Fundamentals of Chemistry of Elastomers and its

Applications in Injectables Packaging

Darshana Chavan
11 & 13 Nov 2019

©2019 by West Pharmaceutical Services, Inc.

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.
Content

▪ Rubber 101 – An Introduction to Rubber Formulations

- Material
- Manufacturing Process & Controls
▪ Considerations in Selecting a Packaging Component
- Rubber formulations
- Designs
- Coatings and Lamination
- Post Processing & Packaging
Rubber 101 – An Introduction to Rubber Formulations

© 2017, West Pharmaceutical Services, Exton, 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.
Introduction

Stoppers

Serum Lyo

Flip-Off Seal
Rubber

▪ Common name given by Priestly to isoprene because of its ability to

“rub” pencil marks from paper.

▪ Formally referred to as an “Elastomer”, which is any material that can

be stretched to twice its original length and upon release return rapidly
to its original length.
Vulcanization / Curing

▪ In its natural state, rubber is not a useful engineering material. Left unmodified,
an elastomer will flow under an applied force with little “memory” of its original
structure.

▪ Crosslinking of the elastomers generates a 3-dimensional network

▪ Crosslinking = Vulcanization = Curing and refer to the process by which

individual polymer chains are transformed into a network
Elastomer

Main ingredient in a rubber formulation.

Can be classified according to:

1. Chemical Structure - Function of reactive double bonds in the main

or side chain of elastomer.
a) Saturated - e.g. butyl/halobutyls
b) Unsaturated - e.g. natural rubber, isoprene

2. Source
a) Natural b) Synthetic

3. Molding Process
a) Thermoset - Compression molding and injection molding
b) Thermoplastic - Injection molding
Halobutyl Structure

Butyl + Cl2 Chlorobutyl More than 90 % of

Isoprene units are
halogenated
Butyl + Br2 Bromobutyl

CIIR/BIIR ●
CH3 CH2Hal

CH2 C CH2 C=C CH2

CH3 H
Hal = Cl or Br
Elastomer Types – Properties

▪ Halobutyls – Bromobutyl, Chlorobutyl

➢ Better chemical cleanliness and stability
➢ Lower level of extractables compared to isoprenes
➢ Good barrier to water and oxygen
➢ Reduced functional properties performance

▪ Polyisoprene / Natural Rubber

➢ Good functional properties performance
➢ Poor barrier to water and oxygen
➢ Higher level of extractables
➢ Natural rubber may be cytotoxic
Stopper Manufacturing & Quality Controls
Stopper Manufacturing Process

Raw Mat. & Aux

Incoming
Weighing controls

Mixing

Mixing controls
Calendaring
In-process
controls
Compression Molding

Molding
controls
Trimming

Std Wash

AQL controls

LF washing & Siliconization

ISO5 Packing

Final inspection

RS finished goods
Typical Rubber Testing

Raw Stock
▪ Ash Content – Measure of amount of inorganics
▪ Rheology – Flow properties of rubber during curing
Molded Stock
▪ Specific Gravity – Density
▪ Shore A Duro – Measure of hardness
▪ Dispersion – Check for good homogeneous mix
▪ Color – Check for homogenous mix
Impact on Drug products

▪ Instability of raw material quality will affect manufacturing process and

final stopper products quality
▪ If contamination is in raw material, it may possibly transfer into drug
products
▪ Insufficient curing or over curing will affect physical and chemical
properties of stoppers, and indirectly have impact on stability of drug
products
Dimensional Controls

▪ Representative test samples

▪ Sample in accordance to ANSI/ASQ Z 1.4-2003
▪ Test for AQL & dimensions in accordance to West specs
▪ Released only if criteria are met
Impact on Drug products

▪ Disqualified dimensions:
− Affect machinability
− Pop up
− Seal Integrity

▪ Particles and Foreign matters:

− Drug contamination risk
− Injected into patients
Formulation Controls

▪ Formulation controls are guaranteed within the production upstream

▪ However, West can perform batch-certification compliance to
compendia standards upon customer request：
− EP 3.2.9
− USP <381>
− JP 7.03
Considerations in Selecting a Packaging Component
Regulatory Requirement

▪ Regulatory Guidelines:
➢ US Code of Federal Regulations
21 CFR 211 cGMPs

§ 211.94 (a) Drug product containers and closures shall not be reactive, additive, or
absorptive so as to alter the safety, identity, strength, quality, or purity of the drug beyond
the official or established requirements.
Regulatory Requirement

▪ Regulatory Guidelines:
➢ FDA Guidance for Industry
Container Closure Systems for Packaging Human Drugs and Biologics, May 1999
“Every proposed packaging system should be shown to be suitable for its intended use: it should
adequately protect the dosage form; it should be compatible with the dosage form; and it should be
composed of materials that are considered safe for use with the dosage form and the route of
administration. If the packaging system has a performance feature in addition to containing the
product, the assembled container closure system should be shown to function properly.”
Formulation

▪ Customer’s drug details:

➢ Drug Name – API
➢ Excipients – Solvent vehicle, preservative
➢ Buffer system / Diluent
➢ Sensitivity to chemical species
➢ pH
➢ Form – Liquid, Powder, Lyophilized cake
➢ Sensitivity to moisture, oxygen, etc
➢ Processing conditions
➢ Storage conditions
Formulation

▪ Protection - Provides adequate protection from factors that can cause a

degradation in the quality of the dosage form over its shelf life
➢ Exposure to light
➢ Loss of solvent
➢ Exposure to reactive gases
➢ Absorption of “water”
➢ Microbial contamination
Formulation

▪ Compatibility - Does not interact sufficiently to cause unacceptable

changes in the quality of either the dosage form or the packaging
component
➢ Loss of potency
➢ pH Change
➢ Degradation of the active drug substance
➢ Discoloration
➢ Brittleness of packaging
➢ Precipitation
➢ Reduction in excipient concentration
Formulation

▪ Potential interactions between drug and stopper:

➢ Adsorption – Concentrated at surface of stopper
➢ Absorption – Dispersed in stopper
➢ Permeation – Transmission through stopper
➢ Leaching – Chemical species migrating from stopper into drug

Adsorptio Absorptio
n n
Formulation – Selection of Stoppers for Lyophilization

▪ Rubber formulation
− Moisture
− Physical Properties
• fragmentation
• resealability

− Chemical Properties
• leachables/extractables
• adsorption and absorption characteristics
Formulation – Selection of Stoppers for Lyophilization

Sources of Moisture in Stopper

▪ Moisture from environment which permeates through stopper (MVT)

▪ Moisture which enters via the stopper-vial interface

▪ Residual moisture from stopper:

− Rubber formulation
− Sterilization process
− Drying cycle
Formulation – Selection of Stoppers for Lyophilization

Typically butyls & halobutyls have lower MVT rates

Comparison of Typical MVT Rates

Freeze-drying/Lyophilization of Pharmaceutical and Biological Products (Louis Rey, Joan Christine May)

Formulation recommendations based on

MVT rates:
4432/50G (MVT = 0.1 g/m2.day)
4023/50G (MVT = 0.1 g/m2.day)
Formulation – Selection of Stoppers for Lyophilization

▪ Raw materials may contribute to residual moisture content in stopper

▪ Affects moisture retention characteristics of stopper

Moisture Results Before Autoclave / Drying Cycles

Average Water
Sample Condition Content
(mg / stopper)
Chlorobutyl Unprocessed 3.989
Chlorobutyl with Fluropolymer
Unprocessed 3.568
laminate
Bromobutyl Unprocessed 3.771
Butyl with Fluropolymer laminate Unprocessed 0.540
Formulation – Selection of Stoppers for Lyophilization

Moisture Absorption

▪ Moisture may be absorbed by stopper directly from environment but

mostly is driven in due to steam sterilization

▪ Formulation dependent

▪ Amount of residual moisture dependent on drying cycle

Formulation – Selection of Stoppers for Lyophilization

▪ Stopper moisture retention & MVT both play a part in affecting lyo cake
moisture content
▪ Moisture content dependent on sterilization & drying parameters –
customer evaluation needed to ensure lyo dryness met
▪ Choosing a suitable formulation, as well as optimizing the drying time is
critical in reducing moisture increase in lyo cake
Design

▪ Affects:
− Fit into vials
− Seal integrity
− Sterility, Moisture ingression
− Functional performance of the stopper
− Overall stability of the drug
Design

▪ Consists of:
➢ Application type:
− Serum / Liquid
− Lyo – Igloo, 2-legged, 3-legged
− IV
− Laminated
➢ Size – 13mm, 20mm, 28mm, 32mm, others
➢ Vial type – Non-blow back, US/EU blow-back
Design – Application Type

▪ Serum / Liquid

▪ Lyo – Igloo, 2-legged, 3-legged

▪ IV

▪ Laminated
Design – Vial Type

▪ Serum / Liquid Stoppers

Anti-pop ring

US Blow-back EU Blow-back
Design - For Lyophilization

▪ Igloo (Single vent)

▪ Stable when placed on vial
▪ Can get out of axis when closed

▪ 2-legged (Split)
▪ May be unstable when placed on vial
▪ Higher tendency for intertwining
▪ Can be pushed in evenly
Design - For Lyophilization

▪ No. of vents
▪ Rate limiting factor to sublimation is the lyo cake
▪ No. of vents has little effect on lyo process
Coatings & Lamination
Rubber Surface Coating / Lamination

Coating / Lamination

Lubricity Barrier Films

Silicone Oil B2-Coating Fluorinated Polymer Films

FluroTec®,
TeflonTM
Flurotec®
 Lubricity – Silicone Oil

▪ Polydimethylsiloxane (DC 360 Medical Fluid)

▪ 350 centistokes – USA
▪ 1000 centistokes – Europe / Asia-Pacific

Advantages Disadvantages
▪ Commonly used ▪ Particles/droplets may
▪ Applied by tumbling or be found in drug
as emulsion with WFI product.
▪ Low cost ▪ Silicone level may be
inconsistent if process
is not validated.
 Lubricity – B2-Coating

▪ High molecular polydimethylsiloxanes cross-linked on the surface of

rubber closures by UV light

▪ Does not alter chemical and biological stopper properties

▪ B2-Coating capabilities in Europe, Japan and US

Standard B2-Coating Levels

B2- B2- B2-

40 coated to
Top surface
42
Top surface coated to 44 coated to
Top surface
maximum level (level 4) maximum level (level 4) maximum level (level 4)

Bottom surface is Bottom surface coated to Bottom surface coated

not coated (level 0) half the maximum level to
(level 2) maximum level (level 4)
Design – Laminated Stopper

▪ Some drugs may be very sensitive or contains aggressive content

which require the use of a laminated stopper
− Minimize absorption/adsorption
− Minimize extractables from the elastomer
− Improve general drug/closure compatibility
− Proper sealing provided through uncoated sealing area
− Add lubricity, which helps to lower particles in solution
Design – Laminated Stopper

▪ Provides proper sealing provided through un-laminated sealing area

Design – Laminated Stopper

▪ Reduced extractables from base formulation and improves general

drug-closure compatibility

Un-laminated FluroTec Blank

Migration of organic components into n-heptane monitored by GC

West Coating and Film

✓ FluroTec® -- ETFE
✓ Good barrier between drug and
closure, reduce leachables from
elastomeric components
B2 Coated
✓ Improve lubricity
FluroTec® Laminated ✓ Lower particles
Untreated ✓ Transparent, can be radiated
✓ Ideal solution in combination with
B2 to minimize product loss or
failures
FluroTec® is a registered trademark of West Pharmaceutical Services, Inc., in the United States and other jurisdictions. FluroTec ® and B2 technology are licensed from
Daikyo Seiko, Ltd
 FluroTec® vs FEP

FluroTec® FEP Film

▪ Flexible film ▪ Inflexible film

▪ Available in more designs ▪ Must be flat
▪ Serum stoppers, Lyo ▪ Available in limited
stoppers, Plungers design
▪ Serum stoppers only
Post Processing & Packaging
Finishing & Packaging

▪ How does the stopper fit into the drug manufacturing line?
▪ Does the drug manufacturer prefer to:
− Wash and siliconize their own stoppers?
− Eliminate washing and siliconization and go straight to sterilization?
− Totally eliminate all stopper processing steps and go straight to filling?

▪ What type of sterilization is used?

▪ What type of filling line is used?
Finishing & Packaging

▪ Wash and siliconize their own stoppers

→ Standard grade – No WFI wash by supplier
▪ Eliminate washing and siliconization and go straight to sterilization
→ Ready-to-Sterilize (RS) grade – Washed in pharmaceutical washer with
WFI and siliconized
▪ Totally eliminate all stopper processing steps and go straight to filling
→ Ready-to-Use (RU) grade – Washed, siliconized in pharmaceutical
washer, sterilized
Finishing & Packaging

▪ Ready-to-Sterilize (RS) grade:

➢ Bioburden
➢ Endotoxin
➢ Particulates
➢ Silicone oil level
Available from West as Westar RS and comes with DMF filing

▪ Ready-to-Use (RU) grade:

➢ Sterility
➢ Endotoxin
➢ Silicone oil level
➢ Residual moisture for lyo stoppers
Available from West as Westar RU and comes with DMF filing
Finishing & Packaging

▪ Type of sterilization used affects the type of packaging:

➢ Steam sterilization
− Autoclavable bag with material which allows steam to pass through
(Tyvek)
➢ Gamma sterilization
− Clean PE bag
Finishing & Packaging

▪ Type of filling line affects the type of packaging:

➢ Normal fill/finish line
− Bulk packaging – SterilizableBag / PE bag

➢ Restricted Access Barrier System (RABs) / Isolator

− Portbags
Summary

▪ Rubber 101 – An Introduction to Rubber Formulations √

- Material
- Manufacturing Process & Controls
▪ Considerations in Selecting a Packaging Component √
- Rubber formulations
- Designs
- Coatings and Lamination
- Post Processing & Packaging