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
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2. AVI - Machine Overview
Glass Barrel Remover
(De-Trayer)
Inspection Machine
Glass Barrel Inserter
(Re-Trayer)
Good Pieces
Product for inspection
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
Missing closure part
Bent Needle Shield
Fit of closure part/Total
length
Foreign particles
Solution in rib
Dirt/abrasion
Damage/deviation
Stopper position
Upside-down (180°)
Crooked stopper
Double stopper
Under- and Overfilling
Empty syringe
Dirt/Abrasion
Damage/Deviation
Scratches/Cracks zone 1
Airline over total length
Closure Part
Unit 5 (TV 8/9)
& 7 (TV 12/13)
Solution
Dirt/Abrasion
Damage/ deviation
Broken bridge
Pierced Needle Shield
Foreign particles
Unit 6 (TV 10/11)
0
OUTFEED
INFEED
Solution
Glass splinters
1
2
Unit 11 (HV)
3
4
Solution
Unit 1 (TV 1)
Leaking system
Glass Barrel
Damaged finger rest
Broken
Unit 8 (TV 14/15)
Unit 9 (CA) and 10 (OD)
Glass Barrel
Solution
Stopper
Scratches/Cracks zone 2
Discoloration, Turbidity
Missing stopper
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2. AVI – Machine overview
Eject 0
Eject 1
Eject 2
Eject 3
Glass Barrel
Damaged finger rest
B k
Broken
Solution
Discoloration, Turbidity
Solution
Foreign particle
Solution
Glass splinter
Under and overfilling
UnderEmpty syringe
Leaked system
Stopper
Foreign particle
Solution in rib
Dirt/ abrasion
Damage/ deviation
Stopper position
Crooked stopper
Double Stopper
Stopper
Missing stopper
0
OUTFEED
INFEED
1
2
3
4
Eject 4
After a machine failure or
power break down, all
remaining syringes in the
machine are ejected here.
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3
Stopper
Upside-down (180°)
Glass Barrel
Dirt/Abrasion
Damage/Deviation
Scratches/Cracks area 1
Scratches/Cracks area 2
Airline over total length
Closure Part
Dirt/Abrasion
Damage/Deviation
Broken bridge
Pierced Needle Shield
Missing closure part
Bent Needle Shield
Fit of the closure part/Total
length
Other defects
Wrong primary packaging
component
ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA
3. Qualification / Validation Approach
•
•
•
•
Design Qualification
Installation Qualification
Operational Qualification
Performance Qualification
(DQ)
(IQ)
(OQ)
(PQ)
• PQ 1: Knapp test with Test kit
• PQ 2: Knapp test with 3 commercial lots
Æ in this presentation, focus on PQ
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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
Classification
Eject 0
3. AQL
(Good Pieces of Eject 0-4)
Rejects
AQL V l
AQL-Values
according
di to
t MVI (ISO 2859)
Good Pieces (FRR)
Critical, Major, minor
Rejects
Eject 1
Eject 2
Good Pieces (FRR)
Lot size = Sum of syringes of Ejects 0-4
Rejects
Sampling randomized of the Good Pieces
(FRR) from Ejects 0-4:
Good Pieces (FRR)
n = 125 (Lot size less than 3.200)
Eject 3
Eject 4
Rejects
j
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
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
Classification
Eject
j
0
Eject 1
Eject 2
Eject 3
Eject 4
3. AQL
4. Batch Evaluation
(Good Pieces of
Ejects 0-4)
Rejects
Good Pieces (FRR)
Evaluation according to AVI
Evaluation matrix
Rejects
Good Pieces (FRR)
Rejects
minor:
X ≤ limit Æ Batch Release
X > limit Æ Deviation/Measures
Major:
X ≤ limit Æ Batch Release
X > limit Æ Deviation/Measures
Critical:
X ≤ limit Æ Batch Release
X > limit Æ Deviation/Measures
Good Pieces (FRR)
Rejects
Good Pieces (FRR)
Rejects
Rejects (total)
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
[email protected]
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