HVAC

Saffron Pharmaceuticals (Pvt.) Ltd.
19 Km. Sheikhupura Road, Faisalabad-Pakistan.
PRESENTED BY

INTRODUCTION
BASICS THAT WE SHOULD KNOW
HVAC
FUNCTION
VALIDATION
RESPONSIBILITIES
PRE
REQUISITE
HVAC
Validation

HVAC
FUNCTION
VALIDATION
RESPONSIBILITIES
PRE
REQUISITE
HVAC
VALIDATION
H V A C
Heating Ventilating Air Conditioning
HVAC

HVAC
FUNCTION
VALIDATION
RESPONSIBILITIES
PRE
REQUISITE
HVAC
VALIDATION
3
2
1
PURPOSE
• Provide a
specific set of
environment
condition
required for
manufacturing
process.
FUNCTIONS
• Heating and
cooling
• Humidifying
and
dehumidifying
• Cleaning the air
• Regulate air
flow
• Pressurization
USES
• Prevent
contamination
• Provide
comfortable
working
conditions

HVAC
FUNCTION
VALIDATION
RESPONSIBILITIES
PRE
REQUISITE
HVAC
VALIDATION
Validation is the
documented act of
proving that any
procedure, process,
equipment, material,
activity or system
actually leads to the
expected result.
VALIDATION
As per FDA, May
1987, A ct i o n of
proving that any
equipment works
correctly and leads
to the expected
result is equipment
q u a l i f i c a t i o n .
EQUIPMENT VALIDATION

HVAC
FUNCTION
VALIDATION
RESPONSIBILITIES
PRE
REQUISITE
HVAC
VALIDATION
01 02 03
Quality
Assurance
• E n s u r e t h e
o v e r a l l
requalification
• P r e p a r a t i o n ,
r e v i e w , a n d
a p p r o v a l o f
p r o t o c o l
• H a n d l i n g o f
d e v i a t i o n s .
• Impart training
o f t h e t e a m
• C o m p i l e a n d
r e v i e w o f
r e p o r t s .
Quality
Control /
Microbiology
• R e v i e w t h e
protocol and
r e p o r t .
• Perform and
p r o v i d e
environmental
m o n i t o r i n g
reports of the
manufacturing
area for the
microbial load
as per schedule
to record all
observations
Engineering
• Review the
protocol and
r e p o r t .
• P r o v i d e
e x e c u t i o n
s u p p o r t
• E n s u r e
p r o p e r
operation of
the system
04 05
External
Agency
• Execution of
tests as per
p r o t o c o l .
• Collection of
d a t a
• Preparation
of final test
cer tificates
User
Department
• P r o v i d e
e x e c u t i o n
support during
requalification.
• R e v i e w t h e
protocol and
r e p o r t .

HVAC
FUNCTION
VALIDATION
RESPONSIBILITIES
PRE
REQUISITE
HVAC
VALIDATION
1 Daily cleaning of the area.
2 Required materials and
instruments are available.
3 The gowning procedure of
plant personnel and
external agency shall be
done as per the respective
SOP for Entry and exit to
the Aseptic area.
5 Fogging cleaning shall be done
prior to performing the
requalification activity.
6 Personnel qualification of the
external party shall be done as
per the respective SOP
"Qualification of personnel for
working in the aseptic area".
4 Personnel hygiene of personnel.
8 External party agreement,
respective valid SOP, and
traceability certificates of
instruments.
9 Calibration of instruments or
equipment used for testing like
Anemometer, Aerosol
photometer, Non-viable particle
counter, etc.
7 Training records of the external
parties.

HVAC
FUNCTION
VALIDATION
RESPONSIBILITIES
PRE
REQUISITE
HVAC
VALIDATION
HVAC
SYSTEM VALIDATION

HVAC(AHU) is
HEART
of Pharmaceutical Industries

HVAC
01
02
03
04
05
06
07
08 02 - Pressure differentials
04 -Microbial count
Air flow pattren - 07
Partical count - 05
measurment
01 - Air flow measurment
Temperature, Relative - 08
humidity
Recovery test - 06 03 - Filter integrity
testing
Validation parameters

TESTS RE-QUALIFICATION FREQUENCY
Integrity Testing HEPA Filter
Pressure Differential Test
Temperature and Relative Humidity Test
Once every six months.
At Every Filter replacement.
Once every six months.
At Every Filter replacement.
For 3 days (Every six month) Continuous monitoring
For 3 days(Every six month) Continuous monitoring
Air Flow Pattern Test Once in a year.
Cleanliness Class Verification Non Viable
Particulate count. At-rest condition and in
operation for ISO class 5, 6, 7, and 8
Once in every six months for three consecutive
days at a defined location.
At Every Filter replacement
Microbial monitoring Once in every six months for three consecutive days
Recovery Test Once in a year.
Air Velocity Measurement and Calculation
of Air Changes

Air
velocity
test Objective
It expresses that air is delivered at
required velocity by AHU through
HEPA filters and it helps in calculation
of ACPH (Air Changes Per Hour).

Number of measuring points
• Four Corners & One Centre point of Filter
1 2
3
4
5

.
• The formula to calculate the ACPH is as follows-
Air changes per hour (ACPH) =
Total CFM X 60
Room volume
❑ Apparatus Required:-
• Anemometer,
• Capture hood.
• A calibrated instrument should be used for measurement.
❑ Acceptance criteria:-
• Air velocity and Air Change Per Hour (ACPH) shall be within the design specification.
• A variation in air volume shall not be ±20% from the design CFM
❑ Result:-
• Refer enclosed file named FORM-A of respective AHU requalification report.
• Traceability certificates should be enclosed along with the requalification report.
1. AIR VELOCITY, THE AIR VOLUME, AND AIR CHANGES PER HOUR (ACPH)
MEASUREMENT:

Filter
integrity
test
Objective
• This test is performed to confirm that
the filter system is properly installed
and that leaks have not developed
during use

1-Aerosol Photometer:
2-Aerosol Generator:
capable of generating particle of
0.05 μm to 2.0 μm size.
To measure the concentration of
aerosol
3-Aerosol Source Substances:
• PAO (Poly Alfa Olefin)
• DOP (Di-Octyl Phthalarte) : Not in use now as
considered carcinogenic
• DOS (Di-Octyl Sebacate) or DEHS (Di-2-Ethyl
Hexyl Sebacate)
• PSL (Poly Styrene Latex)
1
2
3
Apparatus used for Test:

Procedure
Introduce the
specific challenge
aerosol upstream of
the filter(s) and
searching for leaks
by scanning the
downstream side of
the filter
The concentration
of the aerosol
challenge upstream
of the filter should
be between 20
mg/m3 and 80
mg/m3
Measure the
downstream
concentration by
holding the probe
approximately 3
cm from the face
of filter
Scanning rate: 15 /
X (cm/s)
Where X = probe
dimension
perpendicular to
scan direction
(expressed in cm)
Scanning should be
performed over the
entire downstream
face of each filter,
the perimeter of each
filter, the seal
between the filter
frame and the grid
structure, including
its joints.
1 2 3 4
5

04
01
02
03
As per ISO 14644-3, Leakage should not be
greater than 0.01% of the challenge aerosol
concentration
If any leakage is more than 0.01% of the
upstream aerosol concentration, repair it.
Repair patches on filter should not exceed maximum
of 5% of the total filter face area
Total no of patches should not exceed 5 number/
filter.
Acceptance criteria

Differential
pressure
test Objective
This test is carried out to determine the
capability of air system to provide
pressure gradient among the different
rooms.

Electronic
micro
manometer,
Mechanical
differential
pressure
gauge
Inclined
manometer
Apparatus used for test

The differential
pressure should be
as per predefined
room design
As per EU Guidelines &
WHO (TRS No. 961),
adjacent rooms of different
grades should have a
pressure differential of
approximately 10–15 Pascal
As per Schedule M,
differential pressure between
areas of different
environmental standards
shall be at least 15 Pascal
Acceptance criteria

Temperature
and
relative
humidity
test Objective
Temperature and relative humidity are
monitored to demonstrate that
respective rooms contain predefined
temperature and RH

• Psychrometer
• Thermometer
• Dew point sensor,
• Digital thermo
hygrometer

2
1
The temperature and relative
humidity depend on the
product and nature of the
operations carried out
As per Schedule M, temperature
and humidity in the aseptic areas
shall not exceed 27 °C and relative
humidity 55%, respectively unless
there are product specific
requirements
Acceptance criteria

Air
flow
pattern
test Objective
The purpose of airflow direction test
and visualization is to confirm that the
airflow direction and its uniformity
conform to the design and performance
specifications.

02
01
Smoke/Fog
Generator
Reagents used to
generate smoke:
• Glycerine + Water
• Ice Water
• Titanium tetrachloride

01
02
03
Place the smoke generator and generate the
smoke below the supply HEPA filter and
observe the smoke Pattern. Same way observe
the smoke pattern near return riser
Airflow study is also performed to see the
airflow direction between adjacent rooms.
Carry out the Videography of
entire Airflow study.
Procedure

Air Flow should be
Unidirectional
01
Air should flow
towards return riser
02
Air should flow from room
having higher pressure to
adjacent room having less
pressure.
03
Acceptance criteria

Non-Viable
Particle
Count Objective
It measures concentration of non
viable air borne particle and confirms
that respective area/rooms meet
predefined condition of air borne
particles

4- Sample Volume and Sampling time per
location:
As per ISO 14644-1, the volume sampled
at each location shall be at least 2 L with
minimum sampling time at each location
of 1 minute
3- Rationale for sampling location shall be
dependent on man movement, material
movement, area of product exposure,
manual intervention and location likely to
have more air borne particles like return
riser
2- No. of sampling location=
√X i .e. square root of Room
area in square meter
1-Measurement shall be done at
working height and in two states
i. e. “at rest” & “in operation”.
Procedure
Procedure

Grade At rest In
operatio
n
At rest In
operatio
n
0.5μ 5.0μ 0.5μ 5.0μ
A 3520 20 3520 20
B 3520 29 352000 2900
C 352000 2900 352000
0
29000
D 352000
0
29000 Not identified
Grade At rest In
operatio
n
At rest In
operatio
n
0.5μ 5.0μ 0.5μ 5.0μ
A 3520 20 3520 20
B 3520 293 352000 2930
C 352000 2930 352000
0
29300
D 352000
0
29300 Not identified
As per EU Guideline & WHO (TRS No. 961) As per Schedule M:
Acceptance criteria

Recovery
study Objective
This test is performed to determine the
ability of the installation to eliminate
airborne particles

5 1
2
3
4
2-
The cleanroom area to be
examined should be then
contaminated with an aerosol
while the air-handling units are
in operation
3-
Commence measurements at 1
min intervals. Note the time
when the particle concentration
reaches the 100 x target
concentration threshold (t100n).
4-
Note the time when the
particle concentration
reaches the target
cleanliness level (tn).
1-
Measure the clean room or
clean zone air borne non-
viable particle counts at
rest condition
5-
Recovery Time: tn - t100n
Procedure

Acceptance criteria
As per WHO (TRS No. 961), the
recovery period should not be more
than 15-20 min.

Viable
particle
count Objective
It measures concentration of viable air
borne particle and confirms that
respective area/rooms meet predefined
condition of microbial contamination

01
02
03
Sampling locations are selected
based on activity in critical area
Preincubated SCDA Plates are
generally used for microbial
monitoring
Collect samples
04
After sampling, all the plates are
incubated and no. of Colony Forming
Units (CFU) is observed.
Procedure

Acceptance criteria
Grade Air Sample
(CFU/m3)
Settle Plates
(diameter 90
mm)
(CFU/4
hours)
Contact Plates
(diameter 55
mm)
(CFU/plate)
A <1 <1 <1
B 10 5 5
C 100 50 25
D 200 10 50
Grade Air Sample
(CFU/m3)
Settle Plates
(diameter 90
mm)
(CFU/4
hours)
Contact Plates
(diameter 55
mm)
(CFU/plate)
A <1 <1 <1
B 10 5 5
C 100 50 25
D 500 10 50
As per EU Guideline & WHO (TRS No. 961): As per Schedule M:

The system should be revalidated under the following
conditions.
• If any major changes or modification in the system is
done.
• Any major changes have been done in the respective
room or module, which is affecting the environmental
condition.
• If any major maintenance has taken place in the
system which can affect the performance of the air
handling system.
• Periodic requalification.
9. RE-QUALIFICATION CRITERIA:

Any deviation observed during requalification shall be recorded and investigated.
A) Description of deficiency and date observed
B) The person responsible for corrective action and date assigned.
C) Corrective actions are taken and the date conducted.
10. DEVIATION (IF ANY):

• The requalification report shall consist of a
summary document, in narrative form, which shall
briefly describe the activity performed along
with the observations recorded in relevant
exhibits.
• This report shall also include the related
documents and attachments/ annexures which
were completed at the time of revalidation
activity.
11. REQUALIFICATION SUMMARY:

• The report shall be evaluated and proper
references/conclusions/recommendations shall be recorded by
Quality Assurance.
• The report shall be evaluated and finally approved by Quality
Assurance.
12. APPROVAL OF REQUALIFICATION REPORT:

13. LIST OF FORM/ANNEXURE:
LIST OF FORM:
Form Title
A
B
C
D
E
F
G
H
I
Air velocity/airflow measurement and calculation of air changes.
Filter integrity test.
Differential pressure measurement
Temperature and humidity measurement.
Airflow pattern test
Non-viable particle count test.
Recovery
Viable particle count- Passive air sampling
Viable particle count- Active air sampling

List of Annexure: • Requalification report shall include the following annexure:-
S No.
01
02
03
04
05
06
07
08
09
Report of Air velocity and ACPH.
Report of filter integrity.
Report of Temperature and Relative Humidity.
Report of Differential pressure.
Report of Non-viable particle count.
Environment Monitoring Report for Passive air sampling.
Environment Monitoring Report for Active air sampling.
Recovery study test report.
CD of Airflow pattern test.
ANNEXURES

S No.
10
11
12
13
14
15
16
17
18
ANNEXURES
Calibration certificate of Differential pressure gauge.
Calibration certificate of data loggers.
Calibration certificate of Anemometer.
Calibration certificate of the aerosol photometer.
Calibration certificate of a particle counter.
Training Records.
SOP of an external agency
Personal Monitoring report.
Traceability Certificates

15. REFERENCES
1. WHO-TRS 937 HVAC
2. ISO 14644-1
3. ISO 14644-2
4. Quality Assurance of Pharmaceuticals, A Compendium of Guidelines and Related Materials. 2nd
ed., Vol. 2. 2007.
5. ISO 14644-3, Cleanrooms and associated controlled environments- Test methods
6. EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary
Use, Volume 4, Annexure 1
7. WHO Technical Report Series, No. 961 (2011), Annexure 6
8. Schedule M
9. Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing–Current Good
Manufacturing Practice, U.S. Department of Health and Human Services Food and Drug
Administration Center for Drug Evaluation and Research (CDER) Center for Biologics
Evaluation and Research (CBER) Office of Regulatory Affairs (ORA), Pharmaceutical CGMPs;
2004.

19 Km. Sheikhupura Road, Faisalabad-Pakistan.

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