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.