HVAC SYSTEM

DESIGN & ENGINEERING

FOR
PHARMACEUTICAL PLANTS
Jakarta,22nd July 08, Semarang,23rd July 08

Ravi Saxena-Head Engineering-nne pharmaplan-India

Slide 1 of 28
Origin
Origin and
and Transmission
Transmission of
of Contamination
Contamination

Air Starting
material
bulkware
Personnel

Equipment
Water Packaging material

Slide 2 of 28
Think of a facility where

• You are crawling in the technical floor to check

some leakage in duct
• Room is extremely cold when equipment is not
running and humidity is high
• Searching hard to find ports for integrity testing
of filter
• You are smelling cephalosporin at the entrance
• Aseptic room is running under negative pressure
as operator is sleeping at night

Slide 3 of 28
Think of a facility where

• No space after HEPA filter bank to scan for

aerosol
• Almost every room is fed with independent
AHU.
• Doors are either not closed complete or so tight
that could not be opened easily.
• Solvent smells through out the plant.

Slide 4 of 28
 Purpose
Purpose Of
Of HVAC
HVAC System
System

• To provide protection to the product and avoid

contamination of product.

• To provide the indoor environment suitable as

per process and product characteristics and
cGMP/GEP norms considering the requirements
of various hygiene zones

• To protect personnel from harmful potent/toxic

product exposure.

• To provide environmental protection

Slide 5 of 28
 Design
Design Pre-Requisites
Pre-Requisites

–Process/product category (bulk api/formulations -

general, betalactum, cytotoxic etc.)

–Type of product ((tablets, capsules, ointment, syrups,

parenterals ( LVP/SVP) etc.))

–Temperature (23+/-2*C or ??)

–Relative humidity (30 - 60% or <55% or ??)

–Hygiene levels of protection

(ISPE level-I, II & III or ISO-5,7,8)

–Safety concepts (hazardous/ potent)

–GMP conformance ( EU, USFDA, WHO, TGA etc.)

Slide 6 of 28
 Design
Design Philosophy
Philosophy

– AHU distribution / zoning

– room wise temperature (23+/-2*c)

– Room wise relative humidity (30-60% or <55%)

– Differential pressure concept(dp)

– AHU schematics

– Safety concepts and features proposed

– Control & automation philosophy

Slide 7 of 28
 Effect
Effect Of
Of Relative
Relative Humidity
Humidity On
On Cooling
Cooling
Media
Media Temperature
Temperature andand Power
Power Consumption
Consumption

10.00 Brine
Chilled Chemical
8.28
Water Dehumidification
8.00
Chilled Water / Brine Temperature (OC)

6.89
6.00
4.94
4.00

2.83
2.00

0.50
0.00
60 55 50 45 40 35 30

-2.00
-2.56
0.99 kw/TR 1.11 kw/TR
-4.00
RH %
The figure are tentative and may vary substantially due to various parameters depending on case to case.

Slide 8 of 28
AHU Distribution & Pressure Differential for Solid Dosage Facility

Corridor
Coating -2 Coating -1
Preparation

Corridor 2500mm Wide

Service Service

Tablet Tablet
Comp.-3 Comp.-4

Slide 9 of 28
 HVAC Schematic for Aseptic Processing Area
HDPE INSECT MESH LEGEND :
EXHAUST AIR FRESH AIR
AIR FLOW MEASURING STATION
VOLUME CONTROL DAMPER - MANUAL
LOUVER F
COOLING COIL FIRE DAMPER
F-9 FILTER
M
MOTORISED PVC MOISTURE MOTORISED DAMPER
DAMPER ELIMINATOR
COOLING COIL
CENTRIFUGAL
CENTRIFUGAL BLOWER PVC MOISTURE ELIMINATOR
RETURN AIR

CHAMBER

CHAMBER
BLOWER (SUPPLY)

SUPPLY AIR
MIXING

MIXING
(RETURN)
PLENUM

VARIABLE SPEED HOT WATER COIL

PLENUM
SUPPLY AIR GRILLE / DIFFUSER
RETURN AIR GRILLE / DIFFUSER
VSD F
TERMINAL HEPA
F-9 FILTER
MOTORISED F-6 FILTER HOT WATER
COIL F-6 FILTER
DAMPER CELAN STEAM
DOUBLE HDPE WIRE MESH
SOUND ATTENUATOR
F
TEMP. 22 ± 3 ° C

TEMP. 22 ± 3 ° C

TEMP. 22 ± 3 ° C

TERMINAL HEPA FILTER

R H 35% - 60%

R H 35% - 60%

R H 35% - 60%
CLASS - B

CLASS - B
CLASS - B

RETURN AIR GRILLE

M M M

Slide 10 of 28

HVAC SCHEMATIC FOR CLASS- B

 HVAC Schematic for Class D Processing Area

EXHAUST AIR (MOTORISED)

EXHAUST AIR (MANUAL)

FRESH AIR (MANUAL)

FRESH AIR
(100%)

(100%)
PREFILTER G-4 SYNTHETIC WASHABLE
LEGEND
DOUBLE HDPE WIRE MESH
H-13 FILTER (HEPA FILTER) AIR FLOW MEASURING STATION
MOTORISED VOLUME CONTROL DAMPER - MANUAL
DAMPER F
M M
FIRE DAMPER
CENTRIFUGAL CENTRIFUGAL M
BLOWER BLOWER
(RETURN) (SUPPLY) MOTORISED DAMPER
VARIABLE SPEED VARIABLE SPEED
RETURN MIXING SUPPLY
AIR AIR COOLING COIL
CHAMBER PLENUM
PLENUM
PVC MOISTURE ELIMINATOR

VSD VSD
HOT WATER COIL
F
SUPPLY AIR GRILLE / DIFFUSER
HOT WATER COIL
F M
MOTORISED F-6 FILTER F-9 FILTER RETURN AIR GRILLE / DIFFUSER
DAMPER COOLING COIL PVC MOISTURE ELIMINATOR
H-13 HEPA FILTER

F-9 FILTER

F-6 FILTER
G-4 PREFILTER

DOUBLE HDPE WIRE MESH

SUPPLY AIR GRILLE/ DIFFUSER
SOUND ATTENUATOR

RETURN AIR GRILLE WITH G-4

SYNTHETIC WASHABLE FILTER

Slide 11 of 28
 HVAC Schematic for Class O Processing Area
(Critical processing areas of non-sterile formulations)
LEGEND
M

F AIR FLOW MEASURING STATION

CENTRIFUGAL
BLOWER VOLUME CONTROL DAMPER - MANUAL
EXHAUST AIR (MOTORISED DAMPER)
(100%) (RETURN) F
VSD RETURN FIRE DAMPER
DOUBLE HDPE WIRE MESH AIR
PLENUM M

EXHAUST AIR (MANUALLY OPERATED MOTORISED DAMPER

DAMPER)
MOTORIZED MIXING DAMPER VSD COOLING COIL
M
CENTRIFUGAL PVC MOISTURE ELIMINATOR
FRESH AIR (MANUALLY OPERATED
BLOWER
DAMPER) (SUPPLY) HOT WATER COIL

CHAMBER
MIXING
VARIABLE SPEED
PREFILTER G-4 SUPPLY
SYNTHETIC WASHABLE AIR SUPPLY AIR GRILLE / DIFFUSER
PLENUM
FRESH AIR RETURN AIR GRILLE / DIFFUSER
(100%)
F
VSD H-13 HEPA FILTER
MOTORISED
DAMPER M F-9 FILTER F-9 FILTER
F-6 FILTER HOT WATER COIL
F-6 FILTER
COOLING COIL PVC MOISTURE ELIMINATOR
G-4 PREFILTER

DOUBLE HDPE WIRE MESH

SOUND ATTENUATOR

MINI PLEAT HEPA FILTER (H-13)

RETURN AIR GRILLE WITH G-4

SYNTHETIC WASHABLE FILTER

Slide 12 of 28
 HVAC Schematic for Class F Area
(For warehouse, secondary packaging, QC Lab. etc.)
DOUBLE HDPE
INSECT MESH
LEGEND
AIR FLOW MEASURING STATION

VOLUME CONTROL DAMPER - MANUAL

CENTRIFUGAL
BLOWER F
(SUPPLY) FIRE DAMPER
M
MIXING SUPPLY
AIR MOTORISED DAMPER
CHAMBER PLENUM

COOLING COIL

F PVC MOISTURE ELIMINATOR

F F-6 FILTER HOT WATER COIL

COOLING COIL HOT WATER COIL
G4 FILTER SUPPLY AIR GRILLE / DIFFUSER
PVC MOISTURE ELIMINATOR
RETURN AIR GRILLE / DIFFUSER

H-13 HEPA FILTER

F-9 FILTER
SUPPLY AIR GRILLE / DIFFUSER
F-6 FILTER

G-4 PREFILTER

DOUBLE HDPE WIRE MESH

TEMP. <25 ° C

R H --

RETURN AIR GRILLE/DIFFUSER

Slide 13 of 28
 NNE
NNEPharmaplan
Pharmaplan Recommendations
Recommendations
(user-defined,
(user-defined,Process-specific
Process-specificadaptations
adaptationspossible)
possible)

Official Standard NNE Pharmaplan

EU-GUIDE A B C D O E F

ISO 14644-1 5 5 5 7 7 8 8 -- 9 -- -- -- -- --

Air change/h 0,45m/s + 20%* 40-60 30-40*** >20 5-15 5-10 3-10

Prefilter F7+F9 F7+F9 F7+F9 F7+F9

F7+F9+H13 F6/F7 F6
Terminal filter HEPA/H14 HEPA/H13 HEPA/H13 HEPA/H13
Positive pressure +15** +15** +15** +15** +15** 0 0
[Pa]
Return air intake near
X (X) - - - - -
the floor
Temperature [°C] 20-24 20-24 20-24 20-24 19-26 19-30 19-30

Rel. humidity <55% <55% <55% <60% <60% <65% <65%

* settling speed when displacement current with little turbulence

** 0.005 inch water column (FDA) ~12.7 Pa
comfort criterion according to VDI 2083: rH 65-30%, activity-related T 18-
24°C
***According “Aseptic Guide” FDA an air change rate
20-1 is necessary (class 100.000 in operation)

Slide 14 of 28
 HVAC
HVACSystem:
System:
Current
Current Technology
Technologyand
andQualification/Validation
Qualification/Validation
Air change rate / air velocity

Max. particle Air velocity

Clean Room Classes Air change rate
concentration per m³ (laminar flow)
ISO 14644-1 EU - GMP ≥ 0,5 µm h-1 m/s
ISO 1
ISO 2 4
ISO 3 35 540 * 0.45
ISO 4 352 540 * 0.45
ISO 5 A 3.520 540 * 0.45
ISO 6 B 35.200 20-60
ISO 7 C 352.000 > 20
ISO 8 D 3.520.000 > 10
ISO 9 35.200.000

* refer to 3 m room height

Slide 15 of 28
 EU-Hygiene
EU-Hygiene Zones
Zones A-D
A-D &
& ISO
ISO Comparison
Comparison

Hygiene Zone A B C D
Activity Aseptic Environment of A, Filling of products that Preparation of products
manufacturing of Transfer to closed can be terminally that can be terminally
products that product systems sterilized, preparation of sterilized in largely closed
cannot be sterile from open aseptic products that can be systems; surroundings of
filtered, filling of products and parts sterile filtered, isolators (EU minimum
all aseptic in direct contact surroundings of requirement)
products with product isolators and bottle
pack (FDA´s policy)
EU-GUIDE A B C D
ISO 14644-1 5 5 5 7 7 8 8
3
Particles/m ** Rest* Oper. Rest* Oper. Rest* Oper. Rest* Oper.
≥0.5 µm <3.500 <3.500 <3.500 <350.000 <350.000 <3.500.000 <3.500.000 --
≥5 µm <1 <1 <1 <2.000 <2.000 <20.000 <20.000 --
3
CFU/m -- <1 -- <10 -- <100 -- < 200
* after clean-up phase of 15-20 min
** air sampling method

Slide 16 of 28
 Hygiene
Hygiene Zones-
Zones-
NNE
NNEPharmaplan
PharmaplanRecommendations
RecommendationsO*-F
O*-F

Hygiene Zone O* E F
Activity Manufacturing of open, Operational area Operational area Non-
non-sterile products Manufacture without open manufacture (Labs, QC,
product (receipts, administration, workshops,
warehouse, packing etc.) engineering, canteen)
Particles/ Rest*** Operation Rest*** Operation Rest*** Operation
m3**
in principle no requirements,
≥ 0.5 µm <3.500.000 -- -- --
non-GMP
in principle no requirements,
≥ 5 µm <20.000 -- -- --
non-GMP
in principle no requirements,
CFU/ m3 -- -- -- --
non-GMP
* In accordance with hygienezone D, without being legally binding, however;
Pharmaplan recommendation “internal customer standard” user-defined, process-
specific
adaptations are possible.
** Air Sampling method
*** after clean-up phase of 15-20 min

Slide 17 of 28
HVAC system: Current Technology and Qualification/Validation
Separation efficiency of fine filters P > 0.5 µm
35.000 350.000 3.500.000 35.000.000
P/m3 2
Separation efficiency for P > 0.5 µm
35.000.000
17.500.000
F6 30%
3.500.000
F7 60%

F9 85% 350.000

7.000.000
35.000

example: 3.500

Primary particle quantity: 35.000

17.500.000
350.000
filter: F7 + F9 1.050.000

secondary particle quantity: 1.050.000 3.500.000

P/m3
35.000 350.000 3.500.000 35.000.000

Slide 18 of 28
Building Automation Schematic for HVAC
System

Slide 19 of 28
 Myth
Myth And
And Reality
Reality

MYTH
• Differential pressures are a
function of Air Changes
• Cleanable/washable Filters
can be cleaned endlessly
REALITY
• Differential pressures are
NOT a function of Air
Changes.
• No filter can be cleaned
endlessly.Its pore size
increases after each wash

Slide 20 of 28
 Tests
Tests to
to be
be conducted
conducted
To
To validate
validate aa pharmaceutical
pharmaceutical facility
facility

– Air balancing & pressure balancing

– Temperature & RH recording

– Differential/ over pressure measurements

– Air change rate calculation

– Hepa filter integrity (DOP testing)

– Non viable particle count test (if HEPA installed/ as

per ISO-14644)

– Viable particle count

Slide 21 of 28
 Tests
Tests to
to be
be conducted
conducted
to
to Validate
Validate AA Pharmaceutical
Pharmaceutical Facility
Facility
– Air flow pattern

– Sweep over time (recovery)

– Water balancing

– Pressure drop across filters

– Testing under load and no load (when

equipment not running )conditions

– Audio/visual safety alarm checks

Slide 22 of 28
Technical
Technical Documents
Documents to
to be
be Furnished
Furnished
By
By Suppliers
Suppliers

– MOC Certificates of Contact surfaces( eg AHU

inner skin, gaskets)

– Test Certificates of All the components like

Blowers, Motors,Coils, Filters etc

– Calibration certificates with Traceability

certificates from National Standard Test Lab

– Performance characteristic curves

– FAT ( Factory acceptance test reports)

– Operation & Maintenance Manuals

Slide 23 of 28
Technical
Technical Documents
Documents to
to be
be Furnished
Furnished
By
By Suppliers
Suppliers

– Log books

– As built drawings with Tag numbering

as per SOP

Slide 24 of 28
 Important
Important Features
Features For
For A
A
Validatable
Validatable System
System

– Sufficient space in AHU after HEPA filter bank to

allow personnel entry for scanning (DOP testing)

– Sufficiently big size of access doors in AHU

– Differential pressure measuring and DOP

charging ports in terminal HEPA filter housing

Slide 25 of 28
 Latest
Latest Trends
Trends

– Double skin AHUs with separate supply

and return blowers

– Microprocessor(DDCs) based building

automation system

– Variable pumping system

– Less Number of Bigger AHUs catering

to multiple rooms rather than multiple
small AHUs for each process room

Slide 26 of 28
 An
AnEXCELLENT
EXCELLENTandandSTATE-OF-THE
STATE-OF-THE–ART –ART
HVAC
HVACSystem
SystemDesign
Designfor
forPharma
Pharmafacility
facilityIs
IsPossible
Possible
Through
ThroughaaCombination
Combinationof
of

Engineering
Engineeringknowledge
knowledge Process
Processunderstanding
understanding

GMP
GMPand
andRegulatory
Regulatory
requirements
requirements

EHS
EHSrequirements
requirements Product
Productunderstanding
understanding

Slide 27 of 28
 Thank you
for your attention
Slide 28 of 28
QUESTIONS

?
Slide 29 of 28