Product/patient Oriented Contamination Control - … Oriented Contamination Control 14 0,0 0,2 0,4...

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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

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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


Contamination

Particles• Airborne particles ≥ 0.1‐ ≥ 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• 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)


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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, O2use), optically or DNA


Contamination mechanisms

• Particle (mcp) deposition– Gravitation– Turbulent impaction

• Particle Deposition Rate PDR = number/m2/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


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Critical location

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


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


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Air cleanlinessAir Cleanliness by Particle concentration can be classified by ISO 14644‐1:2015: C = Cn=10

N/(10d)2,08


Table for classification of air clealiness by particle concentration

0,1 µm 0,2 µm 0,3 µm 0,5 µm 1 µm 5 µm1 10

2 100 24 10

3 1,000 237 102 35

4 10,000 2,370 1,020 352 83

5 100,000 23,700 10,200 3,520 832

6 1,000,000 237,000 102,000 35,200 8,320 293

7 352,000 83,200 2,930

8 3,520,000 832,000 29,300

9 35,200,000 8,320,000 293,000

ISO Class

number (N)

Maximum allowable concentrations (particles/m3) for particles equal to and

greater than the considered sizes, shown below:

Sample collection limitations for both particles in low concentrations and sizes > 1 ummake classification at

this particle size inapprpopriate, due to potetial losses in the sampling system.

Sampling and statistical limitations for particles in low concentrations make classification inappropriate.

Surface cleanliness

Surface Cleanliness by Particle concentration is described by ISO 14644‐9:2012: Cs = CSCP,n = 10

M/D


0.1‐1 µm 1 µm 5 µm 10 µm 50 µm 100 µm 500 µm

1 10

2 100 20 10

3 1,000 200 100

4 10,000 2,000 1,000 200 100

5 100,000 20,000 10,000 2,000 1,000 200

6 1,000,000 200,000 100,000 20,000 10,000 2,000

7 10,000,000 2,000,000 1,000,000 200,000 100,000 20,000

8 10,000,000 2,000,000 1,000,000 200,000

ISO SCP

Class

number (M)

Maximum allowable concentration (particles/m2) for particles equal to and

greater than the considered sizes shown below:

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Particle deposition rate

• PPDR Limit = PDRL= PDR*D/10

• Related to ISO 14644‐9: PDR = ΔCs/time of exposure


PDRL PDR (number of particles/m2/hour)

≥5µm ≥10µm ≥20µm ≥50µm ≥100µm ≥200µm ≥500µm

1 2.0 1.0 0.5 0.2 0.1 0.05 0.02

10 20 10 5 2 1 1 0.2

100 200 100 50 20 10 5 2

1,000 2,000 1,000 500 200 100 50 20

10,000 20,000 10,000 5,000 2,000 1,000 500 200

100,000 200,000 100,000 50,000 20,000 10,000 5,000 2,000

1,000,000 2,000,000 1,000,000 500,000 200,000 100,000 50,000 20,000

Relation air and surface cleanliness

SCP Class

Cleanroom class

PDRL

ISO Cleanroom Class: Air Cleanliness by Particle concentrationSCP: ISO Surface Cleanliness by Particle concentrationPDRL: Particle Deposition Rate level

Activity can cau

se re‐en

tering of

particles from dirty surfaces

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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:

– NDc = PDRDc* Area * time of exposure– NDc = CDc* uDc * Area * time of exposure


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.

Product/patient Oriented Contamination Control 14

0,0

0,2

0,4

0,6

0,8

1,0

0 20 40 60 80 100 120 140 160 180 200

m

Particle size in µm

Estimated of value m,

ratio microbial and particle deposition

ISO 8

ISO 7

ISO 6

ISO 5

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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


Main source of (microbe carrying) particles

MCP’s


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Example: impact personnel

• Good cleanroom garment:• Cleanroom 5*4*3 = 60 m3

• 2 operators• Removal efficiency 60 %• 20 air changes ‐> 1,200 m3

• Number of particles/m3:• N0.5 = 12,000,000/1,200/0.6

= 16,700 /m3 ‐> ISO 6 level• N5 = 360,000/1,200/0.6

= 500 /m3 ‐> ISO 7 level

• PDR50 = 1,200/20 = 60 /m2/hr ‐>


Particle size Number per minute

0.5 100,000

1 40,000

5 3,000

25 60

50 10

Assume a critical area of 100 cm2 = 0.01 m2 is exposed during 8 hours:N50 = 60*0.01*8= 5 on productIf m50 = 0.5 then 2 or 3 cfu

Monitoring

• Air cleanliness with– Particle counter 0.3 – 10 µm– Particle deposition monitor > 5‐15 µm

• Surface cleanliness– Direct– Indirect

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1

10

100

1 10 100 1.000

Nu

mb

er

of p

art

icle

s p

er

dm

2 p

er h

ou

r

Particle size in um

Typical Particle Deposition distributions

standard well cleaned dirty cleanroom

Cumulative size distribution of deposited particles

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Cleanroom installation

Personnel

Cleaning

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Realtime measurements in Operating Room

• Door

• Operating table

• Return air ducts

• Measurement locations C5, C6 and C7.

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Knee operation: data C5: particles ≥ 0,5 and ≥ 5 µm


Realtime measurement preparation room

• Return duct

• Door(s)

• Protected area

• Horzontal UDF

• Measurement locations C5, C6 and C7.


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Preparation room C5, C6 and C7


Screen shot Real‐time data: Number of particles > 15 µm per 5 minutes

Product/patient Oriented Contamination Control 24SMI Pharmaceutical Microbiology 24SMI Pharmaceutical Microbiology 24SMI Pharmaceutical Microbiology 2430 October 2017

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ScreenshotDifferential Particle Distribution, Real‐time data

2

3

1

5 44


Screenshot Real‐time data: Cumulative particle size distribution

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Real‐time particle deposition

0,00000

0,01000

0,02000

0,03000

0,04000

0,05000

0,06000

0,07000

0,08000

0,09000

0,10000

0

1

2

3

4

5

6

7

8

9

10

Cumulatieve

PAC

Num

ber o

f Pa

rticles / Mea

suremen

t

Number of Particles > 15 µm & Cumulative PAC


Differential particle size and obscuration distribution on sensor


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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 dm2 per hour 29

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