PQRI PODP Extractables & Leachables Workshop · 4/7/2018 · Generally has better barrier properties than plastic, ... Transformation Chemistry P O O O P O O O O [ O ] [1] PQRI PODP

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)

2

Simple Systems

Bottle – Glass or PlasticClosure – Rubber or Plastic

Packaging – Container Closure Systems (CCS)

3

Complex Systems

Multi-layered Systems

Leachables can diffuse from the outer layers and into the drug

Combination Products

4

Very Complex SystemsStore and Deliver the Drug

Materials Used In Pre-Filled Syringes

5

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

6

Polymer Primary Packaging – Direct Contact

7

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


Molding

InjectionMolding

Cast FilmLine

Mold

Photos Courtesy of Ciba

10

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

11

Phosphites – Transformation Chemistry

POO

O

P OO

O

O

[ O ]

[1]


Phosphites – Degradation Chemistry

POO

O

PO

O

OH

PO

OH

OH

POH

OH

OHOH

OH

OH

+

[ H2O ]

+

[ H2O ]

[ H2O ]+ 3 2


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

14

MasterbatchersConverters

Pigments

Polymer – Carrier ResinAlso Contains Additives

New Polymer

Secondary Packaging - Indirect Contact

15

Pigments

Dyes

ResidualSolvents

Photoinitiators

. +hν

C

HO

O

CHO

O

.

Adhesives

• Somewhat Characterized• Still Some Surprises

P

O

C

O

C

O

16

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

17

Contaminants

• Not Well Characterized• Surprises!!!

??? ???

???

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=gv2x6-ML51o2RM&tbnid=RoagGsA1AFwn9M:&ved=0CAUQjRw&url=http://www.komatsuforkliftusa.com/default.asp/upage_id%3D0/apage_id%3D1406/INDUSTRY%20SOLUTIONS&ei=YUBgUpDeM9ja4AOwyYGAAw&psig=AFQjCNG3892hZf4aOlp5osXNezv93UdYsg&ust=1382125892798263

http://www.google.com/imgres?start=166&sa=X&biw=1536&bih=770&tbm=isch&tbnid=K93jj7k_nKTsyM:&imgrefurl=http://www.poppytalk.com/2011/02/diy-scrap-pallet-plank-wall.html&docid=M3DIDPv27DzttM&imgurl=http://2.bp.blogspot.com/-xAEp_SPwTkk/TWV-cDr8XjI/AAAAAAAAby8/y32VEy--UYY/s1600/pallet2.gif&w=500&h=291&ei=8z5gUt6lK7He4APsp4C4AQ&zoom=1&ved=1t:3588,r:78,s:100,i:238&iact=rc&page=8&tbnh=171&tbnw=294&ndsp=25&tx=182.4000244140625&ty=91.60003662109375

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

18

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

Vibranium???

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&docid=mMgaxOx5KslFvM&tbnid=oyR1omULAMyyQM:&ved=0CAUQjRw&url=http%3A%2F%2Fwww.halloweencostumes.com%2Fchild-captain-america-shield.html&ei=0rdSU4vZIdSssQSThoBQ&bvm=bv.65058239,d.aWw&psig=AFQjCNH4W-Djd5I6WviPE3VkMWGM2ZCl1A&ust=1398016288558714

19

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),


20

Copolymers


21

21

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

22

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


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!

23

Polymer Properties

24

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


Labels – Leachables Risk

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

25

PET > PP > HDPE > LDPEHomopolymers better than Copolymers

PET Has Excellent Barrier Properties –Maintains Carbonation


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

26


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


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

28

Documents

PQRI PODP Extractables & Leachables Workshop · 4/7/2018 · Generally has better barrier properties than plastic, ... Transformation Chemistry P O O O P O O O O [ O ] [1] PQRI PODP