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away as to minimize the introduction, generation and retention of the particles inside the room.
Clean rooms are needed to reduce contaminations levels in the product or services performed.
1.Particles and Fibers 2.Chemicals 3.Bacteria 4.Electrostatic Charges In all types of clean rooms, particles and fibers are undesirable although the minimum size of particle, which is undesirable, will vary. In the pharmaceutical and medicinal devices industries it is though unwise to introduce particles into the patient. In all types of clean rooms, spillage of chemicals from one part of the process may be undesirable in other part of the process. The Pharmaceutical industries are very concerned with bacteria because of the danger to the patient. Many of the surfaces of clean room are poor conductors i.e. plastics and can develop and retain a high electrostatic charge. It may be necessary to clean these surfaces in such a way as to leave a film of antistatic agent to conduct the change away.
Cost effectiveness in relation to requirement can be best be achieved by considering the clean room in the Critical and General zones.
0.1 0.2 0.3 0.5 5.0 1 10 100 1,000 10,000 100,000 35 7.5 3 1 NA 350 75 30 10 NA NA 750 300 100 NA NA NA NA 1,000 7 NA NA NA 10,000 70 NA NA NA 100,000 700
In the new 209E published in 1992 the air borne concentration in the room are given in metric units i.e. per m3 and the classification of the room defined as the logarithm of the air born concentration of the particles 0.5m. E.g.: - a class M3 room has a particle limit for particles 0.5m of 1000/m 3.
BS 5295:
Class 1: The particle count shall not exceed a total of 3000 particles/m 3of a size of 0.5 or greater. The greatest particle present in any sample shall not exceed 5 . Class 2: The particle count shall not exceed a total of 3000 particles/m 3of a size of 0.5 or greater; 2000 particles/m 3 of size 0.5 or greater; 30 particles of a size 10 or greater Class 3: The particle count shall not exceed a total of 1,000,000 particles of a size of 1 or greater; 20,000 particles/m3 of size 5 or greater; 4000 particles/m 3 of a size 10 or greater; 300 particles of a size of 25 or greater Class 4: The particle count shall not exceed a total of 200,000 particles of a size of 5 or greater; 40,000 particles/m3 of size 10 or greater; 4000 particles/m 3 of a size 25 or greater.
Table: - 2 Selected ISO 209 airborne particulate cleanliness classes for clean rooms and Clean zones Numbers maximum concentration limits (particles/m3 of air) for Particles (N) equal and larger than the considered size 0.1 mm ISO 1 ISO 2 ISO 3 ISO 4 ISO 5 ISO 6 ISO7 ISO 8 ISO 9 The above classification derived from formula: Cn = 10N [0.1/D] 2.08 Cn= Maximum permitted concentration (particles/ m 3 of air) of air born particles. N = ISO classification number which shell not exceed the value of 9 D = Considered particle size in mm. 10 100 1000 10,000 100,000 1,000,000 0.2 mm 2 24 237 2370 23700 237000 10 102 1020 10200 102000 4 35 352 3520 35200 352000 3520000 35200000 8 83 832 8320 83200 832000 8320000 29 293 2930 29300 293000 0.3 mm 0.5 mm 1.0 mm 5.0 mm
The manufacture of sterile products should be carried out in clean areas, entry to which should be through air locks for personal and / or for equipment and materials. The various operations of component preparations, product preparation and filling should be carried out in separate areas within the clean area. Manufacturing operations are divided into two categories 1.Those where the product is terminally sterilized 2.Those which are conducted aseptically at some or all stages Each manufacturing operation for sterile products require an appropriate environmental cleanliness level in the operational stage in order to minimize the risk of particulate or microbial; contamination of the product. In order to meet IN OPERATION condition these areas should be designed to reach certain specified air- cleanliness level in the At Rest occupancy state. The AT REST state is the condition where the installation is complete with production equipment installed and operating but with no operating personnel present The in operation state is the condition where the installation is functioning in th e defined operating mode with the specified number of personnel working. For the manufacture of sterile medicinal products normally 4 grades can be distinguished: GRADE A: The local zone for high risk operations eg. Filling zone, stopper bowls, open ampules and vials , making aseptic connections. Normally such conditions are provided by a laminar airflow workstation. Laminar airflow system should provide a homogenous air speed of 0.45 m/s 2.0% (guidance value) at the working position. GRADE B: In case of aseptic preparation and filling, the background environment for grade A zone. GRADE C &D: Clean areas for carrying out less critical stages in the manufacture of sterile products. Table: - 3 Air borne particulate classification for Grade A, B, C & D
Maximum permitted number of particles /m3 Grade 0.5mm A B C D 3500 3500 350,000 3,500,000 At rest 5mm 0 0 2,000 20,000 0.5mm 3500 350,000 3,500,000 Not defined In n operation 5mm 0 2000 20,000 Not defined
(a) In order to reach the B, C, & D air grades, the number of air changes should be related to the size of the room and equipment and personnel present in the room. The air system should be provided with appropriate filters such as HEPA for grade A, B, & C. (b) The guidance given for the maximum permitted number of particles in the at rest conditions corresponds approximately to the US. Federal Standards 209E and the ISO classification as follows. GRADE A & B correspondence with class 100, M 3.5, ISO 5 GRADE C with class 10,000, M 5.5, ISO 7 GRADE D with class 100,000, M 6.5, ISO 8
Aseptic preparation:
Components after washing should be handled in at least a grade D environment. Handling of sterile starting materials and components unless subjected to sterilization or filtration n through a microorganism remaining after later in the process, should be done in a grade A environment with a grade B background. Preparation of solutions which are to be sterile, filtered during the process should be done in a grade C environment; if not filtered, the preparation of materials and product should be done in a grade A environment with a grade B background.. Preparation and filling of sterile Ointment, Creams, Suspensions and Emulsions should be done in a grade A with a grade B background, when the product is exposed and is not subsequently filtered. Table: - 4 Comparison of various standards: Country & standard Date of current issue USA 209D USA 209E Britain BS5295 Australia AS1386 France AFNORX44101 Germany VDI2083 1990 onwards 1 2 3 ISO standard
1988
1992
1989
1989
1972
1997
1 Class 10 100
C D E or F
4,000
3 4 5
G or H J K
35 350 3500
400,000 4,000,000
4 5 6
6 7 8
References:
1. Scott SO. 1993, Handbook of International Environmental Standards. 2. Knovel (Firm), Bill Bennell,Graham C. 2003, Pharmaceutical Production and Engineering Guide. 3. Roy SB. 2001, The clean air act. 4. Winfield AJ. ,Richards RME., 2004, Pharmaceutical Practice. 5. Nigel A. Halls.1994, Achieving Sterility in Medical and Pharmaceutical products. 6. Kenneth EA. 1993, Pharmaceutical dosage forms: Parenteral Medications 7. Graham C. 1998,Pharmaceutical Production Facilities: Design and Applications