Environmental Monitoring Considerations

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					Environmental Monitoring
     Considerations
    Nancy Roscioli, Ph.D.
  Don Hill and Associates, Inc.
      Environmental Monitoring
            Components
•   Airborne nonviable particulate monitoring
•   Airborne viable contaminant monitoring
•   Viable contaminant monitoring of surfaces
•   Viable contaminant monitoring of personnel
•   Temperature and humidity monitoring
•   Pressure differential monitoring
      Environmental Monitoring
            Components
• Water monitoring:
  –   Total organic carbon
  –   Conductivity
  –   Microbial Contaminants
  –   Endotoxin
     General Environmental
    Monitoring Considerations
• Monitoring frequencies and strategies
  – Establishment of a meaningful and manageable
    program
• Sampling and testing procedures
• Establishment of effective alert and action
  limits
• Trending of results
     General Environmental
    Monitoring Considerations
• Investigation and evaluation of trends as
  well as excursions from alert and action
  limits
• Corrective actions to be implemented in
  response to environmental monitoring
  excursions
• Personnel training - sampling, testing,
  investigating excursions, aseptic technique
      Scope of Environmental
       Monitoring Program
• Should include monitoring of all
  environments where products and their
  components are manufactured
  – All areas where there is a risk of product
    contamination
• Should include monitoring of all water used
  for product manufacturing as well as feed
  water to the final water purification system
  (WFI System)
Regulatory Basis for Environmental
       Monitoring Program
• CFR GMP regulations
• FDA Guidance Documents
• USP Informational Chapter
              21 CFR 211.42
• Aseptic processing areas:
  –   Easy to clean and maintain
  –   Temperature and humidity controlled
  –   HEPA filtered air
  –   Environmental monitoring system
  –   Cleaning and disinfecting procedures
  –   Scheduled equipment maintenance and
      calibration
               21 CFR 211.46
• Ventilation, air filtration, air heating and
  cooling:
   – Adequate control over microorganisms, dust,
     humidity and temperature.
   – Air filtration systems including prefilters and
     particulate matter air filters for air supplies to
     production areas.
 Guideline on Sterile Drug Products
  Produced by Aseptic Processing
• Defines critical and controlled
  manufacturing areas
• Recommends airborne nonviable and viable
  contaminant limits
• Provides some guidance on monitoring
  frequencies for critical areas
 Guideline on Sterile Drug Products
  Produced by Aseptic Processing
• Recommendations for air pressure
  differentials
• Includes guidance on aseptic media fills
• Note: This guidance document was written
  in 1987 and is in need of revision
Microbial Evaluation and Classification
  of Clean Rooms and Clean Zones
• USP General Information Chapter <1116>
• Establishment of clean room classifications
  – Federal Standard 209E
• Importance of EM program
• Personnel training in aseptic processing
• Establishment of sampling plans and sites
  – suggested sampling frequencies
Microbial Evaluation and Classification
  of Clean Rooms and Clean Zones
• Establishment of alert and action limits
• Suggests limits for airborne, surface and
  personnel contaminant levels.
• Methods and equipment for sampling
• Identification of isolates
• Aseptic media fills
• Emerging technologies - barrier; isolator
       Federal Standard 209E
• “Airborne Particulate Cleanliness Classes in
  Clean Rooms and Clean Zones
• Approved by the GSA for use by all Federal
  Agencies
• Frequently referenced for controlled
  environment particulate requirements:
  Classes 100, 10,000 and 100,000 (based on
  particles > 0.5µ)
 Guidance for Industry for Sterile Validation
Process Validation in Applications for Human
        and Veterinary Drug Products
• Scope limited to final drug product manufacturing
  and data required for application submission
  (NDA, BLA)
• Requests information on:
   – Buildings and facilities
   – Manufacturing operations for drug product
      • Filter validation
      • Validation of hold times
 Guidance for Industry for Sterile Validation
Process Validation in Applications for Human
        and Veterinary Drug Products
• Requests information on:
  – Sterilization and depyrogenation
  – Media fills and actions taken when they fail
  – Microbiological monitoring of the environment
     • Airborne microorganisms, personnel, surfaces,
       water system, product component bioburden
  – Yeasts, molds, anaerobes
  – Exceeded EM limits
Viable and Nonviable Contaminant
             Limits
  Classifi- Nonviable (>0.5µ)   Viable (CFU)
  cation ft3         m3         ft3    m3
  Class    100      3,530       0.1    3.5
  100
  Class    10,000   353,000     0.5    18
  10,000
  Class   100,000 3,530,000 2.5        88
  100,000
            Controlled Area
• Preparation or manufacturing area where
  nonsterile product, in-process materials and
  product-contact equipment surfaces,
  containers and closures are exposed to the
  environment
• Control nonviable and viable contaminants
  to reduce product /process bioburden
• Class 100,000 or Class 10,000
            Controlled Area
• Capping areas are now considered
  controlled manufacturing areas
  – Should be supplied with HEPA filtered air
  – Should meet class 100,000 conditions during
    static conditions
             Critical Area
• Aseptic processing area where sterile
  products, components or in-process
  products are exposed to the environment
  and no further processing will occur.
• Air quality must be Class 100 during
  processing
• Local Class 100 areas are often utilized
  during open processing steps during drug
  substance manufacture.
              Critical Area
• The area just preceding the sterile core
  should be one classification higher than the
  core.
Nonviable Particulate Monitoring
• Airborne cleanliness classifications should
  be met during operations
• Nonviable monitoring should occur
  routinely during operations
• Monitoring during static conditions is done
  as part of HVAC qualification and may be
  done periodically after that to insure area
  meets acceptable conditions before use or
  following cleaning
Nonviable Particulate Monitoring
• Locations for monitoring should be
  established during performance
  qualification; probes placed close to work
  surface
• Monitoring frequencies vary:
  – For aseptic processing areas, during each use
  – For other, controlled areas, varies from each
    use to weekly or less depending on use of area
Nonviable Particulate Monitoring
• HVAC Validation and Maintenance
  Considerations:
  – Air velocity, airflow patterns and turbulence
    should be validated; smoke studies to determine
    flow patterns during static and dynamic
    conditions
  – HEPA filter integrity testing
  – HEPA filter efficiency testing
  – Air pressure differentials
         Microbial Monitoring
• Airborne viable contaminants
• Surface contaminants
  –   walls
  –   equipment surfaces
  –   countertops
  –   floors
• Personnel contaminants
        Microbial Monitoring
• Monitoring methods should be capable of
  detecting molds and yeasts
• Should also be able to detect anaerobes
  – Most often, this is an issue associated with
    products filled anaerobically (with nitrogen
    overlay)
• All lots of media for EM sampling should
  be growth promotion tested
        Microbial Monitoring
• Routine microbial monitoring should take
  place during operations (for airborne
  contaminants) and immediately following
  operations (for surfaces and personnel).
• Airborne monitoring frequencies:
  – Each use for aseptic processing areas
  – Varies from daily to weekly to less frequently
    for controlled areas depending on use
        Microbial Monitoring
• Personnel and surface monitoring
  frequencies vary:
  – Aseptic processing - after every fill
  – Other controlled areas - varies from daily to
    weekly or less for surfaces
  – Personnel monitoring often restricted to aseptic
    area personnel and personnel working in Class
    100 hoods performing tasks such as inoculation
        Microbial Monitoring
• Monitoring of surfaces and airborne
  contaminants during rest periods (following
  cleaning)
  – Important for confirming adequacy of cleaning
    procedures
  – Indicates whether HVAC system is operating
    properly
  – NOTE: Disinfectant effectiveness studies also
    required for cleaning agents used in the facility
        Microbial Monitoring
• Monitoring frequencies and procedures are
  influenced by a number of factors:
  – Stage of manufacturing
  – “Open” or “closed” manufacturing step
  – Single or multiple product manufacturing
        Microbial Monitoring
• Establishment of monitoring locations
  should be based on performance
  qualification studies during dynamic
  conditions
  – gridding study to determine worst case
    locations/most meaningful locations
• Should also establish common flora - will
  aid in investigations
 Setting Alert and Action Limits
• Action limits (for the most part) have been
  established in a variety of guidance
  documents
• Alert limits
  – Lower than action limits
  – Reflect actual historical results under normal
    processing conditions
           Exceeding Limits
• Alert limits are designed to provide some
  warning that environmental quality is
  approaching action limit and allow you time
  to correct.
• Exceeding alert limit triggers a warning
  response - i.e., alert affected area personnel
• Exceeding multiple alerts - triggers action
  level response
             Exceeding Limits
• Action limit excursions require
  investigations
  –   Speciation of organism(s)
  –   Review batch records from date of excursion
  –   Review other recent EM data (trends)
  –   Review cleaning records
  –   Interview personnel
  –   Product impact - must quarantine until
      determined
           Exceeding Limits
• Excursions from action limits require
  corrective actions that may include:
  – More rigorous or additional monitoring
  – More rigorous cleaning
  – Retraining of personnel
  – Procedural changes - change to or addition of
    disinfection procedures, for example
  – HVAC maintenance
   Investigations and Corrective
              Actions
• The investigation procedures to be followed
  should be pre-established and included in
  SOPs
• Depending on the outcome of the
  investigation, corrective actions should be
  pre-established to the extent possible
   Investigations and Corrective
              Actions
• Imperative that EM results be linked to
  product release so that affected products are
  not released until investigation completed
• Material Review Board or equivalent should
  be consulted prior to releasing product that
  was potentially affected by adverse
  environmental conditions
                  Trending
• Should trend monitoring results
  (environmental and water)
  – Periodic (quarterly or monthly) review by QA
    and others
  – Re-evaluation of action and alert limits on an
    annual basis
  – This trending information is generally included
    in the Annual Product Review
    Temperature and Humidity
• Control of temperature and humidity
  required for aseptic processing areas
  – 21 CFR 211.42(c)(10)(ii)
• Generally 65°F and 35-50% humidity are
  average
  – Too high - Increases personnel shedding
  – Too low - Increase static electricity
    Temperature and Humidity
• Temperature should be controlled
  throughout all manufacturing areas
• Temperature and humidity should be
  monitored and controlled in warehouse
  areas where temperature/humidity sensitive
  raw materials are stored
  – If not able to control humidity, need procedure
    to follow if humidity exceeds limit
 Water Requirements
Test      Potable Purified WFI
          Water Water
TOC       none    500 ppb 500 ppb
Conduc-   none     See USP Table
tivity
Micro.    500      100      10 CFU/
Purity    CFU/ml   CFU/ml   100 ml
Endo-     none     none     0.25
Toxin                       EU/ml
         Water For Injection
• Defined by USP
• Water purified by distillation or reverse
  osmosis
• Prepared from water complying with the
  U.S. EPA National Primary Drinking Water
  Regulations
• Contains no added substance
             Purified Water
• Defined in USP
• Obtained by a suitable process, usually one
  of the following:
  – deionization
  – reverse osmosis
  – combination
             Potable Water
• Meets National Drinking Water Regulations
• 40 CFR Part 141
• Periodic monitoring in-house as well as
  periodic certificates from municipality (if
  applicable)
    Water System Monitoring
• WFI Systems
  – Microbial quality and endotoxin
     • Daily system monitoring
     • Each use point at least weekly
  – TOC and Conductivity
     • Weekly system monitoring
     • can be taken from worst case point (end of loop,
       return to tank)
    Water System Monitoring
• Purified Water Systems
  – Weekly monitoring of system for:
     • microbial quality
     • TOC
     • conductivity
                   Water Use
• WFI
  –   Solvent for preparation of parenteral solutions
  –   Formulation of mammalian cell culture media
  –   Formulation of purification buffers
  –   Final product formulation
  –   Vial and stopper washing
  –   Final rinse for product equipment
                 Water Use
• Purified Water
  – Preparation of terminally sterilized
    microbiological media
  – Initial rinsing/cleaning
  – Laboratory use
  – Feed for WFI system
                Water Use
• Potable Water
  – Non-product contact uses
  – Feed for purified water system
  Microbial Monitoring Devices
• Slit-to-Agar (STA) - Powered by vacuum,
  air taken in through a slit below which is a
  slowly revolving plate.
• Sieve impactor - Vacuum draws in air
  through perforated cover which is impacted
  onto petri dish containing nutrient agar
  Microbial Monitoring Devices
• Centrifugal Sampler - consists of a
  propeller that pulls a known volume of air
  into the unit and then propels the air
  outward to impact on a nutrient agar strip
• Sterilizable Microbiological Atrium
  (SMA)- similar to sieve impactor; cover
  contains uniformly spaced orifices; vacuum
  draws in air which is impacted on agar plate
  Microbial Monitoring Devices
• Surface Air System Sampler - An
  integrated unit containing an entry section
  with an agar contact plate; behind is a motor
  and turbine that pulls air in through the
  perforated cover and exhausts it beyond the
  motor.
• Settle plates - qualitative; may be useful in
  worst case locations
  Microbial Monitoring Devices
• Surface contaminant monitoring devices:
  – Contact Plates - plates filled with nutrient
    agar; for regular surfaces
  – Swabs - useful for hard to reach or irregular
    surfaces; swab placed in suitable diluent and
    inoculated onto microbiological plate
     Monitoring Considerations
• Remote sampling probes - validate use of
  tubing
• Must sample adequate quantity of air to be
  statistically meaningful.
  – 80-100 ft3/min
• Must validate growth promotion after
  exposure of settle plates (or other plates) for
  prolonged time periods.

				
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