ISO 14644 2015 - Pharmig x.pdf

Revision to Parts 1 and 2: 2015

Revision to Parts 1 and 2: 2015

Tim Sandle

Welcome

Welcome

 Pharmig is a non-profit making professional organisation, establishedPharmig is a non-profit making professional organisation, established

in 1991, t

in 1991, that represents the interests of ihat represents the interests of individuals who wndividuals who work in, ork in, havehave responsibil

responsibility fority for, or work alongside microb, or work alongside microbiology withiniology within pharmaceutical, healthcare, cosmetics & NHS Industries. pharmaceutical, healthcare, cosmetics & NHS Industries.



 It provides a focus for continuing professional development and servesIt provides a focus for continuing professional development and serves

as a unique network for the exchange of microbiological information as a unique network for the exchange of microbiological information through training courses, conferences, publications and its website through training courses, conferences, publications and its website forum.

forum.



 Organising meetings, training courses, conferences and producing publicationsOrganising meetings, training courses, conferences and producing publications

that provide topical information and views on

that provide topical information and views on microbiologically related topicsmicrobiologically related topics



  Advancing  Advancing the sciencthe science e of microbiology of microbiology and its pand its practical apractical applicationplication



 InfInfluencing the development of regulations and guidelinesluencing the development of regulations and guidelines

surrounding microbiology surrounding microbiology



  Acting  Acting as a as a confidential forum confidential forum for for the the dissemination dissemination of informationof information

conc

Presenter

Presenter





Dr. Tim Sandle

Dr. Tim Sandle

 Pharmig committeePharmig committee

member member   PharmaceuticalPharmaceutical Microbiology website: Microbiology website: http://www.pharmamic http://www.pharmamic roresources.com/ 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

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

 _–

 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

Cleanrooms

Cleanrooms

 – Personnel

 – Gowning  – Behaviours

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.

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

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

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

Change A

 _–

 particle locations #1

 New approach to selection of locations for particle counting  Previous approach:

N

_L

=

A

 N_Lis 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 #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

increase in particle count

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

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

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 (V _s) = [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.

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

 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

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}

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

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

 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.

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

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,

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

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://w ww.pharmig.org.uk/en/products/publications/ or email: [email protected]