1. World Health Organization
25 May, 2019
Good Manufacturing Practices: HVAC
Heating, Ventilation and Air- Conditioning (HVAC)
Part 1: Introduction and overview
Hearing, Ventilation and Air Conditioning (HVAC) Part 1 Introduction and overview
WHO Technical Report Series, No. 961, Annex 5

2. Good Manufacturing Practices: HVAC
World Health Organization
Good Manufacturing Practices: HVAC
25 May, 2019
Objectives
To understand:
The need for HVAC systems
The role of HVAC in protection:
Product
Personnel
Environment
The role of HVAC in dust control
HVAC system design and its components
Commissioning, qualification and maintenance
1. Introduction
Heating, ventilation and air-conditioning (HVAC) play an important role in ensuring the manufacture of quality pharmaceutical products. A well designed HVAC system will also provide comfortable conditions for operators.
These guidelines mainly focus on recommendations for systems for manufacturers of solid dosage forms. The guidelines also refer to other systems or components which are not relevant to solid dosage form manufacturing plants, but which may assist in providing a comparison between the requirements for solid dosage-form plants and other systems.
HVAC system design influences architectural layouts with regard to items such as airlock positions, doorways and lobbies. The architectural components have an effect on room pressure differential cascades and cross-contamination control. The prevention of contamination and cross-contamination is an essential design consideration of the HVAC system. In view of these critical aspects, the design of the HVAC system should be considered at the concept design stage of a pharmaceutical manufacturing plant.
Temperature, relative humidity and ventilation should be appropriate and should not adversely affect the quality of pharmaceutical products during their manufacture and storage, or the accurate functioning of equipment.
This document aims to give guidance to pharmaceutical manufacturers and inspectors of pharmaceutical manufacturing facilities on the design, installation, qualification and maintenance of the HVAC systems. These guidelines are intended to complement those provided in Good manufacturing practices for pharmaceutical products (1) and should be read in conjunction with the parent guide. The additional standards addressed by the present guidelines should therefore be considered supplementary to the general requirements set out in the parent guide.
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3. World Health Organization
HVAC
25 May, 2019
Introduction and Scope
HVAC systems can have an impact on product quality
It can provide comfortable conditions for operators
The impact on premises and prevention of contamination and cross-contamination to be considered at the design stage
Temperature, relative humidity control where appropriate
Supplement to basic GMP text
Heating, ventilation and air-conditioning (HVAC) play an important role in ensuring the manufacture of quality pharmaceutical products. A well designed HVAC system will also provide comfortable conditions for operators.
When operators are uncomfortable, due to heat or high humidity, they can shed particles which can become a source of contamination to the environment and product(s).
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4. World Health Organization
HVAC
25 May, 2019
This presentation focuses on HVAC systems for OSD
To fully understand the technical issues, it is important to know the definitions of the terms used
These include:
Contamination and Cross-contamination
As built, at rest, in operation
Infiltration, exfiltration etc
Discuss the scope of the guideline and explain some of the terms used.
See the glossary of the guideline
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5. World Health Organization
25 May, 2019
HVAC
For example: What is contamination?
It is "the undesired introduction of impurities (chemical/ microbial/ foreign matter into or on to starting material or intermediate – during sampling, production, packaging or repackaging".
Impurities could include products or substances other than the product manufactured, foreign products, particulate matter, micro- organisms, endotoxins (degraded microorganisms), etc.
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.
Glossary

6. World Health Organization
25 May, 2019
HVAC
What is Cross-contamination?
"Contamination of a starting material, intermediate product, or finished product with another starting material or product during production".
Cross-contamination can result from, e.g.
Poorly designed, operated or maintained air-handling systems and dust extraction systems
Inadequate procedures for, and movement of personnel, materials and equipment
Insufficiently cleaned equipment
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.
Glossary,

7. World Health Organization
25 May, 2019
HVAC
Cross-contamination can be minimized by, e.g.
Personnel procedures
Adequate premises
Use of closed production systems
Adequate, validated cleaning procedures
Appropriate levels of protection of product
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) 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.

8. World Health Organization
25 May, 2019
HVAC
Starting materials
Personnel
Procedures
Validated processes
Equipment
Premises
Environment
Packing materials
Factors contributing to quality products

9. World Health Organization
HVAC
25 May, 2019
Consider the following when designing an HVAC system:
Layout of the premises
Product range
Airlocks, Lobbies, Doors
Required pressure differentials
Air flows
Temperature and relative humidity
Prevention of contamination and cross contamination
Heating, ventilation and air-conditioning (HVAC) play an important role in ensuring the manufacture of quality pharmaceutical products. A well designed HVAC system will also provide comfortable conditions for
HVAC system design influences architectural layouts with regard to items such as airlock positions, doorways and lobbies. The architectural components have an effect on room pressure differential cascades and cross-contamination control. The prevention of contamination and cross-contamination is an essential design consideration of the HVAC system. In view of these critical aspects, the design of the HVAC system should be considered at the concept design stage of a pharmaceutical manufacturing plant.
Temperature, relative humidity and ventilation should be appropriate and should not adversely affect the quality of pharmaceutical products during their manufacture and storage, or the accurate functioning of equipment.
operators.
When operators are uncomfortable, due to heat or high humidity, they can shed particles which can become a source of contamination to the environment and product(s).
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10. World Health Organization
HVAC
25 May, 2019
The guideline further focuses on three concepts of the system:
Product protection
Contamination
Cross-contamination
Environmental conditions
Personnel protection
Prevent contact
Comfort conditions
Environment protection 4

11. World Health Organization
HVAC
25 May, 2019
Protection: Product and personnel
Areas of manufacturing should be classified as "clean areas; clean zones; cleanrooms; or controlled areas”
To achieve a clean area classification – control :
Building finishes and structure
Air filtration
Air change rate
Room pressure
Temperature
Relative humidity
Material and personnel flow
Outside environment
Occupancy and type of product
4.1.1 Areas for the manufacture of pharmaceuticals, where pharmaceutical starting materials and products, utensils, primary packing materials and equipment are exposed to the environment, should be defined as “clean areas”, “clean zones”, “controlled areas” or “cleanrooms”.
4.1.2 The achievement of a particular clean area condition depends on a number of criteria that should be addressed at the design and qualification stages. A suitable balance between the different criteria will be required in order to create an efficient clean area.
4.1.3 Some of the basic criteria to be considered which affects room cleanliness should include:
• building finishes and structure
• air filtration
• air change rate or flushing rate
• room pressure
• location of air terminals and directional airflow
• temperature
• relative humidity
• material flow
• personnel flow
• gowning procedures
• equipment movement
• process being carried out (open or closed system)
• outside air conditions
• occupancy
• type of product.
• cleaning standard operating procedures (SOPs)

12. World Health Organization
HVAC
25 May, 2019
Air filtration and air change rate needed to attain classification
Risk assessment. Normally need 6 – 20 air changes per hour
Air change rate is dependent on factors, e.g.
Required condition
Product characteristics
Quality of filtration of air
Particles generated (operators, machines, process)
Room configuration
Supply and return / extract air locations
Air required (room heat load, containment)
Balance and room pressure requirements
4.1.4 Air filtration and air change rates are important factors to ensure that the defined clean area classification is attained.
4.1.5 The air change rates should be determined by the manufacturer and designer, taking into account the various critical parameters. Primarily the air change rate should be set to a level that will achieve the required clean area classification.
4.1.6 Air change rates normally vary between 6 and 20 air changes per hour and are normally determined by the following considerations:
• level of protection required
• the quality and filtration of the supply air
• particulates generated by the manufacturing process
• particulates generated by the operators
• configuration of the room and air supply and extract locations
• sufficient air to achieve containment effect
• sufficient air to cope with the room heat load
• sufficient air to maintain the required room pressure.

13. World Health Organization
HVAC
25 May, 2019
The classification should be achieved in the state as specified (1):
"As built"
Bare room, without equipment or personnel
4.1.7 In classifying the environment, the manufacturer should state whether this is achieved under “as-built” (Fig. 2), “at-rest” (Fig. 3) or “operational” (Fig. 4) conditions.
4.1.8 Room classification tests in the “as-built” condition should be carried out on the bare room, in the absence of any equipment or personnel.

14. World Health Organization
HVAC
25 May, 2019
The classification should be achieved in the state as specified (2):
"At rest"
Equipment may be operating, but no operators present
4.1.9 Room classification tests in the “at-rest” condition should be carried out with the equipment operating where relevant, but without any operators. Because of the amounts of dust usually generated in a solid dosage facility most clean area classifications are rated for the “at-rest” condition.
4.1.9

15. World Health Organization
HVAC
25 May, 2019
The classification should be achieved in the state as specified (3):
"In operation"
Normal production process with equipment and personnel
Clean up time validated – normally about 20 minutes
Room classification tests in the “operational” condition should be carried out during the normal production process with equipment operating, and the normal number of personnel present in the room. Generally a room that is tested for an “operational” condition should be able to be cleaned up to the “at-rest” clean area classification after a short clean-up time. The clean-up time should be determined through validation and is
generally of the order of 20 minutes.
4.1.10

16. World Health Organization
HVAC
25 May, 2019
Control of contaminants
Protect materials and products during manufacture
Airborne contaminants – effective ventilation and filtration
External contaminants - effective filtration
Internal contaminants - dilution and flushing, or displacement airflow
Level of protection: Airborne particulates and level of filtration considered critical
Materials and products should be protected from contamination and
cross-contamination during all stages of manufacture (see also section 5.5
for cross-contamination control).
Note: contaminants may result from inappropriate premises (e.g. poor design,
layout or fi nishing), poor cleaning procedures, contaminants brought
in by personnel, and a poor HVAC system.
Airborne contaminants should be controlled through effective ventilation.
External contaminants should be removed by effective fi ltration of the supply air (See Fig. 5 for an example of a shell-like building layout to enhance containment and protection from external contaminants.)
Internal contaminants should be controlled by dilution and fl ushing of contaminants in the room, or by displacement airfl ow (See Figs 6 and 7 for examples of methods for the fl ushing of airborne contaminants.)
Airborne particulates and the degree of fi ltration should be considered critical parameters with reference to the level of product protection required.

17. World Health Organization
25 May, 2019
HVAC
Manufacturing Environment requirements
Cleanroom Class A / B
Cleanroom Class C
Cleanrm. Class D
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.
Others
Therapeutic risks

18. World Health Organization
HVAC
25 May, 2019
Level of protection and air cleanliness determined according to:
Product to be manufactured
Process to be used
Product susceptibility to degradation
Personnel should not be a source of contamination
Personnel should not be a source of contamination.
The level of protection and air cleanliness for different areas should be determined according to the product being manufactured, the process being used and the product’s susceptibility to degradation .

19. World Health Organization
25 May, 2019
HVAC
Tools to help achieve the desired Level of Protection
Air Handling
System
Production Room
With
Defined
Requirements
Supply
Air
Outlet
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.

20. World Health Organization
25 May, 2019
HVAC
Tools to help achieve the desired Level of Protection (2)
Cleanroom Class
defined by
Critical Parameters
Additional Measures
Air Handling
System
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 such as gowning, cleaning procedures, dust control, containment.
We are going to discuss some of these measures.

21. World Health Organization
25 May, 2019
HVAC
Examples of Levels of Protection
Types of Clean room classes
A, B, C, D
Critical and controlled
Level 1, 2 or 3
ISO4.8, 5, 7 or 8
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.

22. World Health Organization
HVAC
World Health Organization
25 May, 2019
Examples of levels of protection
4.1.17
Example of area
Condition
Level
Area with normal housekeeping, e.g. warehouse
General
Level 1
Area where steps are taken to protect exposed material/product, e.g. dispensing
Protected
Level 2
Area with defined, controlled, monitored environmental conditions to prevent contamination and degradation
Controlled
Level 3
The level of protection and air cleanliness for different areas should
be determined according to the product being manufactured, the process
being used and the product’s susceptibility to degradation (Table 1).

23. World Health Organization
25 May, 2019
HVAC
All operations within a pharmaceutical facilility should be correlated to well-defined clean room classes, and can be included in a hygiene concept.
Example:
List other…. X
Filling for aseptic process
Filling for terminal sterilisation
Depyrogenisation of containers
Preparation of solutions for aseptic filling
Preparation of solution for terminal sterilisation
Washing of containers D C B A
Cleanroom Class
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.