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CONTROLLED AREA
Manufacturing area where non-sterile product and in process material contact equipment surfaces or are exposed to the environment
Viable and nonviable contaminants are controlled to specific levels
Class 100,000 and Class 10,000
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CRITICAL AREA
Aseptic processing area where sterile products/components are exposed to the environment and no further processing will occur
Class 100
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ROOM CLASSIFICATION(CLASS NAMES)
ISO US FS 209E USP SI
3 1 M 1.5
4 10 M 2.5
5 100 M 3.5
6 1,000 M 4.5
7 10,000 M 5.6
8 100,000 M 6.5
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ROOM CLASSIFICATIONLIMITS IN PARTICLES > 0.5µm
ISO US FS 209E ISO (m3) FS 209E (ft3)
3 1 35.2 1
4 10 352 10
5 100 3,520 100
6 1,000 35,200 1,000
7 10,000 352,000 10,000
8 100,000 3,520,000 100,000
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BUILDING
Sufficient space to allow proper cleaning, maintenance, and
manufacturing functions orderly operations contamination control
Sealed windows, flush surfaces
Changing rooms/washing facilities
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BUILDING (cont.)
Clean utilities such as gasses, water
HVAC system
Filtration of air – HEPA’s
Airflow from critical to less critical areas
Air lock to maintain positive pressure
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ENVIRONMENT/HVAC SYSTEM VALIDATION
HVAC air velocity, airflow patterns
HEPA filter integrity and efficiency
Air pressure differentials 0.04 to 0.06 inches of water gauge
Cleaning and sanitization/disinfection studies
Airborne non-viable particle counts
Airborne viable particle counts
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EXAMPLE (www.fda.gov/cdrh/qsr/06bldng.html)
Specifications for a medical device assembly facility
Class 10,000
Particles > 0.5µm Guess ??
Air Pressure 0.05 inches of water
Temperature 72 + 2.5°F
Air Velocity 90 feet/minute
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REGULATORY BASIS FOR ENVIRONMENTAL MONITORING
CFR GMP regulations
FDA Guidance Documents
USP Informational Chapter <1116>
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ENVIRONMENTAL CONTROL21 CFR 820.70 (c)
“Where environmental conditions could reasonable be expected to have an adverse effect on product quality, the manufacturer shall establish and maintain procedures to adequately control these environmental conditions”
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ENVIRONMENTAL MONITORING COMPONENTS
Non-Viable Particles Air
Microbial Contamination Air Surface
Pressure Differential
Water quality
Temperature and Humidity
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PRODUCT BIOBURDEN
Does not have to be part of an environmental monitoring program
Test performed on a non-sterile product to determine its microbial load
Reflects the quality control of manufacturing process and raw materials
Needed to verify adequacy of sterilization process
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ENVIRONMENTAL CONTROL21 CFR 820.70 (c)
An uncontrolled environment may result in inconsistent bioburden levels
Bioburden spikes may exceed the sterilization process capability to achieve the desired SAL
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MICROBIAL IDENTIFICATION
USP <1116> An environmental monitoring program should
include identification of the flora obtained from sampling.
ANSI/AAMI/ISO TIR 15843:2000 Characterization of bioburden is required to
reduce the frequency of dose audits
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ENVIRONMENTAL MONITORING PROGRAM
Documented in SOP
Details procedures used for monitoring
Includes sampling sites
Specifies sampling frequency
Describe investigation when Alert or Action levels are exceeded
Describes methods for trend analysis
Training
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AIRBORNE PARTICULATE COUNT
AKA total particulate count
Detection of particles > 0.5 µm (outside of US particles > 5.0 µm are counted)
Monitoring is recommended during operations
Optical particle counting equipment is commonly used
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MICROBIAL MONITORING
Assess the effectiveness of sanitization practices and of personnel
Provides sufficient information to ascertain that the environment is controlled
Is conducted during normal operations
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MICROBIAL MONITORING
Room air
Compressor air
Surfaces Equipment Sanitization containers Floors Walls Personnel garments
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Airborne Viable Particulate Count- Methods
Passive monitoring Settling plates Not generally recommended in US
Active monitoring Solid culture medium impaction Testing of known volumes of air that allow
quantification by unit of volume air
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AIRBORNE VIABLE PARTICULATE COUNT - EQUIPMENT
Passive air monitoring Petri dish with agar
Active air monitoring Slit-to-Agar (STA) Sieve Impactors Centrifugal Impactors Filtration Liquid Impingement Gelatin Filter Sampler
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SURFACE MICROBIAL MONITORING METHODS
Contact Plates
Flexible Films
Swabs
Surface Rinse Methods
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PERSONNEL MONITORING
Garments Chest Sleeves Other areas are sampled for qualification
Gloves Finger impressions
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EXAMPLE OF SAMPLING SITES
System Site
Environmental air (filling) Near open containers
Room air Proximal to work areas
Water Point of use
Surface (facility) Floor, door handles, walls
Surface (equipment) Filling line, control panels
Compressed air Farthest from compressor
Laminar air flow Near high activity areas
Operator Finger impressions
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SAMPLING FREQUENCY
Sampling Area Frequency
Class 100 or less Each shift
Class 10,000 Each shift
Some support areas Twice/week
Product/container contact areas Twice/week
Other support areas > Class 100,000
Once/week
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TRAINING PROGRAM
Personal hygiene/habits
Illness
Clothing/gowning practices
Introduction to microbiology
GMPs
Introduction to aseptic techniques
Participation in media fills to demonstrate aseptic skill level
Must be documented
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ALERT AND ACTION LEVELS
Alert Level A level than when exceeded indicates a
process may have drifted from its normal operating condition. Warning that does not warrant a corrective action
Action Level A level than when exceeded indicates a
process has drifted from its normal operating condition. Documented investigation and corrective action required
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AIR - ACTION LEVELS
Class CFU/m3 CFU/ft3
100 < 3 < 0.1
10,000 < 20 < 0.5
100,000 < 100 < 2.5
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EQUIPMENT/FACILITIES SURFACE – ACTION LEVELS
Class CFU per Contact Plate100 3 (including floor)
10,000 5
10,000 10 (floor)
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PERSONNEL GEAR SURFACE – ACTION LEVELS
ClassGloves
(cfu/plate)Clothing (cfu/plate)
100 3 5
10,000 10 20
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ACTION LEVEL INVESTIGATIONS
Review of: Maintenance records Sanitization documentation Operational parameters
Identification of microbial contaminants
Training of personnel
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CORRECTIVE ACTIONS
Training of personnel
Additional sampling
Increased frequency of sampling
Additional sanitization
Additional product testing
Evaluation of the need to revise SOPs
Product impact/disposition documented
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WATER REQUIREMENTS
Test WFI Purified PotableTOC 500 ppb 500 ppb None
Conductivity See USP See USP None
Microbial 10 CFU/100mL 100 CFU/mL 500 CFU/mL
Endotoxin 0.25 EU/mL None None
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WATER SYSTEMMONITORING FREQUENCY
Test WFI System Purified WaterEndotoxin Daily * None
Microbial Daily * Weekly
TOC Weekly Weekly
Conductivity Weekly Weekly
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ENVIRONMENTAL MONITORINGSURVEILLANCE SUPPORT
Alert and Action Levels
Data Management Collection, trend analysis and interpretation
Isolates Characterization
Investigation/Corrective Actions
Documentation
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REFERENCES
“Fundamentals of Environmental Monitoring”, Supplement TR 13, PDA J. Pharm. Sci. & Tech. 55(6), 2001.
United Stated Pharmacopeia 30, <1116> Microbiological Evaluation of Clean Rooms and Other Controlled Environments. The United States Pharmacopeia Convention Inc., Rockville, MD. pp 589-596 (2007).
United Stated Pharmacopeia 30, <797> Pharmaceutical Compunding-Sterile Preparations. The United States Pharmacopeia Convention Inc., Rockville, MD. pp 334-351 (2007).
United States Food and Drug Administration “Medical Device Quality Systems Manual” (January 1997).
THANK YOU
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