EN/ISO Cleanroom

Standards BS EN ISO
14644-1&2:2015
Classification &
Monitoring
A Refresher & Update
webinar slidepack
12th May 2021
 EN/ISO Cleanroom Standards
BS EN ISO 14644-1&2:2015
Classification & Monitoring
A Refresher & Update

Gordon Farquharson
May 2021
President CCN; Chair UK BSI LBI/030; Chair CEN TC243; UK HoD ISO TC209
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Learning Objectives
Learn how contamination control standards specify
requirements for Critical Environmental Control Parameters
 Essential features of BS EN ISO-14644-1:2015 – Classification
of air cleanliness
 For Life-Sciences , the link with GMP Annex 1, Manufacture of
Sterile Medicinal Products
 Link to BS EN ISO 14644-2:2015 – Monitoring (to provide
performance evidence)

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 ISO Cleanroom Standards

ISO 14644-1:2015 Classification of air cleanliness:

Note this edition was published on the 15th December 2015.

Classification of air cleanliness by particle number concentration in cleanrooms
and associated controlled environments.
 Defines the concentration of all (total) airborne particles (does not
differentiate bio- contamination)
 Limited to a designated range of considered threshold particle sizes from ≥0.1
to ≥5.0 micron particles for specification of particle concentration limits. Using
a particle counter.

3  Generic standard, not application specific.

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Something about airborne Particle Counters

 Light scattering device
 Light Scattering Airborne Particle Counter
 LSAPC
 Counts number & Size BY Number and Intensity of
flashes
 ISO 21501- 4 specifies performance and calibration
of LSAPCs

Image courtesy of
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 BS EN ISO 14644-1:2015 Cleanroom Standard
Defines classification by
 ISO Class
 Occupancy State
 Designated particle sizes (minimum one size; if more, then dia D2 ≥ 1.5 x dia D1.
3 Occupancy States
 As Built
 At Rest
 Operational
Specifies
 Number of sampling locations for classification
 The sample size required at each location
 How to evaluate the data to determine the class
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Use correct cleanliness designation

 Designation
 ISO class number (1-9)
 Occupancy State
 Designated Particle size(s)
 Example - ISO Class 4; at rest; 0.2 m, 0.5 m
 USE correct reference to the standard
 ISO 14644  no meaning
 ISO 14644-1 would always mean the latest version.
 ISO 14644-1:2015 is a specific edition.
 BS EN ISO 14644-1:2015 is the British version.
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 ISO 14644-1:2015 – Classification by Table 1
• c. Too many
particles these
sizes-
coincidence
error!
• d.Too few
particles these
sizes
• e. Low
concentration &
losses in
sampling.
• f. Particles ≥ 5.0
m not included in
ISO Class 5. See
clause C7.

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Notes to Classification Table 1

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 Number of Sampling Locations – BS EN ISO 14644-1:2015
 Look up table (was new in 2015)
 Vertical plane for horizontal UDAF
 Horizontal plane for vertical UDAF
Note: UDAF = (unidirectional airflow)

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Table A.1 - Look-up

table for MINIMUM
number sampling
locations.

Statistical basis is: 95%

confidence that at least
90% of the zone will comply
with the class limit.

Can choose more

locations if you wish.
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 A.4.4 Sample Size Calculation – ISO 14644-1:2015

• Each location - Min 2 litre sample; Min 1 minute sample time.

• Sample volume at each location the same.
• Can apply ‘Sequential sampling (Annex D) for very large sample sizes/times.

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Class Evaluation – ISO 14644-1:2015

 All locations must comply with the class limits.
 Can average multiple counts at each location.
 The 95% UCL from the 1999 version has been removed.
There are more sampling locations. For 100 m2 , now 16
was 10.
 Special guidance for dealing with EU GMP Annex 1, Grade A
and B ≥ 5.0 
requirements. (What I call the 5 micron challenge!)

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 The environmental control requirements defined in GMPs
 Environmental cleanliness levels
 Airborne particles
 Microbiological contamination
 Airborne

 Surfaces

 Pressure differentials
 Air-change rates implied by recovery time
(ventilation effectiveness)
 Uni-directional airflow velocities
 Air filtration (final filters) requirements
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Annex 1- Table of area/zone Cleanliness (particles)

At Rest In Operation
Microbiological
Grade Max Particles ≥ stated sizes (also finger dabs and contact
plates)

Air sample 90mm settle

0.5µ 5.0µ 0.5µ 5.0µ plate
cfu/m3
cfu/4hr

A 3 520 20 3 520 20 <1 <1 Not included in ISO

Class 5 in BS EN
ISO 14644-1:2015
B 3 520 29 352 000 2 900 10 5
Must use the Macro-
C 352 000 2 900 3 520 000 29 000 100 50 particle descriptor

D 3 520 000 29 000 Not defined Not defined 200 100

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 Dealing with the GMP Annex 1 20 & 29 limits
Remember…..ISO Standards are the Toolbox for Classification –
to be used in conjunction with the levels defined in the GMP
Guidance.

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Sample Size Calculation - ISO 14644-1:2015 for

Annex 1

 Always based on the largest considered particle size.  For Grade B (operational), 1 min sample
 For Grade A (at rest, operational) 20 parts/m , Vs = 1000 litre For Grade C&D, 1 min sample
3

 For Grade B (at rest) 29 parts/m3, Vs = 693 litre

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 Example - Industrial integrated vial line Working
out the number of sampling locations

Cap Overseal
Wash Depyrogenisation & Fill & stopper
cool

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Number of sample locations – real world

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 Number of sample locations – real
• Divide the cleanroom into logical
world zones:
• By ISO Class
• By areas or regions
• Don’t locate directly beneath a
un-diffused HEPA supply in
non-UDAF rooms

Grade B areas
8 x 1 = 8 m2  4 locations
(8 x 2.75) – (1.5 x 1.75) = 19.37 m2
 6 say 7 locations
Grade A areas
1.5 x 4 = 6 m2  3 locations
1.25 x 4 = 5 m2  3 locations
1.5 x 1.75 = 2.63 m2  2 locations

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“Operational” monitoring BS EN ISO 14644-2:2015

Clean room and clean air devices should be
routinely monitored in operation and the
monitoring locations based on a formal risk
analysis study and the results obtained during
the classification of rooms and/or clean air
devices.

 Provides risk based guidance for developing and implementing a monitoring system.
 Provides some minimum requirements. GMPs are more specific and include levels/values.
 Guidance on ‘Real Time’ monitoring & ‘Periodic tests’.
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 Parameters to be monitored (NA- UK national annex)
 When frequent or
continuous monitoring
systems are provided,
intervals can be extended.
 Continuous automated
systems are most common
for room pressures and
particle concentrations.
 A written monitoring
rationale should be
available.
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Filling Machine ‘Real Time’ Particle Monitoring

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 Setting Alert and Action levels
 Part 2 has Informative Annex B “Considerations for setting
alert and action levels”.
 Establish normal operating range – (likely to need time to refine).
 Alerts give warning of a drift before Action levels are reached –
(time to do something about it).
 Ensure instrument calibration programme is established.
 Ensure you have considered impact of equipment and facility
operations.
 May need to set delay time on alarms - (to tolerate normal
short term transients).
 Review data for trends.
 Define a clear response plan for Alerts & Actions.
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Summary & Conclusions

 ISO-14644-1&2:2015 – Classification of air cleanliness & Monitoring –
are the core Cleanroom Standards. It’s what differentiates a cleanroom
from other controlled spaces.
 Remember the Standards are generic
 Use the correct nomenclature/terminology
 Understand how to apply the standards correctly in the real world.
 In the Life Science sector, ensure you understand the link
between regulations (GMPs) and the standards. The standards
are generic.
 Ensure there is a clear plan for moving from Classification to
Operational Monitoring.
 Keep a look out for the revision to the standards.

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 And finally – Contacting the CCN

Want to join the Contamination Control

Network or find out more ?

Go to
https://www.theccnetwork.org/

Thanks for your attention

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Further reading on Cleanroom subject matter

(click on cover for links)

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 Thank you from the

Contact the Contamination Control

Network
www.theCCNetwork.org
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S
Y
S
CRI T I CAL
E
M
S
This presentation has been
prepared and delivered by:-
Gordon J
Farquharson
Principal
Critical Systems Ltd
Consulting in Safety & Quality Critical
Systems Guildford, Surrey, GU1 2SY, UK
tel +44 (0)1252 703 663
[email protected]
www.critical-systems.co.uk

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