PHARMACEUTICAL ELASTOMERIC CLOSURES

PHARM 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, Illinois
Over 12,000 Employees
Operating in more than 19 countries
New York Stock Exchange ATR
2013 Net Sales: 2.52 billion USD
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APTAR PHARMA - ORGANIZATION

Aerosol, spray and dispensing drug

Elastomeric closures
delivery technologies

SVP stoppers LVP stoppers Syringe components

SERUM LYO

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Aptar Stelmi: Elastomeric Closures - Facts and Figures

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.

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Application Fields

Small molecules Biologics

Vaccines Animal Health

Anti-thrombotics Other

SVP stoppers LVP stoppers Syringe components

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 PRODUCT LINE

PRE-FILLED SYRINGE AND AUTO-

STOPPERS
INJECTOR COMPONENTS

PLUNGERS Large Volume Parenteral

0.5ml, 1ml long, 1-3ml, 5ml, 10ml, 20ml, (INFUSION)
by-pass 1-3ml
Stoppers for glass vials 28/29mm,
32mm, 34mm, DIN and ISO ;
Injection sites for IV bags
TIP CAPS
Ribbed Tip Caps (RTC) - Luer lock and
Luer cone - Mushroom Small Volume Parenteral
(SERUM, ANTIBIO)
13 and 20mm, ISO and blow back
SOFT & RIGID NEEDLE SHIELD
1/2 inch, 5/8 inch, 1 inch
LYOPHILIZATION
PLUNGERS FOR CARTRIDGES 13mm, 20mm, 28mm, 32mm
1.5ml, 3ml
DIAGNOSTIC
Other rangeDIN 14, DIN 18, DIN 22
DROPPER BULBS
0.2ml, 0.8ml, 1ml
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AGENDA

Aptar Stelmi Overview

Elastomeric closures requirements

Pure Formulations and PremiumCoat

From unwashed to Ready To Use components

Take away

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Elastomeric Closures requirements
Fundamental principle:
integrity guaranteed during packaging, storage and administration to the patient

PATIENT SAFETY

CONTAINER
CLOSURE EASE OF USE – REGULATORY
DRUG STABILITY
INTEGRITY - PATIENT CONFORT
STERILITY

Avoid losses & leakages
Avoid evaporation (water,
solvent, active ingredients)
Protect from water, light,
ozone
Avoid external contamination
Compatible with sterilization
methods (steam – gamma)
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Avoid active ingredient Avoid damaging needle Compliance with the
modification Avoid fragmentation pharmacopoeias
Enable multipiercing
Good functional
properties for syringes
Note that machinability on the filling lines is also key
 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
VERY LOW PERMEABILITY
The most impermeable to gases and steam

CHEMICAL INERTNESS
Simpler vulcanization systems
No need for antioxidants in the formulation
Low level of extractable/leachables

PHYSICAL AND CHEMICAL RESISTANCE

Resistance to heat, oxidization, ozone and aging
Self-sealing properties

OTHER PROPERTIES
Low 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
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APTAR STELMI VERSATILE HALOBUTYL FORMULATIONS
6422 6720
CHLOROBUTYL FORMULATION BROMOBUTYL FORMULATION
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
Lower hardness,(43) higher elasticity: Higher hardness (51):
Outstanding coring & seal sealing Outstanding machinability
properties Low moisture: preferred formulation for
Main applications: freeze dried products & powders
small molecules, unbuffered NaCl Zinc free
solutions; vaccines
Main applications:
Main components: Few limitations, including WFI (5 mL),
Liquid LVP & SVP stoppers liquid, freeze dried & powdered products
syringe plungers
Main components: All LVP & SVP
antibiotic & lyo stoppers, syringe plungers

- Different base elastomers - Different fillers

12
- Different curing system - Different ionic profiles
Coated Materials and Assemblies
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

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 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 Ethylene tetrafluoroethylene

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 CONFIDENTIAL

A combination of container closure integrity and improved

compatibility

ETFE Film area

for an improved
compatibility with
the drug product

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 A combination of container closure integrity and improved
compatibility

Non coated (with film) area

for an improved sealing
ETFE Film area
for an improved
compatibility with
the drug product

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Container Closure Integrity: similar behavior of non-coated stopper
and PremiumCoat™
In severe conditions, after 6 months, we observed, no differences
between a coated and a non coated stopper (with non blow black
vials*)

Days
*6R non blow-back Schott Vial
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PremiumCoat

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

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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)

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 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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 Production Process of elastomeric closures

FINISHING QUALITY
RECEIVING WEIGHING MIXING MOLDING TRIMMING RELEASE
PACKAGING CONTROLS

FORMULATION DESIGN WASHING/ SILICONIZING

DRYING / PACKAGING

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 RTS :ULTRACLEAN 6 EVOLUTION WASHING PROCESS
QUALITY
RECEIVING WEIGHING MIXING MOLDING TRIMMING FINISHING RELEASE
CONTROLS

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)

Bioburden < 0,25 CFU/cm²

Endotoxins < 0,03 UE/ml
(0,06 UE/cm²)
PCI* < 2,9

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* :Particle Count Index = 0.1x(25-50µm) + 0.2x(50-100µm) + 1x(>100µm)
 QUALITY
RECEIVING WEIGHING MIXING MOLDING TRIMMING FINISHING RELEASE
CONTROLS

Validated Process Comprehensive CoA, including

Reduction in bacterial endotoxins Physico-chemical results
Bacterial decontamination Bioburden, endotoxins and PCI (results and
Particulate decontamination specifications)
Consistent siliconization level Visual check
Absence of residual detergent Dimensional check

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 Sterile Process of elastomeric closures

PRODUCTION PROCESS & VALIDATION & DOCUMENTATION &

IRRADIATION
MICROBIOLOGICAL RE-VALIDATION REGULATORY FIELD
CONTAMINATION

STERILITY GUARANTEED

Centre de photocopie Centre de photocopie

>Comprehensive >Certificate of
>Specific >Specific >Specific >Integrity indicator
validation and re-validation >Validated range sterility
organisation primary configuration and integrity check
(including bag seals and 18 – 32 kGY >DMF type V
>More frequent packaging of palletisation
transport)
controls for gamma >Validation file
irradiation >Dose Audit
>Certificate of
>Ageing study irradiation

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 From Ready to Sterilize to Ready to Use
Transferring the washing and sterilization operations to the supplier

IPC
Reception
Investment Development Validation Re-validation Regulatory Audits
controls
Monitoring

RTS* $

Systèmes informatiques
Equipment Steam Sterility Supplier
Area Sterilization Monitoring Filing In-house

RTU
STERILE
Guarantees
Aptar
Stelmi

* + steam sterilization in-house

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 TAKE AWAY
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.

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 Thank you for your attention !

APTAR STELMI
Le Raspail - Paris Nord II
22, avenue des Nations - B.P. 59415 Villepinte
95944 Roissy CDG Cedex
Tel: +33 (0)1 48 63 56 56 - Fax: +33 (0)1 48 63 56 99
E-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, which
are hereby incorporated by reference, or by the particular agreements or contracts under which the products are
provided. APTAR manufactures its products to meet standard specifications, and does not guarantee that its products
meet other specifications not previously agreed upon in writing. All information contained herein is purely informative
and is provided without any promise, representation, or warranty, express or implied, of any kind, including - without
limitation - any warranties of merchantability, fitness for a particular purpose, or non-infringement of any intellectual
property rights. any reliance on the information contained herein shall be at your own risk.

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