Design and Operations of Clean Room| Pharmacy

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1. Welcome to My Presentation Topic: Design and Operation of Clean Rooms Presented by Md. Shakil Sarker SID: PHA 20008 3rd Year 1st Semester Department of Pharmacy MBSTU

2. A clean room or area is a room with different environmental control of particulate and microbial contamination, constituted and used in such a way as to reduce the introduction, generation and retention of contaminants within the area. In another word, a clean room is a room in which the concentration of air hold particle is controlled to a specified limit. Definition of Clean Room

3. The possible sources of contamination are as follows 1. External Sources 2. Internal Sources : It encompasses the followings A. Atmosphere: This includes a) Dusts b) Droplets c) Free Organisms B. Operator: This includes a) Breaths b) The hands c) Clothing d) The hair C. The working surface D. Equipment’s E. Raw materials Source of contamination

4. 1. External Sources External contamination is brought primarily through a) Air conditioning system b) Make up air In addition, external contaminants can in filtrate through Building door Windows Cracks and wall Pipes The cables and ducts Source of Contamination

5. Source of Contamination Primarily the external contamination is controlled by a) High efficiency filtration b) Space pressurization c) Sealing of the space of penetration 2. Internal Sources A. Atmosphere The environment may become contaminated by the following materials. a) Dust : They carry soil borne bacteria. e.g. Saprophytes and Cocci . In addition, pathogenic anaerobic sporing rods are quite common. Indoor air also contain Staphylococcus and B Hemolyticus etc.

6. Source of Contamination b) Droplets Large numbers of droplets are excreted from the respiratory tract by coughing and sneezing and may contain organisms. c) Free organisms Bacteria and viruses free from dusts-droplets are uncommon, but naked yeast and mold spores are often abundant. B. Operator : This includes the followings a) Breaths : In normal breathing few organisms are passed into the atmosphere. But coughing and sneezing contain many organisms. e.g. Staphylococcus aureas .

7. Source of Contamination b) The hands : These are major means of transmitting infections. c) Clothing : Part of the atmospheric dust that becomes engulfed in the fiber of the fabrics can considerably raise the level of contamination around a person who is working carelessly. d) The hair: Part of the atmospheric dust that becomes engulfed in hair can considerably raise the level of contamination. C. The working surface : This is a potential source of contamination because organisms will sediment on to it from the air. D. Equipment : Working surface and the external surface of the equipment are potent sources of contamination. E. Raw materials : Raw materials may account for a high proportion of microbial and inert particticulate contamination included into the pharmaceutical products.

8. Classification of Clean room Clean rooms are classified based on the particle counts per cubic fit of air and are defined in terms of the maximum number of particle is in the range of 0.5 μ or larger than 5 μ or larger size. Generally two systems exists for the classification of clean room 1. The British Standard 2. The Unites States Federal Standard These two systems are compared in the following table

9. Classification of Clean room All clean room and working stations designed by this standard must be capable of meeting at least one of the following classes; Class 100 : Class 100 clean room is defined as a room in which the particle count in the air is not more than a total of 100 particles per cubic foot of the size 0.5μ and larger. Class 10,000 : Class 10,000 clean room is defined as a room in which the particle count in the air is not more than a total of 10,000 particles per cubic foot of the size 0.5μ and larger. or 65 particles per cubic foot of the size 5μand larger. Class 100,000 : Class 100,000 clean room is defined as a room in which the particle count in the air is not more than a total of 100,000 particles per cubic foot of the size 0.5μ and larger. or 700 particles per cubic foot of the size 5μand larger.

10. Airflow Systems There are mainly four methods of controlling the atmospheric contamination. 1. Conventional air flow : This is also known as turbulent air flow and is distinguished by its method of air supplying system. 2. Unidirectional air flow : This is also known as laminar air flow. In this system the air is supplied linearly from a high efficiency filter and passes in a unidirectional manner through the room. 3. Mix flow : This is a conventional type of air flow but where the product is exposed to contamination, a unidirectional cabinet or work-station is used. 4. Isolator or micro-environment flow : This is also used within a clean room to give the highest level of protection against contamination. The isolator is shown to have a unidirectional supply of air.

11. Conventional air flow In the Conventional air flow system filtered air is pumped into the room to produce a positive pressure, compared to the exterior and in a turbulent fashion. The foreign particles already present may flash out and maintain a clean condition. Air enters into the room through the filter in the ceiling or high up in the wall and leaves from the room trough carefully cited outlets or outlet ducts fitted in low down on the opposite wall or in the floor at a distance from the inlet. Conventional air flow is defined in terms of the number of air changes per hour. The air flow should not be less than 2 poise per hour.

12. Unidirectional air flow (Laminar air flow) Laminar flow cabinet is an asepsis cabinet where laminar air flow is used. This can be classified into two types of construction - i. Horizontal ii. Vertical Construction: It consists of two types of filter, a fan & cabinet body. Filters : (a) Prefilter: It is a glass fiber & able to retain 97% of particles of 5µm or greater. (b) Absolute filter or high efficiency filter: This filter is capable of removing 99.9%-99.99% of particles & bacteria of 0.3 µm & above. Advantages : (i) In this cabinet the risk of contamination during aseptic processing or sterility testing is very low. (ii) It can be placed anywhere of the asepsis room & the power point of the fan. Disadvantages : (i) Cabinets vertical flow are necessary to protect the operator when working pathogenic organisms.

13. Unidirectional air flow (Laminar air flow)

14. There are four mechanism of air filtration 1. Straining 2. Impingement 3. Attractive forces 4. Diffusion Straining : If the pores of the filter medium through which the fluid is flowing are smaller than the material, which is to be removed then the material will be retained. In this case filtration occurs in the surface of the filter. Impingement : Suspended particles with in-sufficient momentum may not follow the fluid path, but impinge on the filter fibre and are retained due to the attractive forces between the particle and the fibre. Attractive forces: Electrostatic and other surface forces may exert sufficient hold on the particles to attract and retain them on the filter medium. Diffusion : Particles are filtered through the filter media due to the concentration gradient. Mechanisms of Air Filtration

15. HEPA Filters Air can be filtered using HEPA (High Efficiency Particle Air) filters. They are usually used in biological safety cabinets. HEPA filters are at least 99.97% efficient for removing particles >0.3 μm in diameter. Examples of areas where HEPA filters are used include rooms housing severely neutropenic patients and those operating rooms designated for orthopedic implant procedures. HEPA filter efficiency is monitored with the dioctylphthalate (DOP) particle test using particles that are 0.3 μm in diameter.

16. Fibrous Filters Porosity : 70 to >99% Fiber size : <1 to 100 micron Examples: Cellulose fiber, glass fiber, plastic fiber. Low velocity : 10 cm/sec Need large filter area

17. Temperature and Humidity Control of Clean room Temperature control: An advantages of heating as asepsis room by the ventilation system is the elimination of radiators. The heater section of a ventilation usually warms the air by pipes containing water or steam. Humidity control: The atmosphere of an asepsis room become unpleasantly dirty if bunsens are burning & the heating unit is operating. A humidifying plant is required to increase. The humidity is about 55%.

18. Factors of designing and construction of clean room Different factors are to be considered is designing an ideal clean room. (a)Site : The clean room should be away from stairs, lift shafts & corridors by which air borne microorganisms can travel around the room building. (b)Size : The main factors controlling the size of the room is the maximum number of people using it at any one time. A large fairly high room is more pleasant to work in. ( c) Windows : The windows must be double glassing where the inner sheet being fixed & the outer are made openable for cleaning. (d) Doors : The clean room should be entered through an air lock with double doors. (e) Surfacing materials: The floors, walls & bench tops of an asepsis rooms must be- Easily cleaned, Smooth, Impervious, Resistant to chemicals. (i) Floors: The floors should be made of Terrazzo, Linoleum and Plastics. (ii) Wall & ceiling: It should be made of Tiles, Hard gloss paint on smooth plasters, Plastic laminated board (iii) Bench tops: It should be made of Stainless steel, Plastic laminates.

19. Factors of designing and construction of clean room (f) Services : An clean room will require the following services- (i) Ventilation: in removal of microorganisms control of humidity& provision of fresh air. (ii) Electricity: for lighting & sometimes for hot plate, UV lamp, aerosol producer or vacuum pump (iii) Gas: for the bunsen burner. (iv) Composed air & vacuum: for clarification & bacterial filtration. (v) Nitrogen: for replacement of air by inert gas. (vi) Water: for the necessity in the washing room. (vii) A method of dealing waste

20. Personnel Protective Clothing The clothing include- 1. Gowns & trousers 2. Head-dress 3. Mask 4. Gloves 5. Footwear (1) Gowns & Trousers: It must completely cover the clothes underneath. It must be long. Buttons should be made of rubber & sterilized. It can be sterilized by autoclaving. Modern clothing for industrial asepsis room is often of closely woven terylene. Long trousers are not often worn. (2) Head-dress : Complete enclosure in a hood long enough to tuck into the neck of the gown is desirable . A cap into which the hair is pushed is much less decorous. (3) Masks : The mask may be made from gauze, muslin, linen, card, paper & transparent plastics. Mask should be sterile & changed frequently.The efficiency of a mask depends on the material, the design, fittings & the period of use. (4) Gloves : Some articles that are externally unsterile must be handled with rubber gloves . (5) Foot-wear : Rubber shoes & surgeon’s boots are uncomfortable if worn for long. Leather shoes with low heels & rubber soles are easy to keep clear if never used outside the suite. Overshoes of terylene may be used in industrial asepsis laboratories.

21. Personnel Protective Clothing

22. Cleaning and Disinfection of clean room Three types of cleaning methods are available- (i) Dry cleaning (ii) Wet cleaning (iii) Disinfection (i) Dry cleaning : Dry cleaning of floors can be done by- Brooms: Are unsuitable because they disperse large amounts of dust into the air. Vacuum cleaners: Very useful for prevent the tiny particles from passing the fabric. Mops: Impregnated with dust retaining oil are very useful if it is regularly cleared. (ii) Wet cleaning : Floors: Mopping with really hot water containing detergent is adequate for cleaning. Walls & furniture: -Wiping with a slightly damp -Clean cloth is sufficient (iii) Disinfection : Frequent disinfection is unnecessary in a well- ventilated and efficiently cleaned room. The mop should be soaked the previous night in a separate quantity of the solution to saturate if with the disinfectant. e.g.- synthetic phenol, quarternary ammonium compound.

23. Commissioning Test of clean and aseptic rooms British standard 5295 list the tests and procedures which should be used to confirm that the room meets the required designated specifications. These tests and procedures includes the followings A. Final filter installation test : This test is carried out to demonstrate that, the filter is not damaged, filter holding frame do not leak at the connection. This test can be performed by the bubble point test. B. Induction leak test: This test demonstrates that, particle cannot enter into the room through the leak in the construction joint. This is carried out by measuring the size of the leak or by microscopic examination. C. Filter efficiency test: This is also carried out by the bubble point test. D. Particulate contamination controlling test : This is used to demonstrate that, the number and size distribution of particulates in the room air do not exceed the level specified for the particular class of room. Microscopic examination and direct reading light scattering photometer are used for such measurement. E. Air pressure test: This test determines the pressure difference between the clean room and adjacent area. This is usually carried by using a sensitive monometer. F. Temperature and Humidity : This test demonstrates that the specified limit for temperature and humidity can be achieved, maintained and usually carried out by a psycometer.

24. Commissioning Test of clean and aseptic rooms G. Air flow test: This test is carried out to demonstrate that the air velocity or uniformity or laminar air flow in the room, comply with the required standard. H. Noise level test : Noise level measurement is taken to determine the sound frequency or noise sound for equipment, especially for oscillary equipment. The measurements are taken at one meter from air inlet and at work benches. I. Lighting test: The quality of the general illumination within the area and also at the work benches is measured by using a potable photoelectric photometer. J. Microbiological test: This test is carried out to determine the number of the microbial contamination resulting from the introduction of the personnel, equipment or other things into the area.

25. Monitoring Test of clean and aseptic rooms Monitoring test is carried out to ensure the performance of the room as well as to ensure that the designed conditions are maintained. The test should be carried out repeatedly and regularly. The British standard recommends minimum interval for repeated testing. The testing parameters are given below- a) Air pressure, temperature and humidity measurements should be recorded continuously. b) Particulate contamination should be determined daily for aseptic room and weekly for clean room. c) Tests for air flow velocity and uniformity should be carried out at the three months interval. d) Tests for filter efficiency should be conducted yearly. But, tests should be repeated after repair and maintenance. e) It is recommended that, the settle plate, Agar plate, contact plate, sterility test and swab should be carried out during each workshop. f) The process simulation should be conducted at three three months interval.

26. The operation of clean and aseptic room The aim of the aseptic technique is to prevent the access of microorganism during the preparation and testing of the pharmaceutical products. There are several classes of pharmaceutical products for which the terminal heat treatment is not possible. For these preparations aseptic technique is used. For example A. Thermolabile soluble substance stable in solution : Solution of these substances can be filtered through a bacteria proof filter, but aseptic technique is required to prevent the contamination of the filtrate during the collection and while it is being filled & packed as well as sealed in the final container. For e.g. Thyamine-HCl injection. B. Thermolabile soluble substance unstable in solution: Filtration through a bacteria proof filter is impractible because these medications are not sufficiently stable in solutions for longer period. They must be preserved aseptically in a sterile solvent. For e.g. Chronic Gonadotropin injection. C. Thermolabile suspension stable in vehicle : Example: Propyliodon and Propyliodon Oily injection D. Thermolabile powder that require dilution with other powder : Example: Antibiotic dusting powder E. Thermolabile powder that require incorporation of a semisolid base: Example: The eye ointment BP.

27. Key factors in clean room operations The preparation of sterile pharmaceutical products requires special facilities, designed to eliminate microbial and microbial and particulate contamination at all stages of manufacture. 1.Premises : The premises in which the manufacturing of sterile products take place should provide sufficient space to allow efficient flow of work through all the necessary operation. 2.Storage area : Storage space is required for raw materials, Empty containers, Packaging and labeling materials. 3.Weighing area : The main use of this area is to measure raw materials used for the product. 4.Bottle washing area : All bottles should be washed prior to entry into the clean room. Clean washed areas within the clean room are sometimes used for washing the ampoules, vials and various components just prior to use. 5.Laundry or cleaning area : Access to clean room or areas is permitted only via the changing area. The operators must exchange their outdoor clothing for working in the clean room. 6.Preparation : There are Clean room areas for the collection of water, Preparation of solution and final bulk product

28. Key factors in clean room operations 7.Filling area: This is the most critical area. The product is filled into the final container via a filler of suitable size and then sealed and send out of the clean room area. 8.Sterilization area: If the product is not aseptically produced, it has to be sterilized in this area. 9.Inspection and labeling : Once the product has been sterilized, the contents are inspected for defects and then labeled. 10.Bonded area and release: Lockable area where the product is kept until it passes all the requirements of Q.C. After qualifying the requirements of QC &QA the product is released for use.

29. REFERENCES 1. US Food and Drug Administration, Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice, 2004. 2. European Commission: Enterprise and Industry Directorate-General, EudraLex–The Rules Governing Medicinal Products in the European Union – Volume 4 – EU Guidelines to Good Manufacturing Practice – Medicinal Products for Human and Veterinary Use, Annex 1: Manufacture of Sterile Medicinal Products (corrected version), 2008. 3. International Organization for Standardization (ISO), ISO14644-4, Cleanrooms and Associated Controlled Environments–Part 4: Design, Construction and Startup, 2001. Thank You