Monday 8 th July Symposium 1 - Environmental Monitoring of Production Areas

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1 Monday 8 th July 2013 Symposium 1 - Environmental Monitoring of Production Areas Dealing with Environmental Monitoring Out of Specification Results and Changes to ISO David Buckley Rev 2 1 Kaoru Ishikawa 1940 s; known for Democratizing Statistics The Basic Seven Tools made statistical analysis less complicated for the average person Good Visual Aids make statistical and quality control more comprehendible. 1

2 What are the Basic Seven Tools of Quality? Fishbone Diagrams (Kaoru Ishikawa) Histograms Pareto Analysis Flowcharts Scatter Plots Run Charts Control Charts Non-conformities fall into three main areas System Related Product Related Process Related People are the greatest source of biocontamination Unpredictability and uncertainty of Human behaviour 80% of the species found in the human upper respiratory tract cannot be recovered (IMHO move to RABS is inevitable) 2

Dip stick stability competent location documented Laboratory or production error?

3 Easy 6M Man, Mother Nature, Materials, Machines, Measurement, Methods Environment Materials Machines Temperature Sample Qualification Light Solutions Maintenance Time Ancillary material choice Humidity Dip stick stability competent location documented Laboratory or production error?? Tare weight Proficient Correct one used Uncertainty Supervised Capable Calibration Trained Validated Measurement People Methods 3

Media Handling Filling line with Isolator and Tunnel HEPA-Filter defect waterfilter defect productfilter defect Ventfilter for nitrogen defect waterfilter not sterile productfilter not sterile

4 Media Handling Filling line with Isolator and Tunnel HEPA-Filter defect waterfilter defect productfilter defect Ventfilter for nitrogen defect waterfilter not sterile productfilter not sterile Contamination with Water during filter test primary packaging material not sterile Vials not sterile productcontact parts not sterile Bulksolution not sterile gloves defect Filter Materials Personnel Isolator has no overpressure Environment not sterile Positive Sterility Test gloves not sterile 4

C a u s e Man Method Method Environment Man Method Method Environment Measurement Measurement Materials Putting it together Compare all causes 2 at a time 2

5 C a u s e Man Method Method Environment Man Method Method Environment Measurement Measurement Materials Putting it together Compare all causes 2 at a time 2 points in the column of more important cause or 1 each if equal Sum of column gives relative importance or a weighting factor Comparison Matrix Cause Materials 5

6 Used Ishikawa and looked at 6M Man Floor scores low Machine Method Material Environment Measurement 6

7 Production error, or lab error 7

8 PW, WFI score high 1 st example 8

9 Production error, or lab error Production error, or lab error 9

10 Production error, or lab error Production error, or lab error 10

11 Production error, or lab error Production error, or lab error 11

12 Production error, or lab error 12

13 Summary 13

27 ISO14644, 1 and 2 TC209 mission Gordon J Farquharson, is convenor ISO TC209 WG1 Apply good science and statistics Remove confusion and inconsistencies Simplify terms, Use more precision Use a

14 27 ISO14644, 1 and 2 TC209 mission Gordon J Farquharson, is convenor ISO TC209 WG1 Apply good science and statistics Remove confusion and inconsistencies Simplify terms, Use more precision Use a Table for Classification instead of the universal formula 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 28 14

15 Proposed changes Simplify classification process If possible remove need to evaluate 95% UCL for 2-9 sample locations Review cleanroom classification procedure make it more applicable to rooms in operation - contamination isn't expected to be evenly distributed current assumption Generally update the standard to current thinking and industry requirements Avoid radical change to current ISO cleanliness classes

16 Air flow onto a flat surface (left) and a perforated surface (right) 31 What s new 32 16

17 ISO : changes Simplifies and clarifies requirements and guidance tables that specify frequency of testing and monitoring of cleanrooms used to demonstrate continued compliance with the cleanliness classification. Refined how intervals may be extended, provided that automated monitoring systems show the cleanroom is under control. Provide new guidance on aspects that should be considered when configuring a monitoring system for a cleanroom. 33 ISO not in line with ISO No Tables of Classification Not 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) 34 17

detection of failure.... consecutive or regular counting of low levels (of 5.

18 PIC/S EU GMP Overules ISO14644 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 35 ISO Class, old and new ISO

Sample locations The formula proposed for intermediate decimal classes in ISO DIS 14644-1:2010 37 Developments since 2010 Revisions 14644-1 DIS in 2010 because of change in TC209 vision and comments

19 Sample locations The formula proposed for intermediate decimal classes in ISO DIS : Developments since 2010 Revisions DIS in 2010 because of change in TC209 vision and comments new DIS is under development is developed parallel to and will be on monitoring only Vocabulary will be removed and becomes web based DIS in 2011 Surface Cleanliness by Chemical concentrations x will be the Assessment of equipment and materials for cleanroom suitability is reserved for Air Cleanliness by Nanoscale Particle concentration. Classification is extrapolation of to 1 nm is reserved for Cleaning of surfaces to achieve defined levels of cleanliness in terms of particle and chemical classification. Technical Committee 209, & International Confederation of Contamination Control Societies (ICCCS) 38 19

20 ISO Test methods Particle measurement is moved to , Ultrafine particles are moved to nanoscale particles. Supporting tests for the cleanroom performance: Air pressure difference test Airflow test Airflow direction test and visualisation Recovery test Temperature, humidity and micro vibration tests. Supporting tests for the performance of systems and components, which maintain cleanrooms: Installed filter leakage test Containment leak test Electrostatic and ion generator tests Particle deposition test Technical Committee 209, & International Confederation of Contamination Control Societies (ICCCS) 39 ISO Test methods Important changes in test methods: New knowledge in cleanroom technology and contamination control and developments in cleanroom components like Fan Filter Units (FFU s) and measurement equipment are included. Installed filter testing by photometer will be improved to prevent unnecessary contamination. Installed filter testing by particle counter will be simplified and improved. Recovery test will be improved. Particle deposition measurement is extended to particle size distributions. Technical Committee 209, & International Confederation of Contamination Control Societies (ICCCS) 40 20

21 viables 3 sections: 1. Establish control requirements: Product quality attributes, Risk assessment, A distinction between harmless and harmful microorganisms will be made. Classification of Air and Surface Cleanliness by viables: < cfu/m3 -> ACVx 1-4 < 4-300, > 300 cfu/m2 +sample area: 1dm2 or m2 -> SCVx Test methods (air, surface and deposition): New rapid methods will be included. 3. Demonstrate control. Technical Committee 209, & International Confederation of Contamination Control Societies (ICCCS) 41 Surface cleanliness by particle concentrations (2012) ISO SCP class The surface cleanliness by particles is classified by the number of particles 1 µm per m2. The SCP class is the 10log(N1), where N1 is the maximum number of particles 1 µm per m2, The SCP class can be written as 10log(d.Nd ), where Nd is the maximum number of particles d µm per m2 and d is the size (length) of the particle. CN= 10K /d, where CN is Nd per m2 and K = SCP class. Direct and indirect measurement methods are described in the standard. Technical Committee 209, & International Confederation of Contamination Control Societies (ICCCS) 42 21

22 Surface cleanliness by particles - SCP Technical Committee 209, & International Confederation of Contamination Control Societies (ICCCS) 43 SCP measurement Direct Particle surface monitor, Particle Guard, (Stereo) microscope, Black light (qualitative, vision) Plus others Indirect through medium Air, Air flow + particle counter, Liquid Filtrate + weighting or microscopic inspection Liquid particle counter Solid (wiper, tape, sticky roll) + microscopic inspection Technical Committee 209, & International Confederation of Contamination Control Societies (ICCCS) 44 22

23 Future developments 4 contaminants: Particles (0,1 5 µm and macro descriptor), Nanoscale particles (1 100 nm), Chemicals, Viables (micro-organisms). Classification of Air cleanliness for one of the 4 contaminants. Classification of Surface cleanliness for one of the 4 contaminants. Measurement method for classification in standard. Revision of test methods. Technical Committee 209, & International Confederation of Contamination Control Societies (ICCCS) 45 ISO14644 Conclusion TGA voice????? ISO Standards are NOT industry specific, PIC/S still applies Cannot Monitor a process into Control Not enough clarity on differences, issues and guidance on Aseptic vs Non Sterile applications Not enough guidance on Airborne vs Surface biocontamination risks and control Overall seen as not easy to read & use Let good science prevail 46 23

24 Questions 47 24

Environmental Control Requirements. Gordon Farquharson July 2017

Environmental Control Requirements Gordon Farquharson July 2017 Learning Objectives Learn how contamination control standards and guidance sets requirements for Critical Parameters ISO-14644-1 Classification