Tài liệu hệ thống HVAC ( Phần 1a) Giới thiệu và tổng quan
•Download as PPT, PDF•
8 likes•11,026 views
Tài liệu hệ thống HVAC ( Phần 1a) Giới thiệu và tổng quan
Recommended
Recommended
More Related Content
What's hot
What's hot (20)
Similar to Tài liệu hệ thống HVAC ( Phần 1a) Giới thiệu và tổng quan
Similar to Tài liệu hệ thống HVAC ( Phần 1a) Giới thiệu và tổng quan (20)
More from Công ty cổ phần GMPc Việt Nam | Tư vấn GMP, HS GMP, CGMP ASEAN, EU GMP, WHO GMP
More from Công ty cổ phần GMPc Việt Nam | Tư vấn GMP, HS GMP, CGMP ASEAN, EU GMP, WHO GMP (20)
Recently uploaded
Recently uploaded (20)
Tài liệu hệ thống HVAC ( Phần 1a) Giới thiệu và tổng quan
- 1. HVAC | Slide 1 of 26 May 2006 Heating, Ventilation and Air- Conditioning (HVAC) Sưởi, thông gió và điều hòa không khí Part 1 (a): Phần 1(a) Introduction and overview Giới thiệu và tổng quan Supplementary Training Modules on Good Manufacturing Practice WHO Technical Report Series, No. 937, 2006. Annex 2
- 2. HVAC | Slide 2 of 26 May 2006 HVAC Objectives - Mục tiêu To understand – để thấu hiểu The need for HVAC systems (Part 1a) – sự cần thiết của hệ thống HVAC The role of HVAC in protection: - Vai trò của hệ thống HVAC đối với: – Product – Sản phẩm – Personnel – Con người – Environment – môi trường The role of HVAC in dust control (Part 1b) Vai trò của hệ thống HVAC trong việc kiểm soát bụi (Phần 1b) HVAC system design and its components (Part 2) Thiết kế hệ thống HVAC và các bộ phận cấu thành (phần 2) Commissioning, qualification and maintenance (Part 3) Vận hành, đánh giá và bảo trì (phần 3) 1, 2
- 3. HVAC | Slide 3 of 26 May 2006 HVAC Introduction and Scope – Giới thiệu và phạm vi HVAC systems can have an impact on product quality Hệ thống HVAC có thể gây ảnh hưởng đến chất lượng sản phẩm It can provide comfortable conditions for operators Tạo nên sự thoải mái cho nhân viên làm việc The impact on premises and prevention of contamination and cross-contamination to be considered at the design stage Việc ngăn ngừa sự nhiễm và nhiễm chéo được tính đến trong giai đoạn thiết kế. Temperature, relative humidity control where appropriate Kiểm soát nhiệt độ, độ ẩm tương đối thích hợp Supplement to basic GMP text Bổ sung văn bản GMP cơ bản 1, 2
- 4. HVAC | Slide 4 of 26 May 2006 Factors contributing to quality products Các yếu tố cấu thành chất lượng sản phẩm Starting materials Nguyên liệu ban đầu Personnel Con người Procedures Quy trình Validated processes Kiểm soát quá trình Equipment Thiết bị Premises Cơ sở vật chất Environment Môi trường Packing materials Nguyên liệu bao bì HVAC
- 5. HVAC | Slide 5 of 26 May 2006 The manufacturing environment is critical for product quality. Factors to be considered include: Môi trường sản xuất rất quan trọng đối với chất lượng sản phẩm. Các yếu tố được xem xét bao gồm: 1. Light – Ánh sáng 2. Temperature – Nhiệt độ 3. Relative humidity – độ ẩm tương đối 4. Air movement – Trao đổi khí 5. Microbial contamination – Vi sinh gây nhiễm 6. Particulate contamination – tiểu phân gây nhiễm Uncontrolled environment can lead to product degradation Môi trường không kiểm soát có thể gây ảnh hưởng tới chất lượng sản phẩm product contamination (including cross-contamination) nhiễm sản phẩm (gồm cả nhiễm chéo) loss of product and profit Thất thoát sản phẩm và lợi nhuận HVAC
- 6. HVAC | Slide 6 of 26 May 2006 What is contamination? Nhiễm là gì 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". Đó là “Sự xâm nhập không mong muốn của tạp chất (hóa chất/ vi khuẩn /các yếu tố bên ngoài bị nhiễm vào nguyên liệu đầu vào ban đầu hoặc trong quá trình - lấy mẫu, sản xuất, đóng gói hoặc đóng gói lại". Impurities could include products or substances other than the product manufactured, foreign products, particulate matter, micro- organisms, endotoxins (degraded microorganisms), etc. Các chất tạp nhiễm bao gồm sản phẩm hoặc tạp chất khác khác, sản phẩm được sản xuất, các sản phẩm từ bên ngoài, hạt tiểu phân, vi sinh vật, nội độc tố v.v.. HVAC Glossary
- 7. HVAC | Slide 7 of 26 May 2006 What is Cross-contamination? - Nhiễm chéo là gì ? "Contamination of a starting material, intermediate product, or finished product with another starting material or product during production". “Nhiễm là do từ nguyên liệu ban đầu, bán thành phẩm hoặc thành phẩm với các nguyên liệu khác trong quá trình sản xuất". Cross-contamination can result from, e.g. Nhiễm chéo có thể là do các nguyên nhân 1. Poorly designed, operated or maintained air-handling systems and dust extraction systems Thiết kế, vận hành và bảo trì hệ thống xử lý không khí không đúng 2. Inadequate procedures for, and movement of personnel, materials and equipment Quy trình đường đi, di chuyển con người, nguyên liệu, thiết bị không đúng 3. Insufficiently cleaned equipment Thiết bị không được vệ sinh sạch HVAC Glossary, 4.1.11
- 8. HVAC | Slide 8 of 26 May 2006 Contamination Nhiễm Contaminant from Environment Operators Nhiễm từ môi trường nhân viên vận hành Contaminant from Equipment Nhiễm từ thiết bị Cross Contamination Nhiễm chéo Product from Environment Operators Sản phẩm từ môi trường, nhân viên vận hành Product from Equipment Sản phẩm từ thiết bị Cross-Contamination – Nhiễm chéo HVAC
- 9. HVAC | Slide 9 of 26 May 2006 Cross-contamination can be minimized by, e.g. Nhiễm chéo có thể giảm thiểu bằng cách: 1. Personnel procedures – Quy trình đường đi con người 2. Adequate premises – Cơ sở vật chất đầy đủ 3. Use of closed production systems – sử dụng hệ thống sản xuất “kín” 4. Adequate, validated cleaning procedures – thẩm định quy trình vệ sinh đầy đủ 5. Appropriate levels of protection of product – Có hình thức bảo quản sản phầm phù hợp 6. Correct air pressure cascade – Chênh áp phù hợp HVAC
- 10. HVAC | Slide 10 of 26 May 2006 HVAC The guideline further focuses on three concepts of the system: - tập trung vào 3 vấn đề chính Product protection – Bảo quản sản phẩm – Contamination – Nhiễm – Cross-contamination – Nhiễm chéo – Environmental conditions – Điều kiện môi trường Personnel protection – Bảo vệ con người – Prevent contact – Ngăn ngừa tiếp xúc – Comfort conditions – Điều kiện làm việc thoải mái Environment protection – Bảo vệ môi trường làm việc 2
- 11. HVAC | Slide 11 of 26 May 2006 HVAC Protection: Product and personnel Biện pháp ngăn ngừa: Sản phẩm và con người Areas where materials and products are exposed, should be classified as "clean areas” Các khu vực nguyên liệu và sản phẩm được phân loại như là khu vực sạch Achievement of clean area classification depends on factors such as: Kết quả của việc phân loại sẽ phụ thuộc vào: – Building finishes and structure – Kết cấu hoàn thiện nhà xưởng – Air filtration – Lọc khí – Air change rate – Tỷ lệ trao đổi không khí – Room pressure – áp suất phòng – Temperature – Nhiệt độ – Relative humidity – độ ẩm tương đối – Material and personnel flow – đường đi nguyên liệu và con người – Outside environment – môi trường bên ngoài – Occupancy and type of product – Thời gian bảo quản và chủng loại sản phẩm 4.1.1 - 4.1.3
- 12. HVAC | Slide 12 of 26 May 2006 HVAC Air filtration and air change rate should ensure attainment of classification – Lọc khí và tỷ lệ trao đổi khí đảm bảo để đạt được sự phân loại Air change rate is dependent on factors, e.g. – Tỷ lệ trao đổi khí phụ thuộc vào các yếu tố – Level of protection required – Mức độ của yêu cầu ngăn ngừa – Quality and filtration of supply air – chất lượng và khả năng lọc khí – Particulates generated – các tiểu phân được tạo ra – Room configuration – cấu trúc phòng – Containment effect – ngăn chặn có hiệu quả – Room heat load-tải nhiệt trong phòng – Room pressure – áp suất phòng Air change rate normally varies between 6 – 20 air changes per hour Tỷ lệ trao đổi không khí thông thường trong khoảng 6-20 lần/h 4.1.4 - 4.1.6
- 13. HVAC | Slide 13 of 26 May 2006 HVAC The classification should be achieved in the state as specified (1): "As built“ – Phòng trống – Bare room, without equipment or personnel – Phòng trống, không có thiết bị hoặc con người 4.1.7 - 4.1.8
- 14. HVAC | Slide 14 of 26 May 2006 HVAC The classification should be achieved in the state as specified (2): "At rest“ – phòng trạng thái tĩnh – Equipment may be operating, but no operators present Phòng gồm thiết bị (có thể hoạt động) nhưng không có con người vận hành trong đó 4.1.9
- 15. HVAC | Slide 15 of 26 May 2006 HVAC The classification should be achieved in the state as specified (3): "In operation“ – Phòng trạng thái động – Normal production process with equipment and personnel, Điều kiện sản xuất bình thường, gồm cả thiết bị và con người vận hành – Clean up time validated – normally in the order of 20 minutes Cần có thời gian chạy thông thường là 20 phút 4.1.10
- 16. HVAC | Slide 16 of 26 May 2006 HVAC Control of contaminants – Kiểm soát nhiễm External contaminants removed through effective filtration Chất gây nhiễm từ bên ngoài được loại bỏ bởi lọc khí Internal contaminants controlled through dilution and flushing, or displacement airflow Các chất gây nhiễm từ trong phòng được kiểm soát thông qua việc trao đổi không khí trong phòng Airborne particulates and level of filtration considered critical Tiểu phân và cấp lọc là các yếu tố quan trọng 4.1.12 - 4.1.15
- 17. HVAC | Slide 17 of 26 May 2006 Therapeutic risks – ngăn ngừa rủi ro CleanroomClassA/B CleanroomClassC Cleanrm.ClassD Others HVAC
- 18. HVAC | Slide 18 of 26 May 2006 HVAC Level of protection and air cleanliness determined according to: - Mức độ bảo vệ và độ sạch không khí được xác định theo Product to be manufactured Sản phẩm sẽ được sản xuất Process to be used Công nghệ sẽ được áp dụng Product susceptibility to degradation Mức độ nhạy cảm của sản phẩm 4.1.16
- 19. HVAC | Slide 19 of 26 May 2006 Parameters influencing Levels of Protection - các thông số ảnh hưởng đến hiệu quả của hệ thống hvac Number of particles in the air, number of microorganisms in the air or on surfaces Số lượng tiểu phân trong không khí, số lượng vi sinh trong không khí hoặc trên bề mặt Number of air changes for each room Số lần trao đổi không khí cho mỗi phòng Air velocity and airflow pattern Vận tốc khí và lưu lượng khí Filters (type, position) Lọc khí (chủng loại, vị trí lắ đặt) Air pressure differentials between rooms Áp suất chênh lệch giữa các phòng Temperature, relative humidity Nhiệt độ, độ ẩm tương đối HVAC
- 20. HVAC | Slide 20 of 26 May 2006 Tools to help achieve the desired Level of Protection – Các công cụ để đạt được hiệu quả Air Handling System Bộ xử lý không khí Production Room With Defined Requirements Phòng sản xuất Supply Air Khí cấp Outlet Air Khí đầu ra HVAC
- 21. HVAC | Slide 21 of 26 May 2006 Tools to help achieve the desired Level of Protection (2) Các công cụ để đạt được hiệu quả Air-handling system can be the main tool for reaching required parameters Thiết bị xử lý không khí (AHU) là yếu tố chính để đạt được các thông số yêu cầu May not be sufficient as such Need for additional measures such as Cần cho các phương pháp bổ sung như: appropriate gowning (type of clothing, proper changing rooms) trang phục thích hợp (chủng loại, phòng thay đồ) validated sanitation thẩm định vệ sinh adequate transfer procedures for materials and personnel quy trình – đường đi của nguyên liệu và con người HVAC
- 22. HVAC | Slide 22 of 26 May 2006 Cleanroom Class defined by Critical Parameters Phòng sạch được đánh giá bởi các thông số quan trọng Air Handling System Hệ thống xử lý không khí Additional Measures Các yếu tố bổ sung khác Tools to help achieve the desired Level of Protection (2) Các công cụ để đạt được hiệu quả HVAC
- 23. HVAC | Slide 23 of 26 May 2006 Examples of Levels of Protection Types of Clean room classes Các loại cấp độ sạch 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 HVAC
- 24. HVAC | Slide 24 of 26 May 2006 Particles / m3 ≥0.5µm US 209D non- metric US 209E 1992 metric EC cGMP Annex I 1997 Germany VDI 2083 1990 UK BS 5295 1989 Japan JIS B 9920 1989 ISO 14644- 1 1 3,5 0 2 2 10 M 1 35 1 M 1.5 1 3 3 100 M 2 353 10 M 2.5 2 4 4 1.000 M 3 3.530 100 M 3.5 A, B A= unidirectional B= turbulent 3 E or F 5 5 10.000 M 4 35.300 1.000 M 4.5 4 G or H 6 6 100.000 M 5 353.000 10.000 M 5.5 C 5 J 7 7 1.000.000 M 6 3.530.000 100.000 M 6.5 D 6 K 8 8 10.000.000 M 7 Comparing International Cleanroom Classifications Bảng so sánh phân loại cấp độ sạch HVAC
- 25. HVAC | Slide 25 of 26 May 2006 HVAC Examples of levels of protection 4.1.16 Level Condition Example of area Level 1 Mức 1 General Bình thường Area with normal housekeeping, e.g. warehouse Khu vực bảo quản: kho hàng ... Level 2 Mức 2 Protected Area where steps are taken to protect exposed material/product, e.g. dispensing Khu vực có tiếp xúc nguyên liệu/sản phẩm Level 3 Mức 3 Controlled Area with defined, controlled, monitored environmental conditions to prevent contamination and degradation Khu vực được kiểm soát môi trường để chống nhiễm chéo
- 26. HVAC | Slide 26 of 26 May 2006 All operations within a pharmaceutical facilility should be correlated to well-defined clean room classes, and can be included in a hygiene concept. Tất cả hệ thống phụ trợ trong nhà máy dược phẩm phải tương thích với cấp độ sạch. Ví dụ etc. XFilling for aseptic process XFilling for terminal sterilisation XDepyrogenisation of containers XXXPreparation of solutions for aseptic filling – Chuẩn bị các giải pháp cho vô trùng XPreparation of solution for terminal sterilisation – Chuẩn bị các giải pháp cho thiết bị tiệt trùng cuối XWashing of containers – Rửa thùng chứa, bồn chứa DCBACleanroom Class – Cấp độ sạch HVAC
Editor's Notes
- 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
- 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 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.
- 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.
- 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.
- 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.
- 4.1.4 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.
- 4.1.7 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.
- 4.1.9 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.
- 4.1.10 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.
- 4.1.11 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.
- 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.
- 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).
- 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.
- 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.
- 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.
- 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.
- 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.
- 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
- 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).
- 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.