heating, ventilation and air- conditioning (hvac) part 1: introduction and overview good...
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Heating, Ventilation and Air- Conditioning (HVAC)
Part 1:
Introduction and overview
Good Manufacturing Practice
WHO Technical Report Series, No. 937, 2006. Annex 2
(Pharmaceutical products)
Munira Mohamed Nazari
School of Bioprocess
UniMAP
1
HVACObjectives
To understand: The need for HVAC systems The role of HVAC in protection:
Product Personnel Environment
The role of HVAC in dust control HVAC system design and its components (Part 2) Commissioning, qualification and maintenance (Part 3)
1, 2
2
HVACIntroduction and Scope
HVAC systems can have an impact on product
quality It can provide comfortable conditions for operators The impact on premises and prevention of
contamination and cross-contamination to be considered at the design stage
Temperature, relative humidity control where appropriate
Supplement to basic GMP text 1, 2
3
Factors contributing to quality products
Starting materials
Personnel
Procedures
Validated processes
Equipment
Premises
Environment
Packing materials
HVAC
4
The manufacturing environment is critical for product quality. Factors to be considered include:
1. Light
2. Temperature
3. Relative humidity
4. Air movement
5. Microbial contamination
6. Particulate contamination
# Uncontrolled environment can lead to product degradation
product contamination (including cross-contamination)
loss of product and profit
HVAC
5
What is contamination?
It is "the undesired introduction of impurities (chemical/ microbial/ foreign matter into or on to starting material or intermediate – during sampling, production, packaging or repackaging".
Impurities could include products or substances other than the product manufactured, foreign products, particulate matter, micro-organisms, endotoxins (degraded microorganisms), etc.
HVAC
Glossary
6
What is Cross-contamination? "Contamination of a starting material, intermediate product, or finished product with another starting material or product during production".
Cross-contamination can result from, e.g.1. Poorly designed, operated or maintained air-handling
systems and dust extraction systems2. Inadequate procedures for, and movement of
personnel, materials and equipment3. Insufficiently cleaned equipment
HVAC
Glossary, 4.1.11
7
Contamination
Contaminant from
EnvironmentOperators
Contaminant from
Equipment
CrossContamination
Productfrom
EnvironmentOperators
Productfrom
Equipment
Cross-Contamination
HVAC
8
Cross-contamination can be minimized by, e.g.
1. Personnel procedures
2. Adequate premises
3. Use of closed production systems
4. Adequate, validated cleaning procedures
5. Appropriate levels of protection of product
6. Correct air pressure cascade
HVAC
9
HVAC
The guideline further focuses on three concepts of the system: Product protection
Contamination Cross-contamination Environmental conditions
Personnel protection Prevent contact Comfort conditions
Environment protection
2
10
HVACProtection: Product and personnel Areas where materials and products are exposed, should
be classified as "clean areas" Achievement of clean area classification depends on
factors such as: Building finishes and structure Air filtration Air change rate Room pressure Temperature Relative humidity Material and personnel flow Outside environment Occupancy and type of product
4.1.1 - 4.1.3 11
HVAC
Air filtration and air change rate should ensure attainment of classification
Air change rate is dependent on factors, e.g. Level of protection required Quality and filtration of supply air Particulates generated Room configuration Containment effect Room heat load Room pressure
Air change rate normally varies between 6 – 20 air changes per hour
4.1.4 - 4.1.6 12
HVAC
The classification should be achieved in the state as specified (1):
"As built" Bare room, without
equipment or personnel
4.1.7 - 4.1.8
HVAC
The classification should be achieved in the state as specified (2):
"At rest" Equipment may be
operating, but no operators present
4.1.9
HVAC
The classification should be achieved in the state as specified (3):
"In operation" Normal production process
with equipment and personnel,
Clean up time validated – normally in the order of 20 minutes
4.1.10
HVACControl of contaminants
External contaminants removed through effective filtration
Internal contaminants controlled through dilution and flushing, or displacement airflow
Airborne particulates and level of filtration considered critical
4.1.12 - 4.1.15
16
Therapeutic risks
Man
ufactu
ring
En
viron
men
t req
uirem
ents
Clean
roo
m C
lass A / B
Clean
roo
m C
lass C
Clean
rm. C
lass D
Oth
ers
HVAC
17
HVAC
Level of protection and air cleanliness determined according to:
Product to be manufactured Process to be used Product susceptibility to degradation
4.1.16
18
Parameters influencing Levels of Protection Number of particles in the air, number of
microorganisms in the air or on surfaces Number of air changes for each room Air velocity and airflow pattern Filters (type, position) Air pressure differentials between rooms Temperature, relative humidity
HVAC
19
Tools to help achieve the desired Level of Protection
Air Handling System
Production RoomWith
DefinedRequirements
SupplyAir
OutletAir
HVAC
20
Tools to help achieve the desired Level of Protection
Air-handling system can be the main tool for reaching required parameters
May not be sufficient as such Need for additional measures such as
appropriate gowning (type of clothing, proper changing rooms)
validated sanitation adequate transfer procedures for materials and
personnel
HVAC
21
Cleanroom Classdefined by
Critical Parameters
Air HandlingSystem
Additional Measures
Tools to help achieve the desired Level of Protection (2)
HVAC
22
Examples of Levels of ProtectionTypes of Clean room classes WHO, EC, PIC/S: A, B, C, D US FDA: Critical and controlled ISPE: Level 1, 2 or 3 ISO: Class 5, 6, 7 or 8
HVAC
23
COMPARING INTERNATIONAL CLEANROOM CLASSIFICATIONS
Particles / m3
0.5µm
US 209Dnon-
metric
US 209E1992
metric
EC cGMPAnnex I
1997
GermanyVDI 2083
1990
UKBS 5295
1989
JapanJIS B 9920
1989
ISO 14644-1
1
3,5 0 2 2
10 M 1
35 1 M 1.5 1 3 3
100 M 2
353 10 M 2.5 2 4 4
1.000 M 3
3.530 100 M 3.5 A, BA= unidirectional
B= turbulent
3 E or F 5 5
10.000 M 4
35.300 1.000 M 4.5 4 G or H 6 6
100.000 M 5
353.000 10.000 M 5.5 C 5 J 7 7
1.000.000 M 6
3.530.000 100.000 M 6.5 D 6 K 8 8
10.000.000 M 7
HVAC
24
HVAC
Examples of levels of protection
Level Condition Example of area
Level 1 General Area with normal housekeeping, e.g. warehouse
Level 2 Protected Area where steps are taken to protect exposed material/product, e.g. dispensing
Level 3 Controlled Area with defined, controlled, monitored environmental conditions to prevent contamination and degradation
4.1.16
All operations within a pharmaceutical facilility should be correlated to well-defined clean room classes, and can be included in a hygiene concept.Example:
etc.
XFilling for aseptic process
XFilling for terminal sterilisation
XDepyrogenisation of containers
XXXPreparation of solutions for aseptic filling
XPreparation of solution for terminal sterilisation
XWashing of containers
DCBACleanroom Class
HVAC
26
AIR FILTRATION27
HVACAir Filtration
Degree of filtration is important to prevent contamination
Type of filters to be used dependent on the quality of ambient air, return air and air change rates
Manufacturer to determine, select and prove appropriate filters for use considering level of ambient air contamination, national requirements, product specific requirements
4.2.1, 4.2.3
28
Level of protection
Recommended filtration
Level 1 Primary filters, e.g. EN779 G4*
Level 2 and 3 Production area with 100% outside air: Primary plus secondary filter (e.g. EN779 G4 plus F8 filters)
Level 2 and 3 Production area with recirculated plus ambient air with a risk of cross-contamination: Primary plus secondary plus tertiary filter (e.g. EN779 G4 plus F8 plus EN1822 H13 filters)
HVACLevels of protection and recommended filtration
4.2.1
*Filter class should be referenced to the standard test method
HVACContamination should be prevented through
appropriate: Materials for components and construction Design and appropriate access to dampers, filters and
other components Personnel operations Airflow direction Air distribution component design and installation and
location Type of diffusers (non-induction type recommended) Air exhaust (normally from a low level)
4.2.4 – 4.2.10 30
HVAC
HVAC
Airflow patterns
Filtered air entering a production room or covering a process can be
turbulent, or unidirectional (laminar)
• GMP aspect • economical aspect
Other technologies: barrier technology/isolator technology.
32
Unidirectional/laminardisplacement of dirty air
Turbulent dilution of dirty air
Airflow patterns
HVAC
33
PrefilterAirflow patterns
AHU
Main filter
Unidirectional TurbulentTurbulent
1 2 3
HVAC
34
Workbench (vertical) Cabin/booth Ceiling
Airflow patterns (4)
HVAC
35
HVACUnidirectional airflow (UDAF):
Provided where needed over product or material to prevent contamination, or to protect operator
UDAF in weighing areas
The aim is to provide dust containment
Airflow velocity should not affect balance
Position of material, balance, operator determined and validated – no obstruction of airflow or risk
4.3.1 – 4.3.10
36
HVAC
Annex 5, 7.
37
HVAC
Annex 5, 7.
38
HVAC
Infiltration Facilities normally under positive pressure to
the outside Prevent infiltration of unfiltered, contaminated
air from outside Some cases - negative pressure (e.g. penicillin
manufacture). Special precautions to be taken
4.4.1 – 4.4.4
39
HVAC
Cross-contamination General aspects and concepts Displacement concept
low pressure differential, high airflow Pressure differential concept
high pressure differential, low airflow Physical barrier concept
4.5
40
HVAC
General aspects Multiproduct OSD manufacturing, prevent
movement of dust between areas where different products are processed
Directional air movement and pressure cascade can be helpful – dust containment
Normally, corridor at higher pressure than cubicles, cubicles at higher pressure than atmosphere
4.5.1 – 4.5.3
41
HVAC
Containment concepts Pressure cascade regime influenced by:
Product and product group, e.g. highly potent products (in some cases, pressure cascade regime negative to atmosphere)
Processing methods Building structure should be considered including
airtight ceilings and walls, close fitting doors, sealed light fittings
4.5.4 – 4.5.9
42
HVAC
Displacement concept Air supplied to the corridor, through the doors
(grilles) to the cubicles Air extracted at the back of the cubicle Velocity high enough to prevent turbulence in
doorway Requires large air quantities
(Not preferred method)
4.5.10 – 4.5.12
43
HVAC
Pressure differential concept Concept can include high pressure differential, low
airflow, and airlocks in the design Airlock types include: Cascade, sink and bubble type Sufficient pressure differential required to ensure
containment and prevent flow reversal – but not so high as to create turbulence
Consider effect of other items such as equipment and extraction systems in cubicles
Operating limits and tolerances4.5.13 – 4.5.18,
4.5.22
44
HVAC
Pressure differential concept (2) Calibrated monitoring devices, set to alarm
system Monitoring and recording of results Doors open to higher pressure Dust extraction system design
Interlocked with air-handling system No airflow between rooms linked to same
system Room pressure imbalance
4.5.19 – 4.5.26
45
Pressure cascade solidsProtection from cross-contamination
N o te : D ire c t io n o f d o o r o p e n in g re la t iv e t o ro o m p re s s u re 1 5 P a1 5 P a1 5 P aE3 0 P a Pa s s a g e 0 P aA irLo ck R o o m 3 R o o m 2 R o o m 11 5 P a A ir Lo ckA ir Lo ck
N ote : D irection of door opening relative to room pressure
15 Pa
15 Pa15 Pa
E30 Pa
Passage0 Pa
A irLock
Room 3 Room 2 Room 1
15 Pa
A ir LockA ir Lock
HVAC
46
HVAC
Physical barrier concept In some cases, impervious barriers are used to
prevent cross-contamination Spot ventilation Capture hoods
4.5.27 – 4.5.28
47
HVAC
Temperature and relative humidity (RH) Controlled, monitored and recorded where
relevant Materials and product requirements, operator
comfort Minimum and maximum limits Premises design appropriate, e.g. low humidity
areas, well sealed and airlocks where necessary HVAC design – also prevent moisture migration
4.6.1. – 4.6.6
48
HVAC
Temperature and relative humidity (RH) (2) Remove moisture, or add moisture as necessary
DehumidificationRefrigerated dehumidifiers with cooling mediaChemical dehumidifiers
Humidifiers should not be sources of contaminationUse of pure steam or clean steam
No chemicals added to boiler system if these can have a detrimental effect on product (e.g. some corrosion inhibitors/chelating agents) 4.6.7. – 4.6.11
49
HVAC
Temperature and relative humidity (RH) (3)Humidification systems: Design should be such that the
system does not become the source of contamination:
No accumulation of condensate
Avoid evaporative systems, atomizers, water-mist sprays
Suitable duct material, insulation of cold surfaces
Air filters not immediately downstream of humidifiers
Chemical driers – used if not sources of contamination
4.6.12. – 4.6.1850
HVACDust Control
Dust and vapour removed at source Point of use extraction – fixed points or movable
hood – plus general directional airflow in room Ensure sufficient transfer velocity to prevent
dust settling in ducting Risk analysis – airflow direction, hazards,
operator
5.1. – 5.7
51
HVACDust Control (2)
Normally air supplied through ceiling diffusers, and air extracted from low level – aids flushing effect
Extraction of vapours – consider density of vapour Handling harmful products – additional steps needed
e.g. barrier technology, glove boxes totally enclosed garments with air-breathing systems
Fresh air rate supply comfort, odour and fume removal, leakage, pressure
control, etc.5.8. – 5.14
52
HVAC
Protection of the environment (Exhaust air dust)
Exhaust air from equipment and some areas of production carry heavy loads of dust (e.g. FBD, coating, weighing)
Filtration needed to prevent ambient contamination
Not highly potent material EN779 F9 filter recommended
Harmful substances (e.g. hormones) EN1822 H12 (HEPA) filter recommended In some cases two banks of HEPA filters Safe change filter housings ("bag-in bag-out" filters)6.1.1 – 6.1.5
53
HVAC
Protection of the environment (Exhaust air dust) (2)
Filter banks provided with pressure differential indication gauges
Limits indicated, results monitored at regular intervals Manual, Building Management Systems, Building
Automated Systems, System Control and Data Acquisition systems
Automated systems provided with alarm or similar system to indicate OOS 6.1.6 – 6.1.10
54
HVAC
Protection of the environment (Exhaust air dust) (3)
Reverse pulse dust collectors Should be equipped with cartridge filters with compressed air
lance, Continuous operation – no interruption of airflow
Dust collectors with mechanical shakers Used in a manner not to become source of contamination Switched off at times resulting in loss of airflow, and
disruption of pressure cascade Wet scrubbers
Use suitable drainage system for dust slurry Determine exhaust air quality to verify filtration efficiency
6.1.11 – 6.1.15
55
HVAC
Protection of the environment (Fume removal)
Appropriate design, installation, and operation of fume, dust, effluent control
Wet scrubbers Added chemicals for increased adsorption efficiency
Deep bed scrubbers Activated carbon or chemical adsorption granular media Specific to type of effluent Type and volume prepared
6.2.1 – 6.2.5
56
FINISH PART 157