Transcript RADIATION STERILIZATION VALIDATION

MONITORING CONTROLLED
ENVIRONMENTS
Pacific BioLabs Inc.
(510) 964-9000
[email protected]
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
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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 CLASSIFICATION
LIMITS IN PARTICLES > 0.5µm
ISO
ISO (m3)
US FS 209E
FS 209E (ft3)
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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 CONTROL
21 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 CONTROL
21 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 Plate
100
3 (including floor)
10,000
5
10,000
10 (floor)
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PERSONNEL GEAR SURFACE –
ACTION LEVELS
Class
Gloves
(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
TOC
WFI
500 ppb
Purified
Potable
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 SYSTEM
MONITORING FREQUENCY
Test
WFI System
Purified Water
Endotoxin
Daily *
None
Microbial
Daily *
Weekly
TOC
Weekly
Weekly
Conductivity
Weekly
Weekly
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ENVIRONMENTAL MONITORING
SURVEILLANCE 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).
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THANK YOU
Q&A