Is IQ/OQ/PQ part of irradiation - Superevent€¦ · Is IQ/OQ/PQ part of irradiation ... ‘guard...

Is IQ/OQ/PQ part of irradiation process control?

Florent KUNTZ and Alain STRASSER

Aerial-CRT, Illkirch France

International Conference on Applications of Radiation Science and Technology

(ICARST 2017) - 24 to 28 April 2017, Vienna, Austria

Outline

• Introduction - Relevant standards/guides

• Installation, Operational and Performance Qualification

• Control absorbed dose to product

• Associated uncertainties

• The importance of traceable calibration and good practices

• Conclusion

Introduction – Relevant standard/guides

• Installation Qualification

– Irradiator supplied and installed in accordance with its specifications ?

• Operational Qualification – Irradiator, as installed, capable of operating and delivering

appropriate doses within defined acceptance criteria ?

ISO 14470

ANSI/AAMI/ISO 11137-1

ANSI/AAMI/ISO 11137-3

ISO/ASTM 51649, 51702, 51608

ASTM E2303

Sterilization of health care products—Radiation—

Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices

Part 3: Guidance on dosimetric aspects

Introduction – Relevant standard/guides

• Performance Qualification Obtaining and documenting evidence that the equipment,

as installed and operated in accordance with operational procedures, consistently performs in accordance with predetermined criteria

Sterilization of health care products—Radiation—

Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices

Part 3: Guidance on dosimetric aspects

ISO 14470

ANSI/AAMI/ISO 11137-1

ANSI/AAMI/ISO 11137-3

ISO/ASTM 51649, 51702, 51608

ASTM E2303

Gamma plant, Danver Hydromatics, India

Gamma/X Ray process

Operational Qualification

ANSI/AAMI/ISO 11137-3

ISO/ASTM 51702, 51608

Carried out to characterize the irradiator with respect to the distribution and reproducibility of dose and to establish the effect of process interruption on dose

Source activity/geometry Source mechanism Ebeam power/energy Cycle Timer/Laps/Speed Conveyor path(s) Product density/filling Product transition …

Operational Qualification

ANSI/AAMI/ISO 11137-3

ISO/ASTM 51702, 51608 Homogeneous material (various densities)

Example 7 MV X Ray

Density 0.15

DUR 1.33 +/- 0.03

E Beam process

Installation Qualification

1 ENERGY/CURRENT

SPOT SIZE 2

SCAN WIDTH 3

PRODUCT CENTERING

5

CONVEYOR SPEED 6

(8.2)

(8.2)

(8.2)

(8.6) (8.5)

(8.5)

ANSI/AAMI/ISO 11137-3

ISO/ASTM 51649

SCAN UNIFORMITY

PARALLELISM* 4

* optional

Operational Qualification

• Process interruption/Restart for both

conveyor and electron beam (9.3.6)

• Dose distribution • Surface (9.3.4)

• Product Height dependence (9.3.5)

• Inside material (9.3.4, 9.3.8)

• Absorbed dose as function of conveyor speed, beam current, scan width, …(9.3.5)

• Dose variability / reproducibility (9.3.5)

Homogeneous material (various densities)

I / (Speed*SW) in mA.min/m2

Absorbed Dose at surface in kGy

Dsurf = 10,77 * (I/(V*Wb)) + 0,04 K = 10,77 kGy.m2/(mA.min)

Machine variability

Performance Qualification

ANSI/AAMI/ISO 11137-3

ISO/ASTM 51649, 51702, 51608 Each processed product/family !

What for?

•Establish the dose distribution inside the product

•Establish the relation between the routinely monitored

dose and the maximum and minimum dose delivered to

the product

•Establish the uncertainty of the mapping

•Establish the Dose interval allowed for the routine

dosimeter

•Choose a target dose for the monitor dosimeter

Section 10 of ISO 11137-3

Performance Qualification

ANSI/AAMI/ISO 11137-3

ISO/ASTM 51649, 51702, 51608

Gamma: Partial load of labware

P4 P3 P1

P1

P3

P4

DUR 1.24 +/- 0.04

Theoretical relationship

Monitoring Dose vs. Min Dose or Max Dose Dmon

Dmax

Real life (due to variability)

Dmin

Control the dose to product

Variability on DUR

Variability on Rmin/mon and Rmax/mon

Reasons for variability

Variability Uncertainty on dose to product

• dose mapping uncertainty σmap min, σmap max

• machine variability σmach

• dosimeter reproducibility σrep

• dosimeter calibration uncertainty σcal

σtotal min = (σcal2 + σmap min

2 + σrep2 + σmach

2)1/2

σtotal max = (σcal2 + σmap max

2 + σrep2 + σmach

2)1/2

The lower σtotal min, σtotal max the easier the process management

ANSI/AAMI/ISO 11137-3

Dster Dmax acc

• Average minimum dose must exceed dose required for sterilization Dster

• Average maximum dose must not exceed maximum acceptable dose Dmax acc

Dose to product

2.5 %

Dproduct lower Dproduct upper

2σtotmin

2σtotmax

‘guard band’ approach:

Minimum dose to be 2 standard deviations greater than dose required for

sterilization. (same for Dmax acc)

The importance of traceable calibration and good practices

Example of dose intercomparison

CRP: Development of Electron Beam and X Ray Applications for Food Irradiation (DEXAFI)

Evaluate ability of participants to:

- Deliver target dose values - Measure doses actually applied

0 1 2 3 4 5 6 7 8 9

Gamma

E-Beam

X-Rays 3 radiation types

Participating Organisations

13 Participants / Radiation Type

Chengdu China /

g

Japan / EB 10MeV

Syria / g

P. R. China / EB 10MeV

Pakistan / g

Thailand / EB 10MeV

Egypt / g

Poland / EB 10MeV

USA / EB 10 MeV

Hawaï / XRay

Portugal / EB 10 MeV

Vietnam / EB 10MeV

Indonesia / g

Performance indicator: -measured vs. applied dose (dosimetry)

Methods

• 1 kGy • 5 kGy • 10 kGy

-0.15

-0.05

0.05

0.15

0.25

0.35

de

viat

ion

Box plot (filtered)

% deviation (1 kGy) Particip. % deviation

1 -1.6%

2 18.2%

3 4.1%

4 2.7%

5 0.0%

6 7.9%

7 13.9%

8 -12.4%

9 -1.9%

10 6.5%

11 31.8%

12 -11.3%

13 -52.2%*

13 (outlier)

*Outlier (Grubbs test; α=5%)

Criteria 1 kGy

Obs. 12

Minimum -0.1236

Maximum 0.3183

1st Quartile -0.0167

Median 0.0343

3rd Quartile 0.0937

Mean 0.0483

Variance (n-1) 0.0152

Std dev. (n-1) 0.1233

13

α = 5% α = 1%

-3

-2

-1

0

1

2

3

1 2 3 4 5 6 7 8 9 10 11 12Z sc

ore

Participants

Z scores XLSTATS v. 2013.5.06

(Addinsoft)

Results: meas. vs. applied dose

-0.15

-0.1

-0.05

0

0.05

0.1

Box plot (filtered)

-3

-2

-1

0

1

2

3

1 2 3 4 5 6 7 8 9 10 11Z sc

ore

Participants

Z score (filtered)

Particip. % deviation

1 CC 1.2%

2 Pak 7.0%

3 PRC 4.4%

4 Pol 0.6%

5 Egy -2.2%

6 Vie -0.7%

7 Tha -10.9%

8 Syr -13.1%

9 Jap -2.2%

10 Haw 1.5%

11 Por 62.8%*

12 Ind -3.2%

13 USA -65.1%*

11, 13

α = 5%

α = 1% *Outlier (Grubbs test; α=5%)

Criteria 1 kGy

Obs. 11

Minimum -0.1312

Maximum 0.0702

1st Quartile -0.0268

Median -0.0067

3rd Quartile 0.0137

Mean -0.0159

Variance (n-1) 0.0036

Std dev. (n-1) 0.0596

11, 13

(outliers)

12

% deviation (5 kGy)

XLSTATS v. 2013.5.06

(Addinsoft)

Results: meas. vs. applied dose

-3

-2

-1

0

1

2

3

1 2 3 4 5 6 7 8 9 10 11Z sc

ore

Participants

Z scores (filtered) -0.15

-0.1

-0.05

0

0.05

0.1

0.15

Box plot (filtered)

Particip. % deviation

1 CC 0.3%

2 Pak 11.6%

3 PRC 3.0%

4 Pol -4.4%

5 Egy -4.0%

6 Vie 1.0%

7 Tha 2.6%

8 Syr -11.0%

9 Jap -1.0%

10 Haw 1.5%

11 Por 62.0%*

12 Ind -1.3%

13 USA -75.7%*

11, 13

α = 5%

α = 1%

*Outlier (Grubbs test; α=5%)

Criteria 1 kGy

Obs. 11

Minimum -0.1099

Maximum 0.1161

1st Quartile -0.0266

Median 0.0030

3rd Quartile 0.0203

Mean -0.0016

Variance (n-1) 0.0031

Std dev. (n-1) 0.0559

11, 13

(outliers)

12

% deviation (10 kGy)

XLSTATS v. 2013.5.06

(Addinsoft)

Results: meas. vs. applied dose

Particip. 1 kGy 5 kGy 10 kGy

1 -1.6% 1.2% 0.3%

2 18.2% 7.0% 11.6%

3 4.1% 4.4% 3.0%

4 2.7% 0.6% -4.4%

5 0.0% -2.2% -4.0%

6 7.9% -0.7% 1.0%

7 13.9% -10.9% 2.6%

8 -12.4% -13.1% -11.0%

9 -1.9% -2.2% -1.0%

10 6.5% 1.5% 1.5%

11 31.8% 62.8% 62.0%

12 -11.3% -3.2% -1.3%

13 -52.2% -65.1% -75.7% -2

-1.5

-1

-0.5

0

0.5

1

1.5

2

1 2 3 4 5 6 7 8 9 10 12

h(i

)

Participants

Mandel’s h statistics (α = 0.05 / hCrit = 1,815)

% deviation (3 doses)

11; 13

Trueness

11; 13

0

0.5

1

1.5

1 2 3 4 5 6 7 8 9 10 12

k(i)

Participants

Mandel’s k statistics (α = 0.05 / kCrit = 1,687)

Reproducibility

Measured vs. applied dose

The importance of traceable calibration and good practices

Auditing the metrology system:

1. Is dosimetry system calibration performed? When? 2. What is the reference dosimetry system used? 3. Is it traceable to certified calibration lab? 4. Is it in house calibration? In calibration plant? In industrial plant? 5. Does calibration geometry allow Reference dosimeter dose =

Routine dosimeter dose? 6. Has calibration verification been performed? 7. Is measurement instrumentation calibrated/verified? … What about Uncertainty?

0%

5%

10%

15%

20%

25%

< -7% -7% to -5% -5% to -3% -3% to -1% -1% to 1% 1% to 3% 3% to 5% 5% to 7% > 7%

40% of participants only!

Conclusion

• Traceable calibration of dosimetry system(s)

• Traceable dose measurements (monitoring Dose, …)

• IQ/OQ Knowledge of the process

• PQ Capacity of process of delivering appropriate dose to product within defined acceptance criteria

• Process (total) uncertainty assessment

How to prove that the irradiation process is under control?

Conclusion

Process control: as important for industry as for research projects !

ISO 14470

ANSI/AAMI/ISO 11137-1

ANSI/AAMI/ISO 11137-3

ISO/ASTM 51649, 51702, 51608

ASTM E2303

Recommendation:

… apply

IQ/OQ/PQ are definitely part of irradiation process control!

Florent KUNTZ and Alain STRASSER

Aerial-CRT, Illkirch France

International Conference on Applications of Radiation Science and Technology

(ICARST 2017) - 24 to 28 April 2017, Vienna, Austria