MONITORING CONTROLLED ENVIRONMENTS

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MONITORING CONTROLLED ENVIRONMENTS

• Pacific BioLabs Inc.
• [phone]
• info_at_PacificBioLabs.com

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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 gt 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 HEPAs
• 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 gt 0.5µm Guess ??
Air Pressure 0.05 inches of water
Temperature 72 2.5F
Air Velocity 90 feet/minute
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REGULATORY BASIS FOR ENVIRONMENTAL MONITORING

• CFR GMP regulations
• FDA Guidance Documents
• USP Informational Chapter lt1116gt

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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 lt1116gt
• An environmental monitoring program should
  include identification of the flora obtained from
  sampling.
• ANSI/AAMI/ISO TIR 158432000
• 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 gt 0.5 µm (outside of US
  particles gt 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 gt 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 lt 3 lt 0.1
10,000 lt 20 lt 0.5
100,000 lt 100 lt 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 WFI Purified Potable
TOC 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 Water
Endotoxin 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, lt1116gt
  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, lt797gt
  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

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