Final Inspection
Mixing control
Visual, dimensional Inspection
Compounding
Molding
Inspection Of Trimming Edge
Final Inspection List of Defects
Trimming
Final Treatment
Manufacturing Process
Raw Materials and Auxiliaries Weighing Mixing Dimensioning
Incoming Inspection
Overview of the rubber production process
Molding B2-Coating* Trimming Washing/Siliconization Automated Vision Inspection* Packaging Sterilization* Shipping
Lab Testing ( chemical)
Chemical/Physical Tests Acc. EP Other Pharmacopoeias Such As USP, JP Silicone Oil-Testing Functional Tests e.g. ISO 8536, Part 1, POF, etc. Pyrolysis - IR
Specification Limit: ≤ 5 CFUs per 100 cm2 of closure surface area
Proved Clean Index (PCI)
Rinse of ´Ready to Sterilize´ closures with appropriate solution, followed by filtration and counting of particles on filter Quantifies visible particulate into size ranges 25µ - 50µ; 51µ - 100µ; > 100µ Index calculated with larger particles having higher weight Does NOT count silicone particles
Lab Testing ( particulates, microbiology)
Particle Counting Bioburden Endotoxins
Bioburden The level of microorganisms on the closure
Test for ´Ready to Sterilize´ Closures Based on EP Membrane Filtration Method Requires “extraction” from surface Appropriate rinse solutions and culture media Incubation at appropriate temperatures / time
Compression Molding
Dimensioned non vulcanised rubber sheets
Inprocess Check After Molding
Visual Inspection Control of Web Thickness
Trimming
Trimming
General Requirements for Pharmaceutical Elastomers
Prerequisites
Compliance with compendial requirements Ph.Eur., VI, Section 3.2.9 USP 32, Sections <381>,<87> and <88> JP XV, Section 7.03
Vial Applications - Vial Stopper
Chemical and functional requirements
Seal integrity Good compatibility Low extractable/ leachable level Zinc free Low gas permeability Good machinability Clean butyl/ halobutyl formulas nowadays commonly used
Molding Process
Compression Molding Cycle
5. Trimming
1. Mold Preparation
~8 Min. @ 160-170°C
4. Demolding of webs
2. Mold is loaded
3. Vulcanisation
(pressure + temperature)
Particle Limit: ≤ 3.4 PCI
Endotoxins
Biologically active and heat stable material “left behind” by Gram negative bacteria
Test for ´Ready to Sterilize´ closures Extract from closure or component Quantification based on LAL method Results based on extraction volume and closure size
Elastomeric Components for Pharmaceutical Applications
2010 PDA Europe Workshop - Stoppers & Elastomers Mike Schäfers, PhD
© 2009 by West Pharmaceutical Services, Lionville, PA. All rights reserved. This material is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying or otherwise, without written permission of West Pharmaceutical Services
Washing + Siliconization
ISO 8 ISO 5
Metal detector
Packaging
Westar RS : ISO 5
Final Inspection
Final Inspection
List Of Defects For Rubber Parts Dimensional Inspection
Today only raw materials referenced in section 177.2600 „Rubber articles intended for repeated use“ from the Code of
Trends concerning closure materials
Content
Manufacturing Process Chemical Composition, Properties and Applications Washing, Coatings and Siliconisation Final Treatments Quality Evolution Next Generation Quality of Elastomeric Components ´Ready to Use´ Components Visual Inspection
General Requirements for Pharmaceutical Elastomers
Chemical aspects Low amount of extractable substances Compatibility with the drug product Correspond to compendial requirements Biological aspects Non cytotoxic Production process Correspond to requirements of pharmaceutical industry cGMP „ current Good Manufacturing Practices“
Pharmaceutical Elastomer Composition
• • • • • • • • Elastomer Curing Agent Accelerator Activator Antioxidant Plasticizer Filler Pigment = Basic material = Forms cross links = Helps to control the type and rate of cross links = Efficiency of cross links = Helps to avoid degradation of rubber = Processing aid = Helps to define the physical rubber properties = For coloration FederalRegulations (CFR) 21 (Food and Drugs) are used !