PQRI PODP Extractables & Leachables Workshop · 4/7/2018  · Generally has better barrier...

PQRI PODP Extractables & LeachablesWorkshop

Presented by: Michael Ruberto, President – Material Needs Consulting

Sources of Leachables for Injectable and Ophthalmic Container Closure Systems

April 2018

Packaging-Container Closure Systems (CCS)

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Simple Systems

Bottle – Glass or PlasticClosure – Rubber or Plastic

Packaging – Container Closure Systems (CCS)

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Complex Systems

Multi-layered Systems

Leachables can diffuse from the outer layers and into the drug

Combination Products

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Very Complex SystemsStore and Deliver the Drug

Materials Used In Pre-Filled Syringes

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Primary Packaging•Barrel and Piston

•Glass or Plastic•Stopper

•Rubber•Tip Cap / Needle Shield

•Plastic, RubberSecondary Packaging•Over Wrap / Container

•Plastic•Spacers

•Foam or Plastic•Labels

•Paper•Ink•Adhesive

PQRI PODP E&L WorkshopApril 18-19, 2018

Extractables from Glass

Generally has better barrier properties than plastic, however…

• Extractables– Alkali Oxides– Trace Metals– Higher pH DP can Increase Leachables– Silicone – Assists in plunger glide

• Interactions with Drug Products– Particulates - often resulting from the interaction of leached ions

such as Ba or Al with buffers– pH Shifts– Protein and Peptide Aggregation– Tungsten Issues

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Polymer Primary Packaging – Direct Contact

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PrimaryAntioxidants

Slip Agents

NucleatingAgents

SecondaryAntioxidants

DegradationProducts

Polymers are melt processed….

Processing can significantly affect the polymer – what comes out may be different than what went in….

•Temperature• Shear• Exposure / Duration

Photos Courtesy of Ciba

PQRI PODP E&L WorkshopApril 18-19, 20189

Molding

InjectionMolding

Cast FilmLine

Mold

Photos Courtesy of Ciba

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Degradation and Stabilization

React with primaryantioxidants toyield inactiveproducts(ROH and H20)

Reactswithprimary anti-oxidants

Reacts with secondaryantioxidants to yieldinactive products (ROH)

Path of DegradationPath of Stabilization

R-H(Polymer)

R •ROO •

R • +

ROOH

RO • + • OH

Oxygen

Melt ProcessingEnergy (UV Light, Heat)Catalyst Residues

Cycle II Cycle I

R • Alkyl radicalRO • Alkoxy radicalROO • Peroxy radicalROOH Hydroperoxide

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Phosphites – Transformation Chemistry

POO

O

P OO

O

O

[ O ]

[1]

PQRI PODP E&L WorkshopApril 18-19, 201812

Phosphites – Degradation Chemistry

POO

O

PO

O

OH

PO

OH

OH

POH

OH

OHOH

OH

OH

+

[ H2O ]

+

[ H2O ]

[ H2O ]+ 3 2

PQRI PODP E&L WorkshopApril 18-19, 201813

Creating Effects with Surface AdditivesA controlled incompatibility in the polymer

• Antimicrobials• Slip Agents and Lubricants Antistatic AgentsMore Susceptible to Leaching

Wipingor

WashingMigration

hydrophilic headhydrophobic tail

Colorants - Masterbatches and Concentrates

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MasterbatchersConverters

Pigments

Polymer – Carrier ResinAlso Contains Additives

New Polymer

Secondary Packaging - Indirect Contact

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Pigments

Dyes

ResidualSolvents

Photoinitiators

. +hν

C

HO

O

CHO

O

.

Adhesives

• Somewhat Characterized• Still Some Surprises

P

O

C

O

C

O

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A Label can be a Complex Multi-Laminate System

Source: http://www.whitlam.com/learning-center/basic-fundamentals-of-labeling/label-construction

Shipping, Storage, and Environmental

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Contaminants

• Not Well Characterized• Surprises!!!

??? ???

???

How much time do we spend focusing on leachables from secondary packaging and the environment?

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How much confidence do we have in the materials that are used to construct our shield?

Vibranium???

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Polymer Blends

Physical mixture of two or more different types of polymers

To blend different polymers is an easy way to improve certain properties. The most popular blends are PC/ABS , PP/EPM (high impact resistance), PA/PE (high impact resistance also under dry conditions),

PQRI PODP E&L WorkshopApril 18-19, 2018

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Copolymers

PQRI PODP E&L WorkshopApril 18-19, 2018

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Reasons for Crystallization

Key - Lock principle: e.g. different types of PP or PE

Molten phase

Solid phase

Structural Regularity with Little Branching

Compact, Ordered Morphology

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What Type of Polypropylene?Density of 0.907 [g/cm3]; Crystallinity up to 70%, Mp: 160°C - 208°C; Polymerization with Ti/Al, Cr or Metallocene-catalyst; Less stable against UV-light then PE; good chemical resistance.

copo-PP: raco

block **

n

m

homo-PP: isotactic highest crystallinity

syndiotactic

atactic most transparent

*n

*n

n

The tacticity is determined because of the catalyst which is used for the polymerization

PQRI PODP E&L WorkshopApril 18-19, 2018

Useful Polymer Information

• Polymer Type– Homopolymer, Copolymer, Blend, etc.

• Tg and/or Tm

• Molecular Weight Distribution– Monomers and Oligomers

• % Crystallinity• Density• Raw Materials

– Any Chemicals of Concern

• Impacts the Migration Rate of Leachables!

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Polymer Properties

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Highly Organized Polymers Structural Regularity with Little Branching

Higher % CrystallinityHigher DensityGreater Tg and TmMore RigidBetter Barrier Properties

Less Prone to Leachables or Contaminants

HDPE

LDPE

PQRI PODP E&L WorkshopApril 18-19, 2018

Labels – Leachables Risk

• Glass is an Impermeable Barrier – No Leachables Risk• Polymers are Semi-Permeable Barriers

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PET > PP > HDPE > LDPEHomopolymers better than Copolymers

PET Has Excellent Barrier Properties –Maintains Carbonation

PQRI PODP E&L WorkshopApril 18-19, 2018

Analysis of the Extracts

Multiple Separation and Detection Techniques• Volatiles

– Headspace GC/MS

• Semi-Volatiles– GC/MS

• Non-Volatiles– LC/UV/MS

• Inorganics– ICP-MS

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PQRI PODP E&L WorkshopApril 18-19, 201827

Extractables Profile for Plastic and Rubber• Monomers or Oligomers from Incomplete Polymerization• Stabilizers• Stabilizer - Transformation and Degradation Products• Lubricants / Surface Modifiers• Plasticizers• Specialty Additives• Fillers

– PNAs• Rubber Curing Agents

– Nitrosamines– Mercaptobenzothiazoles

5.00 10.00 15.00 20.00 25.00 30.00 35.000

500000

1000000

1500000

2000000

2500000

3000000

3500000

4000000

4500000

5000000

5500000

6000000

6500000

7000000

7500000

8000000

8500000

9000000

9500000

1e+07

1.05e+07

1.1e+07

1.15e+07

1.2e+07

Time-->

Abundance

TIC: 02210302.D

Courtesy of PQRI

PQRI PODP E&L WorkshopApril 18-19, 2018

Summary

• Polymers are Generally a Greater Leachables Risk than Glass–“More Ingredients” - Additives

• Bulk vs. Surface

–Semi-Permeable Barriers

• Well Characterized Container Closure Systems–Primary Packaging–Secondary Packaging

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