Knapp Test

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

Au A u t o m ated at ed Vis Vi s u al Ins In s p ect ec t i o n o f Pre-filled Pre-filled Syringes Wolfgang Weikmann Vetter Pharma-Fertigung GmbH & Co. KG 24-25 February 2010, Tampa

Content 1. Manual Manual Vis Visual ual Ins Inspec pecti tion on (MVI (MVI)) – Basic requirements .

– overview

3. Quali Qualifi fica cati tion on Appro Approac ach h 1. PQ: Pre-test Pre-tests s / Consi Considera deration tions s 2. PQ 1: 1: Knap Knapp p test test (Tes (Testt kit) kit) .

4. Oper Operat atio iona nall Appr Approa oach ch 5. Concl nclusi usion 2

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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 • uncontrolled units, rejects and good pieces! • Scheduled Eye Breaks

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2. AVI - Machi ne Overview

Glass Barrel Remover (De-Trayer)

Inspection Machine

Glass Barrel Inserter (Re-Trayer)

Good Pieces

Product for inspection Ejection o f syring es 4

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2. AVI – Machi ne 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

Foreign particles Solution in rib Dirt/abrasion

Under- and Overfilling Empty syringe Dirt/Abrasion amage ev a on Scratches/Cracks zone 1 Airline over total length

Stopper position Upside-down (180°) Crooked stopper Double stopper

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 Broken

Solution Discoloration, Turbidity

Solution Foreign particle

Solution Glass splinter n er- an over Empty 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

ng

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


3. Qualification / Validation Approach • Design Qualification

(DQ)

• • Operational Qualification

(OQ)

• Performance Qualification

(PQ)

• PQ 1: Knapp test with Test kit • P 

2: Kna

test with 3 commercial lots

in this presentation, focus on PQ 7

3.1 PQ: Pre-tests / Considerations • Definition of Spinning speed • Definition of Ins ection area / windows • Air bubbles • Evaluation of different turbidity levels • Evaluation of different colors of the roduct solution • Detection level of foreign matter depending on different filling levels 8

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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 9

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)

• • Strategy for Manual Classification (Re-inspection) of Ejects 10

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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 t est (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 • O tional: Usa e of standardized articles for better reproducibility in case of replacement due to destruction

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3.2 PQ 1: Knapp t est (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 production conditions as listed in the following:

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3.2 PQ 1: Knapp t est (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 . good pieces 2. AC: tbd. for each inspection unit

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3.2 PQ 1: Knapp t est (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 . 1. Aim: Test of all Inspection units with all defects (1 run with all defects) 2. AC: RR AVI ≥ RR MVI 15

3.2 PQ 1: Knapp t est (Test kit) 3. False Reject Rate – Good pieces 1. Aim: Test of all Inspection units with 2000 2. AC: tbd. for the whole machine

•

AVI Performance Run (Good pieces; at least Placebo) • of detection within 3 technical runs of the same lot ( ≥ 10.000 syringes recommended) • AC: tbd. dependent on Process Capability 16

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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 17

3.3 PQ 2: Knapp test (3 batches) • Acceptance criteria: • Different a

roaches are ossible e. .:

• #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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4. Operational App roach

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4. Operational App roach 2. Manual Visual Classification

3. AQL (Good Pieces of Eject 0-4)

Rejects

- a ues accor ng o

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

n=

Good Pieces (FRR)

o s ze e ween .

an

.

n = 315 (Lot size between 10.001 and 35.000)

Rejects

Good Pieces (FRR)

Good Pieces (FRR)

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4. Operational App roach 2. Manual Visual Classification E ect 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  Batch Release X > limit  Deviation/Measures

Major:


Critical:


Good Pieces (FRR)

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 22

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Thank You! Wolfgang Weikmann Director Pharmaceutical Production / En ineerin Vetter Pharma-Fertigung GmbH & Co. KG Schuetzenstrasse 87 D - 88212 Ravensburg, Germany +49-(0)751-3700-2401 [email protected]

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Knapp Test

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