Revision to Parts 1 and 2: 2015 Tim Sandle · ISO 14644 – parts #1 ISO 14644-1:2015 - Part 1: Classification of air cleanliness ISO 14644-2:2015 - Part 2: Specifications for testing

Revision to Parts 1 and 2: 2015

Tim Sandle

Downloaded from Sterilize.it

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 notmonitoring

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 testingand monitoring to prove continued compliance withISO 14644

ISO 14644-3:2005 - Part 3: Test methods

ISO 14644-4:2001 - Part 4: Design, construction andstart-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 nanoscaleparticle concentration

ISO 14644-13:draft - Part 13: Cleaning of surfaces to achieve defined levels ofcleanliness in terms of particle and chemical classifications

ISO 14644-14:draft - Part 14: Assessment of suitability for use of equipment byairborne 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 monitoringto 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 particlesusing a standard method.

Determine classification of cleanroom according tostandards e.g. Room x is ISO class y.

Distinct from routine environmental monitoring.

Distinct from process monitoring e.g. ongoingassessment 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, orpersonnel present

At rest : condition where the installation is complete with equipment installedand operation in a manner agree upon by the customer and supplier, but with nopersonnel present

Operational : condition where the installation is functioning in the specifiedmanner, with the specified number of personnel and working in the manneragreed 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



Particle sizes Allows for one or more particle sizes to be assessed.

The standard requires the larger particle to be at least 1.5times that of the smallest particle size measured.

But no longer features ≥5.0 µm limit for particles for theGrade 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 wholenumber).

A is the area of the cleanroom or clean zone in square metres (m2) forwhich the square root is taken.

• Taking the surface of the room in square metres, assessing the squareroot and using the obtained number (rounded up) to give the numberof 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 finitepopulation.

Each location can be treated independently with a 95% level ofconfidence that at least 90% of the cleanroom will comply withthe maximum particle limit for the intended class.

Confidence an be increased if desired.

No calculations are required to determine the number oflocations - there is a ‘look-up table’ (Table 1 - the only referencefor all sizes of particle from ISO 1 to ISO 9).


Look up tables #1 Where a room area is not

listed in the look-uptable, the next largestsize is selected.

This method hasgenerally led to anincrease in particle countlocations.


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 counterplaced in each sector. Previous standard – counter placed in approximate centre.

New standard - where the counter is placed within each sectoris determined by the user.

The standard allows counters always to be placed at the samepoint within the sector; randomly placed within the sector; orevenly distributed; or by risk.

Reason: counts no longer assumed to be homogenous within asector.

Addition locations can be added at the discretion of thefacility.


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 fixedequipment. The standard recommends that thefollowing 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 thesampling process.


Change C – sample volumes #1 Volume of air to be sampled at

each location, the volume of airmust be sufficient to detect atleast 20 particles for the largestparticle size limit.

The operative figure is ≥5.0microns

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 litrewould need to be taken at eachlocation.

However, ISO 14644 states thatthe volume needs to be at least 2litres, sampled over a oneminute period.

Therefore, a minimum of 2 litreswould need to be taken at eachlocation.


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 betaken 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 ofthe 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 nolonger permits increments of 0.1. So, to meet EU GMP, anISO 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 classificationinappropriate; and

Sample collection limitations for both particles in low concentrations and sizes greater than1 μm make classification at this particle size inappropriate, due to potential particle lossesin the sampling system.

But Annex 1 of EU GMP requires 5.0 µm particles to beassessed

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 notwithin 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 thecleanroom, eachindividual sector mustpass.

The room is determinedto have met the ISO classprovided that theobtained result does notexceed the desired class.

Sample location

Sample (counts 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 flowair.

• There are no changes to occupancy states, the idealposition is that cleanrooms should be classified whenoccupied (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 tocleanroom classification. This should be by riskassessment.

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 nomore than ±20%). Counters must be certified.

ACP - initialism for ‘Airborne Cleanliness Particles’.

This is to differentiate airborne particles from surfaceparticles.

So ISO class 7 becomes ISO-ACP class 7.

ACV - ‘Airborne Viable Concentration’.

Viable contamination is not addressed further in thestandard.


Actions and implications Rooms require reassessment for number of particle

count locations.

Location of particle counters within a sector to beassigned, 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 limitvalue table. But remains for EU GMP.

No more statistical UCL calculation: there is no need toperform an observation of all measuring points in the roomany longer. Each single measuring point is consideredindividually and has to meet the limit value.

The tubing length to the particle counter should be lessthan 1 m.

The classification number, the sample volumes/ measuringperiod 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: [email protected]


https://www.pharmig.org.uk/en/product/current-perspectives-on-environmental-monitoring-review-1/






https://www.pharmig.org.uk/en/product/guide-to-disinfectants-and-their-use-in-the-pharmaceutical-industry/

https://www.pharmig.org.uk/en/product/guide-to-disinfectants-and-their-use-in-the-pharmaceutical-industry/

https://www.pharmig.org.uk/en/product/microbiological-control-for-non-sterile-pharmaceuticals/




https://www.pharmig.org.uk/en/products/publications/

https://www.pharmig.org.uk/en/products/publications/

mailto:[email protected]

Presenter Dr. Tim Sandle

Pharmig committeemember

PharmaceuticalMicrobiology website:http://www.pharmamicroresources.com/


http://www.pharmamicroresources.com/



Welcome Pharmig is a non-profit making professional organisation, established

in 1991, that represents the interests of individuals who work in, haveresponsibility for, or work alongside microbiology withinpharmaceutical, healthcare, cosmetics & NHS Industries. It provides a focus for continuing professional development and serves

as a unique network for the exchange of microbiological informationthrough training courses, conferences, publications and its websiteforum. 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


Dr. Tim Sandle

If you have any questions please email: [email protected]


Documents

Revision to Parts 1 and 2: 2015 Tim Sandle · ISO 14644 – parts #1 ISO 14644-1:2015 - Part 1: Classification of air cleanliness ISO 14644-2:2015 - Part 2: Specifications for testing