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