heating, ventilation and air- conditioning (hvac) part 1: introduction and overview good...

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