2.4.2
12.2.4.3
12.2.4.4
Commissioning
12.2.4.5
Installation Qualification
12.2.4.6
12.2.4.7
Performance Qualification
Page 16 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
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)
Performance Qualification
(PQ)
Operational Qualification
(OQ)
Design Development
Detail Design
(i.e. What)
IQ Test Plan
(Inc. PDI)
Installation Qualification
(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.
Page 17 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
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.
iii.
Page 18 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
iii.1.1.4.5.2.
Velocity of air.
Page 19 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
Page 20 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
ASHRAE
the
in
reference
the
as-built
Page 21 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
Page 22 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
Page 23 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
Page 24 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
and
connection
to
Page 25 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
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.
Page 26 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
Test
Acceptance Criteria
The HEPA filters must pass the filter integrity test in accordance to
the USP/EP Standards
ii)
iii)
iv)
v)
vi)
vii)
Page 27 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
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.
Page 28 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
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.
Page 29 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
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)
Page 30 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
Page 31 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
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.
Page 32 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
Page 33 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
Page 34 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
Page 35 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
Acceptance Criteria
Verification of Critical
Instrument Calibration
Operational procedure
compliance test
Loss of utility test must not interfere with other ongoing operations.
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.
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
Relative humidity
Audit/Monitoring
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
Page 36 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
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)
Maximum
Time interval
Objective
Filter leakage
12 months
Containment leakage
12 months
Airflow directional
differential.
6 months
12 months
12 months
Verifies Cleanliness
Absence of crosscontamination
and
pressure
Airflow Volume
Airflow Velocity
Verify
unidirectional
airflow and or containment
condition.
12 months
Recovery (time)
12 months
Airflow visualization
Verify required
patterns
12 month
Airflow
direction,
evidence.
airflow
documented
Page 37 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
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.
Page 38 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
iv.
Page 39 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
Limit/Range
Reference
TSI Instrument
Temperature
22 3C
Q-Trak Plus
IAQ-Calc
TH-Calc
VelociCalc Plus
Relative humidity
30% to 65%
Q-Trak Plus
IAQ-Calc
Air movement
80ft/s or 0.25m/s
WHO
VelocioCalc
VelociCalc Plus
VelociaCeck
DP-Calc
AccuBalance
Page 40 of 51
Effective Date:
Ventilation (fresh
air)
Ventilation (CO2)
Particles
concentration in
cleaned HVAC
systems
vi.
1.0
Validation
Plan No.:
VP/MSC/001/R0
Q-Trak Plus
IAQ-Calc
TH-Calc
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
Page 41 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
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
Page 42 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
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:
ix.
Page 43 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
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.
Page 44 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
Acceptance Criteria
Verification of
Performance Qualification
prerequisites
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).
Non-Viable
Particulate
Testing
(Critical
and
Controlled Rooms/Areas
Only)
Dynamic
Conditions
Page 45 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
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.
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.
Page 46 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
Page 47 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
22. Definitions: Definitions of terms and abbreviations relating to this validation plan which
are given below:
Abbreviation
Expansion
HVAC
IQ
Installation Qualification
OQ
Performance Qualification
Performance qualification
PQ
SOP
Facility
FAC
CC
Change Control
Good Manufacturing Practice
GMP
QA
Quality Assurance
QC
Quality Control
VMP
ACUs
XXX
US FDA
USP
CFU
SA
Sterile Area
VP
Validation Plan
GEP
FAT
HEPA
PI&Ds
23. Glossary
Page 48 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
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.
Page 49 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
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
Page 50 of 51
Effective Date:
Version No.:
1.0
Validation
Plan No.:
VP/MSC/001/R0
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.
Page 51 of 51