Environmental Monitoring Considerations

1
Environmental Monitoring Considerations

• Nancy Roscioli, Ph.D.
• Don Hill and Associates, Inc.

2
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

3
Environmental Monitoring Components

• Water monitoring
• Total organic carbon
• Conductivity
• Microbial Contaminants
• Endotoxin

4
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

5
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

6
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)

7
Regulatory Basis for Environmental Monitoring
Program

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

8
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

9
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.

10
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

11
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

12
Microbial Evaluation and Classification of Clean
Rooms and Clean Zones

• USP General Information Chapter
• 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

13
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

14
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)

15
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

16
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

17
Viable and Nonviable Contaminant Limits
18
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

19
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

20
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.

21
Critical Area

• The area just preceding the sterile core should
  be one classification higher than the core.

22
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

23
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

24
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

25
Microbial Monitoring

• Airborne viable contaminants
• Surface contaminants
• walls
• equipment surfaces
• countertops
• floors
• Personnel contaminants

26
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

27
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

28
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

29
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

30
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

31
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

32
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

33
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

34
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

35
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

36
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

37
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

38
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

39
Temperature and Humidity

• Control of temperature and humidity required for
  aseptic processing areas
• 21 CFR 211.42(c)(10)(ii)
• Generally 65F and 35-50 humidity are average
• Too high - Increases personnel shedding
• Too low - Increase static electricity

40
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

41
Water Requirements
42
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

43
Purified Water

• Defined in USP
• Obtained by a suitable process, usually one of
  the following
• deionization
• reverse osmosis
• combination

44
Potable Water

• Meets National Drinking Water Regulations
• 40 CFR Part 141
• Periodic monitoring in-house as well as periodic
  certificates from municipality (if applicable)

45
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)

46
Water System Monitoring

• Purified Water Systems
• Weekly monitoring of system for
• microbial quality
• TOC
• conductivity

47
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

48
Water Use

• Purified Water
• Preparation of terminally sterilized
  microbiological media
• Initial rinsing/cleaning
• Laboratory use
• Feed for WFI system

49
Water Use

• Potable Water
• Non-product contact uses
• Feed for purified water system

50
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

51
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

52
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

53
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

54
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.