Heating, Ventilation and Air- Conditioning HVAC Part 1 a: Introduction and overview

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HVAC. ObjectivesTo understand: The need for HVAC systems (Part 1a) The role of HVAC in protection: Product Personnel Environment The role of HVAC in dust control (Part 1b) HVAC system design and its components (Part 2) Commissioning, qualification and maintenance (Part 3). 1, 2. HVAC. Intr
Heating, Ventilation and Air- Conditioning HVAC Part 1 a: ...

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2. HVAC Objectives To understand: The need for HVAC systems (Part 1a) The role of HVAC in protection: Product Personnel Environment The role of HVAC in dust control (Part 1b) HVAC system design and its components (Part 2) Commissioning, qualification and maintenance (Part 3) 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 infl uences 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, qualifi cation 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. 2. Scope of document These guidelines focus primarily on the design and good manufacturing practices (GMP) requirements for HVAC systems for facilities for the manufacture of solid dosage forms. Most of the system design principles for facilities manufacturing solid dosage forms also apply to other facilities such as those manufacturing liquids, creams and ointments. These guidelines do not cover requirements for manufacturing sites for the production of sterile pharmaceutical products. These guidelines are intended as a basic guide for use by GMP inspectors. They are not intended to be prescriptive in specifying requirements and design parameters. There are many parameters affecting a clean area condition and it is, therefore, diffi cult to lay down the specifi c requirements for one particular parameter in isolation. Many manufacturers have their own engineering design and qualifi cation standards and requirements may vary from one manufacturer to the next. Design parameters should, therefore, be set realistically for each project, with a view to creating a cost-effective design, yet still complying with all regulatory standards and ensuring that product quality and safety are not compromised. The three primary aspects addressed in this manual are the roles that the HVAC system plays in product protection, personnel protection and environmental protection 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 infl uences 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, qualifi cation 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. 2. Scope of document These guidelines focus primarily on the design and good manufacturing practices (GMP) requirements for HVAC systems for facilities for the manufacture of solid dosage forms. Most of the system design principles for facilities manufacturing solid dosage forms also apply to other facilities such as those manufacturing liquids, creams and ointments. These guidelines do not cover requirements for manufacturing sites for the production of sterile pharmaceutical products. These guidelines are intended as a basic guide for use by GMP inspectors. They are not intended to be prescriptive in specifying requirements and design parameters. There are many parameters affecting a clean area condition and it is, therefore, diffi cult to lay down the specifi c requirements for one particular parameter in isolation. Many manufacturers have their own engineering design and qualifi cation standards and requirements may vary from one manufacturer to the next. Design parameters should, therefore, be set realistically for each project, with a view to creating a cost-effective design, yet still complying with all regulatory standards and ensuring that product quality and safety are not compromised. The three primary aspects addressed in this manual are the roles that the HVAC system plays in product protection, personnel protection and environmental protection

3. HVAC 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

5. 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.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.

6. 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. 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.

7. 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.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.

9. 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. 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.

10. HVAC 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

11. HVAC Protection: Product and personnel Areas where materials and products are exposed, should be classified as "clean areas" Achievement of clean area classification depends on factors such as: 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. Protection 4.1 Product and personnel 4.1.1 Areas for the manufacture of pharmaceuticals, where pharmaceutical starting materials and products, utensils and equipment are exposed to the environment, should be classifi ed as ?clean areas?. 4.1.2 The achievement of a particular clean area classifi cation depends on a number of criteria that should be addressed at the design and qualifi cation stages. A suitable balance between the different criteria will be required in order to create an effi cient clean area. 4.1.3 Some of the basic criteria to be considered should include: ? building fi nishes and structure ? air fi ltration ? air change rate or fl ushing rate ? room pressure ? location of air terminals and directional airfl ow ? temperature ? humidity ? material fl ow ? personnel fl ow ? equipment movement ? process being carried out ? outside air conditions ? occupancy ? type of product.4. Protection 4.1 Product and personnel 4.1.1 Areas for the manufacture of pharmaceuticals, where pharmaceutical starting materials and products, utensils and equipment are exposed to the environment, should be classifi ed as ?clean areas?. 4.1.2 The achievement of a particular clean area classifi cation depends on a number of criteria that should be addressed at the design and qualifi cation stages. A suitable balance between the different criteria will be required in order to create an effi cient clean area. 4.1.3 Some of the basic criteria to be considered should include: ? building fi nishes and structure ? air fi ltration ? air change rate or fl ushing rate ? room pressure ? location of air terminals and directional airfl ow ? temperature ? humidity ? material fl ow ? personnel fl ow ? equipment movement ? process being carried out ? outside air conditions ? occupancy ? type of product.

12. HVAC Air filtration and air change rate should ensure attainment of classification Air change rate is dependent on factors, e.g. Level of protection required Quality and filtration of supply air Particulates generated Room configuration Containment effect Room heat load Room pressure Air change rate normally varies between 6 ? 20 air changes per hour 4.1.4 Air fi ltration and air change rates should ensure that the defi ned clean area classifi cation 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 classifi cation. 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 fi ltration of the supply air ? particulates generated by the manufacturing process ? particulates generated by the operators ? confi guration of the room and air supply and extract locations ? suffi cient air to achieve containment effect ? suffi cient air to cope with the room heat load ? suffi cient air to maintain the required room pressure.4.1.4 Air fi ltration and air change rates should ensure that the defi ned clean area classifi cation 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 classifi cation. 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 fi ltration of the supply air ? particulates generated by the manufacturing process ? particulates generated by the operators ? confi guration of the room and air supply and extract locations ? suffi cient air to achieve containment effect ? suffi cient air to cope with the room heat load ? suffi cient air to maintain the required room pressure.

13. HVAC 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 classifi cation tests in the ?as-built? condition should be carried out on the bare room, in the absence of any 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 classifi cation tests in the ?as-built? condition should be carried out on the bare room, in the absence of any equipment or personnel.

14. HVAC 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 classifi cation 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 classify cations are rated for the ?at-rest? condition.4.1.9 Room classifi cation 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 classify cations are rated for the ?at-rest? condition.

15. HVAC 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 in the order of 20 minutes 4.1.10 Room classifi cation 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 classifi cation 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 Room classifi cation 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 classifi cation after a short clean-up time. The clean-up time should be determined through validation and is generally of the order of 20 minutes.

16. HVAC Control of contaminants External contaminants removed through effective filtration Internal contaminants controlled through dilution and flushing, or displacement airflow Airborne particulates and level of filtration considered critical 4.1.11 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. 4.1.12 Airborne contaminants should be controlled through effective ventilation. 4.1.13 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.) 4.1.14 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.) 4.1.15 Airborne particulates and the degree of fi ltration should be considered critical parameters with reference to the level of product protection required.4.1.11 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. 4.1.12 Airborne contaminants should be controlled through effective ventilation. 4.1.13 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.) 4.1.14 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.) 4.1.15 Airborne particulates and the degree of fi ltration should be considered critical parameters with reference to the level of product protection required.

17. 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. 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.

18. HVAC Level of protection and air cleanliness determined according to: Product to be manufactured Process to be used Product susceptibility to degradation 4.1.16 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).4.1.16 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).

19. Parameters influencing Levels of Protection Number of particles in the air, number of microorganisms in the air or on surfaces Number of air changes for each room Air velocity and airflow pattern Filters (type, position) Air pressure differentials between rooms Temperature, relative 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.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.

20. Tools to help achieve the desired Level of Protection 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. 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.

21. Tools to help achieve the desired Level of Protection (2) Air-handling system can be the main tool for reaching required parameters May not be 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.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.

22. 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.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.

23. Examples of Levels of Protection Types of Clean room classes WHO, EC, PIC/S: A, B, C, D US FDA: Critical and controlled ISPE: Level 1, 2 or 3 ISO: Class 5, 6, 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.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.

24. Comparing International Cleanroom Classifications There are different norms for the number of particles in the air. The table (refer to handout 3-2-10) shows that, for 0,5 micrometer particles, there are a number of names, those of the Federal Standard US 209 and the ISO guidelines being the most commonly in use at the moment. However, in the years to come, the ISO nomenclature will be generally adopted. The cleanroom classes for the pharmaceutical cleanrooms are highlighted in the table: We can see for instance that a Cleanroom class of type A corresponds to Non metric class 100 ( 100 particles / ft3 or 3.530 particles / m3) Metric class 3,5 ( logarithmic calculation ) ISO class 5 There are different norms for the number of particles in the air. The table (refer to handout 3-2-10) shows that, for 0,5 micrometer particles, there are a number of names, those of the Federal Standard US 209 and the ISO guidelines being the most commonly in use at the moment. However, in the years to come, the ISO nomenclature will be generally adopted. The cleanroom classes for the pharmaceutical cleanrooms are highlighted in the table: We can see for instance that a Cleanroom class of type A corresponds to Non metric class 100 ( 100 particles / ft3 or 3.530 particles / m3) Metric class 3,5 ( logarithmic calculation ) ISO class 5

25. HVAC Examples of levels of protection 4.1.16 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).4.1.16 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).

26. All operations within a pharmaceutical facilility should be correlated to well-defined clean room classes, and can be included in a hygiene concept. Example: 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.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.


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