Hvac PDF

HVAC
H-V-A-C H-VAK Pharmaceutical plant air quality Management Air Conditioning
www.pharmatechbd.blogspot.com
HVAC
H = Heating V = Ventilation A = Air C = Conditioning
HVAC
What is HVAC? Controlling components and parameters of air Why? As it has great effects on product quality How? By using AHU
HVAC
Definition The 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 of Air
Gases
Component Nitrogen Oxygen Carbon dioxide Argon Quantity 78.02% 20.71% 0.03% 0.001% Oxidation Carboxylation Fe++ Fe+++ Harmful Effects Examples
Component of Air
Solid
Component Quantity Harmful Effects Examples
Dust Particles Drug Particle Microorganism
0.01%
Contamination Cross Contamination
All products All products
Microbial contamination, Antacid & Endotoxin contamination Sterile Preparation
Component of Air
Liquid
Component Moisture
Quantity 0-1.5%
Harmful Examples Effects Hydrolysis, Aspirin, Dissolution, Ranitidine Microbial growth
Parameters of Air
Component Quantity Harmful Effects Examples Drug Degradation, Microbial growth. Photo degradation Contamination Contamination Contamination Thermo labile Drugs. Vitamins, Antibiotics. Nimesulide All products All products All products
Temperature 30-400 C
Light Pressure Flow Movement
Zone Grade A B C D
Process Aseptic filling in final container Background of Zone A Sterile solution preparation Dispensing of starting materials for products terminally sterilized. Production and packing of non sterile products. Secondary packaging Warehousing, QC Labs, General Area.
Particles Limit Class 100 Class 100 Class 10,000 Class 100,000
Air change/hr 40 20 20 20
Filter HEPA HEPA HEPA HEPA
Class 100,000
EU 12
F G
Optically Clean General Area
4 Depends on heat load
EU 9 EU 6
Zone Grade A B C D
Process
Particles Limit(> 0.5 micron /M3 Class 100 Class 100 Class 10,000 Class 100,000
Filter
Aseptic filling in final container Background of Zone A Sterile solution preparation Dispensing of starting materials for products terminally sterilized. Production and packing of non sterile products. Secondary packaging Warehousing, QC Labs, General Area.
HEPA HEPA HEPA HEPA
Class 100,000
F G
Area Aseptic filling Weighing, Processing ( Aseptic)& Filtration of Sterile product Weighing, Processing of Sterile product with terminally sterilization. Ophthalmic ointment Weighing, processing and packing of nonsterile product. a. Capsule b. Hygroscopic Tablet c. Dry Syrup d. Liquid Secondary Packing Warehouse a. Cool store b. Controlled store c. Normal store
Temperature (0c) 15-25 15-25
Humidity ( % RH) 30-45 45-55
Particles ( per M3) 100 10,000
Air Change >40 20-40
15-25
45-55
100,000
20-40
20-28 20-28
30-40 45-75
10,000 100,000
5-20 5-20
20-25 20-25 20-25 20-28 20-28
40-50 40-50 40-50 45-75 45-75
100,000 100,000 100,000 100,000 Clean
5-20 5-20 5-20 5-20 5-20
0-8 20-25 30-35
45-75 45-75 45-75
Clean Clean Clean
5-20 5-20
5-20
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 Patients safety Product Purity Patients 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. ii. iii. iv. v. vi. vii. Starting materials and packaging materials Validated processes Personnel Procedures Equipment Design and quality of premises
Manufacturing environment
Factors contributing to quality products

Validated processes
Personnel
Procedures
Starting materials Equipment
Packing materials Premises Environment

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 tablets 4. Air movement, affecting contamination and crosscontamination 5. 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.
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 Acid Many 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 are 1. Products or substances other than product manufactured 2. Foreign products 3. Particulate matter 4. Micro-organisms 5. Endotoxins (degraded microorganisms)
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, microorganisms 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.
Equipment 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 chips Construction 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
Cross-Contamination ( 3 )
Contaminant from Environment Operators Contaminant from Equipment
Contamination
Product from Environment Operators
Cross Contamination
Product from Equipment
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 crosscontamination. An absence of cross-contamination being detected may just mean the absence of adequate analytical procedures.
From where does Cross-Contamination originate? 1. Poorly designed air handling systems and dust extraction systems 2. Poorly operated and maintained air handling systems and dust extraction systems 3. Inadequate procedures for personnel and equipment 4. Insufficiently cleaned equipment
insufficient control over

1.Design of premises and systems quality 2.Air handling and dust extraction systems 3.Operation and maintenance of air handling and dust extraction systems 4.Procedures for cleaning of equipment and for restriction of movement of personnel 5.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 can be minimized by: 1. Personnel procedures 2. Adequate premises 3. Use of closed production systems 4. Adequate, validated cleaning procedures 5. Appropriate levels of protection of product 6. Correct air pressure cascade
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.
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 crosscontamination.
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
Cleanroom Class A / B Therapeutic risks Cleanrm. Class D Others Cleanroom Class C
Manufacturing Environment requirements
Levels of Protection
Parameters 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 operations Annex 1, 17.3, 17.4 4. Building design and finishes
Types 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, 17.4
Therapeutic Goods Administration (TGA). TGA is Australia's regulatory agency for medical drugs and devices. Pharmaceutical Inspection Convention and Pharmaceutical Inspection Cooperation Scheme (jointly referred to as PIC/S)
A Washing of containers Preparation of solution for terminal sterilisation Preparation of solutions for aseptic filling Depyrogenisation of containers Filling for terminal sterilisation Class Filling for aseptic Cleanroom process etc. X X
D X
X X X
X X
Annex 1, 17.3, 17.4, 17.5

Based 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
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 )
Air Handling System
Supply Air
Production Room With Defined Requirements
Outlet Air
Annex 1, 17.4
Parameters influencing Levels of Protection (2)

1 Number of particles in the air 2 Number of micro-organisms in the air or on surfaces 3 Number of air changes for each room 4 Air velocity 5 Air flow pattern 6 Filters ( type, position ) 7 Air pressure differentials between rooms 8 Temperature, humidity
Parameters influencing Levels of Protection (3)
Cleanroom Class defined by Critical Parameters
Air Handling System
Additional 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 17.16
Zone Grade A B C D
Process
Particles Limit(> 0.5 micron /M3 Class 100 Class 100 Class 10,000 Class 100,000
Filter
Aseptic filling in final container Background of Zone A Sterile solution preparation Dispensing of starting materials for products terminally sterilized. Production and packing of non sterile products. Secondary packaging Warehousing, QC Labs, General Area.
HEPA HEPA HEPA HEPA
Class 100,000
F G
AHU must be located outside the space they are controlling!

Air Handling System
Supply Air
Production Room With Defined Requirements
Outlet Air
Main subsystems
Exhaust air treatment
Fresh air treatment (make-up air)
Terminal air treatment at production room level
Production Room Central air handling unit

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).
Overview components
Exhaust Air Grille Silencer Flow rate controller Fan Filter
Weather louvre
Control damper Heater
+
Prefilter Humidifier Terminal filter
Cooling coil with Heating droplet coil separator
Secondary Filter
Production Room
Re-circulated air
Components
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
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 predetermined dimensions and/or micro-organisms To transport the air
Problems with components

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
Air types
Fresh air (make-up air)
Supply air
Exhaust air
Production Room
Return air (re-circulated)
Function of AHU
Heating Cooling Humidification Dehumidification Filtration
Measurement of Humidity
Air Dry Air Moist Air Unsaturated Air
Saturated Air
Humidity Control
Various Terms
Dry air Moist air Saturated air Absolute humidity Relative humidity Dew point Air which is free from water The mixture of dry air and water When air contains maximum amount of moisture Weight of water per pound of dry air. Unit: grains/ lb. dry air Ratio of actual amount of water & maximum amount of water Temperature at which condensation will just begin with the existing moisture.
Unsaturated air Air which is not saturated
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.
Determination of Maximum amount of moisture in Air

Moisture content capacity of air depends on temperature. Higher temperature air can contain more moisture.
Air temperature 54 60 67 81 85
( 0F)
Maximum amount of moisture (Grains/ lb. dry air.) 62 78 99 161 185

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 , % RH
4. 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
5. 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
6. 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 %
3. % 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 100 Amount 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
Definition A 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. 21 22 23 24 25 26 27 28 29 30 32 34 36
DEPRESSION OF WET BULB 0C 0.5 95 95 96 96 96 96 96 96 96 96 96 96 96 1.0 91 91 91 91 92 92 92 92 92 93 93 93 93 1.5 86 87 87 87 88 88 88 88 89 89 89 89 90 2.0 82 82 83 83 84 84 84 85 85 85 86 86 87 2.5 78 78 79 79 80 80 81 81 81 82 82 83 84 3.0 73 74 75 75 76 76 77 77 78 78 79 80 81 3.5 69 70 71 71 72 73 73 74 74 75 76 77 78 4.0 65 66 67 68 68 69 70 70 71 72 73 74 75 4.5 61 62 63 64 65 66 66 67 68 68 70 71 72 5.0 57 58 59 60 61 62 63 64 64 65 67 68 69 5.5 53 54 55 57 58 59 59 60 61 62 64 65 66 6.0 49 50 52 53 54 55 56 57 58 59 61 62 63 6.5 45 47 48 49 51 52 53 54 55 56 58 59 61 7.0 42 43 45 46 47 49 50 51 52 53 55 56 58
Psychometric chart
Definition A Psychometric chart is a graphical representation of various thermodynamic parameters of moist air.
Psychometric chart
Various Lines
Dry bulb temperature lines Wet bulb temperature lines Absolute humidity lines These are the straight and vertical lines drawn parallel to the ordinate. These are the straight but inclined lines which extend diagonally as shown on the chart 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
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.
REQUIREMENT
Area Aseptic filling Weighing, Processing (Aseptic)& Filtration of Sterile product Weighing, Processing of Sterile product with terminally sterilization. Ophthalmic ointment Weighing, processing and packing of non-sterile product. a. Capsule b. Hygroscopic Tablet c. Dry Syrup d. Liquid Secondary Packing a. Cool store b. Controlled store c. Normal store Humidity (% RH) 30-45 45-55 45-55 30-40 45-75 40-50 40-50 40-50 45-75 45-75 45-75 45-75
45-75
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.
Adsorber wheel Humid room air
Dry air
Regeneration
air
AHU with fan Variable Speed Controller
Air heater
Filter Pressure Gauges
De-humidification
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.
Refrigerants
Numerical designation Chemical name 11 12 13 Chemical Formula Trichloro Monofluro Methane CCl3F CCl2F2 Dichloro Difluro Methane Monochloro Trifluro Methane CClF3
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.

Condenser receives hot, highpressure 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.

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 classes
Standard
Dust filters Aerosol
Coarse
Dp > 10 m
Fine
10 m > Dp > 1 m
HEPA
Dp < 1 m
ULPA
G1 - G4
EN 779 Standard
F5 - F9
H 11 - 13
EN 1822 Standard
U 14- 17
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.
Classification of filters according to their efficiency

Average Efficiency Integral Value Retention in Penetration % 85 0.15 95 99.5 99.95 99.995 0.05 5x10 5x10 5x10
-3 -4 -5
Peak Arrestance Local Value Efficiency Penetration
F9 H11 H12 H13 U14
97.5 99.75 99.975
25x10 25x10 25x10
-3 -4 -5
HEPA or tertiaary filter
Primary panel filter
Secondary filter
Humidifier Heating and cooling units
Silencer
Control damper for air flow

Adsorber wheel Humid room air Dry air Humid room air Air heater
Filter Pressure Gauges AHU with fan Variable Speed Controller
Regeneration air
De-humidification
Air handling unit
1 2
3 4
1 2 3 4
Swirl Type air diffusors Filter with Tightening frame Register outlet terminal filters Screw fixation for register
High induction office type diffusor (avoid)
Low induction swirl diffusor (preferred)

Regulation of room pressure pressure differentials concept
Room pressure gauges Room pressure indication panel
Annex 1, 17.26
Pressure cascade injectables Protection from micro-organisms and particles
Annex 1, 17.24, 17.25

Pressure cascade solids Protection from cross-contamination
Supplementary Training Modules on GMP

Air Handling Systems Heating Ventilation and Air Conditioning (HVAC) Part 3: Design, qualification and maintenance
Module 3, Part 3: Qualification and maintenance
WHO Slide 130 of 27 EDM
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
Air flow patterns (1) Turbulent

dilution of dirty air
Uni-directional / laminar
displacement of dirty air
0,30 m/s
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)

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, 17.4

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.
Prefilter
AHU
Annex 1, 17.3
Main filter
Turbulent
Uni-directional
Turbulent

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

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)
AHU mounted final filter
Filter in terminal position

HEPA Filter
Production Room HEPA Filter
Production Room
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).
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. Thirtysecond 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 (2) AHU
Prefilter
Main filter
Ceiling exhausts 1 2 3
Low level exhausts
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 (3)
Final filter
AHU
Prefilter
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.
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
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 recirculation)

Exhaust Unit
W
Washer (optional)
Central Air Handling Unit Production Rooms Annex 1, 17.24

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

Exhaust Unit
Central Air Handling Unit
Return air
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
as built
air
at rest
air
in operation
air
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 requalification 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 Room differential pressure Airflow velocity / uniformity Airflow volume / rate Parallelism Air flow pattern Uni-directional airflow / LAF 2 N/A 2, 3 2 2 2 2 2, 3 Optional 2 N/A 3 Turbulent / mixed airflow Description
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
Ask the question: What are the alert and action Limits and what procedures are followed if these points are exceeded?
Qualification (OQ, PQ) (2)

Uni-directional airflow / LAF N/A 2 N/A 2 2,3 2,3 Turbulent / mixed airflow
Test Recovery time Room classification (airborne particle) Temperature, humidity
Description 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

Microbiological validation
1. 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
Cleanroom monitoring program (1)

Cleanrooms should be monitored for micro-organisms and particles air
Sampling point
Cleanroom monitoring program (2)
Routine monitoring program as part of quality assurance Additional monitoring and triggers 1. 2. 3. Shutdown Replacement of filter elements Maintenance of air handling systems 4. Exceeding of established limits
Annex 1, 17.37
Cleanroom maintenance program (1)

Schedule of Tests to Demonstrate Continuing Compliance Test Parameter Particle Count Test
Class A, B <= ISO 5 C, D > ISO 5 All Classes All Classes Maximum Time Interval 6 Months 12 Months 12 Months 12 Months Test Procedure ISO 14644 -1 Annex A ISO 14644 -1 Annex A ISO 14644 -1 Annex B5 ISO 14644 -1 Annex B4
Air Pressure Difference Air Flow
Cleanroom maintenance program (2)

Schedule of Additional Optional Tests Test Parameter Installed Filter Leakage Containment Leakage Recovery Air Flow Visualisation
Class All Classes All Classes All Classes All Classes Maximum Time Interval 24 Months 24 Months 24 Months 24 Months Test Procedure ISO 14644-1 Annex B6 ISO 14644-1 Annex B4 ISO 14644-1 Annex B13 ISO 14644-1 Annex B7
Documentation requirements
1. 2. 3. 4. 5. 6. 7.
Description of installation and functions Specification of the requirements Operating procedures Instructions for performance control Maintenance instructions and records Maintenance records Training of personnel (program and records)
Inspecting the air handling plant

1.
Verification of design documentation, including

description of installation and functions specification of the requirements
2. 3. 4. 5. 6. 7. 8.
Operating procedures Maintenance instructions Maintenance records Training logs Environmental records Discussion on actions if OOS values Walking around the plant
Conclusion
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
Further proceedings
This series of explanations will now be followed by:

Group discussion, with a simple exercise Short test
Group Session
Group Session modified layout
MAL = Material Air Lock PAL = Personnel Air Lock


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H-V-A-C H-VAK Pharmaceutical plant air quality Management Air Conditioning

Dust Particles Drug Particle Microorganism

Contamination Cross Contamination

All products All products

Microbial contamination, Antacid & Endotoxin contamination Sterile Preparation

Harmful Examples Effects Hydrolysis, Aspirin, Dissolution, Ranitidine Microbial growth

Light Pressure Flow Movement

Filter HEPA HEPA HEPA HEPA

Optically Clean General Area

4 Depends on heat load

HEPA HEPA HEPA HEPA

Optically Clean General Area

4 Depends on heat load

Temperature (0c) 15-25 15-25

Humidity ( % RH) 30-45 45-55

Particles ( per M3) 100 10,000

Air Change >40 20-40

20-25 20-25 20-25 20-28 20-28

40-50 40-50 40-50 45-75 45-75

100,000 100,000 100,000 100,000 Clean

5-20 5-20 5-20 5-20 5-20

0-8 20-25 30-35

45-75 45-75 45-75

Clean Clean Clean

Harmful Effects of Air

Factors that contribute to quality products:

Factors contributing to quality products

Starting materials Equipment

Packing materials Premises Environment

Environmental factors have a direct influence on a product:

Environmental factors have a direct influence on a product:

Harmful effects of temperature

Thermal degradation of Drugs: Microbial Growth

Harmful effects of temperature

Harmful effects of temperature

Harmful effects of temperature

Dust Particle Control

Harmful Effects of Moisture

Harmful Effects of Moisture

Harmful Effects of Moisture

Harmful Effects of Moisture

Harmful Effects of Moisture

Harmful Effects of Moisture

What are contaminants ?

Product from Environment Operators

Product from Equipment

insufficient control over

Level of Protection Concept

Cleanroom Class A / B Therapeutic risks Cleanrm. Class D Others Cleanroom Class C

Manufacturing Environment requirements

Annex 1, 17.3, 17.4, 17.5

Air Handling System

Production Room With Defined Requirements

Parameters influencing Levels of Protection (2)

Parameters influencing Levels of Protection (3)

Cleanroom Class defined by Critical Parameters

Air Handling System

HEPA HEPA HEPA HEPA

Optically Clean General Area

4 Depends on heat load

AHU must be located outside the space they are controlling!

Production Room With Defined Requirements

Fresh air treatment (make-up air)

Terminal air treatment at production room level

Production Room Central air handling unit

Control damper Heater

Cooling coil with Heating droplet coil separator

Heating unit Cooling unit /dehumidifier Humidifier Filters Ducts

Problems with components

Fresh air (make-up air)

Return air (re-circulated)

Unsaturated air Air which is not saturated

Determination of Volume of Air

Determination of weight of Air

Determination of Maximum amount of moisture in Air