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Revision to Parts 1 and 2: 2015
Tim Sandle
Welcome
 Pharmig is a non-profit making professional organisation, established
in 1991, that represents the interests of individuals who work in, have
responsibility for, or work alongside microbiology within
pharmaceutical, healthcare, cosmetics & NHS Industries.
 It provides a focus for continuing professional development and serves
as a unique network for the exchange of microbiological information
through training courses, conferences, publications and its website
forum.
 Organising meetings, training courses, conferences and producing publications
that provide topical information and views on microbiologically related topics
 Advancing the science of microbiology and its practical application
 Influencing the development of regulations and guidelines
surrounding microbiology
 Acting as a confidential forum for the dissemination of information
concerning all aspects of microbiology
Presenter
 Dr. Tim Sandle
 Pharmig committee
member
 Pharmaceutical
Microbiology website:
http://www.pharmamic
roresources.com/
ISO 14644
 ISO 14644
 International cleanroom standard
 Part 1 in 1999
 12 part standard
 Electronics, healthcare, biotechnology, pharmaceuticals
 Replaced FS 209E in 2001
 Accepted by EU GMP in 2003 for classification but not
monitoring
 FDA aseptic filling guide in 2004.
ISO 14644 – parts #1
 ISO 14644-1:2015 - Part 1: Classification of air
cleanliness
 ISO 14644-2:2015 - Part 2: Specifications for testing
and monitoring to prove continued compliance with
ISO 14644
 ISO 14644-3:2005 - Part 3: Test methods
 ISO 14644-4:2001 - Part 4: Design, construction and
start-up
 ISO 14644-5:2004 - Part 5: Operations
ISO 14644 – parts #2
 ISO 14644-6: 2004 - Vocabulary
 ISO 14644-7:2004 - Part 7: Separative devices (clean air hoods, gloveboxes,
isolators and mini-environments)
 ISO 14644-8:2013 - Part 8: Classification of air cleanliness by chemical
concentration (ACC)
 ISO 14644-9:2012 - Part 9: Classification of surface cleanliness by particle
concentration
 ISO 14644-10:2013 - Part 10: Classification of surface cleanliness by chemical
concentration
 No part 11 in draft
 ISO 14644-12:draft - Part 12: Classification of air cleanliness by nanoscale
particle concentration
 ISO 14644-13:draft - Part 13: Cleaning of surfaces to achieve defined levels of
cleanliness in terms of particle and chemical classifications
 ISO 14644-14:draft - Part 14: Assessment of suitability for use of equipment by
airborne particle concentration
Cleanrooms
• Cleanrooms
– Design
• Air
– Filtration (HEPA)
– Pressure differentials
– Air changes
– Clean-up times
– UDAF: air velocity
– Personnel
– Gowning
– Behaviours
– Cleaning and disinfection
ISO 14644
 Became live in December 2015:
 ISO 14644-1 - Classification of air cleanliness
 ISO 14644-2 - Specifications for testing and monitoring
to prove continued compliance by ACP.
 Both parts deal with particles only
ISO 14644 Part 1 - purpose
 Classification is the process of qualifying the
cleanroom environment by the number of particles
using a standard method.
 Determine classification of cleanroom according to
standards e.g. Room x is ISO class y.
 Distinct from routine environmental monitoring.
 Distinct from process monitoring e.g. ongoing
assessment of aseptic filling.
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 operation in a manner agree 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 and working in the manner
agreed upon
9 classes
In Operation:
Grade A = ISO class 4.8
Grade B = ISO class 7
Grade C = ISO class 8
Grade D = Not determined, class 8 normally applied
1999 version
ISO 14644 - introducing the revised standard
Particle sizes
 Allows for one or more particle sizes to be assessed.
 The standard requires the larger particle to be at least 1.5
times that of the smallest particle size measured.
 But no longer features ≥5.0 µm limit for particles for the
Grade A equivalent class for classification.
 This does not replace EU GMP requirements. ≥0.5 and
≥5.0 µm need to be assessed for monitoring.
Change A– particle locations #1
 New approach to selection of locations for particle counting
 Previous approach:
NL = 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 metres (m2) for
which the square root is taken.
• Taking the surface of the room in square metres, assessing the square
root and using the obtained number (rounded up) to give the number
of locations, to be positioned equidistantly.
Change A– particle locations #2
Change A– particle locations #3
• The new method is based on hypergeometric distribution.
 Opposite to binomial distribution.
 Samples are drawn randomly without replacement from a finite
population.
 Each location can be treated independently with a 95% level of
confidence that at least 90% of the cleanroom will comply with
the maximum particle limit for the intended class.
 Confidence an be increased if desired.
 No calculations are required to determine the number of
locations - there is a ‘look-up table’ (Table 1 - the only reference
for all sizes of particle from ISO 1 to ISO 9).
Look up tables #1
 Where a room area is not
listed in the look-up
table, the next largest
size is selected.
 This method has
generally led to an
increase in particle count
locations.
Look up tables #2
Cleanroom Room size 1999 version
location
numbers
Revised no.
of locations
A 200 m2 15 23
B 36 m2 6 9
C 8 m2 3 4
Change B – position of counters #1
• Once the number of locations has been selected, the room
is divided up into equal sectors and a particle counter
placed in each sector.
 Previous standard – counter placed in approximate centre.
 New standard - where the counter is placed within each sector
is determined by the user.
 The standard allows counters always to be placed at the same
point within the sector; randomly placed within the sector; or
evenly distributed; or by risk.
 Reason: counts no longer assumed to be homogenous within a
sector.
 Addition locations can be added at the discretion of the
facility.
Change B – position of counters #2
 To align with GMP, the location should be orientated
to the point of greatest risk e.g. close to fixed
equipment. The standard recommends that the
following is accounted for:
 Room layout;
 Equipment layout;
 Airflow patterns;
 Position of air supply and return vents;
 Air-change rates;
 Consideration should be given to any unintended bias in the
sampling process.
Change C – sample volumes #1
 Volume of air to be sampled at
each location, the volume of air
must be sufficient to detect at
least 20 particles for the largest
particle size limit.
 The operative figure is ≥5.0
microns
Volume to be sampled (Vs) =
[20 x 1000 (constant)]
Class limit particles (largest size)
 For example, Grade C
 Volume to be sampled
= 20 x 1000 = 0.69 litres
29,000
 Therefore, a minimum of 1 litre
would need to be taken at each
location.
 However, ISO 14644 states that
the volume needs to be at least 2
litres, sampled over a one
minute period.
 Therefore, a minimum of 2 litres
would need to be taken at each
location.
Change C – sample volumes #2
 For example, Grade B
 Volume to be sampled =
20 x 1000 = 6.9 litres
2,900
 Therefore, a minimum of 7 litres would need to be
taken at each location.
 Grade A – more complicated…
Change D – class limits #1
 The Grade A issue
 EU GMP Grade A does not equal ISO class 5, because of
the different 5.0 µm limits
 29 count limits for ISO 14644 class 5
 20 count limit for EU GMP Grade A.
 Where intermediate classes are required the standard no
longer permits increments of 0.1. So, to meet EU GMP, an
ISO class of 4.5 would need to be selected in theory.
Change D – class limits #2
 De-emphasis on the 5 μm ISO Class 5 limit:
 Sampling and statistical limitations for particles in low concentrations make classification
inappropriate; and
 Sample collection limitations for both particles in low concentrations and sizes greater than
1 μm make classification at this particle size inappropriate, due to potential particle losses
in the sampling system.
 But Annex 1 of EU GMP requires 5.0 µm particles to be
assessed
 Options:
 Just classify Grade A for 0.5 µm and use 0.5 µm / 5.0 µm for operations,
 Or continue with 20 or 29 as a limit as an additional option for 5.0 µm.
 Standard states: “In some situations, typically those related to specific process requirements,
alternative levels of air cleanliness may be specified on the basis of particle populations that are not
within the size range applicable to classification.”
 This means continuing with one cubic metre per location.
 BUT attempting this for 5.0 µm size particle could be difficult due to potential particle loss from
tubing.
Cleanroom Room size 1999 sample
time (entire
room)
Revised
sample time
(entire room)
X 200 m2 45 minutes 23 minutes
Y 36 m2 36 minutes 9 minutes
Z 8 m2 36 minutes 4 minutes
Cleanroom Room size 1999 sample
time per
location
Revised
sample time
per location
X 200 m2 3 1
Y 36 m2 6 1
Z 8 m2 12 1
Assuming one available particle counter:
Assessment of results #1
 Record the results for each sample location.
 Convert the results to one cubic metre for the room:
 Result per room =
No. particles @each location (or average) x (conversion factor to make one cubic
metre)
Volume of air sampled @each location
 For example:
 Using a particle count that counts at 28.3 litres per minute (or one cubic foot
per minute), each result would need to be multiplied by 35.3
 Using a particle counter counting at 50 litres per minute, each result would be
multiplied by 20.
 Individual results must be within limits per sector (unless more than one
sample per sector)
Assessment of results #2
 There is no longer a
‘grand total’ for the
cleanroom, each
individual sector must
pass.
 The room is determined
to have met the ISO class
provided that the
obtained result does not
exceed the desired class.
Sample
locatio
n
Sample
(count
s per
28.3
litres)
Counts
per
cubic
metre
(x 35.3)
Limit
for 0.5
µm
Pass /
Fail
1 52 1836 352,000 Pass
2 12 424 352,000 Pass
3 91 3201 352,000 Pass
4 97 3424 352,000 Pass
5 19 682 352,000 Pass
6 7 271 352,000 Pass
Example: Grade B cleanroom,
assessed for 0.5 µm particles using
a 1-minute counter
Change E – probe positions
• The counter probe must be orientated into the airflow (for
unidirectional air) or pointed upwards for turbulent flow
air.
• There are no changes to occupancy states, the ideal
position is that cleanrooms should be classified when
occupied (at the normal occupancy level).
Clarification of test certification
 Test certificates must state:
 Name and address of the testing organization.
 Date of testing.
 No. and year of the publication of the relevant part of ISO 14644 e.g.
ISO 14644: 1 – 2015.
 Location of cleanroom (or clean zone).
 Specific representation of locations e.g. diagram.
 Designation of cleanroom:
 ISO class (plus EU GMP)
 Occupancy.
 Particle count sizes considered.
 Test method used (and any departures or deviations).
 Identification of test instrument and calibration certificate.
 Test results.
ISO 14644 Part 2
 Very little change:
 Reclassification is a minimum of annual (change).
 EU GMP states aseptic filling to be six-monthly, unless justified.
 Requirement for a monitoring strategy in addition to
cleanroom classification. This should be by risk
assessment.
 Levels are likely to be higher during processing.
Other changes
 Recommendation that particle counts that meet ISO
21501 are used (error rate at each particle size of no
more than ±20%). Counters must be certified.
 ACP - initialism for ‘Airborne Cleanliness Particles’.
 This is to differentiate airborne particles from surface
particles.
 So ISO class 7 becomes ISO-ACP class 7.
 ACV - ‘Airborne Viable Concentration’.
 Viable contamination is not addressed further in the
standard.
Actions and implications
 Rooms require reassessment for number of particle
count locations.
 Location of particle counters within a sector to be
assigned, accounting for risk.
 Sample sizes to be re-calculated.
 Decision on 5.0 µm particles for Grade A.
 Contract test costs may alter:
 More locations but,
 Shorter sample run times.
Summary
 The number of measuring points is no longer calculated as
the square root of the surface but given in a table.
 5 µm particles for ISO 5 has been dropped from the limit
value table. But remains for EU GMP.
 No more statistical UCL calculation: there is no need to
perform an observation of all measuring points in the room
any longer. Each single measuring point is considered
individually and has to meet the limit value.
 The tubing length to the particle counter should be less
than 1 m.
 The classification number, the sample volumes/ measuring
period remain unchanged compared to the version of 1999.
Pharmig publications
Current perspectives on Environmental Monitoring –
Review # 1
Guide to Disinfectants and their use in the
Pharmaceutical Industry
Microbiological Control for Non-Sterile
Pharmaceuticals
See:
https://www.pharmig.org.uk/en/products/publications/
or email: info@pharmig.co.uk
Dr. Tim Sandle
If you have any questions please
email:
info@pharmig.org.uk

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ISO 14644 - introducing the revised standard

  • 1. Revision to Parts 1 and 2: 2015 Tim Sandle
  • 2. Welcome  Pharmig is a non-profit making professional organisation, established in 1991, that represents the interests of individuals who work in, have responsibility for, or work alongside microbiology within pharmaceutical, healthcare, cosmetics & NHS Industries.  It provides a focus for continuing professional development and serves as a unique network for the exchange of microbiological information through training courses, conferences, publications and its website forum.  Organising meetings, training courses, conferences and producing publications that provide topical information and views on microbiologically related topics  Advancing the science of microbiology and its practical application  Influencing the development of regulations and guidelines surrounding microbiology  Acting as a confidential forum for the dissemination of information concerning all aspects of microbiology
  • 3. Presenter  Dr. Tim Sandle  Pharmig committee member  Pharmaceutical Microbiology website: http://www.pharmamic roresources.com/
  • 4. ISO 14644  ISO 14644  International cleanroom standard  Part 1 in 1999  12 part standard  Electronics, healthcare, biotechnology, pharmaceuticals  Replaced FS 209E in 2001  Accepted by EU GMP in 2003 for classification but not monitoring  FDA aseptic filling guide in 2004.
  • 5. ISO 14644 – parts #1  ISO 14644-1:2015 - Part 1: Classification of air cleanliness  ISO 14644-2:2015 - Part 2: Specifications for testing and monitoring to prove continued compliance with ISO 14644  ISO 14644-3:2005 - Part 3: Test methods  ISO 14644-4:2001 - Part 4: Design, construction and start-up  ISO 14644-5:2004 - Part 5: Operations
  • 6. ISO 14644 – parts #2  ISO 14644-6: 2004 - Vocabulary  ISO 14644-7:2004 - Part 7: Separative devices (clean air hoods, gloveboxes, isolators and mini-environments)  ISO 14644-8:2013 - Part 8: Classification of air cleanliness by chemical concentration (ACC)  ISO 14644-9:2012 - Part 9: Classification of surface cleanliness by particle concentration  ISO 14644-10:2013 - Part 10: Classification of surface cleanliness by chemical concentration  No part 11 in draft  ISO 14644-12:draft - Part 12: Classification of air cleanliness by nanoscale particle concentration  ISO 14644-13:draft - Part 13: Cleaning of surfaces to achieve defined levels of cleanliness in terms of particle and chemical classifications  ISO 14644-14:draft - Part 14: Assessment of suitability for use of equipment by airborne particle concentration
  • 7. Cleanrooms • Cleanrooms – Design • Air – Filtration (HEPA) – Pressure differentials – Air changes – Clean-up times – UDAF: air velocity – Personnel – Gowning – Behaviours – Cleaning and disinfection
  • 8. ISO 14644  Became live in December 2015:  ISO 14644-1 - Classification of air cleanliness  ISO 14644-2 - Specifications for testing and monitoring to prove continued compliance by ACP.  Both parts deal with particles only
  • 9. ISO 14644 Part 1 - purpose  Classification is the process of qualifying the cleanroom environment by the number of particles using a standard method.  Determine classification of cleanroom according to standards e.g. Room x is ISO class y.  Distinct from routine environmental monitoring.  Distinct from process monitoring e.g. ongoing assessment of aseptic filling.
  • 10. 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 operation in a manner agree 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 and working in the manner agreed upon
  • 11. 9 classes In Operation: Grade A = ISO class 4.8 Grade B = ISO class 7 Grade C = ISO class 8 Grade D = Not determined, class 8 normally applied 1999 version
  • 13. Particle sizes  Allows for one or more particle sizes to be assessed.  The standard requires the larger particle to be at least 1.5 times that of the smallest particle size measured.  But no longer features ≥5.0 µm limit for particles for the Grade A equivalent class for classification.  This does not replace EU GMP requirements. ≥0.5 and ≥5.0 µm need to be assessed for monitoring.
  • 14. Change A– particle locations #1  New approach to selection of locations for particle counting  Previous approach: NL = 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 metres (m2) for which the square root is taken. • Taking the surface of the room in square metres, assessing the square root and using the obtained number (rounded up) to give the number of locations, to be positioned equidistantly.
  • 15. Change A– particle locations #2
  • 16. Change A– particle locations #3 • The new method is based on hypergeometric distribution.  Opposite to binomial distribution.  Samples are drawn randomly without replacement from a finite population.  Each location can be treated independently with a 95% level of confidence that at least 90% of the cleanroom will comply with the maximum particle limit for the intended class.  Confidence an be increased if desired.  No calculations are required to determine the number of locations - there is a ‘look-up table’ (Table 1 - the only reference for all sizes of particle from ISO 1 to ISO 9).
  • 17. Look up tables #1  Where a room area is not listed in the look-up table, the next largest size is selected.  This method has generally led to an increase in particle count locations.
  • 18. Look up tables #2 Cleanroom Room size 1999 version location numbers Revised no. of locations A 200 m2 15 23 B 36 m2 6 9 C 8 m2 3 4
  • 19. Change B – position of counters #1 • Once the number of locations has been selected, the room is divided up into equal sectors and a particle counter placed in each sector.  Previous standard – counter placed in approximate centre.  New standard - where the counter is placed within each sector is determined by the user.  The standard allows counters always to be placed at the same point within the sector; randomly placed within the sector; or evenly distributed; or by risk.  Reason: counts no longer assumed to be homogenous within a sector.  Addition locations can be added at the discretion of the facility.
  • 20. Change B – position of counters #2  To align with GMP, the location should be orientated to the point of greatest risk e.g. close to fixed equipment. The standard recommends that the following is accounted for:  Room layout;  Equipment layout;  Airflow patterns;  Position of air supply and return vents;  Air-change rates;  Consideration should be given to any unintended bias in the sampling process.
  • 21. Change C – sample volumes #1  Volume of air to be sampled at each location, the volume of air must be sufficient to detect at least 20 particles for the largest particle size limit.  The operative figure is ≥5.0 microns Volume to be sampled (Vs) = [20 x 1000 (constant)] Class limit particles (largest size)  For example, Grade C  Volume to be sampled = 20 x 1000 = 0.69 litres 29,000  Therefore, a minimum of 1 litre would need to be taken at each location.  However, ISO 14644 states that the volume needs to be at least 2 litres, sampled over a one minute period.  Therefore, a minimum of 2 litres would need to be taken at each location.
  • 22. Change C – sample volumes #2  For example, Grade B  Volume to be sampled = 20 x 1000 = 6.9 litres 2,900  Therefore, a minimum of 7 litres would need to be taken at each location.  Grade A – more complicated…
  • 23. Change D – class limits #1  The Grade A issue  EU GMP Grade A does not equal ISO class 5, because of the different 5.0 µm limits  29 count limits for ISO 14644 class 5  20 count limit for EU GMP Grade A.  Where intermediate classes are required the standard no longer permits increments of 0.1. So, to meet EU GMP, an ISO class of 4.5 would need to be selected in theory.
  • 24. Change D – class limits #2  De-emphasis on the 5 μm ISO Class 5 limit:  Sampling and statistical limitations for particles in low concentrations make classification inappropriate; and  Sample collection limitations for both particles in low concentrations and sizes greater than 1 μm make classification at this particle size inappropriate, due to potential particle losses in the sampling system.  But Annex 1 of EU GMP requires 5.0 µm particles to be assessed  Options:  Just classify Grade A for 0.5 µm and use 0.5 µm / 5.0 µm for operations,  Or continue with 20 or 29 as a limit as an additional option for 5.0 µm.  Standard states: “In some situations, typically those related to specific process requirements, alternative levels of air cleanliness may be specified on the basis of particle populations that are not within the size range applicable to classification.”  This means continuing with one cubic metre per location.  BUT attempting this for 5.0 µm size particle could be difficult due to potential particle loss from tubing.
  • 25. Cleanroom Room size 1999 sample time (entire room) Revised sample time (entire room) X 200 m2 45 minutes 23 minutes Y 36 m2 36 minutes 9 minutes Z 8 m2 36 minutes 4 minutes Cleanroom Room size 1999 sample time per location Revised sample time per location X 200 m2 3 1 Y 36 m2 6 1 Z 8 m2 12 1 Assuming one available particle counter:
  • 26. Assessment of results #1  Record the results for each sample location.  Convert the results to one cubic metre for the room:  Result per room = No. particles @each location (or average) x (conversion factor to make one cubic metre) Volume of air sampled @each location  For example:  Using a particle count that counts at 28.3 litres per minute (or one cubic foot per minute), each result would need to be multiplied by 35.3  Using a particle counter counting at 50 litres per minute, each result would be multiplied by 20.  Individual results must be within limits per sector (unless more than one sample per sector)
  • 27. Assessment of results #2  There is no longer a ‘grand total’ for the cleanroom, each individual sector must pass.  The room is determined to have met the ISO class provided that the obtained result does not exceed the desired class. Sample locatio n Sample (count s per 28.3 litres) Counts per cubic metre (x 35.3) Limit for 0.5 µm Pass / Fail 1 52 1836 352,000 Pass 2 12 424 352,000 Pass 3 91 3201 352,000 Pass 4 97 3424 352,000 Pass 5 19 682 352,000 Pass 6 7 271 352,000 Pass Example: Grade B cleanroom, assessed for 0.5 µm particles using a 1-minute counter
  • 28. Change E – probe positions • The counter probe must be orientated into the airflow (for unidirectional air) or pointed upwards for turbulent flow air. • There are no changes to occupancy states, the ideal position is that cleanrooms should be classified when occupied (at the normal occupancy level).
  • 29. Clarification of test certification  Test certificates must state:  Name and address of the testing organization.  Date of testing.  No. and year of the publication of the relevant part of ISO 14644 e.g. ISO 14644: 1 – 2015.  Location of cleanroom (or clean zone).  Specific representation of locations e.g. diagram.  Designation of cleanroom:  ISO class (plus EU GMP)  Occupancy.  Particle count sizes considered.  Test method used (and any departures or deviations).  Identification of test instrument and calibration certificate.  Test results.
  • 30. ISO 14644 Part 2  Very little change:  Reclassification is a minimum of annual (change).  EU GMP states aseptic filling to be six-monthly, unless justified.  Requirement for a monitoring strategy in addition to cleanroom classification. This should be by risk assessment.  Levels are likely to be higher during processing.
  • 31. Other changes  Recommendation that particle counts that meet ISO 21501 are used (error rate at each particle size of no more than ±20%). Counters must be certified.  ACP - initialism for ‘Airborne Cleanliness Particles’.  This is to differentiate airborne particles from surface particles.  So ISO class 7 becomes ISO-ACP class 7.  ACV - ‘Airborne Viable Concentration’.  Viable contamination is not addressed further in the standard.
  • 32. Actions and implications  Rooms require reassessment for number of particle count locations.  Location of particle counters within a sector to be assigned, accounting for risk.  Sample sizes to be re-calculated.  Decision on 5.0 µm particles for Grade A.  Contract test costs may alter:  More locations but,  Shorter sample run times.
  • 33. Summary  The number of measuring points is no longer calculated as the square root of the surface but given in a table.  5 µm particles for ISO 5 has been dropped from the limit value table. But remains for EU GMP.  No more statistical UCL calculation: there is no need to perform an observation of all measuring points in the room any longer. Each single measuring point is considered individually and has to meet the limit value.  The tubing length to the particle counter should be less than 1 m.  The classification number, the sample volumes/ measuring period remain unchanged compared to the version of 1999.
  • 34. Pharmig publications Current perspectives on Environmental Monitoring – Review # 1 Guide to Disinfectants and their use in the Pharmaceutical Industry Microbiological Control for Non-Sterile Pharmaceuticals See: https://www.pharmig.org.uk/en/products/publications/ or email: info@pharmig.co.uk
  • 35. Dr. Tim Sandle If you have any questions please email: info@pharmig.org.uk