Post on 30-Jan-2018
PHARMACEUTICAL ELASTOMERIC CLOSURESPHARM Connect – Budapest, 2015
Bruno Morchain - Technical Support Engineer
AGENDA
Aptar Stelmi Overview
Elastomeric closures requirements
Pure Formulations and PremiumCoat
From unwashed to Ready To Use components
Take away
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Headquarters in Crystal Lake, IllinoisOver 12,000 EmployeesOperating in more than 19 countriesNew York Stock Exchange ATR2013 Net Sales: 2.52 billion USD
PHARM Connect 2015 – Aptar Stelmi3
Aerosol, spray and dispensing drug
delivery technologiesElastomeric closures
APTAR PHARMA - ORGANIZATION
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SVP stoppers LVP stoppers Syringe components
SERUM LYO
PHARM Connect 2015 – Aptar Stelmi
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Solution Provider in the Elastomeric Closure Market - leader in production of Prefilled Syringes Components
600 associates and 2 mirrored manufacturing sites in France
Partner with most of the global players in Pharma – 50 years of expertise
Multiple FDA, Anvisa, EMA inspections – 700+ customers in 70 countries
100% production in ready to sterilize (RTS) or ready to use (RTU)
State-of-the-art International Technical Center run by dedicated experts and equiped with the latest technologies
Continuous upgrading of production processes
Deep understanding of pharmaceutical processes incl. freeze-drying, sterilization, filling and finishing.
Aptar Stelmi: Elastomeric Closures - Facts and Figures
PHARM Connect 2015 – Aptar Stelmi
Small molecules
Vaccines
Anti-thrombotics
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Application Fields
PHARM Connect 2015 – Aptar Stelmi
Biologics
Animal Health
Other
SVP stoppers LVP stoppers Syringe components
PRODUCT LINE
� PLUNGERS 0.5ml, 1ml long, 1-3ml, 5ml, 10ml, 20ml, by-pass 1-3ml
� TIP CAPS Ribbed Tip Caps (RTC) - Luer lock and Luer cone - Mushroom
� SOFT & RIGID NEEDLE SHIELD1/2 inch, 5/8 inch, 1 inch
� PLUNGERS FOR CARTRIDGES1.5ml, 3ml
� Large Volume Parenteral (INFUSION)
Stoppers for glass vials 28/29mm, 32mm, 34mm, DIN and ISO ; Injection sites for IV bags
� Small Volume Parenteral (SERUM, ANTIBIO)
13 and 20mm, ISO and blow back
� LYOPHILIZATION13mm, 20mm, 28mm, 32mm
� DIAGNOSTICDIN 14, DIN 18, DIN 22 Other range
� DROPPER BULBS 0.2ml, 0.8ml, 1ml
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STOPPERSPRE-FILLED SYRINGE AND AUTO-
INJECTOR COMPONENTS
PHARM Connect 2015 – Aptar Stelmi
AGENDA
Aptar Stelmi Overview
Elastomeric closures requirements
Pure Formulations and PremiumCoat
From unwashed to Ready To Use components
Take away
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PATIENT SAFETY
CONTAINER CLOSURE
INTEGRITY -STERILITY
DRUG STABILITY EASE OF USE –PATIENT CONFORT REGULATORY
� Avoid losses & leakages
� Avoid evaporation (water,
solvent, active ingredients)
� Protect from water, light,
ozone
� Avoid external contamination
� Compatible with sterilization
methods (steam – gamma)
� Avoid active ingredient
modification
Elastomeric Closures requirements
Fundamental principle: integrity guaranteed during packaging, storage and administration to the patient
� Avoid damaging needle
� Avoid fragmentation
� Enable multipiercing
� Good functional
properties for syringes
� Compliance with the
pharmacopoeias
PHARM Connect 2015 – Aptar Stelmi
Note that machinability on the filling lines is also key9
AGENDA
Aptar Stelmi Overview
Elastomeric closures requirements
Pure Formulations and PremiumCoat
From unwashed to Ready To Use components
Take away
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HALOBUTYL: CHLOROBUTYL & BROMOBUTYL
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VERY LOW PERMEABILITYThe most impermeable to gases and steam
CHEMICAL INERTNESSSimpler vulcanization systems
No need for antioxidants in the formulation
Low level of extractable/leachables
PHYSICAL AND CHEMICAL RESISTANCEResistance to heat, oxidization, ozone and aging
Self-sealing properties
OTHER PROPERTIESLow moisture content (used for lyophilized product)
Process performance
APPLICATION� Prolonged contact with the drug product (stoppers, plungers)� Formulations in compliance with international compendia (USP, EP, JP)� Bromobutyl preferred for lyophilized applications
PHARM Connect 2015 – Aptar Stelmi
APTAR STELMI VERSATILE HALOBUTYL FORMULATIONS
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� Lower hardness,(43) higher elasticity: Outstanding coring & seal sealing properties
� Main applications:small molecules, unbuffered NaClsolutions; vaccines
� Main components: Liquid LVP & SVP stopperssyringe plungers
� Higher hardness (51):Outstanding machinability
� Low moisture: preferred formulation for freeze dried products & powders
� Zinc free
� Main applications:Few limitations, including WFI (5 mL), liquid, freeze dried & powdered products
� Main components: All LVP & SVP antibiotic & lyo stoppers, syringe plungers
� Aptar Stelmi most widely used formulations worldwide
� Aptar Stelmi modern and pure formulations
� Versatibility: range of compatibility, range of components
� Compliance with EP, USP, ISO, JP
� Compatibility with steam, EtO & gamma sterilization
- Different base elastomers - Different fillers
- Different curing system - Different ionic profiles
6422CHLOROBUTYL FORMULATION
6720BROMOBUTYL FORMULATION
Coated Materials and Assemblies
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Components could be delivered in a single material� Ex: plunger in formulation 6720 grey
Components could be co-injected� Ex: elastomer + thermoplastic
Components could be assembled� Ex: Needle Shields made of 4800 grey + a polypropylene shell to make a Rigid
Needle Shield
A film could be added to minimize the contact between the elastomer and the drug� Ex: ETFE film on stopper
PHARM Connect 2015 – Aptar Stelmi
Purposes of coatings
Enhances compatibility - filters extractables coming from the elastomer
For sensitive products - Minimizes absorption and adsorption phenomena
Minimizes particles
Increases lubricity
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Focus on the ETFE film
Inert material
Chemical resistance to various solvents
Compatible with rubber molding process
No use of additives for a proper adhesion
Sustains Gamma-irradation
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Ethylene tetrafluoroethylene
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A combination of container closure integrity and improvedcompatibility
CONFIDENTIAL
PHARM Connect 2015 – Aptar Stelmi
ETFE Film area for an improved
compatibility with the drug product
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A combination of container closure integrity and improvedcompatibility
Non coated (with film) area for an improved sealing
ETFE Film area for an improved
compatibility with the drug product
PHARM Connect 2015 – Aptar Stelmi
Container Closure Integrity: similar behavior of non-coated stopper and PremiumCoat™
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In severe conditions, after 6 months, we observed, no differencesbetween a coated and a non coated stopper (with non blow black vials*)
PHARM Connect 2015 – Aptar Stelmi*6R non blow-back Schott Vial
Days
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Combination of a state-of-the-art formulation with a ETFE inert Film
Significantly reduces leachable level
Proven Technology
Facilitates project development
Available and supported worldwide
PremiumCoat
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Shape : Small Volume Parenteral stopper
Nature of the coating: Fluoropolymer Film (ETFE)
Coated area: surface of contact with drug
Rubber formulation: Bromobutyl
Finishing: UC6 Evolution (Ready to Sterilize with final rinse with WFI)
PHARM Connect 2015 – Aptar Stelmi
AGENDA
Aptar Stelmi Overview
Elastomeric closures requirements
Pure Formulations and PremiumCoat
From unwashed to Ready To Use components
Take away
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Logical evolution from unwashed to “Ready To Use”
Introduction of the first “Ready-to-Sterilize” components 1974
UltraClean 6 finishing introduction (last rinse in WFI) 1990
First approval of the UltraClean 6 finishing (RTS) in the USA 1992
DMF type V for the finishing UltraClean 6 1997
Sterile plungers for prefilled syringes 2003
Introduction of the finishing UltraClean 6 evolution 2005
Sterile stoppers 2008
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RECEIVING WEIGHING MIXING MOLDING TRIMMING FINISHING PACKAGING
QUALITY CONTROLS RELEASE
FORMULATION DESIGN WASHING/ SILICONIZING DRYING / PACKAGING
Production Process of elastomeric closures
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RTS :ULTRACLEAN 6 EVOLUTION WASHING PROCESS
� Washing and first rinsing operations in highly purified water (EP), in compliance with the FDA guidance
� Final rinsing: WFI - Aptar Stelmi custom overflow rinsing
� DMF Type V (covering all Aptar Stelmi facilities)
RECEIVING WEIGHING MIXING MOLDING TRIMMING FINISHING QUALITY CONTROLS RELEASE
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Bioburden < 0,25 CFU/cm²
Endotoxins < 0,03 UE/ml
(0,06 UE/cm²)
PCI* < 2,9
PHARM Connect 2015 – Aptar Stelmi
* :Particle Count Index = 0.1x(25-50µm) + 0.2x(50-100µm) + 1x(>100µm)
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RECEIVING WEIGHING MIXING MOLDING TRIMMING FINISHING QUALITY CONTROLS RELEASE
Validated ProcessReduction in bacterial endotoxins
Bacterial decontamination
Particulate decontamination
Consistent siliconization level
Absence of residual detergent
Comprehensive CoA, includingPhysico-chemical results
Bioburden, endotoxins and PCI (results and specifications)
Visual check
Dimensional check
PHARM Connect 2015 – Aptar Stelmi
PRODUCTION PROCESS &
MICROBIOLOGICAL
CONTAMINATION
VALIDATION &
RE-VALIDATIONIRRADIATION
DOCUMENTATION &
REGULATORY FIELD
STERILITY GUARANTEED
>Specific organisation
>More frequent controls
>Specific primary packaging
>Specific configuration of palletisation for gamma irradiation
>Integrity indicator
and integrity check
>Certificate of sterility
>DMF type V
>Validation file
>Certificate of irradiation
>Validated range
18 – 32 kGY
>Comprehensive validation and re-validation (including bag seals and transport)
>Dose Audit
>Ageing study
Centre de photocopie Centre de photocopie
Sterile Process of elastomeric closures
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Investment Development Validation Re-validation
IPC
Monitoring
Regulatory AuditsReception
controls
RTS*
RTU
STERILE
Systèmes informatiques
$
$
EquipmentArea
SterilityMonitoring Filing
SupplierIn-house
Steam Sterilization
Aptar Stelmi
Guarantees
* + steam sterilization in-house
Transferring the washing and sterilization operations to the supplier
From Ready to Sterilize to Ready to Use
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Global leader and preferred partner, specialized in elastomeric closure solutions (stoppers and Pre-Filled Syringes components) for injectable drug delivery systems.
Solution Provider: high purity formulations, PremiumCoat, RTS, RTU.
State-of-the-art manufacturing processes.
Premium Quality and Technical Expertise based on more than 50 years of success on the regulated markets.
TAKE AWAY
Thank you for your attention !
APTAR STELMILe Raspail - Paris Nord II
22, avenue des Nations - B.P. 59415 Villepinte95944 Roissy CDG Cedex
Tel: +33 (0)1 48 63 56 56 - Fax: +33 (0)1 48 63 56 99E-mail: aptarstelmi@aptar.com - Website: www.aptarstelmi.com
APTAR’s obligations with respect to its products are governed solely by its standard terms and conditions for sale, whichare hereby incorporated by reference, or by the particular agreements or contracts under which the products areprovided. APTAR manufactures its products to meet standard specifications, and does not guarantee that its productsmeet other specifications not previously agreed upon in writing. All information contained herein is purely informativeand is provided without any promise, representation, or warranty, express or implied, of any kind, including - withoutlimitation - any warranties of merchantability, fitness for a particular purpose, or non-infringement of any intellectualproperty rights. any reliance on the information contained herein shall be at your own risk.
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