Conor MurrayChairman - Irish Cleanroom Society

Head of Delegation for Ireland at ISO TC 209

Update on ISO CleanroomStandards – 14644 & 14698

www.cleanrooms-ireland.ie

2

Conor Murray, an Engineer by profession is an independent Technical Expert on GMP Cleanrooms and Biosafety Labs Conor is a founder member and Chairman of the Irish Cleanroom Society, (ICS). Conor is a past Chairman of the ICCCS, (International Confederation of Contamination Control Societies) and currently Chairman of the ICEB, (International Cleanroom Education Board)Conor is Head of Delegation for Ireland representing the NSAI at ISO TC 209 and is on WG 01 & WG 02Conor is Convener of Sub Group 13, (Cleanrooms) on the Health Care Standards Consultative (HCSC) committee Conor's particular areas of expertise include Green and Energy Efficient Modular Design, Lifecycle Sustainability, Process Integration, RABS and Fast Track Clean Build Construction

Conor Murray Bio

Irish Cleanroom Society

ISO 14644 & 14698 Overview

ISO DIS 14644 -1 & -2:2011 – WG 01

14698 -1 & -2:2003 – WG 02

Presentation Content

3

4

Irish Cleanroom Societywww.cleanrooms-ireland.ie

The Irish Cleanroom Society (ICS) is a not for profit membership subscription based organisation formed in 1998 to represent cleanroom professionals in IrelandThe ICS is affiliated to the International Confederation of Contamination Control Societies (ICCCS)The primary focus is to promote best practice knowledge and skills, understanding and harmonisation of cleanroom and contamination control technology and standards among users and professionals in Life Sciences, Healthcare, Food, Microelectronics and Micromanufacturing

Irish Cleanroom Society

5

ICS Objectives

Promote the development of cleanroom and contamination control technologies throughout Ireland

Heighten the awareness of cleanroom and contamination control technology among all users inc industry, educational, institutional establishments, government bodies & the public

Assist in the standardisation and harmonisation of cleanroom and contamination control

Organise seminars, exhibitions and peer to peer forum workshops for the dissemination of knowledge & experience gained in cleanroom and contamination control technology

Represent Ireland on the international stage

6

ICS & Education

Education and Training are at the core of ICS activitiesThe ICS has been a major contributor to the CTCB-I (Cleanroom Testing and Certification Board -International) since its inauguration in 2002 and has provided nearly 20 Cleanroom Technology and Testing courses with over 200 candidates from Ireland and around the world Since 2005 the ICS has helped lead the ICEB initiative of the ICCCS to accredit, harmonise & licence cleanroom training courses across national cleanroom societies with the emphasis on certification through examination

7

ICS on the International Stage

The ICS represents Ireland at international level on ISO TC 209 for cleanroom standarisation where Ireland is a voting member Conor Murray is Head of Delegation for Ireland & a subject matter expert on the TC & a number of WGs The ICS is an active member of the ICCCS, International Confederation of Contamination Control SocietiesICS an active member of the International Cleanroom Education Board (ICEB)Ireland hosted the 21st biennial symposium in 2008

8

ICS Linkages in Ireland

The National Standards Authority of Ireland are the Irish representative body in CEN and ISO Standards organisationsTheir Health Care Standards Consultative (HCSC) committee has established a subcommittee, SC 13 concerning cleanroomsThe Irish Cleanroom Society play a leading part in this. Conor Murray is Convener of SC 13 and represents Ireland at ISO TC 209 concerning Cleanrooms and associated controlled environmentsThe ICS works closely with FAS on cleanroom training and up skilling

9

International Cleanroom Education Board (ICEB)Part of International Confederation of Contamination

Control Societies (ICCCS)Set up in 2007ICS playing a significant leadership role internationallyCTCB-I initiative set up with S2C2 in 2001CTCB-I now includes Scandinavian Countries (R3) of

Norway, Sweden and Denmark & The Netherlands (VCCN)

Capturing interest from the US, Baltic, Far East, South Africa, Egypt

ICS Initiatives - Education

10

5 ICEB accredited coursesCleanroom Testing – CTCB-I (‘03 250)Advanced Cleanroom Technology - CTCBi

(‘05 100)Airborne Particle Counting – CTCB-I (‘08 20)Introduction to Cleanrooms - SSE (‘09 50)Cleanroom Cleaning - FLO (‘09 40)

ICS Initiatives - Education

11

ICS & International Associations

12

Participation in Working Groups in TC 209 on

cleanroom standards

WG 01 - revision of ISO 14644 - 1 & 2 Classification by

total airborne particles

WG 02 - revision of ISO 14698 – Biocontamination

(Irish Biocontamination Mirror Group)

WG 03 - revision on ISO 1464 - 3 Metrology

ICS Initiatives - ISO TC 209

13

ICS & ISO TC 209

14

15

ISO 14644 & 14698

- Overview

ISO 14644 & 14698 Standards

ISO Document Title

ISO-14644-1 Classification of Air Cleanliness - 1999

ISO-14644-2 Testing for Continued Compliance to -1 - 1999

ISO-14644-3 Test Methods & Metrology - 2005

ISO-14644-4 Design, Construction & Start Up

ISO-14644-5 Cleanroom Operations

ISO-14644-6 Terminology - 2007

ISO-14644-7 Separative Enclosures

ISO-14644-8 Classification of Airborne Molecular Contamination - 2007

ISO-14698-1 Biocontamination: General Principles - 2003

ISO-14698-2 Biocontamination: Eval’n & Interpretation of Data - 2003

Status

WG01

WG01

WG03

2001

2004

SG06

2004

WG08

WG02

WG02

16

ISO 14644 & 14698 Standards

ISO Document Title

ISO-14644-1 Classification of Air Cleanliness - 1999

ISO-14644-2 Testing for Continued Compliance to -1 - 1999

ISO-14644-3 Test Methods & Metrology - 2005

ISO-14644-4 Design, Construction & Start Up

ISO-14644-5 Cleanroom Operations

ISO-14644-6 Terminology - 2007

ISO-14644-7 Separative Enclosures

ISO-14644-8 Classification of Airborne Molecular Contamination - 2007

ISO-14698-1 Biocontamination: General Principles - 2003

ISO-14698-2 Biocontamination: Eval’n & Interpretation of Data - 2003

Status

WG01

WG01

WG03

2001

2004

SG06

2004

WG08

WG02

WG022 new standards under development to cover 2 new standards under development to cover

SCP via WG9 & SCP via WG9 & --9 and SCC via WG8 & 9 and SCC via WG8 & --1010

17

ISO 14644 TD Proposal

Deals with the role of an ISO 14644 Technical Document as an Overview, Introduction, Explanation and Context in dealing with updates and changes to ISO 14644 & ISO 14698 re airborne and surface cleanliness classification by total particles, viable, chemical and nano particles

Approved in Milan 2011- to be presented to ISO TC 209 in Zurich, September 2012

18

ISO 14644 Issues

Historical development and focus on Airborne Particles

New standards deal with surfaces, chemicals and nanoparticles

Need backward compatibility

Where to put the history, context, perspective, objectives, usage & application notes

19

Existing definition of cleanroom relates to airborne particles ie total particle concentration in air

New definition needs to address the concept of a controlled environment where the control could be total particles, viables or chemicals in air and/or on a surface

20

ISO 14644 Issues

ISO 14664/ 14698 StructureTotal

ParticlesViable

Biocontamination Chemical Nano-particles

ACC

SCC

Airborne

Surface

ACP

SCP

ACN ?

SCN ?

ACV

SCV

TotalParticles

ViableBiocontamination Chemical Nano-

particles14698-1 14698-214698-1 14698-2Surface

Airborne 14644-1

14644-9

14644-8

14644-10

14644-?

14644-?

21

ISO Support StandardsStandard

14644-6 Terminology Terminology

14644-7 Separative Devices Separative Devices

Design, Construction & Startup

14644-5 Operations Operations

14644-4 Design, Construction & Startup

Testing for Ongoing Compliance to 14644-1

14644-3 Test Methods Supporting Test Methods

14644-2 Testing for Ongoing Compliance to14644-1

Existing New

14698-? Supporting ?

22

23

ISO DIS 14644 -1 & - 2

24

Apply good science and statistics

Remove confusion and inconsistencies

Simplify terms

Use more precision

Use a Table for Classification instead of the

universal formula

ISO DIS 14644 -1 & -2

25

DIS Vote May ‘11 – unanimous but > 200 comments

Differences over no of samples for confidence level and maximum area to determine classification

Differences over method of selection of sample locations, application of statistics – random selection

Differences over treatment of 5 micron particles

Differences over normative use of ISO 21501-4

ISO DIS 14644 -1Copenhagen

26

DIS Vote May ‘11 – unanimous

Decided to remove classification and keep to

Periodic Testing & Monitoring

Agreed that Classification and Periodic Testing are

NOT the same – amount of testing

Differences over inclusion of Differential Pressure

ISO DIS 14644 -2Copenhagen

27

ISO 14698 -1 & -2:2003

- Biocontamination WG 02

28

ISO 14698 -1 & -2: 2003

29

ISO 14698 not in line with ISO 14644No Tables of ClassificationNot up to date with Risk Assessment & Risk Management techniques (eg ICH Q9 QRM)No Check Lists of “Things to Consider”Not up to date with technology advances in Rapid Microbiological Methods (RMM) & Instantaneous Microbiological Detection (IMD) (eg ATP, Bioluminescence)

ISO 14698 Issues

30

Cannot “Monitor a process into Control”Not enough clarity on differences, issues and guidance on Aseptic vs Non Sterile applicationsNot enough guidance on Airborne vs Surface biocontamination risks and controlOverall seen as not easy to read & use

ISO 14698 Issues

IS O/TC 2 09 N 187 Re solutions from ISO/ TC 20 9 Mee ting 9-10 Nov em be r 2007 Résolutio ns de l' ISO/T C 209 (19 èm e réu nion, 9 et 10 Novembre 2007) Re solution 1 IS O/TC 209 reso lves th at WG 2 co mmence s work on these two documents :

a. C lassi fication of airb orne bioconta minatio n in c leanroo ms, inc luding metho ds of measure ment a nd their valida tion.

b. C lassi fication of s urf ace biocontaminatio n in c le anroo ms, including method s of measure ment a nd their valida tion.

At t he appropriat e time during the de velopment of these docu ments, t he position of IS O 14 698

Parts 1 a nd 2 sh ould b e cons idered, as wel l as a Risk Manage ment St andard. (All in fa vor)

ISO TC 209Preliminary Work Items WG02

31

32

ISO Standards are NOT industry specific -Bird’s Eye view from 25,000 feetNormative (Must do) & Informative (Should do)Based on good science with clear and

independent guidance Short & concise, easy to read & use

Check Lists, flow charts, suggested methods, options on best practice methods, choices, examples.

ISO Standard Principles

33

Working Group is a team of international experts nominated by each member countryTerms of reference set by TC 209Duration varies but typically 2 - 5 yearsAct as Subject Matter Experts (SMEs) in their

field

ISO Working Group Principles

34

Capture best science and international expertise“Get all the toys on the table” and play with themEverything on the tableOpen dialogue encouraged until the endLet “good science” prevail

ISO Working Group Principles

Current measurement ‘technologies’ limited to orders of magnitude resolution, especially in low density populationsSpecies recovered using these technologies

limited due to incubation methodology (inc media, temperature, pH, aerobic/anerobic, etc.)“Environmental microbiologists recent research

indicate that some species are inter-dependant & one species will not culture successfully

without the presence of the other”

ISO 14698 Challenges- Limitations of Quantitation

35

People are the greatest source of biocontaminationUnpredictability and uncertainty of Human

behaviour“80% of the species found in the human upper

respiratory tract cannot be recovered”

ISO 14698 Challenges- Diversity of People

36

Below limit of resolution for current technologies

i.e. 1 cfu recovered may be indicative of 1cfu or perhaps >10cfu, impossible to accurately and repeatably determine

Risk of false positives high due to likelihood of accidental contamination during collection and incubation

ISO 14698 Challenges- Issues in clean spaces

37

In some cases, all species are considered harmfulIn some cases there is ‘background counts’ of

cfu of species considered ‘normal and non-harmful’In some cases, some species are considered

‘objectionable’ and are not tolerated at all

ISO 14698 Challenges- Process/ Application Specific

38

“In Grade A and B zones, the monitoring of the ≥5.0 μm particle concentration count takes on a particular significance as it is an important diagnostic tool for early detection of failure.”“... consecutive or regular counting of low

levels (of ≥5.0 μm) is an indicator of a possible contamination event and should be investigated.”Particles ≥5.0 μm could be skin particles

carrying biocontamination

Aseptic Processing- 5μm Particles & EU GMPs

39

ISO 14698- Proposed New Structure

40

41

New ISO 14698 Flowchart

42

New ISO 14698 Flowchart

43

New ISO 14698 Flowchart

44

Risk Analysis/ Assessment

Risk Management

Establishing (Risk) Control

Proposed New ISO 14698 -1- Establishing Control

Identify ‘typical, non-harmful’ species- typical in cleanroom- not harmful to product or application/customer

Identify ‘objectionable’ species- atypical in cleanroom- harmful to product and/or harmful to customer

ISO 14698- Establishing Control Step 1

45

For “normal, non-harmful”:- establish typical ‘background counts’, e.g. <10cfu- establish acceptable incidence of higher than normal counts, where maximum limit is defined- anything above incidence rate or maximum triggers investigation

ISO 14698-Establishing Control Step 2

46

For “Objectionable”:- establish acceptable incidence, including maximum number process will tolerate- anything above incidence rate or maximum triggers investigation

ISO 14698- Establishing Control Step 3

47

Classify your process/cleanroom:“Normal, non-harmful”- species- by ‘background counts’- by acceptable incidence of ‘higher than normal’ (maximum limit is defined)

“Objectionable”- establish acceptable incidence, including maximum number process will tolerate per incidence

ISO 14698- Establishing Control Step 4

48

49

ISO 14698- Airborne Classification

Class *Airborne limit In Operation

cfu/m3

ACVx 1 <10# ACVx 2 < 100 ACVx 3 < 1000 ACVx 4 < 10000

1. *Combined with an appropriate incidence rate2. ‘x’ is the species of interest3. # still under discussion (added error by air collection

method)4. Intermediate classes are permitted, eg SVCx 3,5

Surface Contamination Class (SCV)

*Surface Count Limit (CFU)

Sampled Area

SVCx 1 <4 1 m2

SVCx 2 <40 1 m2

SVC x3 <40 1 cm2

SVCx 4 <300 1 cm2

SVC x5 >300 1 cm2

1. Numbers are open for further discussion

2. *Combined with an appropriate incidence rate

3. ‘x’ is the species of interest

4. Intermediate classes are permitted, eg SVCx 3,5

ISO 14698- Surface Classification

50

51

Next meeting – Zurich Sept 2012

New Work Item Proposal (NWIP)

Formal Vote required for approval

ISO timetable of CD, DIS FDIS, & IS over 3 years

ISO 14698- WG 02

52

Thank You for Your Attention