A general consideration of Environmental Monitoring in Pharmaceutical manufacturing area. Cleanroom Monitoring Tools and Utilities: Author Sreenath Sasidharan (Geltec Healthcare FZE)

1. ENVIRONMENTAL MONITORING
OF CLEAN ROOMS
SREENATH SASIDHARAN
ASSISTANT MANAGER-QC
GELTEC HEALTHCARE FZE

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
• Air Velocity , Air Changes, Filter Integrity

3. ENVIRONMENTAL MONITORING
COMPONENTS- CRITICAL
• Water monitoring:
• Total organic carbon
• Conductivity
• Microbial Contaminants

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

7. REGULATORY BASIS FOR
ENVIRONMENTAL
MONITORING PROGRAM
• CFR GMP regulations
• Regulatory bodies requirements
• 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. 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

11. 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
• Emerging technologies - barrier; isolator

12. FEDERAL STANDARD 209E
• “Airborne Particulate Cleanliness Classes in Clean
Rooms and Clean Zones
• Frequently referenced for controlled environment
particulate requirements: Classes 100, 10,000 and
100,000 (based on particles > 0.5µ)

13. 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

14. 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

15. 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.

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

17. 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

18. 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

19. 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

20. ABPC LIMITS

21. MICROBIAL LIMITS

22. MICROBIAL MONITORING
• Airborne viable contaminants
• Surface contaminants
• walls
• equipment surfaces
• floors
• Personnel contaminants

23. MICROBIAL MONITORING
• Monitoring methods should be capable of detecting
molds and yeasts
• All lots of media for EM sampling should be growth
promotion tested

24. 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 and process

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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

35. TRENDING
• Should trend monitoring results (environmental and
water)
• Periodic (quarterly) 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

36. TEMPERATURE AND HUMIDITY
• Control of temperature and humidity required for
critical areas
• 21 CFR 211.42
• Too high - Increases personnel shedding
• Too low - Increase static electricity

37. 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

38. PURIFIED WATER
• Defined in USP, BP
• Obtained by a suitable process, usually one of the
following:
• deionization
• reverse osmosis
• combination

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

40. WATER SYSTEM MONITORING
• Microbial quality
• Daily system monitoring
• TOC and Conductivity
• Daily to Weekly system monitoring
• can be taken from worst case point (end of loop, return to
tank)

41. WATER SYSTEM MONITORING
• Purified Water Systems
• monitoring of system for:
• microbial quality
• TOC
• conductivity

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

43. WATER USE
• Potable Water
• Non-product contact uses
• Feed for purified water system

44. 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

45. 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

46. 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

47. MICROBIAL MONITORING DEVICES
• Surface contaminant monitoring devices:
• Contact Plates - plates filled with specified agar; for regular
surfaces
• Swabs - useful for hard to reach or irregular surfaces; swab
placed in suitable diluent and inoculated onto microbiological
plate

48. THANK YOU