The need fpr PAT in packaging: 1) The primary package is an integral part of the drug. 2) The sealing process of the package must be validated and monitored. 3) In a PAT framework, 100% inspection of the seal integrity is the ideal approach. Previously there was no process analytical technology for continuous process verification of the sealing process. Sampling was the best option available. Now there is a technological, 100% in-line, non-destructive, testing method. Summary: 1) Sampling provides probabilistic monitoring and cannot provide a solid process analytical control. 2) Thermal imaging technology enables a PAT approach to the induction sealing process with 100% in-line testing and process monitoring => Continued Process Verification 3) Case studies from packaging lines reflect the potential impact of PAT for induction sealing. 4) Reliability of Induction Integrity Verification System tested and proved. *presentation given at IFPAC 2015 session

1. PAT for Packaging
Real time monitoring of pharmaceutical
bottles’ induction sealing process
© Proprietary and Confidential. All Rights Reserved
IFPAC 2015
Presenter: Fabian Schapiro

2. 2
Presentation scope:
 The need for PAT Packaging
 Sealing integrity inspection methods
 What is thermal imaging?
 The induction sealing process
 Case studies
 Reliability test
 Summary
 About DIR Technologies

3. 3
The need for PAT packaging
Guidance for Industry Process Validation:
General Principles and Practices
STEP 1: Process Design
STEP 2: Process Qualification
STEP 3: Continued Process Verification
U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
January 2011
Current Good Manufacturing Practices (CGMP)
Revision 1

4. 4
The need for PAT packaging
PV & PAT
“Systems that promote greater product and process understanding can provide
a high assurance of quality on every batch and provide alternative, effective
mechanisms to demonstrate validation (per 21 CFR 211.100(a), i.e., production
and process controls are designed to ensure quality). In a PAT framework,
validation can be demonstrated through continuous quality assurance where a
process is continually monitored, evaluated, and adjusted using validated in-
process measurements, tests, controls, and process end points.”
FDA’s PAT Guidance, 2004

5. 5
The need for PAT packaging
MAIN REMARKS:
 The primary package is an integral part of the drug.
 The sealing process of the package must be validated and
monitored.
 In a PAT framework, 100% inspection of the seal integrity is the
ideal approach.

6. 6
Sealing integrity verification methods
Vacuum or Pressure
Decay
Sampling
Electro-mechanical
tester
(height + metal detector)
Pressure/Squeezer

7. 7
Sealing integrity verification methods
Method
Vacuum
Decay
Pressure/
Squeezer
EM
Tester
Sampling
Real time,
100% testing
√ √ √ X
No production
slowdown
X X √ X
Process control X X X X
Non-interfering X X X X
Report and trend
analysis
X X X X
Small footprint X X √ √
Reliability √ X X X
Method comparison:

8. 8
Sealing integrity verification methods
Method
Vacuum
Decay
Pressure/
Squeezer
EM
Tester
Sampling Thermal
Imaging
Real time,
100% testing
√ √ √ X √
No production
slowdown
X X √ X √
Process control X X X X √
Non-interfering X X X X √
Report and trend
analysis
X X X X √
Small footprint X X √ √ √
Reliability √ X X X √
Method comparison:

9. 9
What is thermal imaging?

10. 10
What is thermal imaging?
𝑬 𝝀, 𝑻 =
𝟐𝒉𝒄 𝟐
𝝀 𝟓
𝟏
𝒆
𝒉𝒄
𝝀𝑲𝑻 − 𝟏
Planck’s Law of Radiation

11. 11
What is thermal imaging?
Planck’s Law of Radiation

12. 12
What is thermal imaging?

13. 13
Sealing integrity methods
PAT for packaging: I2VS
Thermal imaging solution for in-line induction integrity verification

14. 14
The induction sealing process
FILLER
TORQUER
INDUCTION SEALER
EMPTY
BOTTLES
Defects in the Raw Material:
Defects in the bottle or the liner
Problems in capping:
false torque or crooked cap
Problems in the induction sealer:
Alignment, field fluctuations, etc.
CAPS

15. 15
The induction sealing process
Bent / damaged foil Missing foil
Under-heating Overheating
Crooked capUntorqued cap
Damaged edge
Material related
problems
Capper related
problems
Sealer related
problems
Upside-down
liner

16. Torquer
related
parameter
In the first 2000 bottles of a batch, there is a large
number of rejected bottles.
Most of the rejections are on a parameter that is related
to the tightness of the cap.
Visual inspection of the
rejected bottles confirms
that this is the case (see
picture right).
Based on this information,
the line operator stops the line and adjusts the torquer.
Case study I – Torquer problem
Torquer
problem
Identified

17. 17
Case study I – Torquer problem
Torquer
problem
Identified
Torquer
problem
solved
Torquer
related
parameter
Number of Bottles
Batch continued with an acceptable number
of untorqued caps

18. A consistent group of bottles were found to
differ from the bulk in several parameters.
Visual inspection of the rejected bottles
showed that the bottles were sealed
properly.
The system kept rejecting more of these
bottles, until a closer look revealed the
problem…
Case study II – Mixed liner

19. Liners of different types were mixed
together in the batch.
The system was calibrated to a specific
liner type thus, bottles with a different
liner were detected as
non-compliant and rejected by the
system.
After the problem was identified, the system was used to sort previous batches of
already sealed bottles that were suspected of having a possible liner mix-up.
Without the use the I2VS it would have been necessary to re-work several batches
of thousands of bottles.
Case study II – Mixed liner

20. Defect discovered at the beginning of a batch run – a cut in the liner.
The batch was stopped, the caps
replaced with a new batch and
the defective ones were returned
to the manufacturer.
I2VS enabled the timely
identification of a defective
liner batch, preventing the need
to re-work the full batch.
Case study III – Systematic defect

21. DAY SHIFT NIGHT SHIFT
Case study IV– “Night Shift” effect

22. DAY SHIFT NIGHT SHIFTNIGHT SHIFT
Case study IV– “Night Shift” effect

23. 23
8%
31%
46%
15%
Missing liner
Cold/Partial Sealing
Overheat
Harmed liner
Line monitoring
Case study V– sealer process window

24. 24
77% of failures are related to faults in the induction sealer
8%
77%
15%
Missing liner
Induction Sealer Problems
Harmed liner
Case study V– sealer process window
Line monitoring

25. 25
Case study V– sealer process window

26. 26
Hour #
Quantity
processed
(Population)
Quantity
inspected
(sample size)
False
rejects
True
rejects
# of open seals
found during
inspection
1 4,959 300 2 4 0
2 4,373 300 5 7 0
3 4,990 300 1 4 0
Total 14,322 900 8 15 0
% 6.28% 0.06% 0.10% 0.00%
The above test demonstrates that the reliability of the system in detecting and removing
failed bottles is better than 95%.
In order to increase the certainty, a larger sampling population is required.
Reliability test

27. 1. Sampling provides probabilistic monitoring and can not
provide a solid process analytical control.
2. Thermal imaging technology enables a PAT approach to the
induction sealing process with 100% in-line testing and
process monitoring => Continued Process Verification
3. Case studies from packaging lines reflect the potential impact
of PAT for induction sealing.
4. Reliability of Induction Integrity Verification System tested
and proved
Summary

28. Established: 2009.
Location: Haifa, Israel
Shareholders: Life Sciences Fund - SCP Vitalife
ELBIT Systems (NASDAQ: ESLT)
RAFAEL Advanced Defense Systems
DIR Technologies utilizes sophisticated infra-red detectors and
thermal imaging technology combined with high throughput
imaging & analysis software to provide innovative solutions for the
pharmaceutical industry.
About DIR Technologies

29. 29
Thank you
for your attention