Risk-Based Environmental

Monitoring
Marsha Stabler Hardiman
Senior Consultant Concordia ValSource
Wednesday September 17, 2014
FDA/PQRI
 Presenter
Marsha Stabler Hardiman
• Over 20 years experience in the
Pharmaceutical and Medical
Device industries
• Microbiologist/EM Expert
• Senior Consultant, Concordia
ValSource LLC
 Quality By Design for Sterile Product
Manufacturing – Risk Based EM
• Environmental Monitoring (EM) is Evolving
• Not the same EM Programs of the past
• Sterile Manufacturing Critical Quality Attribute (CQA)
• Absence of biological contamination
• EM is a detection tool to help us achieve this CQA
• Novel Approach to Environmental Monitoring
• Value added and Risk Based EM Programs
• cGMP expectation
 Presentation Outline
• Definitions Environmental Monitoring (EM)
• Regulations
• Room Classifications -EM Program Misconceptions
• Risk-based EM
• Risk Assessment Tool
• Media
• Equipment
• Incubation and Data Collection
• Microbial IDs
 What is Environmental Monitoring?
• Sampling of controlled environments for non-viable and viable air
particulates as well as surface viables
• Allows for assessment of effectiveness of cleaning/disinfection
• Allows for identification of trends
• Facilitate early detection of potential problems
 What is Risk Based EM?
• Application of QRM tools and approaches into your EM Program
design and throughout the product lifecycle
• Understanding your products and processes
• Understanding your microbial contamination risks
• Ensuring that proper risk mitigations are in place to help prevent
contaminations
• Ensuring that EM sample sites selection and sampling frequencies
reflect this understanding and are properly established to best
detect potential contamination
• You are the expert in your products and processes – your EM Program
should reflect this knowledge
 Regulations/Guidance
• ISO 14644-1 “Cleanrooms and Associated Controlled Environments - Part 1:
Classification of Air Cleanliness”, 1999
• USP 1116 “Microbiological Control and Monitoring of Aseptic Processing
Environments”
• USP 1115 “ Bioburden Control of Nonsterile Drug Substances and Products”
• FDA Aseptic Processing Guideline
• EU Annex 1
• Japan Aseptic Processing Guide and JP
• AAMI TIR 52 – Environmental Monitoring for the Manufacture of Terminally
Sterilized Healthcare Products – Medical Device
 Design and Construction of Cleanrooms -
Room Classification
• ISO 14644 assigns ISO classification levels to be used for the
specification of air cleanliness in cleanrooms and associated
controlled environments
• Healthcare ISO 5 -8
Classification – defined per ISO 14644-1
• level (or the process of specifying or determining the level) of
airborne particulate cleanliness applicable to a cleanroom or clean
zone, expressed in terms of an ISO Class N, which represents
maximum allowable concentrations (in particles per cubic meter of
air) for considered sizes of particles
 Airborne Particulate Cleanliness Classes
ISO 14644-1 maximum allowable particle concentrations
Airborne particulate cleanliness shall be designated by a classification number

ISO Class 0.5 µm 5.0 µm

ISO 5 3,520 29
ISO 6 35,200 293
ISO 7 352,000 2,930
ISO 8 3,520,000 29,300

Maximum concentration limits (particles >0.5 or 5 um/m3 of air)

 Definitions of Room Occupancy States
as-built
• condition where the installation is complete with all services connected and
functioning but with no production equipment, materials, or personnel present
at-rest
• condition where the installation is complete with equipment installed and
operating in a manner agreed upon by the customer and supplier, but with no
personnel present
operational
• condition where the installation is functioning in the specified manner, with the
specified number of personnel present and working in the manner agreed upon
The particulate cleanliness of air in a cleanroom shall be defined in one or more
occupancy states and the considered particle size shall be stated
 Common Misperception with ISO 14644
B 4.1.1 - Minimum number of sample point locations based
on formula:
NL = √A
(NL = (square root) of A)
• NL is the minimum number of sampling locations (rounded up to a
• whole number)
• A is the area of the cleanroom or clean zone in square meters.
Room grid based on room area
Specific to nonviable particulate sample locations for cleanroom
classification – evaluates air quality against design – not routine EM
 Establishment of Qualification Study EM
Sampling Plan and Sites
• ISO 14644 grid approach for room classification

• During initial startup, locations for air and surface monitoring

determined
• Locations should include those in close proximity to exposed product, product
contact surfaces
• Prospective risk analysis shall be performed to develop a rationale for the
sampling locations and frequencies
• Not all rooms of the same ISO Class need the same control levels
• Avoid over sampling as well as under sampling – focus on reduction of
contamination sources
• Walls and Floors
 USP <1116> Microbiological Control and
Monitoring of Aseptic Processing Environments
• Significant changes made to USP <1116> in late 2012
• This Chapter is NOW specific to EM of aseptic processing environments
• Sterile products, bulk “sterile” drug substances, sterile intermediates, excipients,
medical devices (i.e., contact lens solutions)
• Risk based sample locations and frequencies with documented rationale
• Table 2 suggests sampling frequency aseptic processing areas
• Rate of occurrence of excursions in place of CFU levels
• Contamination Recovery Rates – percentage of plates showing any microbial
recovery regardless of the number of CFU for each cleanroom (Table 3)
• Action levels should be based on empirical process capability
• If exceed, Table 3 or process capability levels, take corrective action
• ISO 5 excursions > 15 CFU single sample, significant excursion
 USP <1115> Bioburden Control of Nonsterile
Drug Substances and Products
• Describes Microbial Assessment of Non-sterile Product Manufacturing
Environments
• Part of Risk-Based Microbiological Control Program
• Contamination Recovery Rates from <1116> are not intended for non-
sterile environments
• Contamination likely depends on level of human activity and levels of
gowning
• Sampling locations should be selected based on risk evaluation
• Frequency of monitoring should reflect the potential risk associated with
the dosage form
• Products that are resistant to microbial contamination require little to no monitoring
 EM Program’s of the Past
• Viable and Non-Viable
• Center of the Room
• Surface Viable
• Center of Each Wall
• Floor - corner of each room, center of room
IS THIS WRONG?

IS THIS RISK BASED?

 EM Program Risk-based Approach
Two way approach – similar but different
based on prior knowledge:
1 – New EM Program
2 – Reassessment of Current/Existing EM
Program
 New EM Program
• New Facility?
• New Controlled Environment additions to existing facility?
• Any Prior Knowledge contamination types and levels?
Prior knowledge is an input

Assess Microbial Risk of New Area

• Product Type
• Process
 Step 1 - Planning
• Risk Management Planning
• Determine Team/Members – cross functional (Micro, QA, MFGing, Facilities,
Engineering)
• Select Facilitator – not bias to activity
• Define Scope of Risk Activities for EM Program assessment
• Determine the Risk Management Tools to be used
• Determine Scoring to be used – company procedure may already exist
• Determine Communication of Risk Plan
• Who needs to be communicated to, when, how often, how much detail
• Impact to Regulatory Filings
• Costs
 Step 2 - Assess Activity Affecting Microbial
State of Control
• Brainstorm
• Fishbone
• Cross functional team – Microbiologists, Manufacturing, Engineers,
Quality, Facilities
• May want to break down by sub-teams for different rooms if large facility

No need to discuss current controls in place at this point

Simply identifying all areas of microbial risk

 CAUSES OF MICROBIAL CONTAMINATION

MAN (HUMAN) MACHINE MOTHER NATURE

EQ 1
Behavior
Power
EQ 2
Outages
Gowning
HVAC
Fires
Training Utilities
Sinks Floods
Awareness
Airlocks
Washers MICROBIAL
CONTROL

Raw Materials Cleaning

Batch Records Cleaning

Agents/Supplies
Charging Vessel
Hoses

Carts/Cart Tablet Coating

Wheels Raw Material
Gowning Weighing/Dispensing
Materials

MATERIALS METHODS
 Step 3 - Assess Activity and Flow
• Gemba (go see) walk each room/area if possible
• If construction phase, do via paper until you can get in the area
• Best case - Work with engineers prior to design and construction start to identify
microbial risk points and plan them OUT
• Assess planned personnel flow
• Assess planned material flow
• Sample site locations should be based on risk of activity
• Likelihood of contamination from process
• Open or Closed Process
• People likely largest contributors of room contamination if closed process
• Maybe you have a wet process – Gram negatives
• Contamination from other products
 Step 4 – Perform Risk Assessment
• Next use the information obtained in the brainstorming activity and
floor assessment as a foundation to perform a risk assessment
• Include known controls and risk mitigations
• Cross functional team – Microbiologists, Manufacturing, Engineers,
Quality, Facilities

• Preliminary Hazard Analysis (PHA) or Failure Modes and Effects

Analysis (FMEA)
 FMEA Process Example
• Identify Hazards
• Example: Not meeting Air Quality Viable EM Levels
• Identify Harms
• Example: Airborne contamination in controlled environment
• Identify Hazardous Conditions
• Contamination of Room EQ
• Contamination of product contact surfaces
• Contamination of People
• Contamination of work surfaces
• Determine Severity, Occurrence and Detection Scores
• Determine Risk Priority Number (RPN)
• Determine Control Measures in Place
• Example: Cleaning/Disinfection
• Example: HVAC System
• Determine if Additional Controls are Needed
• Example: More Gowning
 Risk Ranking
• Determine HIGH, MEDIUM and LOW risk areas from RPN results
• Could be used to determine frequency or site locations

HIGH – daily
MEDIUM – weekly
LOW – monthly
 Step 5 - Selection of Sample Locations and
Sampling Frequencies
• Use all prior tools to now select your sample sites
• Document your rationale based on the risk of contamination
• Same sized (area) and same class rooms may have different numbers
of required sample sites based on risk of contamination in each room
• Make it about the activity, flow and VALUE ADDED
• UNDERSTAND THE PROCESS IN EACH ROOM and the MICROBIAL RISK
POINTS
• Ability to assess effectiveness of sanitization – for that reason floor
and wall locations may still be needed in your program – reduced
number and justification/thought process
 Reassessment of Current EM Program
• Years of DATA which is KNOWLEDGE which you will use to make
changes to your existing EM Program
• Sample site locations
• Frequency
• Type of media
• Incubation
 Step 1 - Planning
• Risk Management Planning
• Determine Team/Members – cross functional (Micro, QA, MFGing, Facilities,
Engineering)
• Select Facilitator – not bias to activity
• Define Scope of Risk Activities for EM Program assessment
• Determine the Risk Management Tools to be used
• Determine Scoring to be used – company procedure may already exist
• Determine Communication of Risk Plan
• Who needs to be communicated to, when, how often, how much detail
• Impact to Regulatory Filings
• Cost Impact
 Step 2 – Previous Risk Assessment Review
• Do you have a Product and/or Process Risk Assessment which already
identifies the microbial contamination risk points in your processes?
• HOPEFULLY – YES
• If No – This is your step 2, Q8/Q9/Q10 or ISO 14197
• Cross-functional activity
• Fishbone from New EM Program Slides
• Assume Yes
• Perform a review of this document to identify your microbial risk points as a
starting place
 Step 3 – Data Review Current EM
• Assess current EM locations and results
• What are your trouble spots – frequent alerts/actions or recovery of
objectionable organisms
• Flag these – likely keeper for your new EM Program
 Step 4 – Floor Walk/Gemba
• Assess EQ, material and people flow ON THE FLOOR
• Talk to current Production Operators
• Ask them what they see as microbial risk points
• They have VAST knowledge from being on the floor everyday
• Cross functional – smaller group than risk assessment
• Microbiology Lead
• MFGing support
• Most process knowledge
• Where have you had bioburden or water or compressed air
contamination concerns?
 Step 5 – Select New Sample Locations and
Sampling Frequencies
• Document all findings and risk points
• You can perform a modified risk assessment – using knowledge
gained in product and process risk assessments
• Talk about activity, people and flow in each room
• Rationalize new chosen sample locations based on microbial
contamination risks in these areas
• Documentation needs to be a living document, signed off Site Head,
QA Head, Microbiology Management at a minimum.
 Example of Modified Risk Assessment
• Room Number
• Room Description
• Classification
• Current Number V/NV/S locations
• Microbial Risks in Rooms
• People Movements/Flow
• Number Proposed New V/NV/S locations
• Comments discussing rationale based on risk
 Documentation
• Initial Microbial Risk Findings – Fishbone
• Formal Risk Assessment – PHA or FMEA
• Or review of Prior
• Modified Risk Assessment
• Suggest Prepare Report – describe rationale and shows your thought
process
• Sign Off, Retain, Revisit
 Execute Protocol
• If new sample locations and frequency are very different than your
prior EM Program, suggest execution of protocol to collect baseline
data
• Aid in setting alert/action levels
 SOP Changes – Change Control
• Once new locations are selected, documented, agreed upon
• Revise all current SOPS/maps
• EM Software Program – changes/cost
• Regulatory Filing Impact Considerations
 Training Microbiology Staff
• New SOPs
• New Locations
• New Equipment
• New Sample Volumes
• New Sample Frequencies
• New Media
• MENTORING on WHY
• STRESS UNDERSTANDING THE PROCESS
 Rapid Methods

Real time particle

monitoring
-Biological
fluorescence

Continuous
monitoring
 Media Types
Media used should be evaluated for suitability of the intended purpose

• TSA – Soybean-casein Digest Agar

• SDA –Sabouraud Dextrose Agar
• Lower pH 5.6 inhibits bacterial growth – favors growth of fungi
• Chemicals that counteract the effect of antimicrobials
• P80 and Lecithin
• D/E Neutralizer
 Incubation Temperatures
• 20 – 25C
• 30 – 35C
Start high, read, go low, read – 7 days
TSA 30-35C
SDA 20-25C

Have data to support what you are using for incubation times and
temperatures
 Microbial Identifications
• Which ones do I need to ID?
• Gram stain only?
• Genus and species?
• Genetic ID
• Based on risk
• FDA Aseptic Processing Guidance – “genotypic methods have been
shown to be more accurate and precise than traditional biochemical
and phenotypic techniques”-especially valuable for investigations into
failures (sterility test, media fill contamination)
Thank You FDA/PQRI and Attendees
Marsha Stabler Hardiman
ConcordiaValsource LLC

mstabler@concordiavalsource.com
949-412-6683