HVAC -

DESIGN CONSIDERATION
Herny Prasetya

1
Manufacturing of Sterile Product
 STERILE MANUFACTURING

• minimizing risks of contamination

Ø microbiological
Ø particulate matter
Ø endotoxins

Manufacturing of Sterile Product 2

 STERILE PRODUCTION

• Terminal Sterilization
– Objective : to control and minimize all contamination in
the product for the processing stages and then to apply a
sterilization step
• Aseptic Process
– Objective : to control all contamination in the product
during all processing stages

Manufacturing of Sterile Product 3

Type of Contaminants

Particles :
Microba :
• Dust, dirt
Bacteria
• Non organic
Mold
• Organic
Yeast
Product Endotoxin

Other materials : Other MaterialsProduct :

Food & drink Cross Contamination
Cleaning agent
Detergent
Pelumas

Manufacturing of Sterile Product 4

 Source of Contamination examples
Type of Example Derived from Measure to Mitigate Risk
Contaminant (Example)
Non-viable · Metal specks · Equipment Externally derived airborne particles are
(particulates) · Clothing fibers · Operators’ clothing HEPA filtered. Internal contamination is
· Outside air controlled by displacement or dilution air
· Water supply systems.
· Contact parts are cleaned and sterilized
· Separate gowning and de-gowning areas
· Water purification systems

Viable · Bacteria vegetative · People · Minimize or eliminate aseptic core

(micro-organism) and endospore) · Water
· Yeast, molds · Outside air
· Equipment, tools
· Excipients, active
ingredients
interventions
· Airborne particles are diluted with HEPA
filtered air
· Separate gowning and de-gowning areas
· Sterile filtration of solution (0.22µm)
· Steam sterilization or irradiation of
container/closures

Endotoxins · Arising from cell wall · Wet equipment, Limit holding time between washing and
(not normally debris from certain change parts, or sterilization of equipment as well as
associated with organisms (often container./ closure between sterilization and usage.
airborne bacteria) water borne) after a period of time · Dry heat (.2500C) time dependent
exposure
Manufacturing of Sterile Product 5
CONTAMINATION RISKS

Manufacturing of Sterile Product 6

 Heating,Ventilation and Air-conditioning /
HVAC

• Is a system adalah suatu sistem yang

mengondisikan lingkungan melalui
pengendalian suhu, kelembaban relatif,
pergerakan dan mutu udara – termasuk
partikel serta uap yang ada di udara.

Manufacturing of Sterile Product 7

 Heating,Ventilation and Air-conditioning /
HVAC
Plays an important role in supporting the
manufacture of quality pharmaceutical products :
• provide protection for product environment
to which product exposed to,
• provide comfortable condition for operators,
• provide protection for environment from dust,
fume and effluent discharge from production
area.
Manufacturing of Sterile Product 8
KONSEP PERLINDUNGAN

Manufacturing of Sterile Product 9

 HVAC

• Can control only airborne condition

• Cannot remove deposited (surface)
contaminants
However :
• Airborne contaminants can settle and create
surface contaminants
• Surface contaminants can also be disturbed to
create airborne contaminnts

Manufacturing of Sterile Product 10

 HVAC
• Due to its important roles ---à need to be correctly
– designed,
– built,
– commisioned,
– qualified,
– operated and
– maintained
to achieve the proposed usage
• Need most of energy used to operate sterile
pharmaceutical facility
• Good Manufacturing Practice / Cara Pembuatan Obat yang
Baik (CPOB) dan Good Engineering Practice / GEP need to
be considered

Manufacturing of Sterile Product 11

 FACILITY DESIGN and QUALIFICATION
Define Product
Requirement
Good Manufacturing Practice - Good Engineering Practicees

Specification
Define Process Acceptance
Requirement & Design Verification
User & Release
Requirement •Risk • C&Q Plan
Define Assessment • Commissioning • IQ, OQ ,PQ
Specification
Regulatory •Critical Aspects • Qualification Evidence
Requirement • Verification • Quality Unit
•Design
Approval
Qualification
Define
Other/General
Requirement

Quality Risk Management

Risk to Patients Product Quality GMP Compliance Risk (linked to patient risk)

Design Review
Iterative Process Review Risk Assessment

Change Management
Engineering Change Management Operational Change Control

Manufacturing of Sterile Product 12

 USER REQUIREMENT SPECIFICATION

GENERAL REQUIREMENTS (GURS)

• Company Policy
• Cost
• Maintenance
• Technology :
– Conventional cleanroom technology
– Restricted Access Barrier Systems (RABS)
– Isolators

Manufacturing of Sterile Product 13

 USER REQUIREMENT SPECIFICATION
REGULATORY REQUIREMENT

• GMP consideration
• Safety consideration and regulation
• Environment

Manufacturing of Sterile Product 14

 USER REQUIREMENT SPECIFICATION
PRODUCT REQUIREMENT…..CONTOH
• Dosage form : liquid, emulsion, solid fill or semi-solid
• Whether the product support microbial growth
• Will the product(s) include any lyophilized products, any
moisture-sensitive products, or any oxygen-sensitive or light
sensitive products?
• Are any of the products temperature-sensitive?
• Do any of the products have special containment
requirements, such as cytoxic, betalactam, reproductive
hormones?
• How will the product(s) be presented to the consumer (e.g.,
vials, syringes, ampoules, etc.)?

Manufacturing of Sterile Product 15

 USER REQUIREMENT SPECIFICATION
PROCESS REQUIREMENT……CONTOH

• Can the products be terminally sterilized or must they be

aseptically filled?
• Process flow, risk assessment on the critical steps
• Whether the product dosage is low enough to cause concern
with cleaning validation
• Whether the process include freeze-drying process
• Whether the process generate particle or heat
• Open or closed process
• Sterilization process

Manufacturing of Sterile Product 16

 USER REQUIREMENT SPECIFICATION
PROCESS KNOWLEDGE….CONTOH
Process :
- How the materials enter the production area
- At what point the product is exposed to the environment
- How the product is protected until it is filled and sealed
- How the product leaves the aseptic area
Container/closure flow
- How the component enter the sterile/aseptic area (after
sterilization as well as pre-sterilized)
- Whether the components need cooling in aseptic area
- How the sterile stopper bowl is protected, where it is located

Manufacturing of Sterile Product 17

 USER REQUIREMENT SPECIFICATION
PROCESS KNOWLEDGE….CONTOH
Operator :
§ How many operators required in the preparation area, filling
(especially aseptic area)
§ Where operators will stand in the aseptic area under normal
condition
§ How the components are transferred and handled within the
aseptic area
§ At what points in the process operators intervene with sterile
container/closures that product contact and what is the
frequency and type of intervene

Manufacturing of Sterile Product 18

 OPERATOR
• People are the greater source of contamination
• Level of contamination depends on :
– level of gowning
– comfort
– how they perform task
• Contamination :
– non-viable (clothing, skin shed)
– viable (bacteria, mold)

Manufacturing of Sterile Product 19

 Number of Particles Generated
per Second
and per person

ISPE Baseline® Guide,

Volume 3 Sterile
Manufacturing Facilities
Particles/second

Page 163, Figure 11.1

Used with permission from
Camfill Farr.

Particle size (µm)

Laser Conter

Manufacturing of Sterile Product 20

OPERATOR
• Gross volume = 6x2x3 = 36 ft3
• Net occupied volume = 30 ft3
• Zone A = 3,250 particles o.5 µm/m3 = 100 / ft3
• So in 30 ft3 = 3000 particles ≥ 0.5µm
• From previous slide : particle generated =
10,000 /second = 600,000 per min.
• UDAF : air velocity 0.45 m/sec = 1.5 ft/sec
• UDAF volume = 1.5 x (3x2) HEPA area = 9
ft3/second = 540 ft3/min.
• Average particle count = 600,000/540 = 1,111
particle/ft3 --à > limit of class 100
• It is important to keep operator out of class A
area
• Suit must be well fitted, made of small pore
fabric, be closed at neck, hood and cuffs

Manufacturing of Sterile Product 21

 USER REQUIREMENT SPECIFICATION
PROCESS KNOWLEDGE….CONTOH
Equipment :
• What kind of process equipment as well as filling equipment
• Whether any parts of equipment produce high particulate
load to the room
• Whether the equipment need regular operator intervention
• How equipment is maintained, whether in the aseptic area or
from outside
• What type of sterilization equipment is used :
– Static : oven, autoclave, SIP
– Dynamic : tunnel

Manufacturing of Sterile Product 22

 USER REQUIREMENT SPECIFICATION
PROCESS KNOWLEDGE….CONTOH
Sterilizers :
§ Static sterilizers has little effect on the HVAC, although on
door opening
• hot air current may affect normal established airflow
• heat and humidity gain
• should be considered during design and qualification
• However it is constant known quantity
• Dynamic sterilizers :
• may take air or leak it to surrounding areas
• volume changes depending upon air temperature of tunnel
• Require careful integration with the HVAC system
• Serious risks of reversing DP and put product into risks

Manufacturing of Sterile Product 23

 USER REQUIREMENT SPECIFICATION
PROCESS KNOWLEDGE….CONTOH
Facility :
§ Whether :
§ Dedicated or multiproduct
§ Serve both terminal sterilization and aseptic process
§ Whether there is storage requirement for product contact
parts within the aseptic area
§ Required hours of operation for the facility
§ Whether doors are interlocked or alarmed to maintain
pressure differential

Manufacturing of Sterile Product 24

 KLASIFIKASI KEBERSIHAN RUANG
Nonoperasional Operasional
Kelas Jumlah maksimum partilkel /m³ yang diperbolehkan
Kebersihan

Ukuran
> 0,5 µm > 5 µm > 0,5 µm > 5 µm
Partikel

A 3.520 20 3.520 20

B 3.520 29 352.000 2.900

C 352.000 2.900 3.520.000 29.000

Tidak Tidak
D 3.520.000 29.000
ditetapkan ditetapkan

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Manufacturing of Sterile Product 25
 DESAIN SISTEM HVAC
Hal yang biasanya terkait dengan desain :
• Pola aliran personil, peralatan dan material,
• Sistem pembuatan yang terbuka atau tertutup,
• Perkiraan kegiatan pembuatan di setiap ruangan,
• Tata letak arsitektur,
• Finishing dan kerapatan konstruksi ruangan,
• Lokasi dan konstruksi pintu,
• Strategi ruang penyangga udara,
• Strategi pembersihan dan penggantian pakaian,
• Kebutuhan area untuk peralatan sistem tata udara dan
jaringan saluran udara (ductwork), dan
• Lokasi pemasukan, pengeluaran dan pembuangan udara.

Manufacturing of Sterile Product 26

 DESIGN CONSIDERATION
HVAC CRITICAL PARAMETERS
Temperature :
• Operators :
– Higher room temperature affect the comfort of operators
– Causing to release particles (perspiration and respiration)
especially during more strenuous activities
– Heavier gowning needs lower temperature
– Generally 20 – 22oC
• Product :
– May differ from room temperature for operators’ comfort
– May differ from product to product
– If no special requirement : USP suggest 15 – 25oC

Manufacturing of Sterile Product 27

 DESIGN CONSIDERATION
HVAC CRITICAL PARAMETERS

Relative Humidity :
– Special consideration for hygroscopic materials -
à need low RH rooms or enclosure
– Low humidity may create problem :
• Static electricity
• Powder flow
• Condensation
– However RH > 60% lead to mold growth
– Good practice : 45 – 55%

Manufacturing of Sterile Product 28

 DESIGN CONSIDERATION
HVAC CRITICAL PARAMETERS
Pressure Difference :
• A cleanliness cascade using DP --à provide assurance against
infiltration of chemical or bio-contamination from lower grade
environment.
• Adjacent rooms of different Grades should have a pressure
differential of 10 - 15 pascals (guidance values)
• DP can be lower or momentarily go to zero, when a non-
airlocked door is opened
• DP and airflow direction should never reverse
• An area of higher criticality with the same class may be
protected by measurable DP of not less than 10Pa

Manufacturing of Sterile Product 29

 DESIGN CONSIDERATION
HVAC CRITICAL PARAMETERS
Air Change rate
Air change rate is another important cleanroom design
parameter.
• FDA Guide :
– For Class 100,000 (ISO 8) supporting rooms, airflow sufficient to
achieve at least 20 air changes per hour is typically acceptable.
– Significantly higher air change rates are normally needed for Class
10,000 and Class 100 areas.”
• Petunjuk Teknis Sarana Penunjang Kritis - Sistem Tata Udara :
Page 20 : nilai rules of thumb biasanya adalah:
– 6 hingga 20 pertukaran udara/jam untuk ruang Kelas D dan E;
– 20 hingga 40 pertukaran udara/jam untuk ruang Kelas C; dan
– 40 hingga 60 pertukaran udara/jam untuk ruang Kelas B.

Manufacturing of Sterile Product 30

 How Many Air
Changes are Enough?

In addition to meeting these requirements the

following need to be considered when designing
facility air supply.
– Exfiltration loss (pressurisation)
– Heat gain
– Particulate Gain
– Recovery Time

Manufacturing of Sterile Product 31

 Air Balance
What goes in must come out (we deal with rigid enclosures in HVAC)

Supply air Exhaust air to outside

Exfiltration
Enclosure:
(air pushed out by pressure
Room
Air Handler
inside the enclosure)
Infiltration Barrier Isolator
(air pushed in by
pressure Return Air to AHU
in adjoining space)

AIR IN = AIR OUT

Supply + Infiltration = Return + Exhaust + Exfiltration

Manufacturing of Sterile Product 32

 Pressurisation Design - General

Supply Supply

Positive Negative

Leakage Extract Leakage Extract

out in

Manufacturing of Sterile Product 33

 Exfiltration Loss

This is the air that…

Escapes through cracks, passes under doors,
Passes through mouse-holes,
Passes into equipment

Manufacturing of Sterile Product 34

 Estimation of leakage

• Designer must estimate the leakage rate

• Designer must allow for any unknown leakage rates
• Doors should be the main leakage path

Manufacturing of Sterile Product 35

 Heat Gain

This is all of the heat energy that is present in

the room and includes:
• Body Heat from Personnel
• Heat from lighting
• Heat from equipment
• Heat from air that is recirculated without passing
through a cooling coil (e.g. UDAF Hoods)

Manufacturing of Sterile Product 36

 Recovery Time

The "recovery" time for a cleanroom is the

time required for the particle count level to
return to its "at rest" condition after
production ceases and personnel leave the
room. The “recovery” will follow an
exponential curve, so it may take a long time
to achieve its “at rest” condition.

Manufacturing of Sterile Product 37

 Recovery Time

CPOB Annex 1 point 15

• The particle limits 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.
• However for more critical areas ( B and C), is
15-20 minutes enough to keep the room
cleanliness?

Manufacturing of Sterile Product 38

 Airborne Particle Classification
In Operation At Rest
Grade Maximum permitted number of particles/m3 equal to or
above:
0.5 μm 5 μm After 0.5 μm 5 μm
A 3520 20 15 – 20 3520 20
B 352,000 2,900 minute 3520 29
cleanup
C 3,520,000 29,000 352,000 2900
D Not Not 3,520,000 29,000
Defined Defined

Manufacturing of Sterile Product 39

 RECOVERY PERIOD

ISPE Baseline® Guide, Volume 3 Sterile Manufacturing Facilities, Page 168, Figure 11.5
Manufacturing of Sterile Product 40
 HVAC DESIGN PRINCIPLE

Dilution design :
• Important to identify areas of low air movement ---à
o Higher particle concentration
o No critical process
• Use of low level air return/exhaust
• Volume of clean air supply sufficient to offset particle gain
Manufacturing of Sterile Product 41
HVAC DESIGN PRINCIPLE
AIR FILTRATION ARRANGEMENT

Manufacturing of Sterile Product 42

 HVAC DESIGN PRINCIPLE
AIR FILTRATION ARRANGEMENT
• Advantage of the design :
– The main HEPA in AHU ensure that clean air is
supplied to terminal air filter units
– The performance of terminal HEPAs will be
maintained constant for longer period, reduce
maintenance costs and maintenance downtime
– Balancing the ratio of supply and extract
– Additional assurance of HVAC system
performance

Manufacturing of Sterile Product 43

Unidirectional Air Flow (UDAF)

Manufacturing of Sterile Product 44

Unidirectional Air Flow (UDAF)

Manufacturing of Sterile Product 45

 HVAC DESIGN PRINCIPLE
HORIZONTAL VERSUS VERTICAL UDAF

Manufacturing of Sterile Product 46

 HVAC DESIGN PRINCIPLE
HORIZONTAL VERSUS VERTICAL UDAF

Manufacturing of Sterile Product 47

 HVAC DESIGN PRINCIPLE
SUPPLY AND EXTRACT LOCATION
• Optimum number of air supply outlets to achieve
good air distribution and mixing.
– Consider equipment location in the room to avoid
interference between air supply outlets and equipment
intakes/outlets
• Extract/return grills should be located at low level to
minimize upward airflow pattern in the room
– Located at multiple location in the room to assure :
• Desired airflow patterns
• To minimize local areas of excessive particle concentrations

Manufacturing of Sterile Product 48

 HVAC – Ductwork Key Design Issues
• Leakage Rates
• Inspection Ports for
– Filters
– Devices
– Cleaning access door
• Insulation / Rust Inhibition
• Delivered Clean to the Jobsite

NOTE: Ductwork is not specifically mentioned in cGMPs, but

clearly the entire delivery system must be considered as
“equipment” to be controlled.

Manufacturing of Sterile Product 49

 AIR HANDLING UNIT (AHU)
DESIGN CONSIDERATION
General arrangement :
• Operate at positive pressure to minimize ingress of dirty air
• Internal component should be non-shedding and located
upstream of AHU system HEPA
• If chemical dehumidification is used, the desiccant should not
support microbiological growth and be non-shedding.
• The internal finish should ne non-shedding and have minimum
of ledges to prevent dust accumulation.
• The unit must be cleanable and able to withstand
fumigation/disinfection if necessary.
• To minimize effect of the system’s performance due to wind
pressure, location of fresh air intake and exhaust outlet should
be considered

Manufacturing of Sterile Product 50

TYPICAL ASEPTIC DESIGN

Manufacturing of Sterile Product 51

 SUMMARY
OPERATIONAL CONSIDERATION
• Understand operator contribution to the
contamination in the cleanroom so :
– Reduce numbers of operator in clean area
– Understand people traffic route and possibly increase
airflow to the busiest area, i.e. change room.
• Process consideration :
– Where the process generate particle
– Where the product expose to environment and for
how long --à critical process
– Understand and control heat from process equipment

Manufacturing of Sterile Product 52

 SUMMARY
FACILITY CONSIDERATION
• Good room and equipment finishes, cleanable to minimize re-
entrainment of settle contaminant into the air
• How room will be sanitized
• Door clearances and tolerances
• How long door will be opened
• Opening doors and the effect on room pressure
• Number of air supply outlets versus location and number of
air return/extract to assure air cleanliness
• Avoid unacceptable turbulence or dead spots in clean areas

Manufacturing of Sterile Product 53

 References
• ISPE Baseline Guide Volume 3 : Sterile Product Manufacturing
Facilities
• ISPE Good Practice Guide : Heating, Ventilation and Air
Conditioning (HVAC)
• ISPE Good Practice Guide : Applied Risk Management for
Commisioning and Qualification
• Pedoman CPOB 2012
• Petunjuk Teknis Sarana Penunjang Kritis Industri Farmasi
• WHO TRS 961 Annex 6 : WGO Good Manufacturing Practices for
Sterile Pharmaceutical Products
• ISPE-Pharmaceutical Engineering March/April 2010 : Design,
Validation and Control of Sterile Manufacturing Facilities : A Brief
Overview from the Perspective of Risk Management and Existing
Regulations – Anna Quinto and Jose C. Menezes

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