Product/patient Oriented Contamination Control. Content

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Abel Lawson
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Product/patient Oriented Contamination Control An

Content Product/patient Contamination Contamination

Surface cleanliness Particle deposition rate Cleanroom

1 Product/patient Oriented Contamination Control An alternative look at contamination control Koos Agricola Content Product/patient Contamination Contamination mechanisms Contamination control solutions Air cleanliness Surface cleanliness Particle deposition rate Cleanroom operation Monitoring 30 October 2017 Product/patient Oriented Contamination Control 2 1

Potential harm Product Reject or loss of quality by: Particles Macro particles Chemicals Nanoscale particles On vulnerable surfaces Patient Infection or disease by: Micro organisms Particles carrying

1 5 µm Macro particles > 5 µm Particles not removed by airflow > 25 µm Airborne particles are counted by a Light Scattering Airborne Particle Counter Differential d1 < size < d2 Cumulative size d

2 Potential harm Product Reject or loss of quality by: Particles Macro particles Chemicals Nanoscale particles On vulnerable surfaces Patient Infection or disease by: Micro organisms Particles carrying micro organisms Unhealthy chemicals On vulnerable surfaces 30 October 2017 Product/patient Oriented Contamination Control 3 Contamination Particles Airborne particles µm Macro particles > 5 µm Particles not removed by airflow > 25 µm Airborne particles are counted by a Light Scattering Airborne Particle Counter Differential d1 < size < d2 Cumulative size d Particles on surfaces > 2 dimensional image Length, width, area, perimeter: size = D Depositing macroparticles can be counted by a particle deposition monitor (like a real time settle plate for particles) 30 October 2017 Product/patient Oriented Contamination Control 4 2

Contamination Micro organisms Can multiply under warm and humid conditions Bacteria, spores Fungi, spores Algae

$µm, 12 < D < 25 µm In a cleanroom a fraction of the particles carry microbes The cleaner the class the larger the$ optically or DNA 30 October 2017 Product/patient Oriented Contamination Control 5 Contamination mechanisms

optically or DNA 30 October 2017 Product/patient Oriented Contamination Control 5 Contamination mechanisms

Probability is: PDR * Area*Time of exposure Contact transfer Direct: (by tool, work surface, finger(s)) Indirect:

3 Contamination Micro organisms Can multiply under warm and humid conditions Bacteria, spores Fungi, spores Algae Viruses Mostly on surface of a particle Average particles size of Microbe Carrying Particles (mcp s) is: d = 12 µm, 12 < D < 25 µm In a cleanroom a fraction of the particles carry microbes The cleaner the class the larger the fraction of mcp s The larger a particle the more likely it is a mcp Measured by capability to grow (cfu, O 2 use), optically or DNA 30 October 2017 Product/patient Oriented Contamination Control 5 Contamination mechanisms Particle (mcp) deposition Gravitation Turbulent impaction Particle Deposition Rate PDR = number/m 2 /hr Probability is: PDR * Area*Time of exposure Contact transfer Direct: (by tool, work surface, finger(s)) Indirect: (cross contamination) Contact surface is contaminated by: Deposition 30 October 2017 Product/patient Oriented Contamination Control 6 3

Locations where vulnerable surface(s) is (are) exposed: Determine process flow Project process flow on facility floor

30 October 2017 Product/patient Oriented Contamination Control 7 Contamination control solutions Limit particle

sources Remove particles by air flow Local solutions (clean zones, separate devices) Limit particle concentration on

4 Locations where vulnerable surface(s) is (are) exposed: Determine process flow Project process flow on facility floor Determine potential contamination sources Investigate logistics and procedures around critical location Critical location 30 October 2017 Product/patient Oriented Contamination Control 7 Contamination control solutions Limit particle concentration in the air Separation (Box in box) Segregation (Pressure cascade) Limit entrance of particles Limit particle sources Remove particles by air flow Local solutions (clean zones, separate devices) Limit particle concentration on surfaces Cleaning program by cleaners and personnel Avoid unclean incoming surfaces 30 October 2017 Product/patient Oriented Contamination Control 8 4

5 Air cleanliness Air Cleanliness by Particle concentration can be classified by ISO :2015: C = C n =10 N /(10d) 2,08 Table for classification of air clealiness by particle concentration Maximum allowable concentrations (particles/m 3 ) for particles equal to and ISO Class greater than the considered sizes, shown below: number (N) 0,1 µm 0,2 µm 0,3 µm 0,5 µm 1 µm 5 µm , ,000 2,370 1, ,000 23,700 10,200 3, ,000, , ,000 35,200 8, ,000 83,200 2, ,520, ,000 29, ,200,000 8,320, ,000 Sampling and statistical limitations for particles in low concentrations make classification inappropriate. Sample collection limitations for both particles in low concentrations and sizes > 1 um make classification at this particle size inapprpopriate, due to potetial losses in the sampling system. 30 October 2017 Product/patient Oriented Contamination Control 9 Surface cleanliness Surface Cleanliness by Particle concentration is described by ISO :2012: Cs = C SCP,n = 10 M /D ISO SCP Maximum allowable concentration (particles/m 2 ) for particles equal to and Class greater than the considered sizes shown below: number (M) µm 1 µm 5 µm 10 µm 50 µm 100 µm 500 µm , ,000 2,000 1, ,000 20,000 10,000 2,000 1, ,000, , ,000 20,000 10,000 2, ,000,000 2,000,000 1,000, , ,000 20, ,000,000 2,000,000 1,000, , October 2017 Product/patient Oriented Contamination Control 10 5

6 Particle deposition rate PPDR Limit = PDRL= PDR*D/10 Related to ISO : PDR = ΔCs/time of exposure PDRL PDR (number of particles/m 2 /hour) 5µm 10µm 20µm 50µm 100µm 200µm 500µm ,000 2,000 1, ,000 20,000 10,000 5,000 2,000 1, , , ,000 50,000 20,000 10,000 5,000 2,000 1,000,000 2,000,000 1,000, , , ,000 50,000 20, October 2017 Product/patient Oriented Contamination Control 11 Relation air and surface cleanliness Activity can cause re entering of particles from dirty surfaces PDRL Cleanroom class SCP Class ISO Cleanroom Class: Air Cleanliness by Particle concentration SCP: ISO Surface Cleanliness by Particle concentration PDRL: Particle Deposition Rate level 12 6

7 Relation air and surface cleanliness PDR = C*deposition velocity u Concentration C is high for small particle and low for large particles Deposition velocity u low for small particles and high for large particles C = Source strength/removal air flow # # is determined by supply air volume and particle removal efficiency PDR = ΔCs/time of exposure Microbe Deposition Rate = m * PDR Likelihood of deposition of critical particle Dc is: N Dc = PDR Dc * Area * time of exposure N Dc = C Dc * u Dc * Area * time of exposure 30 October 2017 Product/patient Oriented Contamination Control 13 Ratio microbial and particle contamination The deposition of micro organisms (MDR) is related to the deposition of particles (PDR): MDR = m*pdr m increases with the increase of particle size m increases with the decrease of the particle concentration m is characteristic for a particular cleanroom, after determination PDR data can be used to estimate MDR. Estimated of value m, ratio microbial and particle deposition m 1,0 0,8 0,6 ISO 8 0,4 ISO 7 ISO 6 0,2 ISO 5 0, October 2017 Product/patient Particle Oriented size in Contamination µm Control 14 7

Cleanroom operation During operation Source strength is much higher People

of airflow and distribution of particles (and mcp s)) Equipment Incoming

installation determines concentration airborne particles Cleaning program

October 2017 Product/patient Oriented Contamination Control 15 Main source of

8 Cleanroom operation During operation Source strength is much higher People (particle and microbes) Activity (re entry from unclean surfaces, disturbance of airflow and distribution of particles (and mcp s)) Equipment Incoming goods This is partly controlled by operational procedures Cleanroom installation determines concentration airborne particles Cleaning program determines Surface cleanliness and Impact on particle deposition rate 30 October 2017 Product/patient Oriented Contamination Control 15 Main source of (microbe carrying) particles MCP s 30 October 2017 Product/patient Oriented Contamination Control 16 8

Example: impact personnel Good cleanroom

Removal efficiency 60 % 20 air changes >

= 60 /m 2 /hr > Particle size Number per

5 100,000 1 40,000 5 3,000 25 60 50 10 Assume

01 m 2 is exposed during 8 hours: N 50 = 60*0.

9 Example: impact personnel Good cleanroom garment: Cleanroom 5*4*3 = 60 m 3 2 operators Removal efficiency 60 % 20 air changes > 1,200 m 3 Number of particles/m 3 : N 0.5 = 12,000,000/1,200/0.6 = 16,700 /m 3 > ISO 6 level N 5 = 360,000/1,200/0.6 = 500 /m 3 > ISO 7 level PDR 50 = 1,200/20 = 60 /m 2 /hr > Particle size Number per minute , , , Assume a critical area of 100 cm 2 = 0.01 m 2 is exposed during 8 hours: N 50 = 60*0.01*8= 5 on product If m 50 = 0.5 then 2 or 3 cfu 30 October 2017 Product/patient Oriented Contamination Control 17 Monitoring Air cleanliness with Particle counter µm Particle deposition monitor > 5 15 µm Surface cleanliness Direct Indirect 30 October

Cumulative size distribution of deposited

distributions Number of particles per dm2 per

standard well cleaned dirty cleanroom 19

Operating table Return air ducts Measurement

10 Cumulative size distribution of deposited particles Typical Particle Deposition distributions Number of particles per dm2 per hour Cleanroom installation Personnel Cleaning Particle size in um 30 October 2017 standard well cleaned dirty cleanroom 19 Realtime measurements in Operating Room Door Operating table Return air ducts Measurement locations C5, C6 and C7. 30 October 2017 Product/patient Oriented Contamination Control 20 10

11 Knee operation: data C5: particles 0,5 and 5 µm 30 October 2017 Product/patient Oriented Contamination Control 21 Realtime measurement preparation room Return duct Door(s) Protected area Horzontal UDF Measurement locations C5, C6 and C7. 30 October 2017 Product/patient Oriented Contamination Control 22 11

Preparation room C5, C6 and C7 30 October

12 Preparation room C5, C6 and C7 30 October 2017 Product/patient Oriented Contamination Control 23 Screen shot Real time data: Number of particles > 15 µm per 5 minutes 30 October 2017 Product/patient SMI Pharmaceutical Oriented Contamination Microbiology Control

Screenshot Differential Particle Distribution, Real time data 4 5 4 3 2 1 30 October 2017 Product/patient Oriented Contamination Control

13 Screenshot Differential Particle Distribution, Real time data October 2017 Product/patient Oriented Contamination Control 25 Screenshot Real time data: Cumulative particle size distribution 30 October 2017 Product/patient Oriented Contamination Control 26 13

14 Real time particle deposition 10 Number of Particles > 15 µm & Cumulative PAC 0, , ,08000 Number of Particles / Measurement , , , , , ,02000 Cumulatieve PAC 1 0, , October 2017 Product/patient Oriented Contamination Control 27 Differential particle size and obscuration distribution on sensor 30 October 2017 Product/patient Oriented Contamination Control 28 14

15 Particle Deposition Rate in a PDC 4 cleanroom PDC = 4 means PDR 100 or 10 particles 10 µm or 2 particles 50 µm or 1 particle 100 µm per dm 2 per hour 29 Koos Agricola 30 15

ISO INTERNATIONAL STANDARD. Cleanrooms and associated controlled environments Part 1: Classification of air cleanliness

ISO INTERNATIONAL STANDARD. Cleanrooms and associated controlled environments Part 1: Classification of air cleanliness INTERNATIONAL STANDARD ISO 14644-1 First edition 1999-05-01 Cleanrooms and associated controlled environments Part 1: Classification of air cleanliness Salles propres et environnements maîtrisés apparentés