Elastomeric Components for Pharmaceutical Applications - Actual Quality Trends - Claudia Petersen. -Senior Manager Biotechnology-

Transcription

1 Elastomeric Components for Pharmaceutical Applications - Actual Quality Trends - Claudia Petersen -Senior Manager Biotechnology by West Pharmaceutical Services, Inc., 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, Inc. Overview Requirements for Pharmaceutical Elastomers Pharmaceutical Elastomer Composition New Regulatory Challenges to Pharmaceutical Elastomers Container Closure Guidance Extractables & Leachables Analysis Approach Container Closure Integrity Testing

2 Requirements for Pharmaceutical Elastomers -Overview(1) - Mechanical and functional aspects Compression set Hardness Fragmentation Penetrability Standardized dimensions Physical aspects Resistance to sterilisation Gamma, ETO, Steam Requirements for Pharmaceutical Elastomers -Overview(2) - 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

3 Requirements for Pharmaceutical Elastomers Chemical, biological and if appropriate physical properties are defined by pharmacopoieas ISO standards shall accomplish the requirements of the pharmacopoieas regarding geometries, tolerances and functional aspects Pharmaceutical Elastomer Composition - Evolution - OLD Crepe 40% Barium Sulfate 50% Naphthenic Oil 1% Color 0.5% Titanium Dioxide 2% Zinc Oxide 3% Antioxidant <1% Thiuram <1% Hepteen Base <1% Sulfur <1% Modern Halobutyl 50% Treated Talc 46% Color <1% Titanium Dioxide 2% Unconventional Cure 2% Today only raw materials referenced in section Rubber articles intended for repeated use from the Code of Federal Regulations (CFR) 21 (Food and Drugs) are used!

4 Pharmaceutical Elastomer Composition HPLC USP extract (Solvent C) Old Modern New Regulatory Challenges to Pharmaceutical Elastomers Common documents required by regulatory bodies related to elastomeric components Rubber formula related data - Compendial test data ( USP <381>, EP 3.2.9) - Biological test data ( USP <87>, USP <88>) - BSE/ TSE Statement - Heavy metal statement ( European Directive 94/62/EC)

5 New Regulatory Challenges to Pharmaceutical Elastomers Common documents required by regulatory bodies related to elastomeric components Elastomeric component related data - Item drawing ( dimensions, tolerances) Processing Descriptions (Manufacturing process, Washing, Siliconization) - Type V DMF s in US vs. No system in Europe - Proprietary Know How of supplier New Regulatory Challenges to Pharmaceutical Elastomers Regulatory bodies worldwide are requesting more extensive information on elastomeric closures used as primary packaging for drugs and biologics with special focus on Extractables/Leachables Container Closure Integrity ( CCI) Processing (Washing, Siliconization)

6 Key Regulatory Guidances in USA/EU USA: Draft Stability Testing of Drug Substance and Drug Products (June 1998) Container Closure Systems for Packaging Human Drugs and Biologics (Mai 1999) Draft Drug Product Chemistry, Manufacturing and Controls Information (January 2003) EU: Note for Guidance on Development Pharmaceutics (1998) New Challenges to Pharmaceutical Elastomers --Drug product interactions -- Permeation Leaching Absorption Adsorption These four interactions generally occur at a low rate

7 Container Closure Guidance - General - The only regulatory guidance currently available that is dedicated totally to packaging requirements Specific details on appropriate test methods and acceptance criteria are not given. It is recommended these be based upon good scientific principle for each specific container /closure system Application documents have to prove the suitability of a container closure system Container Closure Guidance - Definition Extractable/Leachable - Extractable Compounds extracted from individual components of the packaging system under appropriate solvent and temperature conditions -> exaggerated conditions Leachable Compounds that migrate from the container/closure (c/c) system of the drug or biologic product under normal conditions of use or during stability studies -> normal conditions

8 Container Closure Guidance - General - Suitability of a c/c system is proven using 4 criteria Protection Compatibility Safety Performance Container Closure Guidance - Safety - Primary packaging materials in direct contact with the dosage form should be manufactured from materials that will not leach harmful or undesirable amounts of substances Extractable/Leachable Studies

9 Container Closure Guidance - Safety - Specific consideration for injectable drug products: If extraction properties of the drug product are expected to be different from that of water (for instance, high or low ph, addition of various excipients) then the drug product should be used as the extracting medium and an extraction profile should be obtained West s General Approach to Extractables and Leachables Analysis

10 E & L-Analysis Approach Why are Leachables important? May interfere with drug product assays May interfere with medical diagnostic tests May increase drug product impurity level to an unacceptable level May react with one or more drug product components May increase toxicity of drug product May act as an adjuvant in immune response system Extractables & Leachables Analysis Step 1 Prescreening Basic non-gmp study evaluation of closure alternatives Protocol can involve multiple temperatures/conditions for acceleration Identifies appropriate closure candidate for full stability and extractable programs

11 Extractables & Leachables Analysis Step 2 Accelerated Method Development and Validation Based upon formulation potential extractable list Evaluate feasibility of base test methods with client drug product Minimum Quantifiable Limits (MQL) and specificity are identified Interferences with degradants are identified Extractables & Leachables Analysis Step 2 - Feasibility/Method Optimization (Continued) Method validation in customer s drug product Method development if feasibility is not successful

12 Extractables & Leachables Analysis Step 3 - Leachables in Stability Samples Expansion of Stability Studies to include Leachables Testing Accelerated and Real Time Samples Functional and Container/closure Integrity Testing as Needed Coordinate Drug Stability Testing Concurrently, if Needed Extractables & Leachables Analysis Step 4 Toxicological Assessment of Leachables Baseline toxicological data of the potential extractables Toxicological evaluation for leachables identified in a client s drug product

13 Extractables & Leachables Analysis - Case Study - A series of methods specific to the potential extractables were identified as feasible for use Minimum quantifiable limits (MQL) and % recovery for the leachables in the drug product were identified Degraded drug product was tested to ensure no interferences with the leachables which could occur over time Extractables & Leachables Analysis - Case Study - Stability samples were tested at time = 0 and time = 6 months for: BHT Proprietary Rubber Cure System Stearate Chloride Calcium Magnesium Polydimethylsiloxane

14 Extractables & Leachables Analysis - Case Study - Samples had been stored under the following conditions: Results for all: 25 60% RH 40 75% RH Below Limit of Quantitation (BLQ) Extractables & Leachables Analysis - Case Study - Analysis of 1 year time-point stability sample 25 60% RH Only Results: H.P.L.C. BHT and Proprietary Cure (BLQ) G.C. Stearic Acid 1.2 ppm I.C. Chloride (BLQ) I.C.P. Calcium and Magnesium (BLQ) A.A. Polydimethylsiloxane 5.2 ppm Product will continue to be tested through shelf-life

15 Container Closure Integrity ( CCI) Examples of FDA Warning Letters referring to CCI 1997 No CCI of finished sterile vials Vacuum in vials not verified over time in stability studies 1998 Sterility failures linked to CCI 1999 CCI studies on pre-filled syringes never conducted 2001 CCI failures linked to defects in vial glassware Root Causes of CCI Failure Component Quality Poorly designed, specified, controlled Seal Quality Lack of process validation Lack of process monitoring and control Wrong vial/stopper combination Improperly seated stopper Improperly applied cap Drug product in sealing area

16 Root Causes of CCI Failure Process Handling Poor equipment design Rough handling Manual techniques or lack of training CCI Testing Absence of CCI tests Insensitive CCI tests Common Container Closure Integrity Tests Pressure Gauge Microbial Ingression Blue Dye Test Plasmaphotometric measurements Bubble Test Helium Leak Detection Laser based technologies

17 Helium Leak Detection based Technologies - The Measurement Technique - The measurement system is based on a helium mass spectrometer The mass spectrometer detects helium under high vacuum Closure system is filled and sealed with helium After achieving vacuum the rate at which helium is leaking from the container/ closure system is determined An algorithm measures the rate of helium detected over a set period of time Helium Leak Detection based Technologies - The Benefits - High sensitivity ( 10-7 cc/second) Fast test method ( ~ 3 minutes) Non destructive Operator independent Leak location with sniffer probe possible

18 Laser based Technologies - The Measurement Technique - Laser light shines through the container headspace Tune the laser frequency to match an internal absorption frequency of target molecule (oxygen, moisture, carbon dioxide) Absorption signal correlates with the total headspace pressure/ concentration of gas in the container Laser based Technologies - The Benefits - High sensitivity Non-destructive & non-invasive No sample preparation Results are operator technique-independent independent Available as at-line equipment Fast technique ( 100 ms 3 seconds)

19 Regulatory Compliance Method Validation Science based method validation (USP 28 General Test <1225>) Accuracy,Precision, Linearity, LOD, LOQ Installation Qualification Components, Utilities, Environmental Operational Qualification Calibration Precision, Accuracy, Linearity, Specificity, LOD, LOQ, Ruggedness using standards Data Storage Regulatory Compliance Performance Qualification Product specific performance assessment

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