Part I: Introduction and overview Supplementary Training Modules on GMP Air Handling Systems Heating Ventilation and Air Conditioning (HVAC) Part I: Introduction and overview Module 3 deals with air handling systems - heating, ventilation and air conditioning (HVAC). Air handling systems are often designed by contractors or engineers who have little exposure to the requirements of the pharmaceutical industry. If they are designed by inexperienced companies this could lead to future operational problems. Inspectors should be in a position to identify potential problems and offer guidance. Whilst instruction in air handling systems is not part of regular pharmaceutical training, because these systems can have a wide-ranging influence on the quality of the pharmaceutical products, it is important for inspectors to have a good basic knowledge of the subject. This module should give inspectors the opportunity to get acquainted with the basics of air handling systems. The module lasts half a day, and is divided into 3 sessions as follows: Presentation: Part 1 45 - 60 minutes Presentation: Part 2 45 - 60 minutes Presentation: Part 3 60 - 90 minutes Group session (optional) 45 - 60 minutes Test paper 45 minutes (Note for the Trainer: the times noted are very approximate. As part of the preparation phase, the trainer will need to get an understanding of the audience and any special issues involved such as language ability. The times for the different sections may then have to be altered accordingly. Allow for breaks of 20-30 minutes about every one-and-a-half hours.) Module3: Part 1: Introduction and overview Slide 1 of 20 WHO - EDM

Objectives To understand: The need and reason for pharmaceutical air handling systems The technical requirements for air handling systems Different types of air handling systems Qualification and monitoring requirements The objectives of this module are: To understand the reasons for having a ventilation system, and its relationship to pharmaceutical production. We will be looking at the purpose of the system, as well as contamination and cross-contamination matters and pharmaceutical parameters. To understand how such a system is built up ( typical HVAC units ). To study different system configurations ( typical HVAC systems ) . Finally, to consider qualification and monitoring issues.

Factors that contribute to quality products: Starting materials and packaging materials Validated processes Personnel Procedures Equipment Design and quality of premises Manufacturing environment Inadequacies in the above factors will lead to sub-standard products. 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 Procedures Validated processes Equipment Premises Environment Packing materials 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.

The manufacturing environment is critical for product quality Light Temperature Humidity Air movement Microbial contamination Particulate contamination Uncontrolled environment can lead to product degradation product contamination loss of product and profit Some environmental factors have a direct influence on a product: Light, for light sensitive products (photo-degradation) Temperature, for temperature sensitive products (many injectables, vaccines) Humidity, often for capsules and always for effervescent tablets Air movement, affecting contamination and cross-contamination Microbial contamination can lead to the destruction of the product and to grave accidents in the case of injectables or sterile products. Particulate contamination is critical in injectable forms These factors, if not properly controlled, can lead to: - product degradation - product contamination - loss of product and profit Cross contamination can lead to sensitization or allergic reactions. In the case of highly potent drugs, it can lead to grave accidents.

What are contaminants ? Contaminants are Products or substances other than product manufactured Foreign products Particulate matter Micro-organisms Endotoxins (degraded micro-organisms) Cross-contamination is a particular case of contamination 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.

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) 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. Annex 1, Glossary

Cross-Contamination (2) From where does Cross-Contamination originate? Poorly designed air handling systems and dust extraction systems Poorly operated and maintained air handling systems and dust extraction systems Inadequate procedures for personnel and equipment Insufficiently cleaned equipment 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

Cross-Contamination ( 3 ) Contaminant from Environment Operators Equipment Cross Product 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 (4) Cross-contamination can be minimized by: 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.

Level of Protection Concept Defines environmental requirements Helps prevent contamination and cross-contamination Allows production under optimal hygiene conditions Takes into account product sensitivity to contamination therapeutic risk 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.

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

Levels of Protection Parameters to be defined: Air cleanliness requirements (filters type and position, air changes, air flow patterns, pressure differentials, contamination levels by particulate matter and micro-organisms) Personnel and material transfer methods Permitted operations Building design and finishes 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 Annex 1, 17.3, 17.4

Levels of Protection International  WHO A, B, C, D National 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 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. Annex 1, 17.3, 17.4

Levels of Protection All operations within a pharmaceutical facilility must be correlated to well-defined cleanroom classes, and can be included in a hygiene concept. Example: etc. 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. Annex 1, 17.3, 17.4, 17.5

Levels of Protection 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 ) 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.

Parameters influencing Levels of Protection (1) 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. Annex 1, 17.4

Parameters influencing Levels of Protection (2) Number of particles in the air Number of micro-organisms in the air or on surfaces Number of air changes for each room Air velocity Air flow pattern Filters ( type, position ) Air pressure differentials between rooms Temperature, humidity 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 Class defined by Critical Parameters Air Handling System Parameters influencing Levels of Protection (3) Cleanroom Class defined by Critical Parameters Air Handling System Additional Measures 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.

Parameters influencing Levels of Protection (4) 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 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. Annex 1, 17.10 to 17.16