who guidelines on gmp hvac (rev1)

7/26/2019 WHO Guidelines on GMP HVAC (Rev1)

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WORLD HEALTH ORGANIZATION

ORGANISATION MONDIALE DE LA SANTE

SUPPLEMENTARY GUIDELINES ON

GOOD MANUFACTURING PRACTICES FOR

HEATING, VENTILATI ON AND AIR CONDITIONING (HVAC)

SYSTEMS FOR NON-STERI LE DOSAGE FORMS

World Health Organization 2004

All rights reserved.

This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft

may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in anyform or by any means outside these individuals and organizations (including the organizations concerned staff and member

organizations) without the permission of WHO. The draft should not be displayed on any website.

Please send any request for permission to:

Dr Sabine Kopp, Quality Assurance & Safety: Medicines (QSM), Department of Essential Drugs and Medicines Policy

(EDM), World Health Organization, CH-1211 Geneva 27, Switzerland.

Fax: (41-22) 791 4730; e-mails: [email protected];[email protected]

The designations employed and the presentation of the material in this draft do not imply the expression of any opinion

whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of

its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate

border lines for which there may not yet be full agreement.

The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or

recommended by the World Health Organization in preference to others of a similar nature that are not mentioned.

Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.

The World Health Organization does not warrant that the information contained in this draft is complete and correct and shall

not be liable for any damages incurred as a result of its use.

This document has been prepared by Mr Deryck Smith of Deryck Smith Consulting Engineers, Faerie Glen, South Africa

as a supplementary WHO Good Manufacturing Practices (GMP) text forHeating, Ventilation and Air Conditioning

(HVAC) Systems. It is built on the existing WHO GMP texts, and makes use of auxiliary documents and manuals aslisted in the reference section. Comments received during the first consultation phase have been evaluated and the text

has been revised accordingly.

Please address any comments and/or corrections you may have on this document to Dr S. Kopp, Quality Assurance and

Safety: Medicines, Essential Drugs and Medicines Policy, World Health Organization, 1211 Geneva 27, Switzerland, fax:

(+41 22) 791 4730 or e-mail:[email protected],with a copy to [email protected], by 15 December 2004.

Working document QAS/02.048/Rev.1

RESTRICTED
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SUPPLEMENTARY GUIDELINES ON

GOOD MANUFACTURING PRACTICES FOR

HEATING, VENTILATION AND AIR CONDITIONING (HVAC) SYSTEMS

FOR NON-STERILE DOSAGE FORMS

CONTENTS

page

1. Introduction .. 3

2. Glossary 4

3. Scope of document ... 8

4. Product protection 94.1 Contamination control 9

4.1.1 Cleanroom concept . 10

4.1.2 Level of protection .. 16

4.1.3 Air filtration to control contamination 17

4.1.4 Contamination by HVAC plant .. 19

4.1.5 Contamination by staff 19

4.1.6 Airflow patterns .. 19

4.1.7 Unidirectional Airflow (UDAF) protection ... 23

4.1.8 Infiltration 24

4.2 Cross-contamination protection ...25

4.2.1 Directional air movement .25

4.2.1.1 Displacement concept 25

4.2.1.2 Pressure differential concept . 26

4.2.1.3 Physical barrier concept 30

4.2.1.4 Selecting the segregation concept . 30

4.2.2 Unidirectional Airflow protection 30

4.2.3 Cross-contamination via HVAC supply air .30

4.2.4 Cross-contamination due to fan failure 31

4.3 Temperature and Humidity . 31

4.3.1 General temperature and humidity requirements 31

4.3.2 Product temperature requirements .. 31

4.3.3 Product humidity requirements ... 31

4.3.4 Microbial growth ..33

5. Personnel Protection . 33

5.1 Protection from dust 33

5.2 Dust classification ... 33

5.3 Unidirectional flow protection 33

5.4 Point extraction . 38

5.5 Directional airflow 38

5.6 Air showers . 39

5.7 Protective enclosures 39


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5.8 Operator comfort .. 40

6. Protection of the Environment 41

6.1 Exhaust air dust . 41

6.2 Fume removal 42

6.3 Effluent discharge . 42

7. Systems and Components .. 42

7.1 Air distribution .. 42

7.2 Air handling unit configurations .. 44

7.2.1 Recirculation system . 44

7.2.2 Full fresh air systems 45

7.2.3 Additional system components . 46

8. Commissioning, Validation and Maintenance ... 47

8.1 Commissioning . 478.2 Validation and qualification . 48

8.2.1 Validation master plan (VMP) .. 49

8.3 What to qualify .. 49

8.4 Setting qualification limits . 50

8.5 Parameters to qualify .. 52

8.6 Maintenance .. 58

8.7 Inspections . 59

References 60

1. INTRODUCTION

Heating, Ventilation and Air Conditioning (HVAC) play an important role in ensuring the manufacture

of quality pharmaceutical products. This guideline mainly relates to HVAC systems for solid dosage

pharmaceutical plants. However, reference is often made to other systems or components which are

not relevant to solid dosage plants, but it is felt that these references help to provide a comparison

between the requirements for solid dosage plants and other systems.

HVAC system design influences architectural layouts, with regards to items such as airlock positions,

doorways and lobbies. The architectural components have an effect on room pressure differentialcascades and cross-contamination control. The prevention of contamination and cross-contamination is

an essential design consideration of the HVAC system. Because of these critical aspects, the design of

the HVAC system should be considered at the concept design stage of a pharmaceutical manufacturing

facility.

Temperature, humidity and ventilation should be appropriate and should not adversely affect the

pharmaceutical products during their manufacture and storage, or the accurate functioning of

equipment.

A suitably designed HVAC system assists in ensuring the manufacture of quality products. A well

designed HVAC system will also result in operator comfort.

This document aims to give guidance to inspectors of pharmaceutical manufacturing facilities, on the

design, installation, qualification and maintenance of the HVAC systems.


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2. GLOSSARY

The definitions given below apply to terms used in this guideline. They may have different meanings

in other contexts.

Absolute humidity (also termed specific humidity or humidity ratio)

The ratio of the mass of water vapour in the air per unit mass of dry air. Expressed in grams/kg or

kg/kg.

Acceptance criteria

Measurable terms under which a test result will be considered acceptable.

Action limit

Action limit is reached when the acceptance criteria of a critical parameter have been exceeded.

Results outside theses limits will require specified action and investigation.

Air Handling Unit (AHU)

Air handling unit, which serves to condition the air and provide the required air movement within a

facility.

Airlock

An enclosed space with two or more doors, which is interposed between two or more rooms, e.g. of

differing classes of cleanliness, for the purpose of controlling the airflow between those rooms, when

they need to be entered. An airlock is designed for, and used, by either people or goods

(PAL= Personnel airlock &MAL= Material airlock).

Alert limit

Alert limit is reached when the normal operating range of a critical parameter has been exceeded,

indicating that corrective measures may need be taken to prevent the action limit being reached.

API

Active pharmaceutical ingredient

As-built condition

This condition relates to carrying out room classification tests on the bare room without any production

equipment or personnel.

ASHRAE

American Society of Heating, Refrigeration and Air Conditioning Engineers.

At-rest condition

This condition relates to carrying out room classification tests with the normal production equipment in

the room, but not operating and without any operators.

Central Air Conditioning Unit

An air handling unit which is centrally located and supplies air to a number of rooms. As opposed to a

local AHU which supplies air to one room only.


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Change control

A formal system by which qualified representatives of appropriate disciplines review proposed or

actual changes that might affect a validated status. The intent is to determine the need for action that

would ensure that the system is maintained in a validated state.

Cleanroom

A room or area with defined environmental control of particulate and microbial contamination,

constructed and used in such a way as to reduce the introduction, generation and retention of

contaminants within the area, and in which other relevant parameters (e.g. temperature, humidity and

pressure) are controlled as necessary.

Commissioning

Commissioning is the documented process of verifying that the equipment and systems are installed

according to specifications, placing the equipment into active service and verifying its proper action.

Commissioning takes place at the conclusion of project construction but prior to validation.

Containment

A process or device to contain product, dust or contaminants in one zone, preventing it from escaping

to another zone.

Contamination

The undesired introduction of impurities of a chemical or microbial nature, or of foreign matter, into or

on to a starting material or intermediate, during production, sampling, packaging or repackaging,

storage or transport.

Critical parameter or component

A processing parameter (such as temperature or humidity) that affects the quality of a product; or acomponent that may have a direct impact on the quality of the product.

Cross-contamination

Contamination of a starting material, intermediate product or finished product with another starting

material or material during production.

Design condition

Design condition relates to the specified range or accuracy of a controlled variable used by the designer

as a basis to determine the performance requirements of an engineered system.

Design qualification (DQ)DQ is the documented check of planning documents and technical specifications for design conformity

with the process, manufacturing, cGMP and regulatory requirements.

Direct impact system

A system that is expected to have a direct impact on product quality. These systems are designed and

commissioned in line with Good Engineering Practice and, in addition, are subject to Qualification

Practices.

Drug substance

Starting materials, such as excipients and active ingredients, used to make up the final pharmaceutical

product.

ECS

Environmental control system, also referred to HVAC


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Facility

The built environment within which the cleanroom installation and associated controlled environments

operate together with their supporting infrastructure.

Good Engineering Practice (GEP)

Established engineering methods and standards that are applied throughout the project lifecycle to

deliver appropriate, cost-effective solutions.

HEPA filter

High Efficiency Particulate Air filter.

HVAC

Heating Ventilation and Air Conditioning, also referred to Environmental Control System (ECS).

Indirect impact systemThis is a system that is not expected to have a direct impact on product quality, but typically will

support a direct impact system. These systems are designed and commissioned according to Good

Engineering Practice only.

Installation qualification (IQ)

IQ is documented verification that the premises, HVAC system, supporting utilities and equipment

have been built and installed in compliance with their approved design specification.

ISO 14644-1

An international standard relating to the classification of clean environments. This standard is set to

replace all existing national standards such as the US Fed. Std. 209, BSS5295, EEC and DIN. Thisguideline will make reference to the ISO classifications. A comparison between the various existing

standards is given in Chapter 8.

ISPE

International Society for Pharmaceutical Engineering

Laminar airflow

Laminar airflow or unidirectional airflow is a rectified airflow over the entire cross-sectional area of a

clean zone with a steady velocity and approximately parallel streamlines (see also turbulent flow).

(Modern standards no longer refer to laminar flow, but have adopted the term unidirectional airflow)

Level of protection

The level of protection defines the level of protection required in various zones of the production

facility.

No impact system

This is a system that will not have any impact, either directly or indirectly, on product quality. These

systems are designed and commissioned according to Good Engineering Practice only.

Non-critical parameter or component

A processing parameter or component within a system where the operation, contact, data control, alarm

or failure will have an indirect impact or no impact on the quality of the product.


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Normal operating range

Normal operating range is the range that the manufacturer selects as the acceptable values for a

parameter during normal operations. This range must be within the operating range.

Operating limits

The minimum and/or maximum values that will ensure that product and safety requirements are met.

Operating range

Operating range is the range of validated critical parameters within which acceptable products can be

manufactured.

Operational condition

This condition relates to carrying out room classification tests with the normal production process with

equipment in operation , and the normal staff present in the room.

Operational qualification (OQ)

OQ is the documented verification that all aspects of a facility, utility or equipment that can effect

product quality, operate as intended through all anticipated ranges. Usually carried out over an

extended period to prove ongoing conformance.

OSD

Oral solid dosageusually referring to an OSD plant that manufactures medicinal products such as

tablets, capsules and powders to be taken orally.

Performance qualification (PQ)

PQ is the documented verification that the process and/or the total process related to the system,

performs as intended throughout all anticipated operating ranges.

Pressure cascade

A process whereby air flows from the cleanest area, which is maintained at the highest pressure to a

less clean area at a lower pressure.

Qualification

Qualification is the planning, carrying out and recording of tests on equipment and a system, which

forms part of the validated process, to demonstrate that it will perform as intended.

Relative humidity

The ratio of the actual water vapour pressure of the air to the saturated water vapour pressure of the airat the same temperature expressed as a percentage. More simply put, it is the ratio of the mass of

moisture in the air, relative to the mass at 100% moisture saturation, at a given temperature.

Standard operating procedure (SOP)

An authorized written procedure, giving instructions for performing operations, not necessarily specific

to a given product or material, but of a more general nature, (e.g. equipment operation, maintenance

and cleaning; validation; cleaning of premises and environmental control; sampling and inspection).

Certain SOPs may be used to supplement product-specific master and batch production documentation.

Turbulent flow

Turbulent flow, or non-unidirectional airflow, is air distribution that it is introduced into the controlledspace and then mixes with room air by means of induction.


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ULPA filter

Ultra-Low Penetration Air filter. (not applicable to normal pharmaceutical installations, but given for

background information)

Validation

The documented act of proving that any procedure, process, equipment, material, activity or system

actually leads to the expected results.

Validation Master Plan (VMP)

VMP is a high level document which establishes an umbrella validation plan for the entire project, and

is used as guidance to the project team for resource and technical planning (also referred to as master

qualification plan).

3. SCOPE OF DOCUMENT

3.1 The guideline focuses primarily on the design and GMP requirements for HVAC systems for

solid dosage facilities. It does not cover requirements for manufacturing sites for the

production of sterile products, however, reference is sometimes made to sterile facilities for

background or comparative purposes. There is very little definitive text relating to the HVAC

or ECS systems for these facilities. However, most of the system design principles for Solid

Dosage manufacturing facilities will also apply other facilities such as liquids, creams and

ointments.

This guideline is intended as a basic guide for use by GMP inspectors. It is not very

prescriptive in specifying requirements and design parameters. There are many parameters

affecting a cleanroom condition and it is, therefore, difficult to implicitly define therequirements for one particular parameter.

Many manufacturers have their own engineering design and qualification standards. However,

these requirements may vary from one manufacturer to the next. Design parameters should,

therefore, be realistically set for each project, with a view to creating a cost-effective design, yet

still complying with all regulatory standards and ensuring that product quality and safety are not

compromised.

The three primary aspects addressed in this manual are the roles that the HVAC system plays in

product protection, personnel protection and environmental protection. These aspects are

represented in the organigram below:


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PRODUCT

PROTECTION

PERSONNEL

PROTECTION

ENVIRONMENT

PROTECTION

Protect from product

cross-contamination

Correct temperature &

humidity

Prevent contact with

fumes

Acceptable comfort

Conditions

Avoid fume

discharge

Avoid effluent

discharge

SYSTEMS

SYSTEM VALIDATION

Contamination(Product & Staff)

Avoid duct

discharge

GMP MANUFACTURING

ENVIRONMENT

Prevent contact

with dust

Fig 3.1 The guide addresses the various system criteria as per the sequence set out in the

organigram.

4. PRODUCT PROTECTION

4.1 Contamination control

Through all stages of processing, products should be protected from contamination and cross-

contamination (refer to section 4.2 for cross-contamination control).

These include contaminants resulting from inappropriate building finishes, plant layout, poor

cleaning procedures, lack of staff discipline and a poor HVAC system.


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4.1.1 Cleanroom Concept

Pharmaceutical manufacturing facilities where pharmaceutical products, utensils and

manufacturing equipment are exposed to the environment, should be classified as cleanrooms.

A cleanroom is an area or zone where the particulate and microbial contamination is limited tospecified levels. Different standards relating to the classification of cleanrooms are referred to

in the table under section 8.5.1.

Normally the level of cleanliness should be defined by the number of contaminants per cubic

metre of room air. The smaller the number of contaminants, the cleaner the room classification.

Pharmaceutical manufacturing facilities should validate their systems to a defined cleanroom

classification, on a risk based approach. Air supply filtration quality, as well as the air change

rate, should ensure that the defined cleanroom classification is attained.

Figure 4.1 below illustrates the ideal shell-like building layout to enhance containment and

protection from external contaminants. The process core is regarded as the most stringently

controlled Clean Zone which is protected by being surrounded by cleanrooms of a lower

classification.

Fig. 4.1 Shell-like containment control concept

In order to achieve a cleanroom environment the contaminants need to be removed. External

contaminants should be removed by efficient filtration of the supply air.


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Internal contaminants should be removed by dilution and flushing of contaminants in the room,

or by displacement airflow (refer to Figs 4.2 and 4.3 below for examples of airborne

contaminant flushing methods).

Fig. 4.2. Turbulent dilution of dirty air


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Fig. 4.3 Unidirectional displacement of dirty air

Explanatory note: To achieve a cleaner condition in a room, more air should be supplied to

further dilute the contaminants. For each increase in cleanroom classification the air change rate

should be increased accordingly.

The ISPE Baseline Guide for Oral Solid Dosage Forms does not stipulate any minimum air

change rate for non-sterile manufacturing facilities. The air change rates are to be determined

by the designer, taking the various critical parameters into account. Many multinational

pharmaceutical manufacturers have their own minimum air change rate standards for oral

dosage facilities, and these typically vary between 6 and 20 air changes per hour.

The number of air changes per hour is one of the most important factors in determining an

efficient air handling system. Primarily the air change rate should be set to a level that willachieve the required cleanroom classification.

The room air change rate is also determined by the following considerations:

The quality and filtration of the supply air

Particulates generated by the manufacturing process

Particulates generated by the operators

Configuration of the room and air terminal locations

Sufficient air to achieve containment effect

Sufficient air to cope with the room heatload

Sufficient air to maintain the required room pressure

A further important concept in specifying cleanroom criteria should be that of the associated

activity.


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Each cleanroom class should be specified as achieving the cleanroom classification under as -

built, at-rest or operational conditions. (There is a significant difference in the air change

rate requirements between as-built, at-rest and operational ratings and, therefore, this

must be specified up front in the design criteria.)

Fig. 4.4 As-built condition


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Fig. 4.5 At-rest condition


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Fig. 4.6 Operational Condition

The as-built condition should relate to carrying out room classification tests on the bare room,

without any equipment or personnel.

The at-rest condition should relate to carrying out room classification tests with the normal

production equipment in the room, but without any operators. Due to the amounts of dustusually generated in a solid dosage facility most cleanroom classifications are rated for the at-

rest condition.

The operational condition should relate to carrying out roomclassification tests with the

normal production process with equipment operating, and the normal staff present in the room.

Generally a room that is tested for an operational condition, should be able to clean up to a

higher at-rest cleanroom classification, after a short clean-up condition. The clean-up time

should normally be in the order of 20 minutes.

The relationship between at-rest and operational room classifications are often presented in

GMP guides, as set out in the table below:


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Room Grade At-rest Condition Operational condition

Maximum number of particles

permitted/m3

Maximum number of particles

permitted/m3

0,5 m 5 m 0,5 m 5 m

A 3 500 1 3 500 1B 3 500 1 350 000 2 000

C 350 000 2 000 3 500 000 20 000

D 3 500 000 20 000 Not defined Not defined

The achievement of a particular cleanroom classification depends on a number of different

criteria. All of the criteria should be addressed at the design stage.

There should be a balance between the different criteria in order to create an efficient

cleanroom.

Some of the basic criteria to be considered should include:

Building finishes and structure

Air filtration

Air change rate or flushing rate

Room pressure

Location of air terminals and directional airflow

Temperature

Humidity

Material flow

Personnel flow

Equipment movement.

Process being carried out

Outside air conditions

Occupancy

4.1.2 Level of Protection

Airborne particulates and degree of filtration should be considered a critical parameter with

reference to the level of product protection required.

There are three levels of protection, as defined in the ISPE OSD Baseline Guide, formanufacturing facilities, as listed below:

Level 1

General:An area with normal housekeeping and maintenance e.g. Warehousing,

Secondary Packing.

Level 2Protected:An area in which steps are taken to protect the exposed drug substance

from contamination or degradation. e.g. Manufacturing, Primary Packing,

Dispensing, etc.

Level 3Controlled:An area in which specific environmental conditions are defined, controlled

and monitored to prevent contamination or degradation of the drug substance.


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The ISPE OSD Baseline Guide further states that there are no particulate classification requirements for

OSD facilities, such as those that exist for aseptic processing. The level of protection and air

cleanliness for different areas should be evaluated based on the product being manufactured, the

process and the products susceptibility to degradation.

The most commonly applied classification for open product zones in a solid dosage plant is a Grade D

classification. This equates to a particulate level classification of ISO 14644-1 Class 8, at-rest,

measured against particle sizes of 0,5 m and 5 m.

Note that the ISO 14644-1 cleanroom standard for air classification has replaced the US Federal

Standard 209 standard.

Cleanroom standards, such as ISO 14644-1 provide the details of how to classify air cleanliness by

means of particle concentrations. Whereas the GMP standards provide a grading for air cleanliness in

terms of the condition (at-rest or operational), the permissible microbial concentrations, as well as other

factors such as gowning requirements. GMPs and cleanroom standards need to be used in conjunctionwith each other in order to define and classify the different manufacturing environments.

4.1.3 Air filtration to control contamination

The degree to which air is filtered plays an important role in the prevention of contamination

and the control of cross-contamination.

The type of filters required for different applications will depend on the quality of the ambient

air and the return air (if applicable) and also on the air change rates. The same cleanliness level

could be achieved with an high air change rate and low grade filters, or a low air change ratewith high grade filters. The table below gives the recommended filtration levels for different

Levels of Protection in a Pharmaceutical facility, bearing in mind that adjustments may need ti

be made to suit local conditions. .

Level of Protection Recommended filtration

Level 1

Primary filters onlyEN779 G4 filters

Level 2 & 3 Production facility operating on 100% outside air:

Primary & Secondary filtersEN779 G4 and F8 filters

Level 2 & 3 Production facility operating on re-circulated plus ambient air:

where potential for product cross-contamination exists.Primary, secondary & tertiary filters - EN779 G4, F8 and EN1822 H13

filters

The filter classifications referred to above relate to the EN1822 and EN779 test standards which

are the latest filter test standards, recommended for international use. (EN 779 relates to filter

classes G1 to F9 and EN 1822 relates to filter classes H10 to U16.)


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Referring to actual filter efficiencies can be very misleading as there are currently many

different test methods, and each results in a different value for the same filter.

Figure 4.7 below gives a rough comparison between the different filter standards.

APPROXIMATION OF EQUIVALENT FILTER STANDARDS

EU Class %(IntegralValue)

EN 779 &EN 1822

99,99995 U16

99,9995 U15

14 99,995 U14

13 99,95 H13

12

11 % 99,5 H12

10 (Average) 95 H11

9 95 85 F9/H10

8 90 75 F8

85 F7

7 80

75

6 70 F6

65

60

55

5 50 F5

45

% 40(Average) 35

4 95 30 G4

90 25

3 85 20 G3

80

75

2 70 G2

65

G1

Fig. 4.7 Comparison of filter test standards

Eurovent Class Eurovent 4/5 (2-9)Eurovent 4/9 (2-9)Eurovent 4/4 (10-14)

Arrestance%

Dust SpotEfficiency

ASHRAE 52/76BS6540 Part 1

(1985)

MPPS, DEHSAerosolEN1822

CEN/TC/195WG1-G1-F9WG2-H10-16


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In selecting filters the manufacturer should have considered other factors, such as particularly

contaminated ambient conditions, local regulations and specific product requirements.

Good prefiltration is not a specific requirement, but it extends the life of the more expensive

filters downstream.

If failure of a HEPA filter would jeopardize the integrity of a product, a back-up HEPA filter in

series should be considered.

4.1.4 Contamination by HVAC plant

Materials for components of an HVAC system should be selected with care, as the materials

from which these are manufactured can liberate particles into the supply air stream.

Any components with the potential for liberating particulate or microbial contamination into the

air stream should be located upstream of the final filters.

Careful selection should be made of any materials downstream of the final filters to ensure that

they cannot rust or oxidize, liberating particulate matter into the air stream.

As far as possible for maintenance purposes, ventilation dampers, filters and other services

should be designed and positioned so that they are accessible from outsidethe manufacturing

areas.

Facility design should be planned so that as many of the services as possible are accessible from

service voids or service corridors.

4.1.5 Contamination by staff

Staff or operators are a source of contamination and the facility design and operating procedures

should be such as to minimise their contamination. .

Directional airflow within production or packing areas should be an important means of

contamination control.

Airflows should be planned in conjunction with operator locations, so as to minimise operator

contamination of the product and also to protect the operator from dust inhalation.

Where the product could be harmful to the operator, an alternative arrangement should be made.

4.1.6 Airflow patterns

Airflow patterns within a production room can effect the spreading of contaminants.

HVAC air distribution components should be selected to prevent contaminants generated within

the room from being spread.

Supply air diffusers of the high induction type should not be used in a cleanroom.

High induction diffusers, typically used for office type air conditioning, provide a high degree

of air mixing by inducing room air into the supply air stream. Contaminants in the room are

drawn vertically up to the ceiling via the induced air stream and mixed with the air being


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supplied into the room. This is a distinct disadvantage in a pharmaceutical manufacturing

facility, as the contaminants liberated by operators, as well as process dust, are drawn into the

supply air and disseminated throughout the room.

Air diffusers should be of the non-induction type, introducing air with the least amount of

induction so as to maximize the flushing effect.

Whenever possible, air should be exhausted from rooms at a low level, as this helps to flush

contaminants from the area.


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Fig. 4.8 Induction diffuser

(not recommended)


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Fig. 4.9 Perforated plate diffuser

(recommended)


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Fig. 4.10 Swirl diffuser (recommended)

4.1.7 Unidirectional Airflow (UDAF) Protection

Unidirectional flow air is sometimes used to provide product protection by supplying a clean airsupply over the product, which minimizes the ingress of contaminants from surrounding area.

(unidirectional airflow is the term that has replaced laminar airflow)

Sampling cubicles, which are normally located in a warehouse, are areas of possible

contamination of starting or raw materials. Containers brought from the warehouse (which is

often a less clean environment) into the sampling cubicle for sampling, should be cleaned prior

to entry to the sampling cubicle. Containers and materials should be protected from

contamination when they are opened. Sampling should normally be carried out under a

unidirectional airflow screen to ensure that clean air is flowing over the container when it is

opened..

Where appropriate the unidirectional airflow should also provide protection to the operator from

contamination by the product.


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Normally unidirectional flow provides a Class A (ISO Class 5, operational, 0.5 m)

environment, but for a sampling cubicle this degree of protection is not required. Sampling

should be carried out in the same environmental class that is required for the further processing

of the product.

A dispensary weigh booth should be provided with unidirectional airflow for product and

operator protection, similar to that described for Sampling.

The unidirectional flow can be either vertical flow or horizontal flow, and the flow pattern that

provides the best protection for a particular application should be selected.

Current GMP guides recommend that UDAF velocities, for Grade A conditions, should be

0.45 m/s, within a range of 20%. However, when UDAF is applied to Sampling and Weighing

a lower velocity can be selected, provided the required protection can be validated.

Fig. 4.11 Diagram indicating horizontal and vertical unidirectional flow

4.1.8 Infiltration

Air infiltration, of unfiltered air, into a pharmaceutical plant should not be the source of

contamination.

Manufacturing facilities should be maintained at a positive pressure relative to the outside, to

limit the ingress of contaminants.


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Where facilities are to be maintained at negative pressures relative to ambient, in order to

prevent the escape of harmful products to the outside (such as penicillin and hormones), then

special precautions should be taken.

The location of the negative pressure facility should be carefully considered with reference to

the areas surrounding it, and particular attention must be given to ensuring that the building

structure is well sealed.

Negative pressure zones should, as far as possible, be encapsulated by surrounding areas with

clean air supplies, so that only clean air can infiltrate into the controlled zone.

4.2 Cross-contamination protection

Through all stages of processing, products should be protected from cross-contamination. This

can be achieved with the aid of the following methods.

4.2.1 Directional air movement

One of the primary tools for cross-contamination control is correct directional air movement,

which may be brought about by a pressure cascade system.

In a multi-product OSD manufacturing area (e.g. tablet manufacturing site), the layout normally

consists of a corridor with production cubicles located on either side of it. Different products

are likely to be manufactured in each cubicle, and care should be taken that dust cannot move

from one cubicle to another. Cross-contamination between products within a single room will

not be addressed, as different products should never be processed in the same area at the sametime.

The pressure cascade should be such that air flows from the corridor into the cubicles, resulting

in dust containment.

The corridor should be maintained at a higher pressure than the cubicles, and the cubicles at a

higher pressure than atmospheric pressure. (There are, however, some instances where cubicles

or processes should be maintained at a negative pressure relative to atmosphere, in order to

contain hazardous substances, such as penicillin or hormones, etc.)

Containment can normally be achieved by one of various means such as:

4.2.1.1 Displacement concept (low pressure differential, high airflow)

A low pressure differential can effectively separate clean and less clean adjacent zones, by

means of a low turbulent displacement airflow. Typically a velocity of greater than 0,2 m/s

should be attained, as if the velocity is too low, turbulence within the doorway could allow dust

to escape.

This displacement airflow should be calculated as the product of the door area and the velocity,

which generally results in fairly large air quantities.

With this concept, the air should be supplied to the corridor, flow through the doorway, and

should be extracted from the back of the cubicle. Normally the cubicle door should be closed


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and the air should enter the cubicle through a door grille, although the concept can be applied to

an opening without a door.

The door containment airflow velocity could be considered a critical parameter, depending on a

risk analysis. This method of containment is not the preferred method, as the measurement and

monitoring of doorway velocities, is difficult.

4.2.1.2 Pressure differential concept (high pressure differential, low airflow)

The high pressure differential between the clean and less clean zones should be generated by

leakage through the gaps of the closed doors to the cubicle.

The pressure differential concept should be carefully considered as to whether it is used alone or

in combination with other containment control techniques and concepts, such as a double door

airlock.

The pressure differential should be of sufficient magnitude to ensure containment and

prevention of flow reversal, but should not be too high so as to create turbulence problems.

The most widely accepted pressure differential, to achieve containment, between the two

adjacent zones is 15 Pa, but pressure differentials of between 5Pa and 20Pa could be acceptable.

A control tolerance of 3 Pa is achievable, and one then needs to analyse what the implications

of the upper and lower tolerances would have on containment.

Where the design pressure differential is too low, and tolerances are at opposite extremities, a

flow reversal can take place. The effect of room pressure tolerances are illustrated in figure

4.12 below

Figure 4.12 Pressure Cascades


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In considering room pressure differentials, transient variations, such as machine extract

systems, should be taken into consideration.

Pressure control systems can be either active/automated or passive/manual. Passive/manual

control is preferable, as it tends to be more stable, is less costly and requires less maintenance.

Manual control systems should be set up during commissioning, and should not change unless

other system conditions change.

Whichever pressure control device is used, the pressures should be validated, monitored and

recorded on a regular basis, to verify compliance.

The pressure differential between adjacent rooms could be considered a critical parameter,

depending on a risk analysis.

Airlocks should be an important component in setting up and maintaining pressure cascade

systems.

For critical installations such as sterile product manufacturing areas, airlocks should have

interlocked doors, so that only one door can be opened at a time to ensure the pressure cascade

is not compromised.

In less critical situations, the doors may not need to be interlocked and the pressure cascade is

reliant on staff discipline.

There are three basic classifications of airlocks that are physically the same, but only thepressure cascade regime differs. The classifications are as follows and are demonstrated by

figures 4.13 to 4.15:


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Fig. 4.13 Cascade airlock

Fig. 4.14 Sink airlock


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Fig. 4.15 Bubble airlock

Cascade airlock - high pressure on one side of the airlock and low pressure on the

other side.

Sink airlock - low pressure inside the airlock and high pressure on both outer sides.

Bubble airlock - high pressure inside the airlock and low pressure on both outer sides.

Wherever possible, the door swing on airlocks should be such that the door opens to the high-

pressure side.

All airlock doors should be provided with self-closers.

Door closer springs, if used, should be designed to hold the door closed and prevent the

pressure differential from pushing the door open.


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4.2.1.3 Physical barrier concept

The use of an impervious barrier to prevent cross-contamination between two zones is the third

segregation concept. (This would typically be the case where a barrier isolator, or pumped

transfer of materials, is used.)

These methods however, are often not practical in an OSD facility, where the transport of

relatively large volumes of materials is involved.

4.2.1.4 Selecting the segregation concept

The choice of which of the above three segregation concepts should be used should largely be

dependent on the type of production process taking place.

The displacement concept should ideally be used in production processes where large amounts

of dust are generated.

The pressure differential concept may normally be used in zones where there is little or no dust

being generated.

The choice of pressure cascade regime and choice of airflow direction should be considered in

relation to the product being handled.

Highly potent products should be manufactured under a pressure cascade regime that is negative

to atmospheric pressure.

The pressure cascade for each facility should be individually assessed according to the producthandled and level of protection required.

Building structure should be given special attention, because of the pressure cascade design.

Airtight ceilings and walls, close fitting doors and sealed light fittings should be in place as

these all have an impact on the HVAC system

The designer should assess all of these items up front, and also advise the architect/developer of

all the implications.

4.2.2 Unidirectional Airflow protection

Unidirectional airflow (UDAF) protection is a further means of preventing cross-contamination

between products. (See also text under clause 4.1.7)

In order to achieve a Grade A condition, unidirectional airflow is required, together with the

correct HEPA filtration, microbial control and a Grade B background.

4.2.3 Cross-contamination via HVAC supply air

The two basic concepts of air delivery to pharmaceutical production facilities should be

considered.

The air handling system either supplies 100% outside air to the facility, or a limited amount of

outside air is mixed with return air from the production rooms.


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Dust laden air, returned to the air handling unit for recirculation purposes, increases the

possibility of cross-contamination in a multi-product plant.

A re-circulation system may be acceptable, provided that suitable filtration is provided and

there are no contaminants (such as fumes and volatiles) which cannot be removed by normal

filtration. A risk analysis is required.

A recirculation system should be provided with HEPA filtersto ensure the removal of return air

contaminants, so as to prevent cross-contamination.

The HEPA filters for this application should have an EN1822 classification of H13.

4.2.4 Cross-contamination due to fan failure

Failure of a supply air fan, return air fan, exhaust air fan or dust extract system fan, can cause a

system imbalance, resulting in a pressure cascade malfunction with a resultant air flow reversal.

Appropriate airflow alarm systems should be in place to sound an alarm if failure of a critical

fan occurs.

Central dust extraction systems should be interlocked with the appropriate air handling systems,

to ensure that they operate simultaneously.

Room pressure imbalance between adjacent cubicles which are linked by common dust extract

ducting should be prevented, as cross-contamination can occur if the dust extract fan fails or is

switched off.

Air should not flow from the room with the higher pressure to the room with the lower pressure,

via the dust extract ducting.

4.3 Temperature and humidity

4.3.1 General temperature and humidity requirements

Temperature and humidity should be controlled where relevant, to ensure compliance with

product manufacturing requirements, and to provide operator comfort where necessary (e.g.

sterile product manufacture).

4.3.2 Product temperature requirements

Temperature requirements for the various products being manufactured should be determined,

and based on this the HVAC temperature control should be set

The operating band or tolerance between the acceptable minimum and maximum temperatures

should not be made too close

4.3.3 Product humidity requirements

Product humidity requirements should be determined before commencing with the design.

Hygroscopic products require special attention, including the HVAC system and building

design.


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Cubicles, or suites, processing products requiring low humidities, should have well-sealed walls

and ceilings and should also be separated from adjacent areas with higher humidities, by means

of suitable airlocks.

Precautions should be taken to prevent moisture migration that increases the load on the HVAC

system.

Humidity control should include removing moisture from the air, or adding moisture to the air,

as relevant.

Moisture removal, or dehumidification, may be achieved by means of either refrigerated

dehumidifiers, or chemical dehumidifiers.

Humidifiers should be avoided, if possible, as they tend to support microbiological growth.

However, humidifiers may occasionally be required to overcome static electricity problems, or

to suit product demands. Moisture addition or humidification may be achieved by means ofinjecting steam into the air stream. A product contamination assessment is required to

determine whether pure or clean steam is required for humidification purposes.

Chemical additives in the boiler make-up water should be specified, to determine if this will

have any detrimental effects on the product when steam humidifiers are used.

Humidification systems should be well drained to ensure that no condensate collects in air

handling systems.

Other humidification appliances, such as evaporative systems, atomizers and water mist sprays,

should not be used, due to the possible microbial contamination risk

When specifying relative humidities, the associated temperature should also be specified.

Generally, suites requiring conditions lower than 45% RH at a temperature of 22C may require

chemical driers to achieve the conditions.

A low temperature chilled water/glycol mixture or refrigerant may be used as a cooling medium

for dehumidification.

Chemical driers or dehumidifiers employing a desiccant, such as silica gel or lithium chloride,

to remove the moisture from the air, should have desiccant wheels of the non-shedding type andshould not support microbial growth.

Where high humidity is required, care should be taken with the insulation of cold surfaces in

order to prevent condensation within the cleanroom or on air-handling components.

Controlling humidity by means of sensing and calculating the absolute humidity should be

preferred to controlling relative humidity, as the absolute humidity control tends to be more

stable.

Relative humidity fluctuates with temperature variations, and this may result in control system

hunting.


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4.3.4 Microbial growth

High temperatures and high humidities may lead to accelerated microbial growth as microbes

proliferate more readily under these conditions.

High temperatures and high humidities cause excessive perspiration from operators. Thisincreases risk of microbial contamination.

At least where there are no specific product-related temperature or humidity requirements, and

operator comfort is not considered important, the microbial risk should be assessed.

5. PERSONNEL PROTECTION

5.1 Protection from dust

Operators health should not be put at risk by being exposed to harmful products. Where

possible, dust should be controlled at source and thus prevented from being released into the

room.

Pharmaceutical product dust and vapour can be harmful to operators, and liberation of these

should be controlled and should be drawn away from the operator.

Airflow should be carefully planned, to ensure that the operator does not contaminate the

product, and so that the operator is not put at risk by the product.

5.2 Dust classification

Dust-related hazards that operators may be subjected to should be assessed. An analysis of the

type of dust, and toxicity thereof, is required and the airflow determined accordingly.

Dust can be roughly classified by size according to the following:

Coarse dust with size range of 50 to 500 m (which settles rapidly)

Fine dust with size range of 1,0 to 50 m (which settles slowly)

Ultra Fine dust with size range of


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protecting the product from contamination from the operator by means of the vertical

unidirectional airflow stream.

Figure 5.1 Operator protection at weighing station

In an application such as a dispensary weigh booth the unidirectional flow velocity should be

considered with regard to the possible disruption of sensitive scale readings.

In a weigh booth situation the aim should be to provide dust containment.

Where necessary, the velocity may be reduced to prevent scale inaccuracies, provided that

sufficient airflow is maintained to provide containment.

An alternative to vertical unidirectional flow protection may be the use of horizontal

unidirectional flow. Careful consideration should be given to the position in which the operator

stands relative to the source of dust liberation.


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Figure 5.2 Operator protection by horizontal air flow

It should be ensured that the operator is not in the path of an airflow that could lead to

contamination of the product.


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Once the system has been designed and validated with a specific operator and process layout,

strict discipline should be maintained to ensure that the SOP is adhered to.

Obstructions in the path of a unidirectional flow air stream may cause even more dust exposure

to the operator.

Fig 5.3 indicates the incorrect use of a scale, which has a solid back. The back of the scale

should not block the return air path, causing air to rise up vertically, resulting in a hazardous

situation for the operator.

Figure 5.3 Operator subject to powder inhalation due to obstruction


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Figure 5.4 indicates a situation where an open bin is placed below a vertical uni-directional flow

distributor.

The downward airflow should be prevented from entering the bin, and then being forced to rise up

again, carrying dust up towards the operators face.

Figure 5.4 Operator subject to powder contamination

due to air flow reversal in bin.

Figure 5.5 shows that sometimes a solid worktop can cause deflection of the vertical unidirectional

airflow resulting in a flow reversal. A possible alternative solution would be to have a 100mm gap at

the back of the table, with the air being extracted here.


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Figure 5.5 Operator subject to powder inhalation due to worktop obstruction

5.4 Point extraction

Wherever possible, the dust or vapour contamination should be removed at source. Pointextraction, as close as possible to the point where dust is generated, should be employed.

Point extraction should be either in the form of a fixed high velocity extraction point or an

articulated arm with movable hood or a fixed extract hood.

Dust extraction ducting should be designed to have sufficient transfer velocity to ensure that

dust is carried away, and does not settle in the ducting.

The required transfer velocity is dependent on the density of the dust; the denser the dust, the

higher the transfer velocity should be. Transfer velocities for pharmaceutical dust, should

generally be in the range of 18 to 20 m/s. Ventilation hand books can provide more detailed

information on the required transfer velocities.

5.5 Directional airflow

Point extraction alone is usually not sufficient to capture all of the contaminants, and general

directional airflow should be used to assist in removing dust and vapours from the room.

Typically in a room operating with turbulent airflow the air should be introduced from ceiling

diffusers and is extracted from the room at low level.

The low level extract should assist in drawing air down and away from the operators face.

The location of the extract grilles should be positioned strategically to draw air away from theoperator, but at the same time prevent the operator from contaminating the product.


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When dealing with the extraction of vapours, the density of the vapour should be taken into

account. If the vapour is lighter than air, then the extract grilles should be at high level, or

possibly at high and low level.

5.6 Air Showers

When operators have been working in a dusty environment, their protective garments could

become coated with a film of dust.

Operators should change out of their protective garments before going to the canteen.

Operators could pass through an air shower, prior to entering the change room, on leaving the

production area.

Air showers should be designed as an air lock, with high velocity air nozzles which blast air

from the sides of the airlock, to dislodge the dust.

Air extract grilles at low level should draw the air away and return it to the filtration system.

Some air showers may also incorporate a vertical laminar

section at the exit end, to additionally flush contaminants away.

5.7 Protective enclosures

When dealing with particularly harmful products, additional steps, such as handling the

products in glove boxes or using barrier isolator technology, should be used.

For products such as hormones or highly potent , operators should wear totally enclosed

garments, as indicated in Figure 5.7.

Fig. 5.6 Air shower


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In this instance a breathing air system should provide a supplyof filtered and conditioned air to the operator. The air supply

to this type of breathing apparatus should normally be through

an air compressor. Filtration, temperature and humidity need

to be controlled to ensure operator safety and comfort.

5.8 Operator comfort

Maximum and minimum room temperatures and humidities should be appropriate.

Temperature conditions should be adjusted to suit the protective clothing that the operators are

wearing.

Typical comfort condition of 18C should be applicable in a sterile manufacturing area where

full protective clothing is worn, whereas 21 to 22C should be comfortable in an OSD facility

where the dress code is less onerous.

Recommended humidity comfort levels of 20%RH to 60%RH should be maintained where

required.

Fresh air rates supplied to the facility should comply with local regulations, to provide operator

comfort and safety and also to provide odour or fume removal.

Fresh air rate should also be determined by the leakage from the building, for pressure control

purposes.

Fig. 5.7 Protectivegarments


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6. PROTECTION OF THE ENVIRONMENT

6.1 Exhaust air dust

Exhaust air discharge points on pharmaceutical facilities, such as from fluid bed driers andtablet coating equipment, and exhaust air from dust extraction systems, carry heavy dust loads

and should be provided with adequate filtration to prevent ambient contamination.

On typical solid dosage plants, where the powders are not highly potent, final filters on a dust

exhaust system should be fine dust filters having a filter classification of F9 according to EN779

filter standards.

On systems where harmful substances such as penicillin, hormones, toxic powders and enzymes

are exhausted, the final filters should be HEPA filters with an H12 classification according to

EN1822 filter standards.

For exhaust systems where the discharge contaminant is considered particularly hazardous, it

may be necessary to install two banks of HEPA filters in series, to provide additional protection

should the first filter fail.

When handling hazardous compounds, safe change filter housings, also called bag-in-bag-out

filters, should be used.

All filter banks should be provided with pressure differential indication gauges, to indicate the

filter dust loading.

Monitoring of filters should be done at regular intervals, to prevent excessive filter loading that

could force dust particles through the filter media, or could cause the filters to burst, resulting inambient contamination.

Filter pressure gauges should be marked with the clean filter resistance, and the change-out

filter resistance.

More sophisticated computer-based data monitoring systems may be installed, with preventive

maintenance plans by trend logging. (This type of system is commonly referred to as a building

management system (BMS), building automation system (BAS) or system control and data

acquisition (SCADA) system.)

An automated monitoring system should be capable of indicating any out-of-specification

condition without delay, by means of an alarm or similar system.

Reverse pulse dust collectors can be used for removing dust from dust extract systems. These

units are usually equipped with cartridge filters that have a compressed air lance inside the

filters. This pulses on a regular basis to blow the dust off the filter cartridges.

Reverse pulse dust collectors should be able to operate continuously without interrupting the

airflow.

Alternative types of dust collectors, e.g. those operating with a mechanical shaker, require the

fan to be switched off when the mechanical shaker is activated, in order to shake the dust off the

filters. This disruption of airflow could occur during a production run, and the loss of airflowcould disrupt the pressure cascade. This may result in cross-contamination.

The mechanical shaker dust collectors should not be used for applications where continuous

airflow is a requirement.


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A wet scrubber can be used, which usually operates on the principal of passing the dust-laden

air through a water spray.

Dust forms a slurry which is then usually passed to a drainage system.

With all the above types of dust collectors and wet scrubbers, the exhaust air quality should be

determined to see whether the filtration efficiency is adequate.

Additional filtration may be required downstream of the dust collector.

Air showers may be used to remove contaminants from garments before leaving the production

facility.

6.2 Fume removal

Although fume, dust and effluent control relating to the ambient are not GMP issues, but rather

environmental issues, they could also become a GMP issue. For example if an exhaust airdischarge point was close to the HVAC system fresh air inlet.

Removal of fumes should be by means of wet scrubbers or dry chemical scrubbers (deep bed

scrubbers).

Wet scrubbers for fume removal should normally have various chemicals added to the water to

increase the adsorption efficiency.

Deep bed scrubbers should be designed with activated carbon filters, or chemical adsorption

granular media. The chemical media for deep bed scrubbers should be specific to the effluent

being treated.

The type and quantity of the vapours to be treated should be known, to select the type of filter

media as well as the volume of media required.

6.3 Effluent discharge

Effluent control should be designed to ensure that systems like wet scrubbers, which could

discharge contaminants into the drainage system, do not become sources of possible risk or

contamination.

7. SYSTEMS AND COMPONENTS7.1 Air distribution

Introduction

Figure 7.1 below indicates a schematic diagram of an air handling system serving rooms with

horizontal unidirectional flow, vertical unidirectional flow and turbulent flow respectively for

rooms A, B and C.


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Normally, systems having a Class A or B and possibly C should have final filters terminally

located.

Fig. 7.1 Horizontal unidirectional flow, Vertical unidirectional flow and Turbulent flow

The following air flow diagram (Fig. 7.2) would typically be for a system with lower

cleanroom classification such as Class D.

HEPA filters may be located in the air handling unit and not terminally.

There may be alternative locations for return air, e.g. room D (low-level return air) and

room E (ceiling return air).

A cleanroom should be designed with low-level return. Where ceiling return air grilles are

used a higher air change rate may be required to achieve a specified cleanroomclassification. Low level return or exhaust air grilles are always preferred, however, this

may not be possible in all instances, where some ceiling return will be needed.


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Fig. 7.2 Air handling system with HEPA filters in AHU.

7.2 Air handling unit configurations

There are various air handling unit (AHU) configurations that may be used on a system.

These are discussed below.

7.2.1 Recirculation system.

The airflow schematics of the two previous systems (Figures 7.1 and 7.2) indicate air-

handling units with return air, or recirculated air, having a percentage of fresh air make-up.

Depending on the airborne contaminants in the return air system, it may usually be

acceptable to use recirculated air, provided that HEPA filters are installed in the supply air

stream to remove contaminants, and thus prevent cross-contamination.

Recirculated air should not be used if there are no HEPA filters installed in the system,

unless the air handling system is serving a single product facility and there is evidence that

there is no possibility of cross-contamination. Recirculation of air from areas where

pharmaceutical dust is not generated, such as secondary packing, will not require HEPA

filters in the system.


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7.2.2 Full fresh air systems

Figure 7.3 below indicates a system operating on 100% fresh air and would typically apply

to toxic products where recirculation of air with contaminants is not advised.

In locations with temperate climatic condition, differences between a system operating on100% fresh air versus a system utilizing recirculated air with HEPA filtration should be

considered.

The required degree of air cleanliness in most OSD manufacturing facilities can normally be

achieved without the use of HEPA filters.

The degree of filtration on the exhaust air should be determined dependant on the exhaust

air contaminants and local environmental regulations.

Fig. 7.3 Full fresh air system

A 100% fresh air system, which employs an energy reclaim feature (shown in Figure 7.4

below), normally employs an energy recovery wheel which transfers heat between the inlet

air and the exhaust air. The potential for air leakage between the supply air and exhaust air

as it passes through the wheel should be prevented. The relative pressures between supply

and exhaust air systems should be such that the exhaust air system operates at a lower

pressure than the supply system.

A risk analysis for potential cross-contamination through an energy wheel should be carried

out. Alternatives to the energy recovery wheel, such as crossover plate heat exchangers and

water coil heat exchangers, may be used.


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Fig. 7.4 Full fresh air system with energy recovery

7.2.3 Additional System Components

An airflow schematic diagram for a typical system serving a low humidity suite, is

represented in Figure 7.5. There are various means of drying air. The most common is theuse of a chemical drier, which uses a rotating desiccant wheel, and which is continuously

regenerated by means of passing hot air through one segment of the wheel. The figure

indicates the chemical drier handling part of the fresh air/return air mixture on a bypass

flow. The chemical drier can be positioned in various positions as follows:

Full flow of fresh/return air

Partial handling of fresh/return air (by-pass airflow)

Return air only

Fresh air only

Precooled air with any of the above alternatives

The location of the chemical drier, and the decision as to whether precooling is required,

should be considered in the design phase.

Additional components that may be required on a system often depend on the climatic

conditions and locations. These are items such as:

Frost coils on fresh air inlets in very cold climates to preheat the air

Snow eliminators to prevent snow entering air inlets and blocking air flow.

Dust eliminators on air inlets in arid and dusty locations

Moisture eliminators in humid areas with high rainfall Fresh air precooling coils for very hot climates


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8. COMMISSIONING, VALIDATION AND MAINTENANCE

8.1 Commissioning

Commissioning should involve the setting up, balancing, adjustment and testing of the entire

HVAC system, to ensure that the system meets all the requirements, as specified in the UserRequirement Specification, and capacities as specified by the designer or developer.

The installation records of the system should provide documented evidence of all measured

capacities of the system.

These data should include items such as the design and measured figures for airflows, water

flows, system pressures and electrical amperages. All these should be contained in theOperating and maintenance manuals (O & M manuals).

Acceptable tolerances are for all system parameters should be specified prior to commencing

with the physical installation

After installation training should be provided in the operation of the system. This training

should include aspects of the O & M manuals. O & M manuals, together with their as-built

record drawings, should be maintained as reference documents for any future upgrades or plant

alterations.

Commissioning should be a precursor to system qualification and validation.

Fig. 7.5 Air handling system with chemical drying


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8.2 Validation and qualification

Validation and qualification are essentially the same concept. Validation is the documented act

of proving that any procedure, process, equipment, material, activity or system actually leads to

the expected results.

Qualification is the act of planning, carrying out and recording of tests on equipment and

systems, which form part of the validation process, in order to demonstrate that it will perform

as intended.

Validation, therefore, refers to the overall concept of validation, including process validation,

while qualification refers to the validation part of equipment and systems. In this sense,

qualification is a part of validation.

Validation is a many-faceted activity, and is beyond the scope of this manual. However, the

basic concepts of validation in relation to the HVAC are set out below.

The organigram below illustrates the relationship between Qualification and validation, e.g. a

number of components or items of equipment could make up a system, and a number of systems

could collectively form a process.

Fig. 8.1 Qualification is a part of validation

As an example, an air handling unit and HEPA filters forming parts of a system would be

qualified; the end product, the quality of the air, would be validated. Systems and equipment

are qualified, whereas processes are validated.

Equip 7Equip 6Equip 5Equip 4

System 2

Equip 3Equip 2Equip 1

System 1

Process


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8.2.1 Validation master plan (VMP)

The validation master plan (VMP) is a document that summarizes the manufacturers overall

philosophy and approach, to be used for establishing performance adequacy.

The VMP for a particular project, such as the HVAC, should describe the What, Why, When,How, Where and Who of the validation process.

It should define the nature and extents of testing expected, and outline the test procedures and

protocols to be followed, to accomplish validation.

Stages of the qualification of the HVAC system should include DQ, IQ, OQ, and PQ.

Design qualification (DQ)

Design qualification is the documented check of planning documents and technical

specifications, for design conformity with the URS, cGMP and regulatory requirements.

Installation qualification (IQ)

Installation qualification is the documentary evidence to verify that the premises, HVAC

system, supporting utilities and equipment have been built and installed in compliance

with their design specification.

Operational qualification (OQ)

Operational qualification is the documented verification that all aspects of a facility,

utility or equipment that can effect product quality, operate as intended through allanticipated ranges.

Performance qualification (PQ)

Performance qualification is the documentary evidence to verify that the plant, system or

equipment operates consistently and reproducibly within the defined specifications and

parameters, for a prolonged period.

8.3 What to qualify

For all HVAC installation components, sub-systems or parameters, critical parametersand non-

criticalparameters should be determined, by means of a risk analysis.

If the component comes into direct contact with the product, or if the parameter affects the

quality of the drug product, then it should be classified as a critical parameter.

Critical parameters should be qualified.

A realistic approach to differentiating between critical and non-critical parameters is required,

in order not to make the validation process unnecessarily complex.

The room humidity, where the product is exposed, should be considered a criticalparameter when a humidity-sensitive product is being manufactured. The humidity

sensors and the humidity monitoring system, should, therefore, be qualified. The heat


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transfer system, chemical drier or steam humidifier, which is producing the humidity

controlled air, is further down the line and may not require operational qualification.

A room cleanliness classification is a critical parameter and, therefore, the room airchange rates and HEPA filters should be critical parameters and require qualification.

Items such as the fan generating the airflow and the primary and secondary filters are

non-critical parameters, and may not require operational qualification.

In the above examples reference is made to non-critical components that may not require

operational (and performance) qualification. However, these components, and in fact the entire

HVAC system, should be subject to design qualification (DQ) and installation qualification

(IQ).

Systems and components, which are non-critical components, should be subject to Good

Engineering Practice (GEP) reviews in lieu of OQ and PQ. GEP assures that the facility has

been built in accordance with plans and specifications and that construction, installation,

commissioning and testing have been performed properly.

Strict change control procedures should be applied to any items that affect critical parameters,

such as the HVAC system or component, control system settings and SOPs that affect critical

parameters.

8.4 Setting qualification limits

The validation master plan (VMP) should be prepared before the system design commences, as

the requirements set out in the VMP will influence the design.

Acceptance criteria and limits cannot be imposed once the system has already been designed

and installed.

The relationships between design conditions, operating range and validated acceptance criteria,

are given in Fig. 8.2 below.


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Fig. 8.2 System operating ranges

Design conditionrelates to the specified range or accuracy of a controlled variable used by the

designer as a basis to determine the performance requirements of an engineered system. Thedesign range should be within the normal operating range.

Normal operating rangeis the range that the manufacturer selects as the acceptable values for

a parameter during normal operations. This range should be within the operating range.

Operating rangeis the range of validated critical parameters within which acceptable products

can be manufactured.

Alert limitindicates that the normal operating range of a critical parameter has been exceeded

and that corrective measures may need to be taken, to prevent the action limit being reached.

(in some cases data review only may be required)

Action limitindicates that the validated acceptance criteria of a critical parameter have been

exceeded and that appropriate countermeasures are required.

During system operational qualification all parameters should fall within the design condition

range. However, during normal operating procedures it is acceptable for the conditions to go

out of the design condition range, but should remain within the operating range.

For example, a moisture-sensitive product could require a room design condition of 35%RH

5%RH, but the normal operating range could be 35%RH 10%RH. The operating range may

be set at 35%RH 15%RH and if the room condition goes above 50%RH (35% + 15%) orbelow 20%RH (35% - 15%), then the action limits have been exceeded.


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Action limit deviations should form part of the batch records as they represent a deviation from

the validated parameters.

The relationship between temperature and humidity should be specified when setting limits for

room temperatures and humidities.

A very tight humidity tolerance, but a wide temperature tolerance, should not be acceptable, as

variances between the maximum and minimum temperature condition will give an automatic

deviation of the humidity condition.

Design condition and normal operating ranges should be set as wide as possible to set

realistically achievable parameters.

8.5 Parameters to qualify

For a pharmaceutical facility some of the typical HVAC system parameters that should be

qualified include:

room temperature (if there is an impact on product quality)

room humidity (if there is an impact on product quality)

supply air quantities for all diffusers

return air or exhaust air quantities

room air change rates

room pressures

room air flow patterns

laminar flow velocities

containment system velocities HEPA filter penetration tests

room particle counts

room clean-up rates

microbiological air and surface counts

Return air and exhaust air quantities are sometimes in conflict with room pressures. At the design

stage it is not always possible to determine exact leakage from building components as this is often

outside of the control of the designer. For example, the leakage through doors is dependent upon the

fit of the doors.

Room return or exhaust air is a variable which is used to set up the room pressure. As room pressure

is a more important criteria than the return air, the latter should have a very wide Normal

Operating Range.

The maximum time interval of the 24 months between tests, as given in the table of ISO 14644

Optional Strategic Tests, should be considered in conjunction with the type of facility under test

and the product Level of Protection. Retesting should also be done when any change takes place,

which could affect system performance.

Requalification of these parameters should be done at regular intervals, e.g. at least annually.

The tables below, giving the recommended time periods for retesting or requalification, are takenfrom the ISO 14644 standard and are given for reference purposes only. The actual test periods may

be more frequent or less frequent, depending on the product and process.


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STRATEGIC TESTS (ISO 14644)

Schedule of Tests to Demonstrate Continuing Compliance

Test Parameter Cleanroom

Class

Max Time

Interval

Test Procedure

Particle Count Test

(Verification of Cleanliness)All classes 6 Months Dust particle counts to be carried

out & result printouts produced.No. of readings and positions oftests to be in accordance withISO 14644-1 Annex B

Air Pressure Difference

(To verify non cross-contamination)

All classes 12 Months Log of pressure differentialreadings to be produced orcritical plants should be loggeddaily, preferably continuously.A 15 Pa pressure differential

between different zones is

recommended.In accordance with ISO 14644-3Annex B5*

Airflow Volume

(To verify air change rates)All Classes 12 Months Air flow readings for supply air

and return air grilles to bemeasured and air change rates tobe calculated. In accordancewith ISO 14644-3 Annex B13*

Airflow Velocity

(To verify unidirectional flowor containment conditions)

All Classes 12 Months Air velocities for containmentsystems and unidirectional flowprotection systems to bemeasured.

In accordance with ISO 14644-3Annex B4*

Fig. 8.3


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RECOMMENDED OPTIONAL STRATEGIC TESTS (ISO 14644)

Schedule of Tests to Demonstrate Continuing Compliance

Test Parameter Cleanroom

Class

Max Time

Interval

Test Procedure

Filter leakage Tests

(To verify filter integrity)All Classes 24 Months Filter penetration tests to be carried

out by competent person todemonstrate filter media and filterseal integrity. Only required onHEPA filters.In accordance with

ISO 14644-3 Annex B6*

Containment leakage

(To verify non cross-contamination)

All Classes 24 Months Demonstrate that contaminant ismaintained within a room by meansof:

airflow direction smoketests

Room air pressures.In accordance with ISO 14644-3Annex B4*

Recovery

(To verify clean up time)All Classes 24 Months Test to establish time that a clean

room takes to recover from acontaminate

who guidelines on gmp hvac (rev1)

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