ISPE Tampa Conference

22-25 February 2010

Tampa, Florida USA

Automated Visual Inspection of

Pre-filled Syringes

Wolfgang Weikmann
Director Pharmaceutical Production / Engineering
Vetter Pharma-Fertigung GmbH & Co. KG
24-25 February 2010, Tampa

Content
1. Manual Visual Inspection (MVI) –
Basic requirements
2 Automated Visual Inspection (AVI) – Machine
2.
overview
3. Qualification Approach
1. PQ: Pre-tests / Considerations
2. PQ 1: Knapp test (Test kit)
3 PQ 2: Knapp test (3 batches)
3.
4. Operational Approach
5. Conclusion

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

1. MVI – Basic requirements

• Enclosed dedicated room
• Incandescent Lamp
(light intensity: 2000-3750 LUX)
• Black & white background
• Reject bin / Eject bin for measurements
• Defect evaluation list (SOP)
• Temperature monitoring of room
• One product per room at a given time!
• Inspection speed
• Obvious separation and placement of
uncontrolled units, rejects and good pieces!
• Scheduled Eye Breaks

2. AVI - Machine Overview

Glass Barrel Remover Glass Barrel Inserter

(De-Trayer)
Inspection Machine (Re-Trayer)

Product for inspection Good Pieces

Ejection of syringes

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

2. AVI – Machine Overview

Unit 2 (TV 2a/3a & 2b/3b) Unit 3 (TV 4/5) Unit 4 (TV 6/7)

Glass Barrel Closure Part Stopper

Under- and Overfilling Missing closure part Foreign particles
Empty syringe Bent Needle Shield Solution in rib
Dirt/Abrasion Fit of closure part/Total Dirt/abrasion
Damage/Deviation length Damage/deviation
Scratches/Cracks zone 1 Stopper position
Airline over total length Upside-down (180°) Unit 5 (TV 8/9)
Crooked stopper & 7 (TV 12/13)
Closure Part Double stopper
Dirt/Abrasion Solution
Damage/ deviation Foreign particles
Broken bridge
Pierced Needle Shield Unit 6 (TV 10/11)
0
Solution
OUTFEED
Glass splinters
INFEED
1
2
Unit 11 (HV)
3
4 Solution
Unit 1 (TV 1) Leaking system

Glass Barrel
Damaged finger rest Unit 8 (TV 14/15)
Broken Unit 9 (CA) and 10 (OD)
Glass Barrel
Stopper Solution Scratches/Cracks zone 2
Discoloration, Turbidity
Missing stopper

2. AVI – Machine overview

Eject 0 Eject 1 Eject 2 Eject 3

Glass Barrel Solution Solution Solution

Damaged finger rest Discoloration, Turbidity Foreign particle Glass splinter
B k
Broken Under and overfilling
Under-
Stopper
Empty syringe
Stopper Foreign particle
Leaked system
Missing stopper Solution in rib
Dirt/ abrasion Stopper
Damage/ deviation Upside-down (180°)
Stopper position Glass Barrel
Crooked stopper Dirt/Abrasion
Double Stopper Damage/Deviation
Scratches/Cracks area 1
0 Scratches/Cracks area 2
Airline over total length
OUTFEED
INFEED Closure Part
1 Dirt/Abrasion
2 Damage/Deviation
Broken bridge
3 Pierced Needle Shield
4 Missing closure part
Bent Needle Shield
Fit of the closure part/Total
Eject 4 length
After a machine failure or
Other defects
power break down, all
Wrong primary packaging
remaining syringes in the
component
machine are ejected here.

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

3. Qualification / Validation Approach

• Design Qualification (DQ)

• Installation Qualification (IQ)
• Operational Qualification (OQ)
• Performance Qualification (PQ)
• PQ 1: Knapp test with Test kit
• PQ 2: Knapp test with 3 commercial lots

Æ in this presentation, focus on PQ

3.1 PQ: Pre-tests / Considerations

• Definition of Spinning speed
• Definition of Inspection area / windows
• Air bubbles
• Evaluation of different turbidity levels
• Evaluation of different colors of the
product solution
p
• Detection level of foreign matter
depending on different filling levels

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

3.1 PQ: Pre-tests / Considerations

• Light intensity
• Regular checks
• Definition of the max. holding time
• Measures to be taken in case of
decrease of light intensity – special
maintenance / definition of acceptance
criteria
• Handling of exchange of lighting
• Burn-in time of LED spare parts to reach
acceptable stability
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3.1 PQ: Pre-tests / Considerations

• Heat-up of syringes during machine
stop Æ Definition of max. break time
without removal of syringes
• Definition of Defect categories
(Assignment of minor, Major and Critical
Æ Creation of Batch Report)
• Assignment of defects to Eject bins
• Strategy for Manual Classification
(Re-inspection) of Ejects

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

3.1 PQ: Pre-tests / Considerations

• Handling / Risk assessment in case of
glass breakage at different locations
within the machine
• Implementation of effective Line Cleaning
and Line Clearance

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3.2 PQ 1: Knapp test (Test kit)

• Creation of a product specific Test
kit (Rejects + Good pieces)
• 500 pieces in total comprising approx. 160
Rejects
• Rejects selected from routine batches as
far as possible
• Optional: Usage of standardized particles
for better reproducibility in case of
replacement due to destruction

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

3.2 PQ 1: Knapp test (Test kit)

• Performance of the Knapp test
• MVI: 20 Visual Inspectors inspect each the
test kit (500 pieces) / routine inspection
conditions

• AVI: Test kit (approx. 160 Rejects) are run

21 times in the „production mode“ of the
AVI machine Æ Aim: simulation of real
production conditions as listed in the
following:

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3.2 PQ 1: Knapp test (Test kit)

• AVI Efficiency Test
1. Reject Rate (RR) – Rejects
1. Aim: Test of each Inspection unit per defect
(10 runs per defect)
2. AC: for each of the single defect categories:
RR AVI ≥ RR MVI
2. False Reject Rate (FRR) – Good pieces
1 Aim: Test of each Inspection unit with 500
1.
good pieces
2. AC: tbd. for each inspection unit

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

3.2 PQ 1: Knapp test (Test kit)

• AVI Laboratory Test Run
1. Reject Rate – Rejects
1. Testing each single Inspection unit
1. Aim: Test of each Inspection unit with
all related defects (10 runs per defect)
2. AC: RR AVI ≥ RR MVI

2 Testing all Inspection units

2.
1. Aim: Test of all Inspection units with all
defects (1 run with all defects)
2. AC: RR AVI ≥ RR MVI

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3.2 PQ 1: Knapp test (Test kit)

3. False Reject Rate – Good pieces
1. Aim: Test of all Inspection units with 2000
good pieces (1 run)
2. AC: tbd. for the whole machine

• AVI Performance Run (Good pieces; at

least Placebo)
• Aim: Determination of the repeatability
of detection within 3 technical runs of the
same lot (≥ 10.000 syringes recommended)
• AC: tbd. dependent on Process Capability

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

3.3 PQ 2: Knapp test (3 batches)

Evaluation
M2.1 + M3.1 = RR AVI
M3.1 + M4.1 = RR MVI
Comparison
RR MVI vs. RR AVI

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3.3 PQ 2: Knapp test (3 batches)

• Acceptance criteria:
• Different approaches
pp are p
possible,, e.g.:
g
• #1: RR AVI ≥ RR MVI for all defect categories,
not dependent on criticality of the defect
• #2: Split into minor, Major and Critical:
• Number of defects with (RR AVI ≥ RR MVI) ≥ (RR
AVI < RR MVI) per Criticality Class

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

4. Operational Approach

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4. Operational Approach
2. Manual Visual 3. AQL
Classification (Good Pieces of Eject 0-4)

Rejects
Eject 0 Good Pieces (FRR) AQL V l
AQL-Values according
di tot MVI (ISO 2859)
Critical, Major, minor
Rejects
Eject 1 Good Pieces (FRR)
Lot size = Sum of syringes of Ejects 0-4

Rejects Sampling randomized of the Good Pieces

Eject 2 (FRR) from Ejects 0-4:
Good Pieces (FRR)

n = 125 (Lot size less than 3.200)

Rejects
j
Eject 3 n = 200 (L
(Lott size
i b between
t 3
3.201
201 and
d 10
10.000)
000)
Good Pieces (FRR)
n = 315 (Lot size between 10.001 and 35.000)

Rejects
Eject 4 Good Pieces (FRR)
Good Pieces (FRR)

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

4. Operational Approach
2. Manual Visual 3. AQL
(Good Pieces of 4. Batch Evaluation
Classification Ejects 0-4)

Rejects
Eject
j 0
Good Pieces (FRR)
Evaluation according to AVI
Evaluation matrix
Rejects
Eject 1
Good Pieces (FRR)
minor: X ≤ limit Æ Batch Release
X > limit Æ Deviation/Measures
Rejects Major: X ≤ limit Æ Batch Release
Eject 2
Good Pieces (FRR) X > limit Æ Deviation/Measures

Critical: X ≤ limit Æ Batch Release

Rejects X > limit Æ Deviation/Measures
Eject 3
Good Pieces (FRR)

Rejects Rejects (total)

Eject 4
Good Pieces (FRR)

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5. Conclusion
• Main topics to be considered upfront:
• Product characteristics
• Evaluation strategy / Assignment of
defects to Eject bins
• Creation of the Test kit
• Acceptable False Reject Rate
• Re-Classification of Ejects
• Performance of lighting
• Preventive maintenance
• Re-Qualification concept

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

Thank You!

Wolfgang Weikmann
Director Pharmaceutical Production / Engineering
g g
Vetter Pharma-Fertigung GmbH & Co. KG
Schuetzenstrasse 87
D - 88212 Ravensburg, Germany
+49-(0)751-3700-2401
Wolfgang.Weikmann@vetter-pharma.com

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