Environmental Characterization of Controlled Rooms

Objectives
 Definitions
 Regulation and Standards
 Clean Rooms design requirements
 Clean Rooms qualification
 Environmental Monitoring

Introduction
 Several changes have occurred within the last years
with regard to non-viable particulate monitoring,
specifically the new Food & Drug Administration’s
(FDA) Guideline on Aseptic Manufacture, September
2004 and the revision of the EU GMP Annex 1,
September 2003.
 In both, the focus on proving control over the
manufacturing environment has been increased.

Clean Rooms and Clean Zones
 “A room which the concentration of airborne particles is
controlled, and which is constructed and used in a
manner to minimize the introduction, generation, and
retention of particles inside the room and in which
other relevant parameters, e.g. temperature, humidity,
and pressure, are controlled as necessary”.
 ISO 14644
 Suites consist of different cleanrooms, where are made
several steps of production.
 It is continued until one reaches the moment of
product filling, closing and sealing.
 Less environmental conditions are required when a
sealed product coming for labeling and inspection.

Standards in the design process.
 The history of cleanroom standards started in the USA.
 By order of American Air Force first standard was made
in March 1961. It was called Technical Manual 00-25-
203. There was description of entering, designing and
cleaning. Also it involves airborne particle
requirements.
 In 1963 was published Federal Standard 209.
 It was entitled "Clean Room and Work Station
Requirements, Controlled Environments".
 There was determined measured size of particle more
than 0.5μm. It was so, because there was not better
equipment to measure smaller particles at those days.

Today there are 2 Standards
 ISO 14644 - standard for Airborne Particulate
Cleanliness Classes in Cleanrooms and Clean Zones.
 ISO 14698, Cleanrooms and associated controlled
environments – Biocontamination control.

US FDA
Guideline on Sterile Drug Products Produced by
Aseptic Processing.
 This document was published in 1987 by USFDA
and revised on September 2004
 Critical Area
 Controlled Area

Critical Area:
“one in which the sterilized dosage form, containers,
and closures are exposed to the environment.
Activities that are conducted in this area include
manipulations of these sterilized materials/product
prior to and during filling/closing operations.”
US FDA

 Not more than (NMT) 100 particles of 0.5µm per
cubic foot
 Measured NMT 1 foot away from work site
 Upstream of the air flow
 Air must be supplied a the point of use as HEPA
filtered laminar air flow.
 Velocity 90 ± 20 feet per minute
 NMT 1 colony forming unit per 10 cubic feet
 Must have positive pressure differential relative
to adjacent less clean areas
 A pressure differential of 0.05 inch of water is
acceptable.
Critical Area

Controlled Area:
“An area in which it is important to control the
environment, is the area where un-sterilized
product, in-process materials, and container/
closures are prepared. This includes areas
where components are compounded, and
where components, in-process materials, drug
products and drug product contact surfaces of
equipment, containers, and closures, after final
rinse of such surfaces, are exposed to the plant
environment.”
US FDA

Controlled Area
 NMT 10,0000 particles of 0.5µm per cubic foot.
 NMT 25 colony forming units per 10 cubic feet.
 Sufficient air flow.
 Positive pressure differential relative to adjacent
uncontrolled areas.
 20 air changes per hour
 Pressure differential of at least 0.05 inch of water
 When doors are open, outward airflow should be
sufficient to minimize ingress of contamination.

Clean room Zones
 A – local zone. For operations that affords high risk for
product quality, e.g. filling, closing, ampoule and vial
opening zones. Usually in such zones is used laminar air
flow which provides similar velocity 0.36-0.54 m/s.
 B – zone, which is circled A-zone, is used for an aseptic
preparation
 C and D – zones for less critical stages of
manufacturing.

Class limits for Federal 209D and
ISO Standards

Air particle classification system

Non-Viable Air Particles Sampling
 A non-viable particle is a particle that does not contain a
living microorganism but acts as transportation for
viable particles.
 Non-viable particles are monitored using particle
counters which do not distinguish between viable and
non-viable particles, but are much more technically
advanced than air samplers.

Viable Air Particles Sampling
 Microbial (Viable) Air Samplers collect a predetermined
volume of air and impact microorganisms against agar-
based growth medium. Once that sample has been
collected and the medium incubated, the results are
expressed in colony forming units per cubic meter.
 For sampling viable particles in the air use, R2STM
(Remote Slit Sampler), Matson/Garvin, SASTM (Surface
Air System), SMATM (Sterilizable Microbial Atrium),
RCS(Reuter Centrifugal sampler), or other qualified air
sampler units will be used.
 For this sampling, sterile (irradiated or sterile filled) TSA
plates, or media strips must be used.

Sample Air Volume
ISO 14644-1 defines the minimum sample volume as “that
volume whereby a minimum number of 20 particles would be
detected if the particle concentration for the largest particle
size were at the class limit for the designated ISO Class”.
The formula is as follows:
Vs = 20/Cn,m x 1000
Where……
Vs : the minimum single sample volume per location in
liters
Cn,m : the class limit (number of particles per cubic meter)
for the largest considered particle size (n) specified for the
class limit(m).

Calculate Sample Size ISO 5
Assembly area (ISO Class 5) C0.5,5 = 3 520
Assembly area minimum sample volume per location
 Vs = 20/3520 x 1000
 Vs = 5.68 Liters
 Vs = 5.68 Liters at 2.83 Liters per minute requires a
nominal sample time of 2.0 minutes per location
 Assembly area (ISO Class 5) 3 x 1 minute per sample

Gowning area (ISO Class 7) C0.5,7 = 352 000
Gowning area minimum sample volume per location
Vs = 20/3520000 x 1000
Vs = 0.0568 Liters
Vs = 0.0568 Liters at 2.83 Liters per minute requires a
sample time of 0.02 minutes per location.
Gowning area (ISO Class 7) 3 x 1 minute per sample
Note that in the case of the Gowning area, 1 minute
minimum sample period specified by ISO 14644-1
applies
Calculate Sample Size ISO 7

• Particle counters have four distinct components; a high intensity
light source, (e.g. helium-neon laser), solid state laser diode; a
photo detection electronics, sample flow system and counting
electronics.
• Briefly, particles pass through the optical chamber of the particle
counter, they are sized and counted in real-time, giving immediate
information relating to contaminant levels.

ISO 5 (A)
 For Aseptic Filling operations these areas are considered
”Critical” environments wherein drug product, stopper
bowls , vials and closures are exposed to environmental
conditions.
 This is an aseptic area (eg, Room, Laminar Flow Hood
(LFH), Biological Safety Cabinet (BSC), Isolator) where the
environmental control is intended to maintain the sterility
of drug product, containers and closures .
 Activities conducted in these areas include critical aseptic
manipulations (eg, making aseptic connections, sterile
ingredient additions, sterile filling and closing operations).

ISO 6 (B)
 Room or Zone that is the immediate background for
ISO 5 Zone.
 Zones where production in-process steps are
performed.
 These environments “are designed” (actually this is
NOT TRUE) to consistently ensure and significantly
limit total particulate contamination.
 ISO 6 Room/Zone that is not the background for an
ISO 5 Room/Zone and is not used for production
activities. Examples of ISO 6 Support rooms/zones
include airlocks, equipment/material storage, gowning
rooms and other support areas.

ISO 7 (C)
 For some facilities, ISO 7 is the immediate
background for ISO 5. There the production in-
process steps are performed.
 Ensure limited exposure of materials to microbial and
total particulate contamination.
 Also serve as zones where nonsterile components,
formulated product, in-process material, equipment and
container-closure are prepared, held or transferred.

 Herein processes are performed primarily in closed
systems. These systems are designed to exclude the
penetration of environmental microorganisms
(eg, bioreactors purification equipment trains).
 ISO 7 Room/Zone that is not the background for
ISO 5 and is not used for production activities (e.g.
airlocks, equipment / material storage, gowning
rooms and other support areas.)
ISO 7 (C) cont.

ISO 8 (D)
 These areas are the zones where the processes are
performed primarily in closed systems.
 The environmental control in these areas minimizes
the contribution or buildup of the level of total
particulate contaminants of articles and components
that are subsequently sterilized.
 These systems are designed to exclude the penetration
of environmental microorganisms (eg, bioreactors and
purification equipment trains).

 Rooms or areas used for bulk production operations.
 For some facilities these areas serve as zones where
nonsterile components, in-process material are
prepared, held or transferred. Examples of additional
operations in ISO 8 Production areas include rooms or
zones where Cell Culture, Buffer Preparation and
Purification operations occur.
 ISO 8 areas not in use for production activities (e.g.
ingress/egress gowning rooms, equipment/material
movement/storage, facility cleaning, corridors,
production control/work rooms .
ISO 8 (D) cont.

Controlled Non-classifed Areas
 Non-classified areas or zones that are part of the
facility layout with defined environmental controls (ie,
gowning, cleaning process, etc.) to reduce the
introduction, generation and retention of
contaminants within controlled classified areas.

 After washing, components should be handled in at least a
grade D environment.
 The preparation of solutions which are to be sterile filtered
is performed in a grade C environment; if not filtered, the
preparation of materials and products must be done in a
grade A environment with a grade B background.
 The handling and filling of aseptically prepared products is
performed in a grade A environment with a grade B
background.
 The preparation and filling of sterile ointments, creams,
suspensions and emulsions is performed in a grade A
environment, with a grade B background, when the
product is exposed and is not subsequently filtered.
Aseptic Operations

Recommended limits for microbial
contamination in the operation
(a) Individual settle plates may be exposed for less than 4 hours.
CFU – colony-forming unit.
Limitation of warning and action for contamination by particles and
microorganisms depends on results of controlling. Also you should provide for
corrective action in case of exceeding these limits

 Cleanroom standards and GMP guidelines require that
rooms are maintained at different pressures to
guarantee different conditions that held in each
cleanroom.
 It is possible to reduce contamination transfer to
prevent an unacceptable flow of air from a lower area
to a higher area.
 Sensible relative room pressure level and its later
support offers main design, commissioning and
operational problems.
Contamination Controls

Cleanroom Contamination
Classification

 The standards say that the room pressure difference
between cleanrooms should be 10-15 Pa.
 These values can be quickly reached, easy to control and
appears to prevent contamination transfer.
 It is good to understand that cleanroom requirements
may define a pressure difference of 10 or 15 Pa but this
guideline is only a means to an end.
 The pressure difference is lesser important when there is
no adverse air flow between the rooms in the suite (this
statement can not be clear).
Pressure difference between
cleanrooms

 The same situation may happen with isolators. But, in
this case due to controlled environment is small, the
displacement effect of gloves is important and must be
taken into account when selecting and finding
pressure differences.
 Ordinary pressure differences for isolators are 15-60
Pa.
cleanrooms

 The exhaust of the cleanroom can be in an outside
neighboring corridor coming through an airlock or
changing area and can be in area where pressure is in
two levels lower than the room.
 Surplus of pressure difference of over 30 Pa can cause
“whistling” through the door cracks and it can be
difficult to open and close swing doors.
cleanrooms

 It can be presented in a tunnel process where a component
is washed, sterilized, and filled as it passes from a
component preparation area into an aseptic filling room.
 The pressure difference will cause air to flow between the
two areas connected by the tunnel.
 This air flow can change the heating descriptions of the hot
air oven and can bring hot spots and damage the tunnel.
 Fluctuation of pressure difference will cause changes in the
volume of air flow.
 This can bring changes in efficiency and difficulty in
validating the system.
cleanrooms

 It is important to guarantee that the rooms are built in an
air-tight way to minimize the air flow out of the room's
envelope.
 But, it is impossible to prevent air flow through the door
cracks from an area of high pressure to one of low pressure.
 Using the following formula we can calculate the amount
of air leakage through small gaps and holes.
 Q = A×a Dp
where Q – air volume (m3/s),
 A – area of air leakage (m2),
 p – pressure difference (Pa), and
 α – coefficient of discharge (0.85)
cleanrooms

 An estimation of door leakage can be calculated if the
detailed sizes of the door are given but the total
leakage will depend on the quality of building
detailing.
 This data can not be known until the commissioning
of the room (e.g. balancing) is made.
 So it is necessary to guarantee that the air handling
system has enough capacity to accommodate more
leakage than is expected.
cleanrooms

Air flow (m3/s) through suite with doors closed

 The isolator technology minimizes human influence
on processing zones.
 In aseptic manufacturing it can considerably decrease
the risk of microbial contamination of product from
environment.
 Transferring materials inside and outside of an
insulator is the main potential source of pollution.
 The environment should be controlled and
corresponds to aseptic manufacture, at least, to zone
D.
Isolators Technology

http://www.bioquell.com/applications/isolators
/
http://www.pharmaceutical-
int.com/article/isolator-technology.html

"blowing - filling - hermetic sealing
 Packages which are filled with a product and sealed are
formed during one continuous work cycle.
 All these operations are spent within one automatic
complex.
 The equipment "blowing - filling - hermetic sealing",
used in aseptic manufacture zone A with an effective
air flow, can be established in a zone C if personnel
will wear clothes applied in zones A and B.
 The "blowing - filling – hermetic sealing" equipment,
which is used in manufacturing of the products which
sterilized, should be established, at least, in zone D.

http://machinedesign.com/content/advanced-blow-fill-seal-0908
"blowing - filling - hermetic sealing

The design of a pharmaceutical cleanroom
suite, must include the following features :
 Exclusion of the environment external to the suite
of cleanrooms
 Removal or dilution of contamination arising from
the manufacturing process
 Removal or dilution of contamination arising from
personnel working in the area
 Containment of hazards arising from the product
 Control of product-to-product cross-
contamination

 Protection of personnel
 Control and management of the flow of material
through the process steps by means of layout and
configuration
 Control and management of personnel movement
by optimizing the arrangement and connection of
individual rooms
 Overall security of the operation by control of the
entry and egress of personnel and materials

 Optimum comfort conditions for personnel
 Special environmental conditions for products, e.g.
low RH for powder filling
 Accommodation of process plant and equipment
to ensure safe and easy use, as well as good access
for maintenance.
 Effective monitoring of the conditions of the room.

Phase Plan:
 Analyze production stages
 Prepare process flow diagrams
 Define activities associated with rooms
 Define environmental quality requirements
 Quantify production, process and space
requirements
 Prepare room association diagrams

 Define the accommodation needs
 Develop layouts and schemes
 Prepare designs and specification
 Undertake the detailed design and construction
process
Phase Plan:

Layout of cleanroom suite for
terminally sterilized injectables

Process Flow
 The staff who works in this manufacture would enter the
suite of cleanrooms through the 'clean changing area'.
 In this room clothes are removed, hands washed, and
appropriate cleanroom clothes put on.
 Raw materials and components, such as containers, would
enter through their corresponding entry airlocks.
 In these airlocks procedures are used to decrease the
contamination which may come from outside to the
cleanrooms.
 Solutions are prepared in the “solution preparation” room
for transfer, directly or indirectly, by pipes or mobile
containers, to the filling operation in the “clean filling”
room.

 Primary containers and closures would be prepared and
washed in the “component preparation” room and
manually transferred to the filling stage or by using a
conveyor system.
 Containers are filled and packed under the unidirectional
flow clean zone in the “clean filling” room.
 Filled and packed, containers of product leave the
cleanroom suite through the terminal sterilization
autoclave.
 At the ending of a work period, personnel would leave the
suite through the changing room where cleanroom
protective suite would be removed.
Process Flow

Layout of cleanroom suite for
aseptic filling

The differences in the process
requirements refer to the following key
variations:
 Rooms are separated into clean and aseptic rooms.
 The barriers between them are created by the oven,
autoclave and transfer hatch for items entering the
aseptic suite, and through the separation of the
“solution preparation” and “aseptic filling” rooms.
 Separate and more exact changing room control is
provided for the aseptic suite, due to the differences
between environmental control of the clean and
aseptic suites.
 Also the isolator can be used in place of the
unidirectional flow workstation.

The most difficult requirement to achieve
correct level of cleanliness of the internal
environment usually is caused by:
 The amount of contamination released in the room.
 The quality of the air supplied to the room.
 The quantity and method of supply of room air, i.e.
conventional/turbulent ventilation or unidirectional
flow, or a combination of both.
 The amount of incoming contamination from areas
adjacent to the room. When isolators are used, many
of the same considerations are required, but generally
the ingress of contamination from outside the isolated
volume is minimized.

Nonunidirectional Airflow Zone
 An area in which the filtered air entering the zone or
passing through the work zone is characterized by
non-uniform velocity or turbulent flow. Such rooms
exhibit non-uniform, random airflow pattern
throughout the enclosure

Turbulent flow air distribution

Unidirectional Airflow Zone
 An area in which the filtered air entering the zone
makes a single pass through the work area in a parallel-
flow pattern, with a minimum of turbulent flow areas.
Unidirectional airflow rooms typically have HEPA or
ULPA filter coverage of 80% or more of the ceiling
(vertical flow) or one wall (horizontal flow).

Unidirectional downflow air distribution

Obstruction caused turbulence in a
laminar flow cleanroom

Filtration and supply air
The use of high-efficiency particle stopper (HEPA) filters
including pleated packs of high-density glass fibre paper
with aluminium or craft paper separators, sealed into a
timber or metal frame with urethane, influenced by
cleanroom technology. In pharmaceutical industry it is
required to install HEPA and ULPA filters of H14 – U17
classes. The most penetrable particle size in below
classification (Table 7) is more than 0.1μm but less than
0.3μm.

Impact of Human activities in
the cleanroom

Qualification / Characterization
 is the process by which classified rooms/zones are
verified to meet established microbial and total
particulate environmental standard requirements
upon sampling testing protocols.

General Requirements
 Risk assessments documentation containing the
rationale for sampling sites, sampling frequency, and
use of settling plates (for filling only).
 Programs must provide data to make effective
decisions about the level of the environmental control
necessary to maintain the required levels of microbial
and total particulate cleanliness.
 Contamination control procedures.

Contamination control procedures:
 Access and flow of personnel and materials within the
facility
 Facility shut-down/start-up and requalification
requirements
 Facility sanitization, including disinfectant effectiveness
and rotation
 Personnel gowning, including training/certification,
results from sampling(s) and good cleanroom practices
 Facility monitoring (eg, temperature, humidity, differential
pressure, and baseline performance)
 Initial and routine facility HEPA Certification (eg, airflow,
air velocity, particulate levels,).

Risk analysis
 A documented risk analysis is suggested to select the
monitoring sites during characterization. The risk
analysis must document the rationale for site selection
and shall be based on the needs of the process and
classified area .

Sample site selection
 Real or potential microbial and particulate
contamination associated with the specific process
performed therein.
 The site selection must be challenged under “as-built”,
“at rest” and “in use” conditions.
 The sites selected shall be qualified to demonstrate
their suitability to demonstrate control and microbial
cleanliness in air and on surfaces.
 The analysis must include the identification of
product contact sources and potential microbial
contamination that are most likely to have an adverse
effect on product quality.

 Sites having greater opportunity for contributing
bioburden to the product should be sampled more
frequently.
 Sampling locations must include those locations
which may have an impact on the product and must be
sampled more often.
 In addition to wall and floor surfaces, representative
surface samples must be taken where human activity
occurred.
 Sampling must not be intrusive to the process to avoid
the probability of product contamination.
Sample site selection

Sample sites number
Sample sites for Total Particulate monitoring by room
can be determined using the following:
 Where:
 NL represents the minimum number of samples
 A is the surface area of room in m²
• The calculation result that is not an integer is to be rounded up to the
next whole number

 Airflow velocity, volume & uniformity tests
 HEPA/ULPA filter installation leak tests
 Air generated aerosol challenge & aerosol photometer
filter scan test method
 Alternative source aerosol particle challenge & discrete
particle counter filter scan test method
 Airborne particle count test
 Room pressurization test
 Airflow parallelism test
 Temperature/RH tests
Cleanroom tests

Cleanroom tests (cont.)
 Lighting level test
 Sound Pressure (Noise) level Test
 Flooring Resistance Test
 Point to Point Test
 Point to Ground Test
 Testing of Swing / Balance voltage and decay time of
ionizers (Electrostatics / Air Ionizer Performance

Sampling plan must include the
followings:
 Room classification
 Room configuration
 Criticality of operations in this room
 Process and material flow
 Sample sites with greatest potential for particulate
contamination
 Gowning requirements
 Cleaning and sanitation procedures

 Personnel quantity per room
 Personnel traffic patterns
 Equipment
 HVAC system (e.g. airflow patterns/design)
 Duration of campaign/manufacturing process
 Process / engineering controls
 In-process monitoring
 Historical data, if available
Sampling plan must include the
followings:

Non Viable Particles Sampling
 Take three (3) one-minute, one-CFM (28.3 liters)
samples per location for better statistical reliability.
 Test Laminar Flow work stations and Barrier isolators
the same way.
 Testing must be performed after any repairs, or
renovations.
 When sampling, test for viable organism at the
same time.

Viable Surface Sampling Sites
The number of sites for air and surface may be
established using the following information:
 Dimension of the room in m2
 formula NL= √A,
 Room classification
As stated before, the number of sites for Viable and Non-
Viable Total particle counts may be established using the
dimension of the room and the formula above
mentioned

There is no industry guidance that defines required number of
surface sample sites. A preliminary number of surface viable
sample sites (foot, walls and ancilliary surface) may be determined
by dividing each classified area by a “key” as follows:
Viable Surface Sampling Sites
Room
Classification
key m2 NL NL
/ key
A
Filling Line
1 200 14 14
A
surroundings
filling line
2 200 14 7
B 3 200 14 5
C 4 200 14 4
D 5 200 14 3

Rationale for Sample Site selection
For routine monitoring must be based on the results of the
testing performed during qualification activities plus the
following factors:
 The location must be based on the process needs and
environmental conditions necessary for the manufacturing
process.
 Equipment surface samples must be included every time
possible.
 Additional sample sites for the filling line, and other
critical production areas (eg, open processing), must be
included when may have a direct impact on the product as
compared to surrounding areas.

The clean room performance is tested studies under
the following stages:
 ”As built”, a test used to establish that the
cleanroom constructor has met his contractual
obligations.
 “At rest”, a test taken with the room fully equipped
ready for production but with no equipment
running and personnel absent.
 “In use”, a test taken with the room fully
operational.
Clean room performance testing

As Built Monitoring
 This operational mode or phase refers to a facility that is
complete and ready for operation with all services connected and
functional, but without equipment or operating personnel in the
facility.
 As Built monitoring is performed when manufacturing related
activity is not taking place. In addition, such monitoring is
appropriate for data gathering during facility qualifications, to
demonstrate baseline data, or other validation activities.
 As Built monitoring may be used to demonstrate the state of the
environmental control in the manufacturing facility before
cleaning and prior to the start of manufacturing operations.
 As Built monitoring includes total and viable particulate
monitoring of the ambient environment, and surface microbial
monitoring.
 Is performed once.

Static Monitoring
 This operational phase refers to a facility that is complete, with
all services functioning and with equipment installed and
operable or operating, on specified, but without operating
personnel in the facility.
 Static monitoring is performed when manufacturing related
activity is not taking place. In addition, such monitoring is
appropriate for data gathering during facility qualifications, to
demonstrate baseline data, or other validation activities.
 Static monitoring is used to demonstrate the state of the
environmental control in the manufacturing facility after
cleaning and prior to the start of manufacturing operations.
 Static monitoring includes total and viable particulate
monitoring of the ambient environment, and surface microbial
monitoring.
 Three (3) sampling is performed after 24hrs of the cleaning
process

In Use Monitoring
 This phase refers to a facility in normal operation, with all
services functioning and with equipment and personnel, if
applicable, present and performing their normal work functions
in the facility.
 “In Use” monitoring is performed to demonstrate the level of
environmental control during production and support
operations in the production environment.
 Routine monitoring should be performed during dynamic
conditions when possible.
 Dynamic monitoring will include total and viable particulate
monitoring of the ambient environment, as well as surface
microbial monitoring.
 Three (3) sampling is performed after 24hrs of the cleaning
process.

Sampling Frequency
The frequency of monitoring may vary from one plant to
another depending of:
 Sample site selection
 Type of facility
 Seasonal variations
 Room design
 Manufacturing process
 Human activity and interventions
 Claning and Sanitization procedures
 Gowning requirements
 Historical data

Critical Areas Monitoring
 The EU Annex 1 says, “A continuous measurement
system should be used for monitoring the
concentration of particles in the grade A zone, and is
recommended in the surrounding grade B areas”.
 The FDA says, “Regular monitoring should be
performed during each production shift. We
recommend conducting nonviable particle monitoring
with a remote counting system. These systems are
capable of collecting more comprehensive data and are
generally less invasive than portable particle counters”.

Grade A Critical Environments
If we look at a filling line the locations that must be
monitored are identified as:
 Sterilisation tunnel - where the sterile vials exit from
 The fill area - location where product is filled into vial
or syringes
 The stopper area - where stoppers are placed onto
vial
 The capping area - where the crimping or capping
occurs

EM program requirements
 for each facility must be outlined in site level procedures
which describe the following:
 Sampling and testing methods
 Monitoring frequency
 Classification and Identification of the areas to be
monitored and sites to be sampled
 Alert and action levels
 Excursion response/investigation, including re-sampling
requirements
 Organism identification
 Length of tubing for sampling and the radii of any bends in
tubing

Sampling Frequency for Routing
Monitoring for C and D Classes
TEST MINIMUM FREQUENCY
Air Particle Monitoring Three Months
HEPA Filter Integrity Testing Yearly
Air Change Rate Calculation 6 Months
Air Pressure
Differentials
Daily
Temperature and
Humidity
Daily
Microbial Monitoring Once a month / During
manufacturing process

Viable Particle Monitoring during
Critical in process activities.
 Air, Surfaces and Personnel Monitoring Should be
done During Aseptic Operations
 Product Contact Surfaces Should be Monitored at the
End of the Aseptic Operation.

Sampling frequency reduction
A reduction in or the number of sites for routine
monitoring can be performed. Such an approach would
require the following:
 A risk analysis and evaluation of historic data collected
from environmental surface sites and air sites, to assess
the potential impact on the overall environmental
cleanliness.
 An analysis of adverse trends must be conducted to
demonstrate that current and proposed sampling
frequencies and sites are adequate for assuring the
overall state of control.

 A review of the validated cleaning and sanitizing
procedures and facility control (HVAC) program to
ensure they have not changed significantly during the
period under review.
 Documentation of the analysis performed.
 Approval of the reduction plan by site Quality Head, or
designee.
 Periodic review of the environmental data to
determine if the reduced sampling frequency and
number of sites remains appropriate.
Sampling frequency reduction
(cont.)

Last Remarks
 A well designed and executed monitoring plan is a
must.
 The monitoring plan has to be designed using
good Judgment so that it can be defended during a
compliance audit.

References
 FDA Guidance for Industry- Sterile Drug Products Produced by Aseptic
Processing - Current Good Manufacturing Process
 http://www.particlecounters.org/
 ISO 13408 Aseptic Processing of Health Care Products
 ISO 14644-1 Cleanrooms & associated controlled environments – Part 1 :
Classification of air cleanliness
 ISO 14698, Cleanrooms and associated controlled environments –
Biocontamination control.
 PIC/S Recommendation on the Validation of Aseptic Processes
 USP 35 <1116> “"Microbiological Evaluation of Clean Rooms and Other
Controlled Environments".
 USP 35 <797> “Pharmaceutical Compounding—Sterile Preparations”

Environmental Characterization of Controlled Rooms

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