Aseptic Room Validation

BY
Dr. K. Prabhakar Reddy, Associate Professor,

St Peters Institute of Pharmaceutical Sciences, Vidyanagar, Hanamkonda.
Pharmaceutical Equipment and Validation
CONTENTS
1. 2. 3. 4. 5. 6. 7. 8. 9.
INTRODUCTION THE DESIGN OF ASEPTIC AREA FACILTY DESIGN SOURCES OF CONTAMINATION MAINTENANCE OF ASEPTIC ROOM STANDARDIZATION OF ASEPTIC AREA ASEPTIC AREA VALIDATION CONCLUSION REFERENCES.
Pharmaceutical Equipment and Validation 2
INTRODUCTION
Asepsis is the practice to reduce or eliminate contaminants (such as bacteria, viruses, fungi, and parasites) from entering the operative field in surgery or medicine to prevent infection. Ideally, a field is "sterile" free of contaminants a situation that is difficult to attain. However, the goal is elimination of infection, not sterility. Aseptic Processing is the processing of drug components ( drug product, containers, excipients, etc.) in a manner that precludes microbiological contamination of the final sealed product.

Contd..

The parenteral preparations differ from all other drug dosage forms because of the unique requirements imposed. They must be exceptionally pure and free from physical chemical and biological contaminations. These products are require to be sterile. These requirements place a heavy responsibility on pharmaceutical industry and pharmacist .
Ideal methods of manufacturing of these sterile products fall into two categories
1.
Terminal Sterilization Process
2.
Aseptic Processing Operation
Comparison of terminal sterilization and aseptic processing

Terminal sterilization
Aseptic processing
Product containers are filled and sealed under high-quality environmental conditions designed to minimize contamination, but not to guarantee sterility. Product in its final container is subject to a sterilization process such as heat or irradiation.
Drug product, container, and closure are subject to sterilization separately, and then brought together. Because there is no process to sterilize the product in its final container, it is critical that containers be filled and sealed in an extremely high quality environment.
TERMINAL STERILIZATION
Drug Product
Container / Closure
Sterilization Process
Sterile Drug Product !
Excipients
Sterilization Process must be compatible with all components !

Aseptic Processing
Drug Product
Sterile Drug Product Sterile Container Aseptic Processi ng Sterile Final Product
Container
Closure
Sterile Closure
Excipient
Sterile Excipient
Can use multiple sterilization processes each optimized for the individual component
THE DESIGN OF ASEPTIC AREA
THE DESIGN OF ASEPTIC AREA FOR THE MANUFACTURE OF PARENTERALS

The design should possess following characteristics: The aseptic room must be designed to prevent contamination of parenteral during processing. It must be cleanable and sanitizable, with a minimum of particles shedding and crevices or other sites where dirt can accumulate.

10
The structural surfaces are of ceiling, walls, and floors, and works surfaces and storage surfaces should be smooth and resistant to cleaning and sanitizing. Work surfaces should be stainless-steel and epoxy coated structural surfaces are preferred. Equipments and instruments also should meet these general requirements. Equipments with non-cleanable, particle-shedding mortars, gears, preferably in stainless steel enclosures.
11
THE DESIGN OF ASEPTIC ROOM

The design of aseptic room includes Site, size, windows, door, surfacing material ( floors, walls & ceiling and bench tops), services, furniture
SITE

As far as possible from rooms to which non pharmaceutical staff have access. It must be adjacent to support areas so that an efficient flow of components may be achieved. Be away from stairs, lift shafts and corridors. Access to the room should be through one or more rooms with washing and changing facilities.
12
SIZE

Size of the room is the maximum number of people using at any one time. Provide adequate space for work load anticipated. Generally large size is preferred but the capital and maintenance cost of the equipment for controlling the microbial content, temperature, humidity of atmosphere are reduced by keeping the room small.
13
WINDOWS Should be made of non-shedding materials preferably with double panel and should flush with walls. Large windows of clear glass are most preferable but they must not open. DOORS Should be air lock with double doors about one meter apart. This prevent a sudden inrush of air when the door is opened. They are two types of doors 1. Sliding Doors 2. Swinging Doors
Surface Materials:
The floors, walls, and bench tops of an asepsis room must be easily cleaned, smooth, impervious, resistant to chemicals, non shedding, non flaking, non cracking, and unbroken 1. FLOORS Flooring should be unbroken and provided with a cove both at the junction between the wall and floors as well as the wall and ceiling. The most suitable materials are terrazzo, linoleum and plastics. Terrazzo (Cement + Crushed Marble): Most suitable materials for flooring. It is spread in plastic form on the site or is available as tiles In both cases expansion joints of ebonite (black) or PVC (various colors) are essential to prevent cracking.
15
Linoleum
Available as a sheet and tile forms in many colors. It can be surface sealed to reduce treading in of dust and marking rubber heels

Plastics

The non- slip or matt-finish grades of PVC are suitable for asepsis rooms. Obtained as sheets or tiles& the joints can be welded.
16
2. walls and ceilings: The possible surfaces are Tiles, hard gloss paint on smooth plaster, plastic laminated board. Walls shall be suitable for flushing some special requirements like electric sockets, gas points, sterilizers Ceilings shall be suitable for light fittings, air-grills flushing; not hanging from the ceiling.

3. Bench tops: The most popular surfaces for asepsis work are stainless steel, plastic laminates.
17
SERVICES:

The location of these services and their servicing or repairing shall not pose any threat to the integrity of the facility. An asepsis laboratory will require many, if not all, of the following Ventilation, Electricity, Gas, Compressed Air or Vacuum, Nitrogen, Water, A Method of Dealing with Waste.
ELECTRICITY: It is used for lighting and sometimes for a hot plate, UV lamp, aerosol producer or vacuum pump. Switches and sockets should be flush fitting and have finger plates of plastic because metals are less resistant to the fluids used for cleaning and disinfection. Most of the controls can be outside the room. Light Fixtures:
18
GAS:
Used for Bunsen burner For easy operating / usage wall fitted service outlets and separate benches are arranged, so that the operator need not to getup to use them. Gas cock should not place under the bench top because the tubing comes up from the front and there is a risk that if the burner is near to edge, therefore it will be pulled off by the elasticity of the tubing or by accidentally catching the latter with arm.

COMPRESSED AIR AND VACUUM: Used for clarification and bacterial filtration.
For these services rotary pumps can provide separately. They are best housed outside the lab because pumps are noisy.

NITROGEN:

Used for replacement of air by an inert gas. A cylinder can be kept near to the vacuum pump and connected via a reducing valve.
WATER:
It is difficult to justify a water supply in the laboratory itself. Hand washing facilities are undesirable, because of the risk of splashing organisms from the hands into the air and onto working surfaces or equipment. If water system is necessary, elbow operated taps, foot operated taps, knee operated taps are arranged along tiled walls. In all above types there is no need to use the cleaned hands for turning of the water.

20
Waste disposal:
Foot operated waste bin is popular (but it need partly sliding from the chair and also the mouth is very small i.e., cant receive large pieces of paper). The better method is to fit the bin at the side of knee space having a metal ring that can be swiveled under or out from the bench.

FURNITURE: Shall be smooth, washable and made of stainless steel and any other appropriate materials other than wood.
21
BENCHES:

The conventional benches may be replaced by tables, wall mounted work shelves are preferred to remove the dust. These tables and work shelves are easily over looked the dust under surface of top. Must be adjustable and comfortable
SEATS:

Adjustable chairs ensures that the users face is well above the front opening of the screen, therefore the breath is kept away from the materials underneath. The fabric must be washable. Comfort is best assured by chairs rather than stools and by upholstered rather than wood or metal, seats and backs.

22
TROLLEYS: Trolleys with removable trays (preferably of stainless steel) are better than tables benches or cupboards for holding spare equipment. DOOR MAT: It is necessary, because the outdoor shoes are heavily contaminated with dust born organisms. It is better useful if the mats are in the air lock and immersed in a detergent disinfectant solution. These mats are available in two types 1) Honeycomb structure like mats and 2) Disposable adhesive faced pad.
23
Screens:

Usually aseptic technique is carried out under screen 1) Shake type and 2) fume cupboard type The shake type consisted of wooden case with sloping front of glass but the most common fabrication material is Perspex. The fume cupboard type used to fit the tall operators like burettes.
24
Facility Design
25
Facilities
Establishing and Maintaining an aseptic environment
Use clean-rooms of various classes to establish an aseptic area Clean rooms use combinations of filtration, air exchange, and positive pressure to maintain clean environment Lower quality clean areas should not be placed next to high quality areas
26
Facilities: General Clean room Design

HEPA / ULPA filters on ceiling Exhaust vents on floor Drains in aseptic processing areas are inappropriate Airlocks and interlocking doors to control air balance Seamless and rounded floor to wall junctions Readily accessible corners Floors, walls, and ceilings constructed of smooth hard surfaces that can be easily cleaned Limited equipment, fixtures and personnel Layout of equipment to optimize comfort and movement of operators
27
Facilities: HEPA Filters

High Efficiency Particulate Air Minimum particle collection efficiency: 99.97% for 0.3m diameter particles. Disposable Filter made of pleated borosilicate glass
28
Facility Design: Clean Area Classification
FS209 Cleanroom classification 100,000 10,000 1000 100
Microbiological Active Microbiological Settling ISO 14644-1 Cleanroom Air Action Levels Plates Action Levels (diam. 0.5um particles/m3 classification (cfu/m3) 90mm; cfu/4hours) 8 3,520,000 100 50 7 352,000 10 5 6 35,200 7 3 5 3,520 1 1
P h a r m a c e u t i c a l Equ i p m e n t a n d Va l i d a t i o n
29
Facilities: Clean room Classification
Class 10,000 clean room Class 100 clean room

http://www.americancleanrooms.com/am/photogallery_08.html Pharmaceutical Equipment and Validation
30
Facilities: Clean room Classification

FS 0 S 4 44 Cleanroom Cleanroom classification classification 00,000 10,000 1000 100 7 6 ia le icro es cfu/m 100 10 7 1 e irflo elocit f m -10 10-1 -40 40-80
0. um articles m 3, 3 0,000 ,000
ir c an es/hr -48 60- 0 1 0- 40 40-480
3 , 00 3, 0
31
Facilities: Pressure Differentials

Used to maintain airflow in the direction of higher cleanliness to adjacent less clean areas A minimum of 10-15 Pascals should be maintained between the aseptic area and an adjacent rooms with differing clean room classifications (doors open)
32
Facilities: Air Lock

Permits the passage of objects and people into a clean room. Consists of two airtight doors in series which do not open simultaneously. Spray down materials with 70% IPA before placing in the airlock
http://news.thomasnet.com/images/large/451/451402.jpg
33
Facilities: Material NOT permitted in a Clean room
Fiber-shedding materials such as cardboard and paper

y Cardboard packaging must be removed and items placed into
non-cardboard containers.
Wood (i.e. wooden pallets) Undesignated charts
34
Facilities: Cleaning
1. Vacuum all accessible surfaces 2. Wipe surfaces with a cleaning solution 3. Mop floors using a lint free polyester mops attached to stainless steel handles
Water should be changed FREQUENTLY

Isolators
The use of isolators prevents direct contact with product However, the use of isolators can lead to relaxation of aseptic practices!
36
SOURCES OF CONTAMINATION 1. 2. 3. 4. 5. 6. 7. The Atmosphere The Breath The Hands Clothing The Hair The Working Surface Equipment
37
MAINTENANCE OF ASEPTIC ROOM

To maintaining the clean and sanitized conditions of aseptic areas requires diligence (care) and dedication of expertly trained custodians. The design of the facilities to be cleanable and sanitizable, a carefully planned schedule should be developed depending on location and its relation to the most critical class 100 areas.
38
Contd Tools used should be non- lining designed for clean room use, held captive to the area and preferably sterilized.

The maintenance of aseptic room depends on cleaning methods, personnel, garments, and environmental control.

39
CLEANINIG METHODS:

They are necessary to remove the dirt.
The cleaning methods includes; dry- cleaning, wet cleaning, and sanitization / disinfection. Dry cleaning: Vacuum cleaners are more prefer, because they prevent tiny particles from passing through the fabric.

Mops impregnated with dust retaining oils also used but they need regular cleaning and reimpregnated.

40
Contd.

Brooms are unsuitable because they disperse large amount of dust into the air. If the floor is semi porous surfaces (such as unpolished linoleum) occasionally treatment with spindle oil. Wet cleaning:
Floors must be mopping with hot water containing detergent

Walls and furniture must be cleaned with clean cloth with slight dampness.
41
Disinfection / sanitization:
This is necessary to possess good hygienic conditions in aseptic area The employees must be trained for this purpose. The sanitization is produced by using different concentrations of sanitizing agents like alcohols, aldehydes, cationic surfactants, chlorhexidine, dyes, phenols, oxidizing agents and halogens.

Mostly liquid disinfectants are preferable because their reliable activity against inherent environmental microorganisms. They should be recognized as supplements to good house keeping. Industrially three bucket system used to sanitized the aseptic room

The UV light rays of 237.5nm radiated by germicidal lamps are an effective surface disinfectant. Different sanitizing shall be used in rotation with sufficient frequency. Dilution of sanitizing agents with fresh distilled water (above 700C) used. Eg; 70% alcohol or 60-70%of isopropyl alcohol used as hand sprays. Formaldehyde or any other equally effective fumigant is recommended for the fumigation of aseptic areas. All these diluted disinfectants shall bear the label clearly like use before etc. Some germicides are recommended for floors, surfaces are synthetic phenols, quaternary ammonium compounds and iodophors.

43
PERSONNEL

Must be neat, orderly and reliable.
They should be in good health and free from dermatological conditions.
If they show symptoms of a head cold, allergies or similar illness are not allowed into aseptic area until recovery.

Aseptic area operators should be given thorough, formal training in the principles of aseptic processing.
Personnel should have sufficient knowledge and skills in aseptic techniques to be employed.

44
CLOTHING: The garments used in asepsis lab includes, gowns and trousers, head dress, masks, gloves, goggles & foot wear. The design of all these to facilitates the contaminants discharged from the body of the operator.
45
ENVIRONMENTAL CONTROL
The facility should be centered on the control of air borne and surface contamination both viable and nonviable. Current aseptically processed parenteral drugs should provided a level of sterility assurance of 1in 3000units. This level is still potentially demanding standard. Therefore to achieve this level of sterility assurance the adequate environmental control program to be designed. Environmental control should be provided by, HVAC (Heating Ventilation and Air Conditioning system) Temperature and humidity control Air filtration (High Efficiency Particulate Air) Air handling system (Central-Air Conditioning) Air motion (laminar air flow) Pressure control system (pressure gradients)
46
The design of suitable installation of above systems provide bacteriologically clean air.

HVAC systems: It should be designed to provide control over the air borne viable and non viable particles To prevent air borne contaminants from entering the clean or aseptic environment ,all air supplied for the environment must be filtered. The level and type if filtration needed depends on level of cleanliness required.
47
Temperature and humidity control:

Temperature control is required to offer primarily a comfortable working environment for operators.

Generally 68-74 0F(19-23 0C) is acceptable range.
Lower temperature are preferred in poorly ventilating manufacturing environment. Certain areas of manufacturing facility (like those ware autoclaves and dry heat sterilization tunnels and ovens) are located ,should provide higher heat loads to a system.

Temperature control in asepsis room by the ventilation system is important. This is advantage of heating because the elimination of radiator which are dust collectors and distributors.

48
Humidity control:
This is very important in asepsis lab because the asepsis room may become unpleasantly dry if several Bunsen's are burning or the heating unit is operating . Generally 45-55%RH is preferred for asepsis. Normal humidity levels can be easily achieved with air conditioning systems. Air dryers can be used to maintain lower than normal humidity levels. Controlled spaces requiring humidity control should be built with vapor proof barrier materials to ensure the minimum of water migrations.
49
Air filtration
It is important for air borne contamination control with using various types of air filters.

Bacteriologic ally clean air can be produced by removing the microorganisms by mechanical filtration or electrostatic precipitations or by destroying them with heat , U.V light or chemicals.

Filtration mechanisms:
Inertial impaction, Direct impaction, Diffusion ,Impingement, Electrostatic forces

Types of filters: Three types, Coarse filters, High efficiency filters and Absolute filters. High efficiency filters: When a higher standard is desired ,these are used. Eg: HEPA
HEPA filter design:

It is a disposal, extended media, dry type filter in a rigid frame . Construction of HEPA Frame: with Board, Plastic, Metallic material. Filter medium: glass micro fiber. Separators: Kraft paper, Al-alloy and plastic. Adhesives: Poly urethane cones and silicate adhesive Gasket: cell neoprene foam or Teflon Most of the micro glass filter media on the market have fireretardant and water proof properties.

51
Principle: Brownian diffusion for small particles. Inertial effect for intermediate particles. Sieving effect for large particles.
Functioning : Recirculation of air or dilution of contaminants. To provide enough capacity to ensure an adequate level of cleanliness by recirculating the air contained with in the environment
52
Air Handling Systems (Central-Air-Condition)

It can be described as the core of the heating, ventilation, & central air condition system. Central systems used for control areas normally employ an air-to-air or air-to-water cooling systems. The filter configuration in the air handling system shall be suitable designed to achieve the following grades of air.

53
Grade
At Rest
In Operation
The maximum number of permitted particles per cubic meter equal to or above 0.5m A B C D 3520 35200 352000 3520000 5m 29 293 2930 29300 0.5m 3500 352000 3520000 Not Defined 5m 29 2930 29300 Not Defined
54
The minimum air changes for grade B and grade C areas shall not be less than 20air changes for hour in a room with good air flow pattern and appropriate HEPA filters. For grade A, LAF work stations the air flow rate shall be 0.3m/sec 20%(for vertical flows) and 0.45m/s20%(for horizontal flows).
55
Air Motion (Laminar air Flow):
The required environmental control of aseptic area has been made possible by the use of LAF originally through a HEPA filter . It bathes the total space with very clean air , sweeping away contaminants. Velocity: 90 fpm 20%. It produce clean air in a vertical, horizontal or curvilinear fashion. LAF clean benches should supply class 100 air. The velocity meter to check the air flow rate. Plastic curtains are installed to maintain unidirectional air flow i.e., the area out side the curtains can be maintain at a slightly lower level of cleanliness than that inside.
56

Today it is accepted to meet class 100 standards. LAF will do an excellent job of maintaining the sterility of an article bathed in the air flow. For most sterility testing operationshorizontal LAF are more preferred than vertical. Entry point is changing room. Changing room should not be used for the entry of anything except personnel. The change room is most conveniently arranged to provide separate three areas black, grey, and white areas for successive stages in the entry process. The black room used to remove and store outer clothing and Jewelers and to change the shoes.
ENTRY PROCEDURES:

57
The grey room is used for a preliminary hand wash using detergent based disinfectants such as Chlorhexidine solution. White room: separated from grey room by a low threshold-bench.& Used for clean room clothing may be worn. Change room doors shall not be opened simultaneously. For Communication An appropriate inter locking system and a visual and or audible warning system may be installed to prevent the opening of the door more than one time. Intercom telephones or speakphones shall be used.

58
Standardization of Asepsis
By Simulation method, calculation method. Mostly used method is Simulation method. Simulation Method/ Media fill method: It is desirable to be able to quantify the risk of contamination in any aseptic fill or transfer procedure. In this method to simulate the aseptic transfer by substituting a microbial growth medium for the product. It involves preparation and sterilization of sterile triptycase soya broth. and filling this broth in to the sterile container under conditions similarly. Incubate at 20 0C - 25 0C and 30-35 0C at least 14 days.
59

If growth occurs contaminants has entered the container during process. To pass the test at 95% confidence not more than 0.1%of the challenged units. This test is a very stringent evaluation of efficiency of an aseptic filling process.
Advanced aseptic processing It is designed to isolate aseptic operations from personnel. Ex: Isolation (barrier) technology. In this technology operations are performed within windowed, sealed walls with operators working through gloves ports. The sealed enclosures are pre -sterilized, usually with paraacetic acid, hydrogen peroxide vapour or steam.

60
Sterile
supplies are introduced from Sterilizable movable modules through uniquely engineered transfer ports or directly from attached sterilizer, including autoclaves and hot air sterilizing tunnels.
Results have been very promising ,giving expectation of significantly enhanced control of the aseptic processing environment. This is used to increase frequency in the processing of sterile products.
61
Advantages To maintain human intervention Increase dramatically the assurance of sterility Inexpensive Allowed for aseptic processing with out the construction of large processing areas, sterile suites or gowning areas.
62
ASEPTIC AREA VALIDATION
63
PURPOSE

To provide the guideline for classification of areas to prevent mix ups or cross contamination
RESPONSIBILITY

It is the responsibility of all departmental managers to follow the procedure. The quality assurance manager is responsible for SOP compliance.
64
PROCEDURE Testing The controlled areas will be subjected to the following set of performance tests: Air flow velocity HEPA filter/leak (DOP) Airborne particle count Air flow patterns Recovery Airborne microbial Surface bio burden
65
The instruments used for these tests should be calibrated and included with the report. The tests will be performed at rest, dynamic, and stress conditions.
66
Air Flow Velocity Test Equipment Air flow velocity: electronic micro anemometer or vane-type anemometer. Procedure Divide the work zone entrance plane into a grid of equal areas. Individual areas should not exceed 0.37 m2 (4 ft2). Support the anemometer sensor probe with a suitable stand.
67
Air Flow Velocity Test (Contd)

Measure the air flow velocity at each test position. Allow at least five seconds for each measurement and record the average reading during that period. Acceptance criteria: The average air flow velocity, should be within 5% of the value specified for the clean room
68
HEPA Filter/Leak Test (DOP)

Equipment
DOP aerosol. DOP aerosol generator. Aerosol photometer.
69
Method
Introduce DOP aerosol upstream of the filter through a test port and search for leaks downstream with an aerosol photometer. HEPA filters 99.99% : challenge aerosol penetration is lower or equal to 0.01% of the upstream concentration HEPA filters 99.97% : challenge aerosol penetration is lower or equal to 0.03% of the upstream concentration HEPA filters 95%: challenge aerosol penetration is lower or equal to 5% of the upstream concentration.
Acceptance criteria
70
Repairs
No repair is authorized without the acceptance of the contractor. If the contractor agrees to repair the filter, the medium to repair the filter should be agreed upon. Each repair must be properly documented on the worksheet.
71
In any case, the maximum surface to be repaired is less than 5% of the visible surface of the filter and any dimension of any repair is maximum 4 cm. Other criteria for repair can be agreed upon with the contractor.
FREQUENCY Initial validation: once Revalidation: every six months for class 100 areas; every year for class10,000 and 100,000 areas respectively.
72
Airborne Particle Count Test Equipment CI-500 laser particulate counter with printer Method 1. Using the particle analyzer, count particles greater than or equal to 0.5 m in diameter 2. If the particle count in the 0.5 m range is less than 50 per cubic foot of air, four additional counts at this location are taken to place these particle counts within a 50% confidence interval. Next repeat steps 1 and 2 with operational personnel present The minimum volume of air to be sampled can be read from Table A The minimum number of sampling points can be read from the Table B
Table A Testing for particles Air volume required 0.1 m 0.1 cft or 2.8 l 0.3 m 0.1 cft or 2.8 l 0.5 m 0.2 cft or 5.6 l 5 m 0.3 cft or 8.4 l Table B Square feet Square meter Sampling points 100 9.2 4 200 18.4 8 400 36.8 16 1,000 92 40 2,000 184 80 4,000 368 160 10,000 920 400
Federal Standard 209 E class limits in particles per cubic foot of size equal to or greater than particle size shown Measured Particles size (m) Class 0.1 0.2 0.3
1 10 100 1,000 10,000 100,000 35 350 NA NA NA NA 7.5 75 750 NA NA NA 3 30 300 NA NA NA
0.5
1 10 100 1,000 10,000 100,000
5.0
NA NA NA 7 70 700
75
Acceptance criteria
At any of the designated critical locations the particulate count shall not exceed 100 particles 0.5 m in diameter and larger per cubic foot of air. The same test should be repeated at ancillary environments. Ancillary environments shall not exceed a particle count of 100,000 particles 0.5 m in diameter and larger per cubic foot of air . Frequency Initial validation: once Revalidation: annually
Air Cleanliness Level: Definition of Classes

Maximum number of particles 0.5 m
Class . Per cf Per cm Per cf
5 m
Per cm
100 100 3.5 10,000 10,000 350 100,000 100,000 3500
65 700
2.3 25
Cf-cubic foot Cm- cubic meter
77
Guidelines for Cleanliness Levels Required during Manufacturing of a Parenteral Drug
Cleanliness level (particles 0.5 m and larger) Warehousing Preparation 100,000 `Not more than 100,000 Filtration 100,000 Not more than 100,000 Filling area 100,000 or better Not more than 100,000 Filling line (point of use) 100 Not more than 100
Operation
Class
78
Air Flow Patterns Test

Equipment White visible or yellow smoke generator, anemometer, 35-mm camera or videotape recorder
Method If the system operates according to the specified operating parameter, begin to generate white visible smoke at the critical locations.. Generate white smoke inside and over each component.
Smoke should flow through these critical areas. If the air returns (back-flows) due to turbulence, the system cannot be accepted and must be rebalanced or adjusted.
Frequency Initial validation: once Revalidation: annually
80
RECOVERY TEST Equipment Visual smoke generator, particles counter, and hot wire anemometer Method With smoke generation output tube located at a pre designated location, generate smoke for 1 to 2 min and shut off. Record the particle count. If it is not 100 per cubic foot or less, repeat the test with the wait interval increased in increments of 0.5 min until counts are less than 100 per cubic foot. Acceptance criteria The recovery time should be not more than 2 min. Frequency Initial validation: once Revalidation: annually
Airborne Microbial Test Equipment Solid surface impactor with a rotating collection surface or staged plates (Anderson-Slate) Method Aseptically prepared collection plates are placed in the sampling apparatus. Sampling time should be 20 min at every location. After the sampling is complete, remove the collection plates, cover, and identify them After incubation, the number of colonies on each plate is counted.
Acceptance criteria The following table provides the Federal Standard 209 E for cleanliness level: Air Cleanliness Guidelines in Colony-Forming Units (cfu) in Controlled Environments (Using a Slit-to-Agar Sampler or Equivalent)
class 100 10,000 100,000 . cfu per cm of air Less than 3 Less than 20 Less than 100 cfu per cf of air Less than 0.1 Less than 0.5 Less than 2.5
83
Suggested Frequency of Sampling on the Basis of Criticality of Controlled Environment

Sampling Area Class 100 or better room designations Supporting areas immediately adjacent To Class 100 (e.g., class 10,000) Other support areas (class 100,000) Potential product/container contact areas Other support areas to aseptic processing areas but non product contact (class 100,000 or lower) Frequency of Sampling Each operating shift
Each operating shift Twice/week Twice/week
Once/week
84
Surface Bioburden Test

Equipment Cotton swabs or RODAC plate (nutrient agar culture medium) Method Take the swab stick from the tube and gently swab 25 cm2 of area (walls, floor, equipment, etc.) and place back in tube containing 5 mL sterile buffer and test or incubate per official procedure.
85
Acceptance criteria The maximum number of colonies per square foot should not exceed the limits in following Tables Surface Cleanliness Guidelines of Equipment and Facilities in cfu Controlled Environment Class 100 10,000 cfu per Plate 3 5
Contact plate areas vary from 24 to 30 cm2. When swabbing is used in sampling, the area covered should be greater than or equal to 24 cm2 but no larger than 30 cm2.
Surface Cleanliness Guidelines in Controlled Environments of Operating Personnel Gear in cfu class cfu per plate* U.S. Customary 100 10,000 Gloves 3 10 Clothing 5 20
Frequency Initial validation: once Revalidate: annually
87
CONCLUSION

Sterile products ,being very critical and sensitive in nature, a very high degree of precautions, preventions and preparations are needed. Dampness, dirt and darkness are to be avoided to ensure aseptic conditions in all areas. There shall be strict compliance in the prescribed standards especially in the matter of supply of water ,air, active material and in the maintenance of hygienic environment.
88
The aim of aseptic technique is to prevent the access of microorganisms during the preparation and testing of pharmaceutical products. Therefore, the aseptic area requires construction features designed for maximum microbial and particulate control.
Finally conclusion should be drawn based on the results of above tests and documentation.
89
REFERENCES
1
Leon Lachman, Herbert A. Lieberman, J0seph L.Kanig. The theory and Practice of Industrial Pharmacy, pp. 618638. Remington: the science and Practice of Pharmacy Vol.II, 20th . Edition, pp. 770-820, 2020-2030. Leon Lachman and Lieberman: Pharmaceutical Dosage Forms- Parenteral Medications Vol. I, 2nd Edition, Revised and Expanded; pp. 325-342.
2. 3.
4. James Swarbrick and James C. Boylan, Marcel Decker Inc., Encyclopedia of Pharmaceutical Technology, Vol. I, pp. 351-368. 5. Michael E Alton: 623-631. Pharmaceutics: the science of Dosage Form Design, pp. 638-641.
90
6.
Cooper and Gunns, Dispensing for Pharmacy Students, Edited by S.J Cater, 12th Edition, pp. 623-631. United States Pharmacopoeia / National Formulary, 2002 Edition, pp. 2206-2211. CGMPs for pharmaceutical Preparations.
7.
8. 9.
Validation Standard Operating Procedures-Second EdnSyed Imtiaz Haider-pp -151, 357 10. US FDA, General Principles of Validation, Center for Drug Evaluation and Research (CDER), Rockville, MD (1987). 11. www.germfree.com 12. www.gonka.com. 13. www.pharmatech.com
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Aseptic Room Validation

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Dr. K. Prabhakar Reddy, Associate Professor,

Pharmaceutical Equipment and Validation

Pharmaceutical Equipment and Validation

Terminal Sterilization Process

Aseptic Processing Operation

Pharmaceutical Equipment and Validation

Comparison of terminal sterilization and aseptic processing

Pharmaceutical Equipment and Validation

Sterile Drug Product !

Sterilization Process must be compatible with all components !

THE DESIGN OF ASEPTIC AREA

Pharmaceutical Equipment and Validation

THE DESIGN OF ASEPTIC AREA FOR THE MANUFACTURE OF PARENTERALS

Pharmaceutical Equipment and Validation

Pharmaceutical Equipment and Validation

THE DESIGN OF ASEPTIC ROOM

Pharmaceutical Equipment and Validation

Pharmaceutical Equipment and Validation

Pharmaceutical Equipment and Validation

Pharmaceutical Equipment and Validation

Pharmaceutical Equipment and Validation

Pharmaceutical Equipment and Validation

Pharmaceutical Equipment and Validation

Pharmaceutical Equipment and Validation

Pharmaceutical Equipment and Validation

Pharmaceutical Equipment and Validation

Pharmaceutical Equipment and Validation

Pharmaceutical Equipment and Validation

Pharmaceutical Equipment and Validation

Facilities: General Clean room Design

Pharmaceutical Equipment and Validation

Facilities: HEPA Filters

Pharmaceutical Equipment and Validation

Facility Design: Clean Area Classification

FS209 Cleanroom classification 100,000 10,000 1000 100

Facilities: Clean room Classification

Class 10,000 clean room Class 100 clean room

Facilities: Clean room Classification

0. um articles m 3, 3 0,000 ,000

ir c an es/hr -48 60- 0 1 0- 40 40-480

Pharmaceutical Equipment and Validation

Facilities: Pressure Differentials

Pharmaceutical Equipment and Validation

Facilities: Air Lock

Pharmaceutical Equipment and Validation

Facilities: Material NOT permitted in a Clean room

Fiber-shedding materials such as cardboard and paper

Wood (i.e. wooden pallets) Undesignated charts

Pharmaceutical Equipment and Validation

Water should be changed FREQUENTLY

Pharmaceutical Equipment and Validation

Pharmaceutical Equipment and Validation

MAINTENANCE OF ASEPTIC ROOM

Pharmaceutical Equipment and Validation

Pharmaceutical Equipment and Validation

They are necessary to remove the dirt.

Pharmaceutical Equipment and Validation

Floors must be mopping with hot water containing detergent

Pharmaceutical Equipment and Validation

Pharmaceutical Equipment and Validation

Must be neat, orderly and reliable.

They should be in good health and free from dermatological conditions.