ENVIRONMENT

MONITORING

Iin Susanti
Seminar ISPE Indonesia
“Environment Monitoring Program in GMP Facilities”
Jakarta, 19 September 2018
Why EM?
• Requirement by Good Manufacturing Practices
• EM program provides information on the quality of
the environment during manufacturing

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ENVIRONMENT MONITORING
• An important means :
– to assess effectiveness of contamination control
measures
– to identify specific threats to the purity of products being
manufactured.
• Not a direct measure of product batch sterility
• Act as an early indication
• The results of environmental monitoring must be
considered when making the decision whether a
production batch can be released

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ENVIRONMENT MONITORING
• EM describes the microbiological testing undertaken
in order to detect changing trends of microbial
counts and micro-flora growth within clean rooms or
controlled environments.
• The results obtained provide information about the
physical construction of the room, the performance
of HVAC system, personnel cleanliness, gowning
practices, the equipment, and cleaning operations.

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Is EM Important?

• Risk Assessment
• GMP for sterile products has clearly defined
Environment monitoring rules
• GMP for non-sterile products has undefined
expectation

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How Critical is EM?

• Depend on:
– Dosage form and use of the products
– Type of manufacturing process:
 Sterile / non-sterile
 Terminal sterilization / aseptic
 Open / closed system

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Effective EM Program
• Sampling of microbiological risk areas within the
plant to find organism before they get into the
product
Sampling Location

• Verifying that all cleaning and sanitizing procedure

are working effectively
Understand baseline of what organisme
are present

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What to Monitor?

• Surface
• People
• Air (Udara)

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What Parameters Should Be Monitored?
• Non-Viable / Physical:
 Particulate
 Temperature
 Humidity
 Room Pressure
 Air changes, airflow patterns, Clean up
time/recovery, Airflow velocity (during qualification)

• Viable / Microbiological:
 Bacteria, Yeast/Mould

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Why Do We Monitor?
• Particulate: verify that HVAC is functioning and
rooms are meeting specifications. Particles are
associated with physical contamination and
indirectly microbiological contamiantion
• Microbiological: Purpose of viable EM:
– Verify cleanroom air and HVAC system
– Monitor effectiveness of cleaning and sanitation
program
– Monitor operator performance
– Monitor aseptic process integrity, esp in class A & B

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How to Do Monitoring? (Method)
• Viables:
 Surfaces & People:
 Contact plate
 Swab
 finger dab (for operator)
 Air:
 Passive: settling plate
 Active: Air sampler

• Non-Viable:
 Active particles sampler

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 Where (Location) to Monitor?
• ISO 14644-1:
 provides a formula for determining the minimum
number of sampling locations for total particulate
count.
 Volume to be sampled at each location in liters.
• Risk Based decision : critical area

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 Examples Lokasi Sampling EM
Class A Class B

• At or above working area • Return air

• Near open filled container • Door handle

• Critical surfaces • Trolleys

• Area that may create /generate • Area that may create /generate

turbulance turbulance

• Curtain / machine door • Wall / floor

• Beneath equipment / floor • Pass through

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 How Frequent?
• FDA Guideline on Aseptic Processing, 2004:
“at least once daily during production for active
samplers.”

• EU / WHO:
“Areas should be monitored during operations.”
“Where aseptic operations are performed,
monitoring should be frequent …

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 How Frequent?
• PDA Technical Report Number 13:
This document suggests the following
frequencies:
– once/shift for class 100, class 10,000
– daily for aseptic support areas and change
room
– weekly for class 100,000

• CONCLUCION: use RISK BASED assessment

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WHO Requirements *)

*) Environmental Monitoring of Clean Rooms in Vaccine Manufacturing Facilities, Points to consider for
manufacturers of human vaccines, WHO 2012

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WHO Recommendations *)
(Particulate Sampling Frequency)

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WHO Recommendations *)
(Microbiological Sampling Frequency)

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RECORDS
• Sample location
• Date of sample taken; duration of sampling
• Batch no. & ED Media
• Operators (who took samples)
• State of room (at rest / in operation); activity
• Incubation condition
• Operator reading the plates and date
• Number of cfu per sample – separate yeast and mold
• Any identification of microorganism
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EM Related Documents
Location map Set up, run, post run
SOP-EM Program
Risk Assessment Location / frequency/ method

Trend Monitoring Periodic trend review EM Isolate Program – Microflora baseline

Method Validation

Test Method Sampling

Incubation / Result
EM OOS investigation
record

Gowning
Other
Growth promotion

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GMP Rules for Class A & B Air Monitoring
• Non Viable Particles
– Grade A must be continuous monitoring during set up and
operation
– Grade B continuous not mandatory but preferred
– Must have SOP for excursion and line clearance
– There is an “association between non-viable particles with
microbes

• Viable Particles
– Variety of method: all have reasons and challenges
– Must be continuous monitoring in Class A & B
– Must monitor operator gloves
– Must establish alert and action limit

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Establishing EM Program
• Engage Microbiologist and Aseptic operators
• Study the fill line, process, critical space
• Study personnel and materials movement
• Conduct air visualisation studies “at rest”then in “simulated
operation
• Risk assessment: worse case location
– Areas with high activity
– Areas with high personnel traffic or areas frequently
touched
– Areas difficult to sanitize effectively

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EM and Batch Release
OOS EM = Batch shall be rejected?
• Depend on outcome of comprehensive
investigation
• In case investigation indicates high risk of
contamination of product, it may lead to batch
rejection
• Risk assessment

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OOS EM - Risk Assessment
• Quantity of contamination (1 CFUor 15 CFU?)
• Only 1 sample contaminated
• Type of organism? Identification: human origin,etc
• Location?
• Distance to open product and/or critical surface

Most probable root cause

assessment of product exposure or impact

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Investigation OOS EM
• Sample type: contact plate, settle plate, dll
• Identity of species – possible source
• Location of sample (distance to critical surfaces)
• Investigate potential sample contamination during sampling
or in Lab.
• Review of operation during time period (include: operator
review, video review, riview logbook, etc)
• Review of relevant air flow pattern
• Review relevant EM data (micro, particles, ΔP, temp., RH)
• Review trend data

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Source of Microorganism
• PERSONNEL:
– Poor aseptic technique
– Behaviour in clean room
– Poor gowning practice
• Trolleys, tank, etc
• Poor material transport / handling
• Inadequate cleaning
• Leak HEPA system

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CAPA for EM
• Find root cause : Source of contamination
• Preventive action:
– Improve aseptic behaviour
– More thorough cleaning step
– Use more aggressive cleaning /sanitizing agent
– Increase sanitizing / decontamination frequency
– Implement closed system
– Replacing equipment with more sanitary model

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 EM for Non-sterile Products
• It is recognized that there is no current regulatory
requirement for microbial control in the manufacture of non-
sterile products
• Use a risk based approach to understand the process,
define where microbial contamination could occur and
effectively determine the best control and monitoring
methods.
• Physical monitoring: Temperature, RH, pressure differential
shall be routinely conducted

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 Environment Monitoring
• Air sampler           • Settling plate

• Contact plate         • Finger dab

• Particle count
Quality should be built 
into the product, and 
testing alone cannot be 
relied on to ensure 
product quality
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