HVAC__.pdf

HVAC

• H-V-A-C• H-VAK• Pharmaceutical plant air quality

Management• Air Conditioning

www.pharmatechbd.blogspot.com

http://www.pharmatechbd.blogspot.com

HVAC

• H = Heating• V = Ventilation• A = Air• C = Conditioning



HVACWhat is HVAC?

Controlling components and parameters of air

Why?As it has great effects on product quality

How?

By using AHU



HVAC

DefinitionThe simultaneous control of various components and parameters of air to the specific limit as required for the manufacturing of quality medicine is known as air conditioning.



Component Quantity Harmful Effects Examples

Nitrogen 78.02%

Oxygen 20.71% Oxidation Fe++ Fe+++

Carbon dioxide 0.03% Carboxylation

Argon 0.001%

Component of Air

• Gases




Dust Particles 0.01% Contamination All products

Drug Particle Cross Contamination All products

Microorganism Microbial contamination, Endotoxin contamination

Antacid &Sterile

Preparation

Component of Air

• Solid



Component Quantity Harmful Effects

Examples

Moisture 0-1.5% Hydrolysis, Dissolution, Microbial growth

Aspirin, Ranitidine

Component of Air

• Liquid




Temperature 30-400

CDrug

Degradation, Microbial growth.

Thermo labile Drugs. Vitamins, Antibiotics.

Light Photo degradation

Nimesulide

Pressure Contamination All productsFlow Contamination All productsMovement Contamination All products

Parameters of Air



Zone Grade

Process Particles Limit

Air change/hr

Filter

A Aseptic filling in final container

Class 100 ≥40 HEPA

B Background of Zone A

Class 100 ≥ 20 HEPA

C Sterile solution preparation

Class 10,000 ≥ 20 HEPA

D Dispensing of starting materials for products terminally sterilized.

Class 100,000 ≥ 20 HEPA

E Production and packing of non sterile products.

Class 100,000 ≥ 6 ≥ EU 12

F Secondary packaging

Optically Clean

≥ 4 ≥ EU 9

G Warehousing, QC Labs, General Area.

General Area Depends on heat load

≥ EU 6



Zone Grade

Process Particles Limit(> 0.5 micron /M3

Air change/hr

Filter








Class 100,000 ≥ 20 HEPA


Class 100,000 ≥ 6


Optically Clean

≥ 4





Area Temperature(0c)

Humidity( % RH)

Particles( per M3)

Air Change

Aseptic filling 15-25 30-45 100 >40

Weighing, Processing ( Aseptic)& Filtration of Sterile product

15-25 45-55 10,000 20-40

Weighing, Processing of Sterile product with terminally sterilization.

15-25 45-55 100,000 20-40

Ophthalmic ointment 20-28 30-40 10,000 5-20

Weighing, processing and packing of non-sterile product.

20-28 45-75 100,000 5-20

a. Capsule 20-25 40-50 100,000 5-20

b. Hygroscopic Tablet 20-25 40-50 100,000 5-20

c. Dry Syrup 20-25 40-50 100,000 5-20

d. Liquid 20-28 45-75 100,000 5-20

Secondary Packing 20-28 45-75 Clean 5-20

Warehouse

a. Cool store 0-8 45-75 Clean 5-20

b. Controlled store 20-25 45-75 Clean 5-20

c. Normal store 30-35 45-75 Clean 5-20www.pharmatechbd.blogspot.com


HVAC

• Product quality depends on air quality• Products can only be as pure as the

environments in which they are produced.



Product Quality

• Efficacy• Product Stability• Patient’s safety• Product Purity• Patient’s Acceptability• Regulatory Compliance



Harmful Effects of Air

• Purity : Product will not be pure due to contaminants

• Stability : Product will be physically and chemically unstable

• Efficacy : Less effective due to decomposition• Safety : May not be safe for patient • Shelf life: Less Shelf life due to decomposition• Acceptability : May be unacceptable to patients



Factors that contribute to quality products:

i. Starting materials and packaging materialsii. Validated processesiii. Personneliv. Proceduresv. Equipmentvi. Design and quality of premises

vii. Manufacturing environment


Presenter

Presentation Notes

A lot of factors contribute to a quality medicine, each of them important and interacting with the others. Most of these factors are described in other training modules, the purpose of this module being to focus on the production environment. The production environment, though less visible, has a predominant role in the quality of the products, but is often ignored. It interacts mostly with premises, sanitation and hygiene. It is necessary to know how the systems controlling the environment operate, and how they are set up, and to verify whether or not they will contribute to the product quality.�


Factors contributing to quality products

Starting materials

Personnel

ProceduresValidated processes

Equipment

Premises

Environment

Packing materials


Presenter

Presentation Notes

All factors contributing to a quality medicine must be seen as interactive.�It is not possible to neglect any of them, as they mutually influence each other.


Environmental factors have a direct influence on a product:

Some environmental factors have a direct influence on a product:

1. Light, for light sensitive products (photo-degradation)2. Temperature, for temperature sensitive products (many

injectables, vaccines)3. Humidity, often for capsules and always for effervescent

tablets4. Air movement, affecting contamination and cross-

contamination5. Microbial contamination can lead to the destruction of

the product and to grave accidents in the case of injectables or sterile products.

6. Particulate contamination is critical in injectable forms



Environmental factors have a direct influence on a product:

• These factors, if not properly controlled, can lead to:

• - product degradation (Physical-Chemical change)

• - product contamination• - sensitization or allergic reactions.• - loss of product and profit• Cross contamination In the case of highly potent

drugs, can lead to grave accidents.www.pharmatechbd.blogspot.com


Harmful effects of temperature

• Thermal degradation of Drugs:

• Microbial Growth




Thermal degradation of Drugs: Chemical Change: Thermo labile drugs

are decomposed if they are stored in higher temperature.

Physical Change: Temperature may change the color, odor and taste of drugs




Thermal degradation of Drugs:

Safety: The degradation may produce toxic product

Efficacy: Drug will be less effective due to thermal degradation

Stability: Both physical and chemical stability of some drugs are affected by temperature

Shelf life: Thermal Degradation will decrease the shelf life of drugs and dosage form




Microbial load: Microbial growth is accelerated by the optimum temperature. 370c temperature promotes the bacterial growth. Microbial load of some drugs, excipients or dosage form will increase if they are stored to 370c.



Dust Particle Control• Harmful effects of dust particle:

– Cross contamination: – Microbial contamination: – Particulate contamination: – Sensitization or allergic reaction:– Product loss

1. Microbial contamination can lead to the destruction of the product and to grave accidents in the case of injectables or sterile products.

2. Particulate contamination is critical in injectable forms









Harmful Effects of Moisture

• Hydrolysis of drugs: Hydrolysis is considered as the major cause of drug decomposition. It may be defined as the reaction of drugs with water. A prime example of this phenomenon is the decomposition of aspirin into salicylic acid and acetic acid.Aspirin ------ Salicylic Acid + Acetic AcidMany drugs are susceptible to hydrolysis and degraded by moisture present in the air.




• Oxidation of drugs: Moisture can increase the rate of oxidation of some drugs. Ferrous Sulphate crystals are more rapidly oxidized in moist air.Fe++ ---- Fe+++




• Physical changes due to chemical decomposition:

• Color Change• Odor Change• Taste Change• Production of Toxic Chemicals




• Physical Stability• Drug dissolution: Moisture is rapidly

absorbed on the surface of hygroscopic drugs causing solution of the drug in that moisture. Ranitidine, Ascorbic Acid, Cloxacillin, Flucloxacillin are very hygroscopic drugs that absorb moisture from air and dissolved in it.




Physical Stability:• Agglomeration of powder: Fine powder may

form lump due to the absorption of moisture from air.

• Moisture regain: Materials may regain moisture from air after drying if it is exposed to humid air.

• Cake Formation: Fine powder may form cake due to the absorption of moisture from air.




• Microbial Growth: Microbial growth is accelerated by the presence of moisture. Above 60% RH promotes the bacterial growth. Microbial load of some drugs, excipients or dosage form will increase if they are exposed to humid air.



What are contaminants ?Contaminants are1. Products or substances other

than product manufactured 2. Foreign products3. Particulate matter4. Micro-organisms5. Endotoxins (degraded micro-

organisms)


Presenter

Presentation Notes

What are contaminants? Contaminants can originate from: Environment (particles, micro-organisms, dust containing other products). Equipment (residues of other products, oil, particles, rust, gaskets, metal) and can be brought into the product by air movements. Contaminants are in fact the presence of anything in the manufactured product which should not be there. Contaminants can be: Products or substances other than the product manufactured (e.g. products resulting from air pollution). Foreign products, such as metal parts from equipment, paint chips,etc. Particulate matter, especially dangerous in injectables. Micro-organisms – a particular problem for sterile products. Endotoxins: Even if killed by thermal treatment, micro-organisms are degraded to endotoxins and can cause damage.


Contaminants• Contaminants can be:

1. Products or substances other than the product manufactured (e.g. products resulting from air pollution).

2. Foreign products, such as metal parts from equipment, paint chips,etc.

3. Particulate matter, especially dangerous in injectables.4. Micro-organisms – a particular problem for sterile

products.5. Endotoxins: Even if killed by thermal treatment, micro-

organisms are degraded to endotoxins and can cause damage.



Contaminants

• Contaminants are in fact the presence of anything in the manufactured product which should not be there.

Cross-contamination is a particular case of contamination



Sources of contaminants

• Contaminants can originate from:

Environment • particles, • micro-organisms, • dust containing other products.



Sources of contaminantsEquipment • residues of other products,• oil, • particles, • rust, • gaskets, • Metal• leaching of plastic components, metal parts (broken

sieves in granulators), brittle gaskets, oil, chips of paint, etc.




Contamination can be brought by operators

objects falling into the product, skin particles, dandruff, fibres from uniforms.




Contamination can be brought by premises

Particle shading Paint chipsConstruction material



Cross-Contamination (1)

What is Cross-Contamination ?

Definition of Cross-Contamination:Contamination of a starting material, intermediate product, or finished product with another starting material or product during production. (WHO) Annex 1, Glossary


Presenter

Presentation Notes

Definition of Cross-Contamination: According to WHO, cross-contamination is “Contamination of a starting material, intermediate product, or finished product with another starting material or product during production”. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second Report. Geneva, World Health Organization, 1992 (WHO Technical Report Series, No. 823). Annex 1: Good manufacturing practices for pharmaceutical products. In other words, cross-contamination is the presence in a particular product of small, traceable quantities of other pharmaceutical products manufactured at the same time in the same premises previously on the same equipment or in the same premises Cross-Contamination is thus only concerned with the presence of traces of products manufactured in-house ! Adequate analytical detection is important to detect traces of contamination. �Validated analytical methods, especially developed for detection purposes, may be necessary to detect cross-contamination. An absence of cross-contamination being detected may just mean the absence of adequate analytical procedures.


Contamination

Contaminant from

EnvironmentOperators

Contaminant from

Equipment

CrossContamination

Productfrom

EnvironmentOperators

Productfrom

Equipment

Cross-Contamination ( 3 )


Presenter

Presentation Notes

Contamination can be air-borne: particles, micro-organisms.� Contamination can also come from equipment: leaching of plastic components, metal parts (broken sieves in granulators), brittle gaskets, oil, chips of paint, etc.� Contamination can be brought by operators (objects falling into the product, skin particles, dandruff, fibres from uniforms).� Likewise, cross-contamination can be either airborne or physically transferred: by bringing traces of a product through ventilation systems by transfer of contaminants from one room to another due to poor pressure cascade through clothing into another product through badly cleaned equipment retaining traces of a product and contaminating another product.


Cross Contamination• Definition of Cross-Contamination:• According to WHO, cross-contamination is “Contamination of a

starting material, intermediate product, or finished product with another starting material or product during production”. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second Report. Geneva, World Health Organization, 1992 (WHO Technical Report Series, No. 823). Annex 1: Good manufacturing practices for pharmaceutical products.

• In other words, cross-contamination is the presence in a particular product of small, traceable quantities of other pharmaceutical products manufactured

• at the same time in the same premises• previously on the same equipment or in the same premises



Cross Contamination• Cross-Contamination is thus only concerned with the

presence of traces of products manufactured in-house !

• Adequate analytical detection is important to detect traces of contamination.

• Validated analytical methods, especially developed for detection purposes, may be necessary to detect cross-contamination.

• An absence of cross-contamination being detected may just mean the absence of adequate analytical procedures.



Cross-Contamination (2)From where does Cross-Contamination

originate?1. Poorly designed air handling systems

and dust extraction systems2. Poorly operated and maintained air

handling systems and dust extraction systems

3. Inadequate procedures for personnel and equipment

4. Insufficiently cleaned equipmentwww.pharmatechbd.blogspot.com

Presenter

Presentation Notes

Cross-contamination is a sure indication of bad practices, as it shows that there is insufficient control over: Design of premises and systems quality Air handling and dust extraction systems Operation and maintenance of air handling and dust extraction systems Procedures for cleaning of equipment and for restriction of movement of personnel Procedures for cleaning of premises �


insufficient control over

1.Design of premises and systems quality 2.Air handling and dust extraction systems3.Operation and maintenance of air handling

and dust extraction systems4.Procedures for cleaning of equipment and

for restriction of movement of personnel5.Procedures for cleaning of premises



Sources of cross-contamination

• cross-contamination can be either airborne or physically transferred:

• by bringing traces of a product through ventilation systems

• by transfer of contaminants• from one room to another due to poor pressure

cascade• through clothing into another product• through badly cleaned equipment retaining traces of a

product and contaminating another product.



Cross-Contamination (4)Cross-contamination can be minimized

by:1. Personnel procedures2. Adequate premises3. Use of closed production systems4. Adequate, validated cleaning

procedures5. Appropriate levels of protection of

product6. Correct air pressure cascade


Presenter

Presentation Notes

There are different ways to prevent or reduce the effect of cross-contamination. Personnel procedures: Clean clothing, and for clean rooms (C, B, A) non-linting clothing, to be washed in special laundries; Personal hygiene on entering a pharmaceutical area. Adequate premises: Minimisation of possibility of accumulation of dust;Premises with good ventilation and dedusting system. Closed production systems: Closed systems, in which product is transferred from one piece of equipment to another one, without being exposed to the atmosphere. Validated cleaning procedures: Manual cleaning procedures may not be reproducible. Level of Protection concept 2: A good hygiene, or Level of Protection concept, specifying requirements for environmental conditions; entry procedures for personnel and material is fundamental for keeping cross-contamination under control. Maintaining the correct air pressure differential between rooms helps prevent cross-contamination. The module on HVAC deals precisely with the last of these ways, namely a good air handling system.


• There are different ways to prevent or reduce the effect of cross-contamination.

• Personnel procedures: Clean clothing, and for clean rooms (C, B, A) to be washed in special laundries; Personal hygiene on entering a pharmaceutical area.

• Adequate premises: Minimisation of possibility of accumulation of dust; Premises with good ventilation and dedusting system.

•



• Closed production systems: Closed systems, in which product is transferred from one piece of equipment to another one, without being exposed to the atmosphere.

• Validated cleaning procedures: Manual cleaning procedures may not be

reproducible.

•www.pharmatechbd.blogspot.com


• Level of Protection concept 2: A good hygiene, or Level of Protection concept, specifying requirements for environmental conditions; entry procedures for

personnel and material is fundamental for keeping cross-contamination under control.

• Maintaining the correct air pressure differential between rooms helps prevent cross-contamination.

• The module on HVAC deals precisely with the last of these ways, namely a good air handling system.



Level of Protection Concept

1. Defines environmental requirements

2. Helps prevent contamination and cross-contamination

3. Allows production under optimal hygiene conditions

4. Takes into account• product sensitivity to contamination• therapeutic risk


Presenter

Presentation Notes

In order to control the environment, the concept of Levels of Protection has been created. Some organizations, such as the International Society of Pharmaceutical Engineers (ISPE), refer to Levels of Protection; others refer to Cleanroom Class or Hygiene Class. This concept defines classes, in which minimum requirements for ventilation, particle numbers, microbial contamination are set for different manufacturing procedures. Other requirements for personnel, materials, etc. are defined as well. By having clearly defined conditions, the following goals can be achieved: Prevention of contamination and cross-contamination Production under optimal hygiene conditions, whereby the following factors are considered: - product sensitivity to contamination - therapeutic risk This is explained in the following slide.


Therapeutic risks

Manufacturing Environm

ent requirem

ents

Cleanroom

Class A / B

Cleanroom

Class C

Cleanrm

. Class D

Others


Presenter

Presentation Notes

The illustation shows that the manufacturing environmental requirements, as defined in the definition of the cleanroom zones, increase with the therapeutic risk. The Level of Protection classes are classified as a function of the product sensitivity to contamination (e.g. aseptically filled products are handled in a higher class than terminally sterilised products) and to the therapeutic risk (stricter environment for injectables, as injectables enter directly into the bloodstream without the additional protection given by the stomach and intestinal barriers ). In order to obtain a constant and well-defined quality level, it is necessary to have well-defined requirements for the cleanroom zones. Level of Protection classes are referred to as Class A, B, C, etc. in the EC countries, whereas other countries may refer to Class 100, 1000, etc or ISO Class 5, 6, 7, etc. These different classes will be discussed later in this module.


Levels of ProtectionParameters to be defined:1.Air cleanliness requirements (filters

type and position, air changes, air flow patterns, pressure differentials, contamination levels by particulate matter and micro-organisms)

2.Personnel and material transfer methods

3.Permitted operations4.Building design and finishes

Annex 1, 17.3, 17.4


Presenter

Presentation Notes

The level of protection classes are characterised by a whole set of background specifications and measures, which are explained in the regulatory guidelines.�These specifications and measures are of a general nature and must be adapted to each particular case. The following parameters must be defined for each Cleanroom class: Air cleanliness requirements (particles, micro-organisms) - Type and position of air filters - Air flow pattern (uni-directional or turbulent) - Number of air changes - Pressure differentials to other rooms - Allowed number of micro-organisms on surfaces Personnel and material transfer methods (gowning, sterilisation, etc.) Permitted operations for production and cleaning (eg. aseptic filling only in class A) Special building requirements – layout & building finishes


Levels of ProtectionTypes of Cleanroom Classes• International WHO A, B, C, D

• National EC, PIC/S, TGA, etc. : A, B, C, D US FDA : critical and controlled ISPE: level 1, 2 or 3 or

cleanroom class Companies : various others

Annex 1, 17.3, 17.4www.pharmatechbd.blogspot.com

Presenter

Presentation Notes

In order to have standardized requirements, regulatory bodies all over the world have defined some Cleanroom classes. The definition of various Cleanroom classes is mainly restricted to sterile manufacturing operations. WHO(*), EC and PIC/S and others mention classes A, B, C and D. The requirements for these classes differ slightly between WHO and EC. US FDA defines only 2 classes: critical and controlled. The ISPE refers to Level 1, 2 or 3 for non-sterile facilities and they refer to the cleanroom class for sterile facilities, ie. class 100, 1000 or ISO 5, 6 etc. There are no cleanroom classes defined by WHO or other regulatory bodies for the production of solids, liquids, creams, etc. It is nevertheless necessary to have one’s own cleanroom class descriptions for these production functions. The manufacturers must, therefore, create their own Level of Protection class definitions and their definitions must be such that the required product purity, as described in the pharmacopeias or in the registration documents, can be achieved at all times. (*) WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-Sixth Report. Geneva, World Health Organization, 2002 (WHO Technical Report Series, No. 902). Annex 6: Good manufacturing practices for sterile pharmaceutical products.


• Therapeutic Goods Administration (TGA). TGA is Australia's regulatory agency for medical drugs and devices.

• Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (jointly referred to as PIC/S)



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

DCBA

Annex 1, 17.3, 17.4, 17.5

Cleanroom Class


Presenter

Presentation Notes

This slide describes a process for sterile products. Please note that this is an example only and protection requirements could be higher depending on the process and equipment used. For other pharmaceutical forms, similar tables have to be generated.


Levels of ProtectionBased on the cleanroom class requirements, various Levels of Protection have to be created, including:• Correlation between process operations and cleanroom classes • Type of operation permitted in each Level of Protection


Presenter

Presentation Notes

The manufacturers should have a Level of Protection Concept for their factories, stating: Correlation between process operations and Cleanroom classes, as shown in the table of the previous slide. Type of operation permitted in each hygiene class. Definition of Levels of Protection classes (parameters, building materials, room requirements, HVAC systems). Requirements for personnel and material in the different classes (clothing, training, type of materials allowed in the respective classes, etc.). Requirements on entry conditions for personnel and material (change procedures, when to change clothing, etc.). The Levels of Protection concept can be part of the Site Master File.


• Definition of cleanroom class (parameters, building materials, room requirements, HVAC systems)

• Requirements for personnel and material in the different classes

(clothing, training, type of materials, etc.)

• Requirements on entry conditions for personnel and material

( change procedures )www.pharmatechbd.blogspot.com


Annex 1, 17.4

Air Handling System

Production RoomWith

DefinedRequirements

SupplyAir

OutletAir


Presenter

Presentation Notes

Basically, an air handling system brings in air of a defined quality, in order to achieve an atmosphere of well-defined temperature, humidity and a defined limit of contamination, and evacuates the air after its passage through the concerned areas. Several parameters can be defined for cleanroom classes, which were mentioned in correlation with previous slides. Factors such as temperature and humidity must be also taken into account where necessary. It is imperative to define these parameters specifically for each cleanroom class and to remember that, within that given class, all defined parameters must be met. For each cleanroom class, these parameters are mainly controlled by the air handling system.


Parameters influencing Levels of Protection (2)

1 Number of particles in the air2 Number of micro-organisms in the

air or on surfaces3 Number of air changes for each

room4 Air velocity5 Air flow pattern6 Filters ( type, position )7 Air pressure differentials between

rooms8 Temperature, humidity


Presenter

Presentation Notes

The acceptable number of particles and the acceptable number of micro-organisms in the air is specified in the WHO guidelines, for the production of sterile products. It is also important to monitor surfaces for micro-organisms. The number of air changes are also described in the guidelines, but it should be noted that the WHO figures may differ from those of other guidelines such as EC and PIC/S. The air velocity is specified in the case of laminar flow installations (air flow pattern), should be in any case sufficient to achieve a proper flushing of the rooms and a short recovery (clean-up) time. Here too, there are differences between the WHO and other guidelines. The air flow patterns also influence the achievement of the hygiene class. Pressure differentials between rooms should be specified and monitored. In some cases, temperature and humidity can be critical for the product (e.g. effervescent tablets, hard gelatine capsules). In sterile areas, where people are heavily gowned, it is important to keep the temperature reasonably low, as people tend to perspire under a gown. Too low a humidity can bring static problems, with dust remaining “attached” to metal surfaces.


Cleanroom Classdefined by

Critical Parameters

Air HandlingSystem

Additional Measures

Parameters influencing Levels of Protection (3)


Presenter

Presentation Notes

Whereas the air handling systems are the most important factor in creating the required environmental conditions for the Cleanroom classes, they alone cannot guarantee that the specifications corresponding to these classes will be met! Additional measures are therefore very important. We are going to discuss some of these measures.


Air handling systems:

• Are the main tool for reaching required parameters

• But are not 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

Annex 1, 17.10 to 17.16www.pharmatechbd.blogspot.com

Presenter

Presentation Notes

Here are some examples of additional measures: Proper gowning, which must be adequately cleaned (lint-free clothing for clean-rooms C, B and A with special laundry and packaging under clean conditions). Good lockers for personnel, with separation between street and work clothing, and with adequate washing and disinfection facilities. Proper sanitation and hygiene practices (dust elimination, wet mopping, dedicated mops for different areas, rotating of disinfectants, etc.). Transfer procedures for material (decontamination measures, separate air locks for entering and outgoing goods, etc.). Proper premises.


Zone Grade

Process Particles Limit(> 0.5 micron /M3

Air change/hr

Filter








Class 100,000 ≥ 20 HEPA


Class 100,000 ≥ 6


Optically Clean

≥ 4





•“AHU must be located outside the space they are controlling!”

Air Handling System

Production RoomWith

DefinedRequirements

SupplyAir

OutletAir


Presenter

Presentation Notes

You will recognize this picture from a previous slide, but we repeat it in order to emphasize the following: An air handling system introduces pre-treated air, in order to provide a manufacturing environment with specified cleanliness, temperature and humidity in order to prevent product contamination and degradation. Air is then exhausted from the manufacturing environment.


+

Production Room

Exhaust air treatment

Central air handling unit

Terminal air treatmentat production room level

Fresh air treatment(make-up air)

Main subsystems


Presenter

Presentation Notes

To understand the air handling systems, it is necessary to know what their components are. A conventional Air Handling System has 4 sub-systems: 1. Air handling of the incoming (fresh) air: elimination of coarse contaminants and protection from frost if necessary. In the case of air re-circulation, the fresh air is also called make-up air. 2. Central air handling unit (AHU), where the air will be conditioned (heated, cooled, humidified or de-humidified and filtered), and where fresh air and re-circulated air, if any, (indicated here by the dotted line) will be mixed. 3. Air handling in the rooms under consideration (pressure differential system, additional filtration, air distribution). 4. Air exhaust system (filtration).


4 sub-systems

• A conventional Air Handling System has 4 sub-systems:

1. Air handling of the incoming (fresh) air: elimination of coarse contaminants and protection from frost if necessary. In the case of air re-circulation, the fresh air is also called make-up air.

2. Central air handling unit (AHU), where the air will be conditioned (heated, cooled, humidified or de-humidified and filtered), and where fresh air and re-circulated air, if any, (indicated here by the dotted line) will be mixed.

3. Air handling in the rooms under consideration (pressure differential system, additional filtration, air distribution).

4. Air exhaust system (filtration).



FilterSilencer

Terminal filter

Weather louvre Control damper

FanFlow rate controller

Humidifier

Heating coil

Cooling coilwith

droplet separator

Production Room

Overview components

+

Prefilter

Exhaust Air Grille

Heater

Secondary Filter

Re-circulated air


Presenter

Presentation Notes

Another way to look at an air handling system is to consider the different components and to know their function. Some of the components, particularly the filters, are essential to ensure the quality of the air. We will later consider individual components in detail. Of course, a well-designed air handling system must not only be properly designed, but also properly installed, qualified and maintained (sealed ducts, tight filters). (The trainer should make the audience aware that this slide is just an example, and that all components may not necessarily be present in each system.)


• Weather louvre

• Silencer

• Flow rate controller

• Control damper

• To prevent insects, leaves, dirt and rain from entering

• To reduce noise caused by air circulation

• Automated adjustment of volume of air (night and day, pressure control)

• Fixed adjustment of volume of air

Components


Presenter

Presentation Notes

A typical HVAC unit consists of a small number of elements only. It is important that these elements are compatible, properly installed, and fulfilling their goal. Whereas a weather louvre and silencer are less critical elements, the components associated with the flow rate control are essential, as they allow adjustment of the air volumes supplied to the rooms, which in turn forms the base for a pressure differential concept: to have an automated or a fixed system is largely a financial matter, but a fixed system is more difficult to set up. Silencer – check internal lining material of silencer as this can cause contamination.


• Heating unit

• Cooling unit /dehumidifier

• Humidifier

• Filters

• Ducts

• To heat the air to the proper temperature

• To cool the air to the required temperature or to remove moisture from the air

• To bring the air to the proper humidity, if too low

• To eliminate particles of pre-determined dimensions and/or micro-organisms

• To transport the air


Presenter

Presentation Notes

Heating and cooling units (batteries), as well as humidifiers are used to adjust the climate in the room (temperature and humidity).� Special de-humidifiers, on a dessiccant base, will be addressed later. Filters are one of the main components, as they determine the size of airborne particles that pass through them, and thus the hygiene class. It is wise to protect the finer filters by pre-filters, thus extending their life cycles, and making them less prone to clogging. Ducts transport the air from the air handling units to and from the rooms. Inspectors must verify that ducts do not have internal insulation as this is a great source of contamination.


• Flow rate controller

• Control damper

• Humidifier

• Cooling battery

• Filters

• Ducts

• Blocked

• Poorly adjusted, bad pressure differential system

• Bad water/steam quality/poor drainage

• No elimination of condensed water/poor drainage

• Incorrect retention rate/damaged/badly installed

• Inappropriate material/internal insulator• leaking

Problems with components


Presenter

Presentation Notes

Problems may arise with components, with the following consequences: Flow rate controllerBlockedNo control of pressure differentials Control damperPoorly adjustedBad pressure differential systems HumidifierBad water/Risks of microbial contamination steam quality Cooling UnitNo eliminationRisks of microbial contamination of condensed water FiltersIncorrect retention Risks of contamination rate(particles, micro-organisms) DamagedFilter integrity fails Badly installedRisks of contamination (particles, micro-organisms) DuctsInappropriate materialDanger of corrosion Leaking duct workIntake of unfiltered air Internal insulationInability to properly clean


+

Production Room

Exhaust air

Return air(re-circulated)

Fresh air(make-up air)

Supply air

Air types


Presenter

Presentation Notes

There are different air types to be considered within the air handling system: Fresh air (if the plant is of the re-circulation type, it is necessary to replace some of the re-circulating air with fresh air, which is then called make-up air). A proportion of about 15% fresh air is normal, but this proportion can vary, depending on factors such as number of people, National Regulatory Authority requirements, the presence of certain substances in the air, leakage due to pressure control, etc. Supply air to the rooms Exhaust air from the rooms Return air (about 85% is being re-circulated)


Function of AHU

• Heating• Cooling• Humidification• Dehumidification• Filtration



Measurement of Humidity

Air

Dry Air Moist Air

Saturated Air Unsaturated Air



Dry air Air which is free from water Moist air The mixture of dry air and waterSaturated air When air contains maximum amount of moistureUnsaturated air Air which is not saturatedAbsolute

humidityWeight of water per pound of dry air.Unit: grains/ lb. dry air

Relative humidity

Ratio of actual amount of water & maximum amount of water

Dew point Temperature at which condensation will just begin with the existing moisture.

Humidity Control

• Various Terms



Determination of Volume of Air

1. Length, height and width of tablet process room are 12 ft, 8 ft and 10 ft respectively. Determine the Volume of air of that room.

Ans.: Volume of air = Volume of Room= Length, x height x width= 12 x 8 x 10= 840 ft3.



Determination of weight of Air

2. Length, height and width of tablet process room are 12 ft, 8 ft and 10 ft respectively. Determine the weight of dry air of that room.

Ans.: Volume of air = Volume of Room= Length, x height x width= 12 x 8 x 10= 840 ft3.Weight of air = Volume x Density

= 840 ft3 x 0.0807 lb/ ft3.= 67.788 lb.



Air temperature ( 0F) Maximum amount of moisture(Grains/ lb. dry air.)

54 6260 7867 9981 16185 185

Determination of Maximum amount of moisture in Air

• Moisture content capacity of air depends on temperature. • Higher temperature air can contain more moisture.



Maximum amount of moisture in Air

3. Length, height and width of tablet process room are 12 ft, 8 ft and 10 ft respectively. Calculate the maximum amount of moisture at 600F. air of that room.

Ans.: Volume of air = Volume of Room= Length, x height x width= 12 x 8 x 10= 840 ft3. Weight of air = Volume x Density

= 840 ft3 x 0.0807 lb/ ft3.= 67.788 lb.

Maximum Amount of moisture= 67.788 lb x 78 Grains/ lb. dry air= 5287.464 grains= 0.755 lb



Determination of AH , % RH4. Capsule process room contains 67.788 lb. dry

air and 4000 grains moisture. Calculate the AH.Answer:AH (Absolute Humidity)= Wt. of moisture per lb. of dry air.= Wt of moisture / Wt of dry air= 4000/67.788= 59 grains/ lb. dry air



Determination of AH , % RH5. Liquid process room contains 100.5 lb. moist air

and 0.5 lb. moisture. Calculate the AH.Answer:AH (Absolute Humidity)= Wt. of moisture per lb. of dry air.= Wt of moisture / Wt of dry air= (0.5 x 7000 grains) / (100.5-0.5)= 3500 / 100= 35 grains/ lb. dry air



Determination of AH , % RH6. Capsule process room contains 100.5 lb. moist

air and 0.5 lb. moisture at 600F. Calculate the AH & %RH.

Answer:AH (Absolute Humidity)= Wt. of moisture per lb. of dry air.= Wt of moisture / Wt of dry air= (0.5 x 7000 grains) / (100.5-0.5)= 3500 / 100= 35 grains/ lb. dry air



%RH = (Actual amount of moisture / amount of moisture in saturation) x 100

• = 35/78*100• =44.87 %



Determination of AH , % RH3. % RH of a room is 80%. The air of the room

contains 0.25 lb. moisture. Calculate the amount of moisture at saturated condition.

Answer:%RH = (Actual amount of moisture / amount of

moisture in saturation) x 100Amount of moisture in saturation = (Actual amount

of moisture / RH) x 100= (0.25 / 80) x100= 0.3125 lb.



Instruments

• Hygrometer: It is an instrument containing dry bulb temperature and wet bulb thermometer.

• Dry bulb thermometer: Temperature recorded by a dry bulb thermometer

• Wet bulb thermometer: Temperature recorded by a wet bulb thermometer

• Observe the dry bulb temperature & wet bulb temperature. Determine the difference. Now various parameters can be determined by using either psychometric table or psychometric chart



Hygrometer



Psychometric Table

DefinitionA Psychometric table is a representation of various thermodynamic parameters of moist air.



Psychometric Table

Determination of Relative humidity:1. Observe the dry bulb temperature & wet

bulb temperature.2. Determine the difference. 3. Now cross point of dry bulb temperature

and depression of temperature in the Psychometric Table indicates the Relative Humidity



Dry Bulb Tem.

DEPRESSION OF WET BULB 0C

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0

21 95 91 86 82 78 73 69 65 61 57 53 49 45 42

22 95 91 87 82 78 74 70 66 62 58 54 50 47 43

23 96 91 87 83 79 75 71 67 63 59 55 52 48 45

24 96 91 87 83 79 75 71 68 64 60 57 53 49 46

25 96 92 88 84 80 76 72 68 65 61 58 54 51 47

26 96 92 88 84 80 76 73 69 66 62 59 55 52 49

27 96 92 88 84 81 77 73 70 66 63 59 56 53 50

28 96 92 88 85 81 77 74 70 67 64 60 57 54 51

29 96 92 89 85 81 78 74 71 68 64 61 58 55 52

30 96 93 89 85 82 78 75 72 68 65 62 59 56 53

32 96 93 89 86 82 79 76 73 70 67 64 61 58 55

34 96 93 89 86 83 80 77 74 71 68 65 62 59 56

36 96 93 90 87 84 81 78 75 72 69 66 63 61 58



Psychometric chart

• Definition• A Psychometric chart is a graphical

representation of various thermodynamic parameters of moist air.



Dry bulb temperature lines

These are the straight and vertical lines drawn parallel to the ordinate.

Wet bulb temperature lines

These are the straight but inclined lines which extend diagonally as shown on the chart

Absolute humidity lines

These are the straight and Horizontal lines drawn parallel to the abscissa.

Relative humidity lines These are the curved lines. The saturation lines show 100% Relative humidity

Psychometric chart

• Various Lines





AH & RH from psychometric chart

• Determine the dry bulb temperature and wet bulb temperature from the hygrometer. Then determine the cross point in the Psychometric chart.

• Now absolute humidity line passing though the cross point indicates the Absolute Humidity.

• Relative humidity line passing though the cross point indicates the Relative Humidity.

• Dew point can be find out from the cross point of Absolute Humidity line and saturation humidity line.



Area Humidity(% RH)

Aseptic filling 30-45Weighing, Processing (Aseptic)& Filtration of Sterile product 45-55Weighing, Processing of Sterile product with terminally sterilization. 45-55Ophthalmic ointment 30-40Weighing, processing and packing of non-sterile product. 45-75a. Capsule 40-50b. Hygroscopic Tablet 40-50c. Dry Syrup 40-50d. Liquid 45-75Secondary Packing 45-75a. Cool store 45-75b. Controlled store 45-75c. Normal store 45-75

REQUIREMENT



Dehumidifier

Dehumidifier

Desiccant Refrigeration



Desiccant type Dehumidifier:

• Desiccant type Dehumidifier:• Desiccants are used in a desiccant type dehumidifier.

Desiccant can adsorb moisture from air. As a result the quantity of moisture in air will decrease. By passing the air through the desiccant again and again, we will get moisture free air. Desiccant type dehumidifier acts on this principle.

• When the unit is started, the fan begins to pass moisture-laden air through the desiccant, which adsorbs moisture from the air making the air moisture free. Desiccant becomes inactive due to adsorption of moisture. Desiccant can be again reactivated by passing hot air through it.



De-humidification

Filter Pressure Gauges

AHU with fan Variable Speed

Controller

air

Air heater

Regeneration

Humid room air

Adsorber wheelDry air


Presenter

Presentation Notes

Dampers to control pressure differentials are important. They can be automated or fixed. As filters get dirty the system pressure losses increase, and if airflow is not regulated, the flow decreases and pressure differentials change. This could cause flow reversal and cross-contamination. Variable speed drives for fan motors are also commonly used to control airflow. In some cases, it is necessary to have very dry air for galenical reasons in certain rooms (production of effervescent tablets and humidity sensitive products in general). To generate dry air, the air supplied to the production is passed over an adsorbant (silicagel, lithium chloride, etc.) where the humidity is removed from the air.� The adsorbant is then re-generated, on a continuous or on a batch-wise base.


Refrigeration type Dehumidifier

• Components: • Refrigerants: Substances that are circulated in a closed

refrigeration system to transfer heat. • Examples:

Trichloro Monofluro Methane Dichloro Difluro Methane Monochloro Trifluro Methane

• Compressor: Circulates refrigerants through a closed system.

• Condenser: It receives hot, high-pressure refrigerants from the compressor and converts it into liquid refrigerants.

• Evaporator: liquid refrigerant is vaporized at lower pressure in evaporator.



Evaporating Coil



Condensed Coil




• Principle:• The content ability of air is temperature

dependent. Hot air can contain more moisture than cool air. Refrigeration type dehumidifier can decrease the temperature of air. As a result air will be first saturated and then excess water will be separated from air. Refrigeration type dehumidifier acts on this principle.




• Principle:• Refrigerants are used in refrigerants type

dehumidifier. These refrigerants are evaporated in the evaporator. Heat is taken by the refrigerants as a latent heat for this conversion. As a result the evaporation coils become very cool. In contact with the evaporating coil, air also becomes very cool. As cool air can contain less moisture, the excess water will be separated from the air.




• When the unit is started, the fan begins to pull moisture-laden air across the evaporating coils making the cool and moisture free. Then the moisture free air is passed through the condenser where the air becomes hot due to the latent heat of condensation of refrigerants in the condenser.



Temperature Control

• Air Cooler• Air Heater



Air Cooler

• Components: • Refrigerants: Substances that are circulated in a closed

refrigeration system to transfer heat. • Examples:

Trichloro Monofluro Methane Dichloro Difluro Methane Monochloro Trifluro Methane

• Compressor: Circulates refrigerants through a closed system.

• Condenser: It receives hot, high-pressure refrigerants from the compressor and converts it into liquid refrigerants.

• Evaporator: liquid refrigerant is vaporized at lower pressure in evaporator.



RefrigerantsNumerical designation Chemical name Chemical

Formula

111213

Trichloro Monofluro MethaneDichloro Difluro MethaneMonochloro Trifluro Methane

CCl3FCCl2F2CClF3



Principle of Air Cooler• Refrigerants are used in air cooler. These

refrigerants are evaporated in the evaporator. Heat is taken by the refrigerants as a latent heat for this conversion. As a result the evaporation coils become very cool. In contact with the evaporating coil, air also becomes very cool. This cool air is distributed in the room.



Principle of Air Cooler• Condenser receives hot, high-

pressure refrigerants from the compressor and converts it into liquid refrigerants. Heat is released from the refrigerant at this conversion. Air from out site the room is passed across the condenser to transfer heat.



Principle of Air Cooler• When the unit is started, the fan begins to

pull hot air of the room across the evaporating coils making the cool and this cool air is distributed in the room. At the same time fan passes the out site air across the condenser and keep it cool by removing heat from the condenser.



Temperature Control



Hot Water Coil• Ideal for a wide variety of

basic, custom, and heavy-duty industrial applications, hot water coils are designed to meet a variety of heating applications. Applications include booster heat, reheat, waste heat reclamation, pre-heat, fluid process heat & more.



Chilled water coil

• For applications including comfort cooling, dehumidification, process cooling, and more.



Filter classesDust filters

Standard Aerosol

FineCoarse ULPAHEPA

10 µ m > Dp > 1 µ mDp > 10 µ m Dp < 1 µ m

F5 - F9G1 - G4 U 14- 17H 11 - 13

EN 1822 StandardEN 779 Standard


Presenter

Presentation Notes

The filtration efficacy depends on several mechanisms, and results in a rough filter classification. The diagram shows the commonly used classification, with current abbreviations G = Gross, F= Fine, H= High, U= Ultra. Filters are certified by the suppliers (challenge/efficiency test), but are often not properly installed or can be damaged. Leak tests (integrity tests), showing leakage of air through the filter itself or through its frame, therefore, have to be performed. Integrity tests are usually only carried out on the Aerosol filters (HEPA & ULPA). Integrity or penetration testing is performed to detect leaks from the filter media, filter frame and seal. The challenge is a poly-dispersed aerosol usually composed of particles ranging in size from one to three microns. The test is done in place and the filter face is scanned with a photometer probe; the measured downstream leakage is taken as a percentage of the upstream challenge. Integrity tests should be carried out with filters installed in the system and should be carried out by an independent body (not the filter supplier). The efficiency test, on the other hand, is used to determine the filter's rating. This test uses a mono-dispersed aerosol of 0.3 micron size particles, relates to filter media, and usually requires specialized equipment. Downstream readings represent an average over the entire filter surface. Therefore, leaks in a filter may not be detected by an efficiency test.


ULPA (Ultra Low Penetration Air) filter.

• a filter with a higher efficiency than a HEPA filter was offered. It had a DOP efficiency of 99.999% and the 12 in. (304.8 mm.) deep version had a clean pressure drop of 273.6 Pa when operating at a face velocity of 250 fpm (1.27 m/s). This filter has helped meet the requirement for cleaner air in facilities needed for the manufacture of microelectronics. It is identified by the generic name ULPA (Ultra Low Penetration Air) filter.









HEPA filters

• The first HEPA filters were developed in the 1940's by the USA Atomic Energy Commission to fulfill a top-secret need for an efficient, effective way to filter radioactive particulate contaminants. They were needed as part of the Manhattan Project, which was the development of the atomic bomb. The first HEPA air filters were very bulky compared to the HEPA air filters that are produced today.



Filter• The filtration efficacy depends on several mechanisms,

and results in a rough filter classification.

• The diagram shows the commonly used classification, with current abbreviations G = Gross, F= Fine, H= High, U= Ultra.

• Filters are certified by the suppliers (challenge/efficiency test), but are often not properly installed or can be damaged. Leak tests (integrity tests), showing leakage of air through the filter itself or through its frame, therefore, have to be performed. Integrity tests are usually only carried out on the Aerosol filters (HEPA & ULPA).



Filter• Integrity or penetration testing is performed to

detect leaks from the filter media, filter frame and seal. The challenge is a poly-dispersed aerosol usually composed of particles ranging in size from one to three microns. The test is done in place and the filter face is scanned with a photometer probe; the measured downstream leakage is taken as a percentage of the upstream challenge. Integrity tests should be carried out with filters installed in the system and should be carried out by an independent body (not the filter supplier).



Filter

• The efficiency test, on the other hand, is used to determine the filter's rating. This test uses a mono-dispersed aerosol of 0.3 micron size particles, relates to filter media, and usually requires specialized equipment. Downstream readings represent an average over the entire filter surface. Therefore, leaks in a filter may not be detected by an efficiency test.



Average EfficiencyIntegral Value

Peak ArrestanceLocal Value

Retention in%

Penetration Efficiency Penetration

F9 85 0.15

H11 95 0.05

H12 99.5 5x10-3 97.5 25x10-3

H13 99.95 5x10-4 99.75 25x10-4

U14 99.995 5x10-5 99.975 25x10-5

Classification of filters according to their efficiency


Presenter

Presentation Notes

This table gives an idea of the efficiency of the filters, calculated across the entire surface (integral value) or in particular spots (local value). Referring to filter ratings by percent efficiency is misleading, as there are so many different types of tests that give different efficiencies for the same filter. This can be very confusing and it is better to refer to the Committee of European Normalisation (EN) test rating i.e. G4, F8, H12, etc.


Primary panel filter

Secondary filter

HEPA or tertiaary filter


Presenter

Presentation Notes

This slide shows Primary Panel filters, which are used mainly for lower filtration efficiency or as pre-filters Secondary filters, consisting of mini-pleated media or filter bags, and is used for higher filtration efficiency. HEPA or tertiary filters, usually being the final filter in the system, providing the highest filtration efficiency. Though there is a strong relationship between filter efficiency and cleanroom class, a filter of a high efficiency does not guarantee a high cleanroom class, as many other elements play a role, such as Air flow (how the air is extracted, how well the room is “flushed”) Air speed and number of air changes Positions of air terminals Layout and presence of objects Personnel and clothing Equipment (not all machines are designed to operate in a clean environment!) Proper installation and proper maintenance


Humidifier SilencerHeating and

cooling units


Presenter

Presentation Notes

This slide shows additional elements of the air handling units. For humidification purposes, especially in clean areas, high purity water should be used, to avoid contamination. The silencer is not important from a GMP point of view, but from an environmental one, as ventilation units can be very noisy. Be sure that the silencers are manufactured of suitable materials as the linings of standard silencers can contaminate air with particulates. Depending on the local legislation, the installation of silencers can be mandatory. The cooling unit is important during the hot season. Be aware that stagnating water (condensed water) can bring bacterial growth, which can contaminate the filters, pass through them (depending on their retention properties) and end up contaminating production areas. It is essential that there is no stagnating water. Cooling coils can be sanitized as well. Do remember that, if filters are not properly maintained, micro-organisms may grow through the filters and be carried towards the production rooms.


Control damper for air flow

De-humidification

Filter Pressure Gauges

AHU with fan Variable Speed

Controller

Humid room air

Air heater

Regeneration air

Humid room airAdsorber wheel Dry

air

Air handling unitwww.pharmatechbd.blogspot.com

Presenter

Presentation Notes

Dampers to control pressure differentials are important. They can be automated or fixed. As filters get dirty the system pressure losses increase, and if airflow is not regulated, the flow decreases and pressure differentials change. This could cause flow reversal and cross-contamination. Variable speed drives for fan motors are also commonly used to control airflow. In some cases, it is necessary to have very dry air for galenical reasons in certain rooms (production of effervescent tablets and humidity sensitive products in general). To generate dry air, the air supplied to the production is passed over an adsorbant (silicagel, lithium chloride, etc.) where the humidity is removed from the air.� The adsorbant is then re-generated, on a continuous or on a batch-wise base.


Swirl Type air diffusors with

terminal filters1 Filter2 Tightening frame3 Register outlet4 Screw fixation for register

1

2

34


Presenter

Presentation Notes

The air flows into the rooms via so-called registers (diffusors), which are built and installed in such a way that the air is distributed evenly. Machinery or furniture can block the passage of air from the register to the exhaust point, creating unflushed zones, where counts of particles and micro-organisms could be higher. It is therefore important to consider the content of a clean room, when planning the HVAC system. In many cases, the terminal filter panel and diffusors are incorporated into one unit. It is also important that the air diffuser supplies air evenly and does not induce the circulation of dust in the room – as illustrated by the next slide.


Low induction swirl diffusor

(preferred)

High induction office type diffusor

(avoid)www.pharmatechbd.blogspot.com

Presenter

Presentation Notes

The diffuser on the left is a normal office type diffuser which induces a lot of air to rise vertically from the floor towards the ceiling. The rising induced air has the potential for carrying a lot of dust upwards which is then spread throughout the room with the air supply. This type of diffuser readily spreads contaminants in the room and should be avoided. The preferred type of diffuser for cleanroom applications is the swirl diffuser, or perforated plate diffuser. These types do not promote the spread of dust within the room.


Annex 1, 17.26

Regulation of room pressure – pressure differentials concept

Room pressure gauges

Room pressure indication panel


Presenter

Presentation Notes

One of the main points in the design of production rooms is the pressure differentials concept. Pressure differentials must be defined, monitored and alarmed in critical cases. The overpressure of each room is measured against a reference point in the factory (point zero). As discussed earlier, the pressure regulation can be fixed or automated. Pressure control can be by means of automatic air flow control dampers (as shown in slide 15) or by means of fan speed control. Whatever the means used it is important to ask the manufacturer how they ensure that the pressure cascade is maintained as the filters get dirty. In the following slides, we are going to see that an overpressure concept can be very different for sterile products and for solid products.


Pressure cascade injectablesProtection from micro-organisms and

particles

Annex 1, 17.24, 17.25


Presenter

Presentation Notes

This slide illustrates the pressure differential system in a sterile area where the overpressure is kept high in the rooms, mainly in the A/B class room, to prevent the entry of micro-organisms. (The level of overpressure is reflected by the absolute pressure in Pascals). To enter all rooms, it is necessary to go through airlocks. In this particular example, the pressure differential in sterile areas is set up at 15 Pa between zones of different cleanliness, in accordance with FDA, EC and PIC/S regulations. Other values may apply in other regions. It must be understood that high pressure differentials have an influence on the stability of building elements such as walls and doors.� Factory layouts must be carefully planned, in order not to have too high a pressure differential between entrance and exit of a sterilising or depyrogenating tunnel, as the air flow may significantly affect the temperature in a tunnel. Pressure differentials must be constantly monitored. The loss of overpressure in a filling room for injectables may mean the loss of the batches under production and the need for complete sanitation of the facility.� It is therefore essential that the systems are designed in such a way that there is no loss of overpressure in case of power loss (overpressure fan should be linked to emergency power grid).


Pressure cascade solidsProtection from cross-contamination


Presenter

Presentation Notes

This slide illustrates the pressure differential system in a solids area where the overpressure is kept high in the corridors, to prevent cross-contamination. In this case, we are not too worried by the microbial contamination, but rather by dust coming out of rooms where process work is being done, and thus contaminating other rooms. The entry into some rooms (containing dangerous products such as hormones, cytotoxics, low RH products or strongly coloured products) is protected by airlocks.


HeatingVentilation andAir Conditioning (HVAC)

Part 3: Design, qualification and maintenance

Air Handling Systems

Supplementary Training Modules on GMP

Module 3, Part 3: Qualification and maintenance Slide 130 of 27WHO -EDM


Presenter

Presentation Notes

In the first and second parts of this module, we have seen what the purpose of cleanroom classes are and how the air handling systems constitute the main factor in reaching the requirements of the cleanroom classes. We have also seen what the different elements of air handling systems are, as well as some risks associated with them. What we now want to study is how these elements are put together, how the systems are designed, and what must be done to ensure that they operate, and continue to operate, correctly. The suggested time for Part 3 is 60 - 90 minutes. At the conclusion of this part there is an optional group session (45 - 60 minutes) and a test paper (45 minutes). (Note for the Trainer: the times noted are very approximate.)


Characteristics of air handling systems

In the following slides, we will study alternatives in air handling systems

Turbulent or uni-directional airflows Filter position Air re-circulation vs fresh air Return air systems (positions) Overpressure requirements


Presenter

Presentation Notes

There are many ways to design an air handling system, and we shall be examining the main alternatives, their advantages and disadvantages.� There are no “absolute” answers, and each factory has different requirements. Turbulent or uni-directional airflows Positioning of filters: filters in terminal position or not Air re-circulation versus fresh air Air return systems at low level or at ceiling level Requirements for overpressure have been discussed in a previous part.


Uni-directional / laminardisplacement of dirty air

Turbulent dilution of dirty air

0,30 m/s

Annex 1, 17.3

Air flow patterns (1)


Presenter

Presentation Notes

There are 2 ways to supply air to a room or a piece of equipment: • Turbulent air flow Uni-directional flow, often called laminar flow The air speed in the uni-directional flow is defined by the WHO at: 0,45 m/s for horizontal units 0,30 m/s for vertical units (most commonly used) It is important to know that the WHO definition(*) for the air speed differs from those of other guidelines. For the air exhaust, in case of a vertical unit, a low return is more favourable, as the air is better distributed in the room. Objects in the room can significantly disturb the flow of air, and even block it, so that there might be pockets without air circulation. During the qualification phase, the air flow is visualized if possible, and air samples are taken in different points, to make sure that there are no such pockets, in which case adjustments to the layout or to the air handling systems must be made. (*) WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second Report. Geneva, World Health Organization, 1992: 59-60 (Technical Report Series, No. 823). Annex 1, 17.3.


Air flow patterns (1)• There are 2 ways to supply air to a room or a

piece of equipment:• • Turbulent air flow• Uni-directional flow, often called laminar flow

• The air speed in the uni-directional flow is defined by the WHO at:

• 0,45 m/s for horizontal units• 0,30 m/s for vertical units (most commonly

used)www.pharmatechbd.blogspot.com



• It is important to know that the WHO definition(*) for the air speed differs from those of other guidelines.

• For the air exhaust, in case of a vertical unit, a low return is more favourable, as the air is better distributed in the room.

• Objects in the room can significantly disturb the flow of air, and even block it, so that there might be pockets without air circulation.

• During the qualification phase, the air flow is visualized if possible, and air samples are taken in different points, to make sure that there are no such pockets, in which case adjustments to the layout or to the air handling systems must be made.

• (*) WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second Report. Geneva, World Health Organization, 1992: 59-60 (Technical Report Series, No. 823). Annex 1, 17.3.




Filtered air entering a production room or covering a process can be turbulent uni-directional (laminar)

GMP aspect economical aspect

New technologies: barrier technology/isolator technology.

Annex 1, 17.3, 17.4www.pharmatechbd.blogspot.com

Presenter

Presentation Notes

As seen in the previous slide, filtered air entering a production room or covering a process can be Turbulent Uni-directional (laminar)� Two aspects have to be considered: GMP aspect: uni-directional air (laminar) installations give a better protection, because of the displacement effect rather than the dilution effect. Economical aspect: turbulent air installations are cheaper, as less air has to be treated. For certain operations, namely in class A, a “laminar flow” must be used. It should be said here that such installations can give a false impression of security, and that the purpose of such installations is that there should be, whenever possible, no human interventions under them during the process.�If interventions have to occur, they should be performed in a well-documented way, and recorded and evaluated for possible damage to the products. The use of barrier technology systems (isolator technology) is highly recommended in cases of operations in class A, or for sterility testing operations.


Air flow patterns (2)• As seen in the previous slide, filtered air entering a

production room or covering a process can be

• Turbulent

• Uni-directional (laminar)

ï Two aspects have to be considered:

• GMP aspect: uni-directional air (laminar) installations give a better protection, because of the displacement effect rather than the dilution effect.

• Economical aspect: turbulent air installations are cheaper, as less air has to be treated.



Air flow patterns (2)• For certain operations, namely in class A, a “laminar

flow” must be used.• It should be said here that such installations can give a

false impression of security, and that the purpose of such installations is that there should be, whenever possible, no human interventions under them during the process.If interventions have to occur, they should be performed in a well-documented way, and recorded and evaluated for possible damage to the products.

• The use of barrier technology systems (isolator technology) is highly recommended in cases of operations in class A, or for sterility testing operations.



PrefilterAir flow patterns (3)

AHU

Main filter

Uni-directional TurbulentTurbulent

1 2 3

Annex 1, 17.3


Presenter

Presentation Notes

This slide shows an HVAC installation feeding 3 rooms, each one with terminal filters, all terminal filters protected by a remote pre-filter. Room 1 has a turbulent air flow, with low level exhaust. Room 2 has a uni-directional air flow, over the largest part of the surface, hence the large number of filters, with low level air returns. Due to the high cost of the ventilation in class A areas, the tendency is to keep these areas as small as possible. Room 3 has a turbulent air flow, with ceiling exhaust.� Good design practices recommend that cleanrooms A, B and C (ISO Class 5, 6 & 7) should have low level air returns.


Air flow patterns (3)• This slide shows an HVAC installation feeding 3 rooms, each one

with terminal filters, all terminal filters protected by a remote pre-filter.

• Room 1 has a turbulent air flow, with low level exhaust.

• Room 2 has a uni-directional air flow, over the largest part of the surface, hence the large number of filters, with low level air returns.

• Due to the high cost of the ventilation in class A areas, the tendency is to keep these areas as small as possible.

• Room 3 has a turbulent air flow, with ceiling exhaust.

• Good design practices recommend that cleanrooms A, B and C (ISO Class 5, 6 & 7) should have low level air returns.



Workbench (vertical) Cabin/ booth Ceiling



Presenter

Presentation Notes

Uni-directional (laminar) flow units exist mostly as vertical, but also as horizontal, units.� Often, we are just dealing with LF workbenches (mainly used in sterility testing) or LF cabins/booths, routinely used in production, for instance on top of a filling machine. In some cases, the units can be integrated into the ceiling of a room and also connected to the central air conditioning system. Due to the high air velocity, it is important to have objects with good aerodynamical properties under the laminar flow. If not, turbulences and, therefore, particles are unavoidable.� Laminar flow units are comparatively expensive. Surfaces covered by them should be reduced to a minimum. Only the product in a critical production phase, and not the personnel, should be under laminar flow (aseptic filling, sterile blending, etc.). Manual interventions should be restricted to a minimum, and should be recorded and evaluated for possible consequences.


Air flow patterns (4)• Uni-directional (laminar) flow units exist mostly as vertical, but also as

horizontal, units.

• Often, we are just dealing with LF workbenches (mainly used in sterility testing) or LF cabins/booths, routinely used in production, for instance on top of a filling machine.

• In some cases, the units can be integrated into the ceiling of a room and also connected to the central air conditioning system.

• Due to the high air velocity, it is important to have objects with good aerodynamical properties under the laminar flow. If not, turbulences and, therefore, particles are unavoidable.

• Laminar flow units are comparatively expensive. Surfaces covered by them should be reduced to a minimum.

• Only the product in a critical production phase, and not the personnel, should be under laminar flow (aseptic filling, sterile blending, etc.). Manual interventions should be restricted to a minimum, and should be recorded and evaluated for possible consequences.



Positioning of filters (1)

Filter in terminal position AHU mounted final filter

Production Room

+

Production Room

HEPA Filter

HEPA Filter


Presenter

Presentation Notes

In some of the previous slides, we have seen filters both in the central air handling units ( AHU ) and terminally mounted at the production rooms. The filtered air entering a production room can be coming from: an air-handling unit, equipped with pre-filtration and the main (HEPA) filter, but at some distance from that room (left drawing); an air-handling unit, equipped with pre-filtration in the AHU, and an additional filter (HEPA) situated immediately on the air outlet (right drawing). In many cases, there are only filters in the AHU. However, for injectables and sterile forms, it is recommended that they be placed in terminal position, though there is a growing tendency to have terminal filters in all rooms where open products are handled. It is recommended that classes A & B (ISO 4, 5 & 6) have terminal HEPA filters. (Refer to: WHO Export Committee on Specifications for Pharmaceutical Preparations. Thirty-second Report. Geneva, World Health Organization, 1992:59-60 (Technical Report Series, No. 823). Annex 1, 17.3.)� If we look at the advantages and disadvantages of terminal or non-terminal filters, we can say that generally speaking, the terminal positioning is more expensive; provides a better protection (any problem arising from the ducts is eliminated); is the preferred method in cleanroom classes with high requirements.


Positioning of filters• In some of the previous slides, we have seen filters both

in the central air handling units ( AHU ) and terminally mounted at the production rooms.

• The filtered air entering a production room can be coming from:

• an air-handling unit, equipped with pre-filtration and the main (HEPA) filter, but at some distance from that room (left drawing);

• an air-handling unit, equipped with pre-filtration in the AHU, and an additional filter (HEPA) situated immediately on the air outlet (right drawing).



Positioning of filters• In many cases, there are only filters in the AHU. However, for injectables

and sterile forms, it is recommended that they be placed in terminal position, though there is a growing tendency to have terminal filters in all rooms where open products are handled. It is recommended that classes A & B (ISO 4, 5 & 6) have terminal HEPA filters. (Refer to: WHO Export Committee on Specifications for Pharmaceutical Preparations. Thirty-second Report. Geneva, World Health Organization, 1992:59-60 (Technical Report Series, No. 823). Annex 1, 17.3.)

• If we look at the advantages and disadvantages of terminal or non-terminal filters, we can say that generally speaking, the terminal positioning

• is more expensive;• provides a better protection (any problem arising from the ducts is

eliminated);• is the preferred method in cleanroom classes with high requirements.



Prefilter

AHU

Main filter

1 2 3

Low level exhausts

Ceilingexhausts



Presenter

Presentation Notes

Filters can be in different positions, when one considers the central AHU and the rooms. This slide shows an HVAC installation feeding 3 rooms, each one with terminal filters, all filters protected by a remote pre-filter. Room 1 has a turbulent air flow, with low level exhaust. Room 2 has a uni-directional (laminar) air flow over the largest part of the surface, hence the large number of filters. Room 3 has a turbulent air flow, with ceiling exhaust.�


Positioning of filters• Filters can be in different positions, when one considers

the central AHU and the rooms.

• This slide shows an HVAC installation feeding 3 rooms, each one with terminal filters, all filters protected by a remote pre-filter.

• Room 1 has a turbulent air flow, with low level exhaust.

• Room 2 has a uni-directional (laminar) air flow over the largest part of the surface, hence the large number of filters.




AHUPrefilter

Final filter

21



Presenter

Presentation Notes

This slide shows an HVAC installation feeding two rooms, each one without terminal filters, but with remote final filters protected by a pre-filter. Room 1 has a turbulentair flow, with low level exhaust. Room 2 has a turbulent air flow, with ceiling exhaust.� If there is no filter in terminal position, it should be ascertained that there are no elements between the main filter and the air outlets which could add contamination. No elements such as fans, heating/cooling batteries, should be situated downstream of the final filter.


Positioning of filters• This slide shows an HVAC installation feeding two

rooms, each one without terminal filters, but with remote final filters protected by a pre-filter.

• Room 1 has a turbulentair flow, with low level exhaust.


• If there is no filter in terminal position, it should be ascertained that there are no elements between the main filter and the air outlets which could add contamination. No elements such as fans, heating/cooling batteries, should be situated downstream of the final filter.



Air re-circulation

The filtered air entering a production room can be

100% exhausted or a proportion re-circulated

GMP aspect economical reasons

Annex 1, 15.10, 17.24


Presenter

Presentation Notes

The filtered air entering a production room can be eliminated at 100% (exhaust air) a proportion re-circulated Re-circulated air must be filtered, at an efficiency rate which is such that cross-contamination can be excluded.� In case of re-circulation, every possible measure of protection must be taken to ensure that the air coming from a production unit and loaded with product particles does not flow to other production units, thereby contaminating them. It makes sense to re-circulate the air for reasons of energy conservation, but there can be a contradiction between pharmaceutical requirements and energy conservation. There are also cases, in which air re-circulation is prohibited, for example if solvents are used or cytotoxic products are manufactured.


Air re-circulation• The filtered air entering a production room can be

• eliminated at 100% (exhaust air)• a proportion re-circulated

• Re-circulated air must be filtered, at an efficiency rate which is such that cross-contamination can be excluded.

• In case of re-circulation, every possible measure of protection must be taken to ensure that the air coming from a production unit and loaded with product particles does not flow to other production units, thereby contaminating them.

• It makes sense to re-circulate the air for reasons of energy conservation, but there can be a contradiction between pharmaceutical requirements and energy conservation.

• There are also cases, in which air re-circulation is prohibited, for example if solvents are used or cytotoxic products are manufactured.



Ventilation with 100% fresh air (no air re-circulation)

Annex 1, 17.24

W

Washer (optional)

Central Air Handling Unit

Production Rooms

Exhaust Unit


Presenter

Presentation Notes

This slide illustrates a typical 100% fresh air setup, where a central unit distributes the fresh, treated air to different production rooms. The exhaust air is collected in a central duct, treated (filtered or washed) and eliminated. The degree of exhaust air filtration will depend on contaminants in the exhaust air and also on environmental regulations.


Ventilation with 100% fresh air (no air re-circulation

• This slide illustrates a typical 100% fresh air setup, where a central unit distributes the fresh, treated air to different production rooms.

• The exhaust air is collected in a central duct, treated (filtered or washed) and eliminated. The degree of exhaust air filtration will depend on contaminants in the exhaust air and also on environmental regulations.



Ventilation with re-circulated air + make-up air

Central Air Handling Unit

Return air

Exhaust Unit


Presenter

Presentation Notes

This slide illustrates a typical re-circulated air setup, where a central unit distributes a mixture of fresh and re-circulated air to different production rooms. A part of the exhaust air is collected in a central duct, treated (filtered) and exhausted. The rest is re-circulated (dotted line). With control dampers, the proportions of fresh and re-circulated air can be adjusted.�


Ventilation with re-circulated air + make-up air

• This slide illustrates a typical re-circulated air setup, where a central unit distributes a mixture of fresh and re-circulated air to different production rooms.

• A part of the exhaust air is collected in a central duct, treated (filtered) and exhausted. The rest is re-circulated (dotted line).

• With control dampers, the proportions of fresh and re-circulated air can be adjusted.



Definition of Conditions

air

as builtair air

at rest in operation


Presenter

Presentation Notes

When defining the requirements for a ventilation system for a room, and when testing it for the specified parameters, it is important to know what exactly has been requested from and specified by the suppliers, as values for particles and micro-organisms may differ largely between the conditions as built, at rest and in operation. Furniture/equipment can have an influence on the air flow and thus the air flushing, and people may influence the quantities of micro-organisms and particles.� Though WHO does not specify different values for both at rest and in operation situations, the need for accurate specifications for planning and operation still exists.


Qualification / Validation issues

A good design is essential, but it has to be complemented by: Qualification of air handling systems Process validation Maintenance and periodic re-qualification Adequate documentation


Presenter

Presentation Notes

We have now seen why air handling plants are necessary, what their components are and what the alternatives are in their design. However, we also have to remember that, once a ventilation system is installed, it is necessary to see how well it performs in comparison to its planned purpose, which is to provide a quality environment of specified parameters for the product. We are now going to see how it is possible to achieve demonstrate document the required purity in practice by: systems qualification and process validation (media fill, for instance) Additionally, good maintenance is essential. The whole process is of course supported by adequate documentation.


• We have now seen why air handling plants are necessary, what their components are and what the alternatives are in their design.

• However, we also have to remember that, once a ventilation system is installed, it is necessary to see how well it performs in comparison to its planned purpose, which is to provide a quality environment of specified parameters for the product.

• .



• We are now going to see how it is possible to • achieve • demonstrate • document the required purity in practice by: • systems qualification and• process validation (media fill, for instance)

• Additionally, good maintenance is essential.

• The whole process is of course supported by adequate documentation



Qualification (OQ, PQ) (1)

Test

Differential pressure on filters

Turbulent / mixed airflow Description Uni-directional

airflow / LAF

Room differential pressure

Airflow velocity / uniformity

Airflow volume / rate

Parallelism

Air flow pattern

2 2

N/A 2, 3

2, 3 Optional

2 2

2 N/A

2 3

1 := As built (ideally used to perform IQ)

2 = At rest (ideally used to perform OQ)

3 = Operational (ideally used to perform PQ)

IQ tests are not mentioned on this slide

Annex 1, 17. 4


Presenter

Presentation Notes

This slide shows a series of tests to be carried out during qualification. There are different tests for the turbulent and for the uni-directional air flows. The differential pressure on filters is an indication of the clogging of the filters: with the charging of dust on the filters, the differential pressure will increase. In order to keep the volume of air constant, the fan speed may increase, with the following consequences: Damage to filters, and passage of unfiltered air Particles and micro-organismes will be “pushed” through the filter units. (Inspectors should check whether pressure differential manometers are installed on the AHUs. Without this means of monitoring the filters, the system could go out of control causing contamination problems.) Airflow patterns are interesting to visualize (smoke tests), as zones without proper flushing can be easily identified. It is also important to monitor air flow velocities for each HEPA filter according to a program of established intervals because significant reductions in velocity can increase the possibility of contamination, and changes in velocity can affect the laminarity of the airflow. Airflow patterns should be tested for turbulence, as these can interfere with the flushing action of the air.


Ask the question: “What are the alert and action Limits and what procedures are followed if these points are exceeded?”



Qualification (OQ, PQ) (2)

Test Turbulent / mixed airflow DescriptionUni-directional

airflow / LAF

Recovery timeRoom classification (airborne particle)Temperature, humidity

N/A 2

2 2,3

N/A 2,3

1 := As built (ideally used to perform IQ)

2 = At rest (ideally used to perform OQ)

3 = Operational (ideally used to perform PQ)

Annex 1, 17. 4

IQ tests are not mentioned on this slide


Presenter

Presentation Notes

The recovery time (clean-up time) is also an important parameter to be determined. Once doors have been opened and people have been entering a room, the original conditions have been disturbed and, for a short while, before recovering, the room does not always correspond to the laid down parameters.�It is important to know how long this period is. There are no regulations laid down as to how long this clean-up time should be. However, the generally accepted time to clean-up from one cleanroom classification to the next higher classification, should be less than 15 minutes. It should also be remembered that a room is to be qualified “in operation” when it has a certain number of people in it. After qualification, the number of people in that room, as challenged during qualification, cannot be exceeded. Temperature and humidity can also be important (comfort in clean areas, stability of effervescent products, etc.)


Microbiological validation1. Definition of alert / action limits as a

function of cleanliness zone

1. Identification and marking of sampling points

2. Definition of transport, storage, and incubation conditions


Presenter

Presentation Notes

For the microbiological validation, it must be remembered that many factors may affect the results. (Note to trainer: If required trainer should clarify diagram using white board.) In order to have meaningful values, allowing corrective actions where necessary, there are a few basic points to be observed: Clearly defined alert and action limits as a function of cleanliness zone (air sampling). Clearly identified and marked sampling points, which should be correlated to production operations. The same sampling points or locations should be used for all future tests to ensure comparative results. Procedures for sampling, transport, storage and incubation as the bacterial � count may be influenced by these operations. These elements have to be fixed and documented before starting the campaigns (as built, at rest, in operation). �


air

Sampling point

Cleanroom monitoring program (1)

Cleanrooms should be monitored for micro-organisms and particles


Presenter

Presentation Notes

The environment should be monitored for particulate quality of the air in addition to microbiological quality. Critical areas should be monitored for particulates on at least a daily basis while the areas are in active use. Air monitoring should be conducted adjacent to the filling location, surface monitoring product contact surfaces (filling needle assembly, stopper track, etc.) and non-contact surface adjacent to areas where product and open containers are present. Periodic monitoring should be carried out to detect any significant changes in particle count from the normal level. Excessively higher numbers of particulates obtained from a given location would indicate something abnormal which should be investigated and promptly corrected.


Cleanroom monitoring program (2)

Routine monitoring program as part of quality assurance

Additional monitoring and triggers

1. Shutdown 2. Replacement of filter elements3. Maintenance of air handling

systems4. Exceeding of established limits

Annex 1, 17.37


Presenter

Presentation Notes

A routine monitoring is of utmost importance and is part of the quality assurance program.� Maintenance and monitoring go hand in hand! Therefore, after initial qualification and validation activities, a routine monitoring program should immediately be implemented. The scope and approach of the routine monitoring program is simular to the activities listed before. This program must be documented and must include clearly defined roles and responsibilities. In certain cases, additional monitoring can be necessary. Triggers for additional monitoring could be: Shutdown. In event of a power failure a time limit should be set based on qualification tests. In other words if the plant is off for longer than a pre-determined time period then the plant must be monitored and cleaned down as per SOP. Replacement of filter elements Maintenance of air handling systems Exceeding of established limits (action limits)


Cleanroom maintenance program (1)

Schedule of Tests to Demonstrate Continuing Compliance

Test Parameter Class Maximum TimeInterval

Test Procedure

A, B<= ISO 5

6 Months ISO 14644 -1 Annex AParticle Count Test

C, D> ISO 5

12 Months ISO 14644 -1 Annex A

Air Pressure Difference All Classes 12 Months ISO 14644 -1 Annex B5

Air Flow All Classes 12 Months ISO 14644 -1 Annex B4


Presenter

Presentation Notes

WHO specifies that clean rooms should be monitored, as part of a regular maintenance program. This slide shows an extract from the ISO 14644 standards, specifying tests to be performed within the frame of such a maintenance program. These standards give some reference as to what to do and when, for the testing of the systems, after installation. The tests to be performed depend on the ISO class considered. Some of the tests, such as the particle count test, require specialized equipment; such services are frequently contracted to outside, specialists.


Cleanroom maintenance program (2)

Schedule of Additional Optional Tests

Test Parameter Class Maximum TimeInterval

Test Procedure

Installed Filter Leakage All Classes 24 Months ISO 14644-1 Annex B6

Containment Leakage All Classes 24 Months ISO 14644-1 Annex B4

Recovery All Classes 24 Months ISO 14644-1 Annex B13

Air Flow Visualisation All Classes 24 Months ISO 14644-1 Annex B7


Presenter

Presentation Notes

Some tests are compulsory, some additional (optional). The air flow visualization (smoke test) is performed using, for instance, steam as a visualization agent. It is a good practice to video-record such tests. Here too, some of the tests, such as the leakage test, require particular equipment. Such services are frequently contracted to outside, specialized companies. This slide concludes the design, qualification and maintenance issues.


1. Description of installation and functions2. Specification of the requirements3. Operating procedures4. Instructions for performance control5. Maintenance instructions and records6. Maintenance records7. Training of personnel (program and records)

Documentation requirements


Presenter

Presentation Notes

The following slides illustrate the documentation requirements for the design, installation, qualification, operation and maintenance of an air handling plant. This documentation, necessary for a good GMP operation of an air handling plant, consists of several elements: Complete description of installation (drawings, installed elements, description of the elements, etc.). Specification of the requirements: What is the system supposed to do? Which values is it supposed to reach? Operating procedures: how to operate the system. Performance control: how to judge if everything is operating perfectly (fan, filters, etc.). How to maintain the system. Maintenance records showing that the system has been properly maintained. Personnel training, showing that human resources are at hand to properly operate and maintain the system.


1. Verification of design documentation, including description of installation and functions specification of the requirements

2. Operating procedures3. Maintenance instructions4. Maintenance records5. Training logs6. Environmental records 7. Discussion on actions if OOS values8. Walking around the plant

Inspecting the air handling plant


Presenter

Presentation Notes

This slide summarizes the main elements of an inspection and the various items to be checked: How was the plant designed? Rationale for chosen solutions? Are they adequate? Has a good documentation system (instructions and records) been set up? Are operating procedures available for inspection? Are maintenance plans implemented? Check the maintenance records. Is environmental contamination being checked? Are records available? Check that training has been carried out by checking the training logs. Are the values in line with the specifications, and if not, what happens? (OOS = Out of Specification values) Finally, a walk through the HVAC plant (often difficult to access, and therefore neglected) will give a good picture on the GMP awareness of the engineering. Check for equipment labeling, flow direction arrows, pressure gauge max and min markings, etc.


Air handling systems:

Play a major role in the quality of pharmaceuticals Must be designed properly, by professionals Must be treated as a critical system

Conclusion


Presenter

Presentation Notes

In conclusion, it can be said that:� Air handling systems Play a major role in the quality of Pharmaceuticals, as they will have a large impact on contamination and cross-contamination. Must be designed properly, by professionals. Many designers of HVAC plants have no relevant pharmaceutical experience. Must be treated as critical systems, in view of their importance, especially in sterile areas.


This series of explanations will now be followed by:

Group discussion, with a simple exercise Short test

Further proceedings


Presenter

Presentation Notes

This series of explanations will now be followed by: Group discussion (optional) (45-60 minutes) Short test (45 minutes)


Group Session


Presenter

Presentation Notes

The diagram, which is given in handout 3-3-26, shows a layout of a small pharmaceutical plant for non-sterile tablets, liquids and soft-gel capsules, as well as aseptically filled eye-drops. The group session participants should indicate on the diagram the required cleanroom classes, room pressures (in Pa), as well as any architectural changes which they think necessary. (This layout is not ideal, but as many different types of operations have been incorporated in the facility as possible, so that different concepts can be addressed.) (Note to trainer: The next handout, 3-3-27, giving suggested modifications, should not be distributed until after the group discussion has taken place.)


Group Session – modified layout

MAL = Material Air Lock

PAL = Personnel Air Lockwww.pharmatechbd.blogspot.com

Presenter

Presentation Notes

This slide indicates the proposed additions, and can be displayed after the group session discussions have taken place. See handout 3-3-27.


HVAC__.pdf

Documents

sterile products

processing of sterile

packing of nonsterile

general area

productsflow contamination

productsmovement contamination

secondary packing

component of air gaseswww