Environmental Monitoring

in
Pharmaceutical Industry
Herny Prasetya

Environmental Monitoring

 Purpose
 Why
 When
 Where, what and how

1
Purpose of Environmental
Monitoring
 Provides important information on the quality of the
environment during manufacturing of drug products

 Prevents the release of poor quality batch if specified

limits are exceeded

 Prevents future reoccurance by analysing trends data

Environmental Monitoring

 Purpose
 Why
 When
 Where, what and how

2
 GMP Basic Principles
 Overall control is essential to ensure products of high
quality
 It is not sufficient that the finished product passes
testing protocols,
protocols, quality must be built into product
 All products should be manufactured under carefully
controlled and monitored conditions.
 GMP should be considered as guidelines with the
objective of ensuring that the products are of the
nature and quality intended; wherever necessary, they
may be adapted to meet individual needs, provided
that established standards of product quality are still
achieved.

Good Manufacturing Practices :

Basic elements in manufacturing :

 Material used
 Method or procedures for production and control
 Millieu / environment where the product is processed
 Machinary : equipment used
 Manpower
Man power involved
 Management

3
 Good Manufacturing Practices :
The manufacturing environment is critical for product quality.
Factors to be considered include:
1. Light
2. Temperature
3. Relative humidity
4. Air movement
5. Microbial contamination
6. Particulate contamination
 Uncontrolled environment can lead to product degradation
 product contamination (including cross-contamination)
 loss of product and profit

Factors Contributing To Product

Product’’s Quality

Personnel

Validated processes
Procedures

Starting materials

Equipment

Packing materials
Premises

Environment

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 Defining The Environment

 What is the optimal manufacturing environment ?

 How does the manufacturing environment affect quality,
contamination and cross-
cross-contamination ?
 How do we arrive at an optimal environment ?

Cleanroom concept

Contamina
ontamination
tion

Dust and dirt Microorganism :

Bacteria
Mold
Product Yeast
Pyrogen

Other materials : Other Product

Cleaning agents
Detergent Cross Contamination
Lubricant

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Definition
Definition
What is contamina
contamination
tion?
?
It is "the undesired introduction of impurities (chemical/
microbial/ foreign matter into or on to starting material or
intermediate – during sampling, production, packaging or
repackaging"".
repackaging

Impurities could include products

products or substances other than the
product manufactured
manufactured,, foreign
foreign products,
products, particulate
particulate matter,
matter,
micro
icro--organisms
organisms,, endotoxins
endotoxins (degraded microorganisms), etc.

Definition
Definition
What is Cross-
Cross-contamination?
"Contamination of a starting material, intermediate
product, or finished product with another starting material
or product during production"
production".

Cross-contamination can result from, e.g.

Cross-
1. Poorly designed,
designed, operated or maintained air
air--handling
systemss and dust extraction systems
system
2. Inadequate procedures for, and movement of personnel
personnel,,
materials and equipment
3. Insufficiently cleaned equipment

6
 Cross-contamination can be
Cross-
minimized by,
by, e.g.
1. Personnel procedures
2. Adequate premises
3. Use of closed production systems
4. Adequate, validated cleaning procedures
5. Appropriate levels of protection of product
6. Correct air pressure cascade

Manufacturing Environment :

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Protection: Product and Personnel
 Areas where materials and products are exposed,
should be classified as "clean areas"
 Achievement of clean area classification depends on
factors such as:
– Building finishes and structure
– Air filtration
– Air change rate
– Room pressure
– Temperature
– Relative humidity
– Material and personnel flow
– Outside environment
– Occupancy and type of product

Manufacturing Environment

Level of protection and air cleanliness

determined according to:
 Product to be manufactured
– Steril : aseptis, termminal sterilization
– Non steril
 Process to be used
 Product susceptibility to degradation

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Manufacturing Environment
Environment requirements
Manufacturing

Cleanroom Class A / B
Cleanroom Class C
Cleanrm. Class D
Others

Therapeutic risks

Cleanliness Class

Class Particle / m3 Particle /ft3

US 209 D WHO /
Non- EC /
ISO 14446-1 metric PIC/S > 0.5 µm > 5 µm > 0.5 µm > 5 µm
1
2 3.5
3 1 35 1
4 10 353 10
5 100 A,B 3,530 29 100
6 1,000 35,300 293 1,000 8
7 10,000 C 353,000 2,930 10,000 83
8 100,000 D 3,530,000 29,300 100,000 830
9 1,000,000 35,300,000 293,000 1,000,000 8,300

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Manufacturing Environment

Parameters influencing Levels of

Protection
 Number of particles in the air,
air, number
number of
microorganisms in the air or on surfaces
 Number of air changes for each room
 Air velocity and airflow
airflow pattern
 Filters (type, position)
 Air pressure differentials between rooms
 Temperature, relative humidity

HVAC

Environmental Monitoring

 Purpose
 Why
 When
 Where , what and how

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Environmental Monitoring

 Qualification
 Classification
 Routine monitoring especially
critical areas

Environmental Monitoring

 Purpose
 Why
 When
 Where, what and how

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Monitoring – Storage Area
 Storage conditions for pharmaceutical products
and materials should be in compliance with the
labelling, which is based on the results of
stability testing.
 Recorded temperature monitoring data should
be available for review.
 Temperature mapping should show uniformity
of the temperature across the storage facility.
 Temperature monitors located in areas that
are most likely to show fluctuations.

Monitoring – Processing Area

Monitoring in non-critical areas (C, D and other classes)

Environmental control:
•Temperature
•Humidity
•Differential pressure
•Particle Reference point
for pressure
•Microbial

Particles
Measurement
Microbial Monitoring

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 Monitoring – Processing Area
Monitoring in critical areas ( Room Class B and LF area = class A )
Environmental control:
•Temperature
•Humidity
•Differential pressure
•Particle
Reference point
•Microbial for pressure

Particles LF
Measurement
Microbial Monitoring

Air flow
speed

Monitoring
 Differential pressure on filters
– to detect initial defects of filters,
– to verify the pressure differential (for a defined flow) meets the value
specified by the vendor,
– to set the correct value of the alarm for triggering a filter replacement.
 Differential pressure between rooms
– Measures
Measures differential pressure existing between the inside of a clean
room and the surrounding areas
– Using a calibrated manometer
– This determination should be made under various operational
conditions
– Also to identify situations when the pressure differential cannot be met
and if the product may be at risk.

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 Differential Pressure Indicators

Monitoring
 Temperature level and uniformity test
– to demonstrate the capability of the clean room / HVAC system to
maintain air temperature wihin the specified limits.
limits.
– Also be used to support qualification of the location of fixed installed
temperature monitoring devices.
 Humidity level and uniformity test
– To demonstrate the capability of the
clean room (HVAC system with (de)humidification units) to
maintain air humidity levels within the specified limits and
over a certain period of time.
– also be used to support qualification of the location of
fixed installed humidity monitoring devices.
 temperature and relative humidity depend on the product and
nature of the operations carried out.

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Monitoring Temperature,
Humidity - Data Logger

Monitoring
 Determination of air flow velocity
– To determine average airflow velocity and uniformity of
velocity within a clean room, clean zone or unidirectional
flow work zone.
– Not recommended
recommended for non-
non-unidirectional airflow;
airflow;
– The airflow velocity is measured at a distance of 30 cm
from the supply source using an anemometer.
– The uniformity of air flow velocity is defined as the relative
standard deviation of the velocity, expressed as a
percentage of the mean as follows: Uniformity = standard
deviation / average velocity * 100.
– The relative standard deviation (or uniformity) should not
exceed 15 %.

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 ANEMOMETER

Monitoring
 Measurement of air volume – air change rate
– To determine average airflow volume and uniformity of
volume wihin a clean room, clean zone or unidirectional
flow work zone.
– The airflow volume is measured from each terminal filter
or supply diffuser by using an electronic microanemometer
with an appropriate airflow hood in a manner that includes
all of the air issuing from each single source.
– Total air volume will be used to determine the air
exchange rate (room air volume per hour) for the clean
room, as defined:
Air exchange rate = total airflow volume / volume of the room.

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 Balometers

Air changes measurement

Monitoring
 Determination of airflow patterns
– Demonstrating the interactions of airflow and equipment
during the OQ phase, demonstrating the effectiviness of
aerodynamic barriers,
barriers, identify dead zones and areas with
turbulence
– Recommended for the initial qualification of cleanliness
zones (HVAC or clean rooms) where a differential
pressures cannot be measured
– Visualisation of the air flow patterns, using a smoke or
other visible aerosol and is designed to show evidence that
all air flows are as expected.
– To be valid, such tests must be documented using video
techniques.

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 Airflow Visualisation

Monitoring

 Filter installation leak test (challenge test)

– Confirm that HEPA filters are properly installed by
verifying there is no by-
by-pass leakage in the installation
(frame, gasket seal, and filter bank framework) and the
filters are free of defects and small leaks in the filter
medium and frame seal.
– Performed by introducing an aerosol challenge upstream
of the filters and scanning immediate
immediately downstream of the
filters and support frame or sampling in a downstream
duct.

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 Filter Integrity Test

HEPA

Sampling Sampling
Supply aerosol
clean air unfiltered air

Dilution system

Aerosol generator

Particle counter clean air Particle counter unfiltered air

Monitoring

 Determination of the recovery time

– To determine whether the clean room or clean zone is
capable of returning to its specified cleanliness class within
a defined time, after being exposed to a source of airborne
particulate challenge.
challenge.
– The result is an important information for correct operation
of the system, because it defines also the minimum “hold“
time which should be taken into account after power
failure, start (recovery), mode change, use of changing
rooms, etc.

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Monitoring - Particle
 Determination of room classification
– To determine that the completed clean room can meet the cleanliness class
specified.
– Measur
easuree the concentration of particles ,that the clean room complies with
the cleanliness class.
– In case of unidirectional airflows, the sample points should include test
points located immediately upstream of the work activity level.
– All sample points must comply with the class limit.
– In the case of class A, this test must be repeated to take into account
generation of particles by operator, equipment or process. The main
purpose is then to identify worst case locations which should also be taken
into account when installing probes for continuous particle monitoring.
– A minimum sample volume of 1m³ should be taken per sample location
– “In operation” classification may be demonstrated during normal
operations, simulated operations or during media fills as worstcase

Particle – Routine Monitoring

 For Grade A zones :

– the full duration of critical processing, including
equipment assembly,
– Except contaminants in the process would damage the
particle counter or present a hazard, e.g. live organisms
and radiological hazards. --  during machine set-
-- set-up
– at such a frequency and with suitable sample size that all
interventions, transient events and any system
deterioration would be captured and alarms triggered if
alert limits are exceeded.

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Particle - Routine Monitoring
 Grade B zones :
– Similar system is recommended
– Particle monitoring system should be determined by the
effectiveness of the segregation between the adjacent
Grade A and B zones.
– should be monitored at such a frequency and with
suitable sample size that changes in levels of
contamination and any system deterioration would be
captured and alarms triggered if alert limits are exceeded.

Particle – Routine Monitoring

 Grade C and D zones :
– The monitoring of Grade C and D areas in operation
should be performed in accordance with the principles
of quality risk management.
– The requirements and alert/action limits will depend on
the nature of the operations carried out, but
– the recommended “clean up period” (recovery time)
should be attained.

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 Particle Counters

Particle Counters :
 System :
– independent particle counters;
– a network of sequentially accessed sampling points connected by
manifold to a single particle counter;
– or a combination of the two.
 must be appropriate for the particle size considered.
 Remote sampling systems : the length of tubing and the
radii of any bends in the tubing must be considered in the
context of particle losses in the tubing.
 For classification : use portable
portable particle counters with a
short length of sample tubing

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 Particle Counters
Probe Measuring device Computer, printer

Transfer of particles Transfer of data

Manifold system

REMOTE SENSORS

Airborne Particle Concentration

Grade At rest (b) In operation

Grade Maximum permitted number of particles/m³
equal to or above
0.5µm 5µm 5µm
0.5µm

A 3,520 20 3,520 20

B 3,520 29 352,000 2,900

C 352,000 2,900 3,520,000 29,000

not
D 3,520,000 29,000 defined not defined

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 Monitoring - Microbial
 Airborne
– Slit To Agar (STA)
– Surface Air Sampler (SAS)
– Reuter Centrifugal Sampler (RCS)
– Settling Plate
 Surface :
– Swab
– Rodac Plate
 Locations with a potential impact to the sterility
assurance of the product

Integrated Monitoring System

Building Automation System (BAS)

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 Microbial Monitoring
Active Air Sampling

Recommended limits for microbial

contamination (*)
Settle plates
Air (diam. 90 Contact plates Glove print
sample mm) cfu/4 (diam. 55 mm) 5 fingers
Grade cfu/m3 hours **) cfu/plate cfu/gloves
A <1 <1 <1 <1
B 10 5 5 5
C 100 50 25 -
D 200 100 50 -

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Monitoring – non sterile

 What is reasonable program for this area

 What are the critical parameter/s
 What are reasonable limits

Failure

 SOP on handling failure/deviation

 Investigation
 Corrective Actions
 Preventive actions

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Conclusion
 Environmental monitoring programme
developed on risk based analysis on :
– Product
– Process
– Level of protection
 Appropriate method
 Appropriate sensors :
– Range
– Accuracy
– Protection

Reference :

 FDA 21 CFR 211

 WHO Training Materials
 WHO Training Material for RH products
 PIC/S PE009-
PE009-9
 Pedoman CPOB 2006
 Others

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