Tampa, Florida USA 1 Automated Visual Inspection of Pre-filled Syringes Wolfgang Weikmann Director Pharmaceutical Production / Engineering 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. Automated Visual Inspection (AVI) Machine overview 3. Qualification Approach 1. PQ: Pre-tests / Considerations 2. PQ 1: Knapp test (Test kit) 3 PQ 2: Knapp test (3 batches) 2 3. PQ 2: Knapp test (3 batches) 4. Operational Approach 5. Conclusion ISPE Tampa Conference 22-25 February 2010 Tampa, Florida USA 2 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 3 Obvious separation and placement of uncontrolled units, rejects and good pieces! Scheduled Eye Breaks 2. AVI - Machine Overview Glass Barrel Remover (De-Trayer) Inspection Machine Glass Barrel Inserter (Re-Trayer) 4 Ejection of syringes Good Pieces Product for inspection ISPE Tampa Conference 22-25 February 2010 Tampa, Florida USA 3 2. AVI Machine Overview Unit 2 (TV 2a/3a & 2b/3b) Glass Barrel Under- and Overfilling Empty syringe Dirt/Abrasion Damage/Deviation Unit 3 (TV 4/5) Closure Part Missing closure part Bent Needle Shield Fit of closure part/Total length Unit 4 (TV 6/7) Stopper Foreign particles Solution in rib Dirt/abrasion Damage/deviation Unit 5 (TV 8/9) & 7 (TV 12/13) Solution Foreign particles Damage/Deviation Scratches/Cracks zone 1 Airline over total length Closure Part Dirt/Abrasion Damage/ deviation Broken bridge Pierced Needle Shield length Damage/deviation Stopper position Upside-down (180) Crooked stopper Double stopper Unit 6 (TV 10/11) Solution Glass splinters Unit 11 (HV) INFEED OUTFEED 0 1 2 5 Unit 1 (TV 1) Glass Barrel Damaged finger rest Broken Stopper Missing stopper Unit 9 (CA) and 10 (OD) Solution Discoloration, Turbidity Unit 8 (TV 14/15) Glass Barrel Scratches/Cracks zone 2 Unit 11 (HV) Solution Leaking system 3 4 2. AVI Machine overview Eject 0 Glass Barrel Damaged finger rest B k Eject 1 Solution Discoloration, Turbidity Eject 3 Solution Glass splinter Under and overfilling Eject 2 Solution Foreign particle INFEED OUTFEED 0 1 2 Broken Stopper Missing stopper Under- and overfilling Empty syringe Leaked system 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 Stopper Foreign particle Solution in rib Dirt/ abrasion Damage/ deviation Stopper position Crooked stopper Double Stopper 6 3 4 Broken bridge Pierced Needle Shield Missing closure part Bent Needle Shield Fit of the closure part/Total length Other defects Wrong primary packaging component Eject 4 After a machine failure or power break down, all remaining syringes in the machine are ejected here. ISPE Tampa Conference 22-25 February 2010 Tampa, Florida USA 4 3. Qualification / Validation Approach Design Qualification (DQ) Installation Qualification (IQ) Installation Qualification (IQ) Operational Qualification (OQ) Performance Qualification (PQ) PQ 1: Knapp test with Test kit PQ 2: Knapp test with 3 commercial lots 7 PQ 2: Knapp test with 3 commercial lots in this presentation, focus on PQ 3.1 PQ: Pre-tests / Considerations Definition of Spinning speed Definition of Inspection area / windows Definition of Inspection area / windows Air bubbles Evaluation of different turbidity levels Evaluation of different colors of the product solution 8 p Detection level of foreign matter depending on different filling levels ISPE Tampa Conference 22-25 February 2010 Tampa, Florida USA 5 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 9 Handling of exchange of lighting Burn-in time of LED spare parts to reach acceptable stability 3.1 PQ: Pre-tests / Considerations Heat-up of syringes during machine stop Definition of max. break time without removal of syringes Definition of Defect categories (Assignment of minor, Major and Critical Creation of Batch Report) Assignment of defects to Eject bins 10 Assignment of defects to Eject bins Strategy for Manual Classification (Re-inspection) of Ejects ISPE Tampa Conference 22-25 February 2010 Tampa, Florida USA 6 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 11 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 12 Optional: Usage of standardized particles for better reproducibility in case of replacement due to destruction ISPE Tampa Conference 22-25 February 2010 Tampa, Florida USA 7 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 Aim: simulation of real 13 AVI machine Aim: simulation of real production conditions as listed in the following: 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 14 1. Aim: Test of each Inspection unit with 500 good pieces 2. AC: tbd. for each inspection unit ISPE Tampa Conference 22-25 February 2010 Tampa, Florida USA 8 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 15 2. Testing all Inspection units 1. Aim: Test of all Inspection units with all defects (1 run with all defects) 2. AC: RR AVI RR MVI 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) good pieces (1 run) 2. AC: tbd. for the whole machine AVI Performance Run (Good pieces; at least Placebo) Aim: Determination of the repeatability 16 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 ISPE Tampa Conference 22-25 February 2010 Tampa, Florida USA 9 3.3 PQ 2: Knapp test (3 batches) 17 Evaluation M2.1 + M3.1 = RR AVI M3.1 + M4.1 = RR MVI Comparison RR MVI vs. RR AVI 3.3 PQ 2: Knapp test (3 batches) Acceptance criteria: Different approaches are possible, e.g.: pp p , 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 18 ISPE Tampa Conference 22-25 February 2010 Tampa, Florida USA 10 4. Operational Approach 19 4. Operational Approach 2. Manual Visual Classification AQL V l di t MVI (ISO 2859) Eject 0 Rejects 3. AQL (Good Pieces of Eject 0-4) AQL-Values according to MVI (ISO 2859) Lot size = Sum of syringes of Ejects 0-4 Sampling randomized of the Good Pieces (FRR) from Ejects 0-4: n = 125 (Lot size less than 3.200) 200 (L t i b t 3 201 d 10 000) Eject 0 Eject 1 Eject 2 Good Pieces (FRR) Rejects Good Pieces (FRR) Rejects Good Pieces (FRR) Rejects Critical, Major, minor 20 n = 200 (Lot size between 3.201 and 10.000) n = 315 (Lot size between 10.001 and 35.000) Eject 3 Eject 4 Good Pieces (FRR) j Good Pieces (FRR) Rejects Good Pieces (FRR) ISPE Tampa Conference 22-25 February 2010 Tampa, Florida USA 11 4. Operational Approach Eject 0 Rejects 2. Manual Visual Classification 4. Batch Evaluation 3. AQL (Good Pieces of Ejects 0-4) j Eject 1 Eject 2 Good Pieces (FRR) Rejects Good Pieces (FRR) Rejects Good Pieces (FRR) Rejects Evaluation according to AVI Evaluation matrix Critical: X limit Batch Release X > limit Deviation/Measures Major: X limit Batch Release X > limit Deviation/Measures minor: X limit Batch Release X > limit Deviation/Measures 21 Eject 3 Eject 4 Rejects Good Pieces (FRR) Rejects Good Pieces (FRR) Rejects (total) 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 22 Performance of lighting Preventive maintenance Re-Qualification concept ISPE Tampa Conference 22-25 February 2010 Tampa, Florida USA 12 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