PAT for PackagingReal time monitoring of pharmaceutical bottles’ induction sealing process

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IFPAC 2015

Presenter: Fabian Schapiro

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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

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The need for PAT packaging

Guidance for Industry Process Validation: General Principles and Practices

STEP 1: Process DesignSTEP 2: Process QualificationSTEP 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

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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

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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.

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Sealing integrity verification methods

Vacuum or PressureDecay

Sampling

Electro-mechanicaltester

(height + metal detector)

Pressure/Squeezer

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Sealing integrity verification methods

MethodVacuum

Decay

Pressure/

Squeezer

EM Teste

r

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:

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Sealing integrity verification methods

MethodVacuum

Decay

Pressure/

Squeezer

EM Teste

r

Sampling

ThermalImaging

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:

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What is thermal imaging?

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What is thermal imaging?

𝑬 ( 𝝀 ,𝑻 )=𝟐𝒉𝒄𝟐

𝝀𝟓𝟏

𝒆𝒉𝒄𝝀𝑲𝑻 −𝟏

Planck’s Law of Radiation

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What is thermal imaging?

Planck’s Law of Radiation

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What is thermal imaging?

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Sealing integrity methods

PAT for packaging: I2VSThermal imaging solution for in-line induction integrity verification

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The induction sealing process

FILLER

TORQUER

INDUCTION SEALEREMPTY

BOTTLES

Defects in the Raw Material: Defects in the

bottle or the linerProblems in capping:

false torque or crooked cap

Problems in the induction sealer: Alignment, field

fluctuations, etc.

CAPS

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The induction sealing process

Bent / damaged foil

Missing foil

Under-heating Overheating

Crooked cap

Untorqued cap

Damaged edge

Material related problems

Capper related problems

Sealer related problems

Upside-downliner

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 problemIdentified

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Case study I – Torquer problem

Torquer problemIdentified

Torquer problemsolved

Torquer related

parameter

Number of Bottles

Batch continued with an acceptable number

of untorqued caps

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

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

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

DAY SHIFT NIGHT SHIFT

Case study IV– “Night Shift” effect

DAY SHIFT NIGHT SHIFTNIGHT SHIFT

Case study IV– “Night Shift” effect

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8%

31%

46%

15%

Missing linerCold/Partial SealingOverheatHarmed liner

Line monitoring

Case study V– sealer process window

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77% of failures are related to faults in the induction sealer

8%

77%

15%

Missing linerInduction Sealer ProblemsHarmed liner

Case study V– sealer process window

Line monitoring

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Case study V– sealer process window

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Hour #Quantity processed

(Population)

Quantity inspected (sample

size)

False rejects

True rejects

# of open seals found

during inspection

1 4,959 300 2 4 02 4,373 300 5 7 03 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

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

Established: 2009.

Location: Haifa, Israel

Shareholders: Life Sciences Fund - SCP VitalifeELBIT 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

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Thank youfor your attention