PQRI PODP Extractables & Leachables Workshop Sources of Leachables for Injectable and Ophthalmic Container Closure Systems

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1 PQRI PDP Extractables & Leachables Workshop Sources of Leachables for Injectable and phthalmic Container Closure Systems Presented by: Michael Ruberto, President Material Needs Consulting April 2018

2 Packaging-Container Closure Systems (CCS) Simple Systems Bottle Glass or Plastic Closure Rubber or Plastic 2

3 Packaging Container Closure Systems (CCS) Complex Systems Multi-layered Systems Leachables can diffuse from the outer layers and into the drug 3

4 Combination Products Very Complex Systems Store and Deliver the Drug 4

5 Materials Used In Pre-Filled Syringes Secondary Packaging ver Wrap / Container Plastic Spacers Foam or Plastic Labels Paper Ink Adhesive 5 Primary Packaging Barrel and Piston Glass or Plastic Stopper Rubber Tip Cap / Needle Shield Plastic, Rubber

6 Extractables from Glass Generally has better barrier properties than plastic, however Extractables Alkali xides 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 PQRI PDP E&L Workshop April 18-19,

7 Polymer Primary Packaging Direct Contact Primary Antioxidants Secondary Antioxidants Degradation Products Nucleating Agents Slip Agents 7

8 Polymers are melt processed. Temperature Shear Exposure / Duration Processing can significantly affect the polymer what comes out may be different than what went in. Photos Courtesy of Ciba

9 Molding Injection Molding Mold Cast Film Line Photos Courtesy of Ciba PQRI PDP E&L Workshop 9 April 18-19, 2018

10 Degradation and Stabilization React with primary antioxidants to yield inactive products (RH and H 2 0) R + H R-H (Polymer) Cycle II R Melt Processing Energy (UV Light, Heat) Catalyst Residues Cycle I xygen R Path of Degradation Path of Stabilization R + RH Reacts with secondary antioxidants to yield inactive products (RH) R Alkyl radical R Alkoxy radical R Peroxy radical RH Hydroperoxide Reacts with primary antioxidants 10

11 Phosphites Transformation Chemistry P [ ] P [1] 11

12 Phosphites Degradation Chemistry P [ H 2 ] P H + H [ H 2 ] H P H H + 3 H [ H 2 ] P H H + 2 H PQRI PDP E&L Workshop April 18-19,

13 Creating Effects with Surface Additives A controlled incompatibility in the polymer Antimicrobials Slip Agents and Lubricants Antistatic Agents More Susceptible to Leaching Wiping or Washing Migration hydrophilic head hydrophobic tail PQRI PDP E&L Workshop 13April 18-19, 2018

14 Colorants - Masterbatches and Concentrates Pigments Masterbatchers Converters New Polymer Polymer Carrier Resin Also Contains Additives 14

15 Secondary Packaging - Indirect Contact C P C Residual Solvents C H hν C. +. H Photoinitiators Pigments Adhesives Dyes Somewhat Characterized Still Some Surprises 15

16 A Label can be a Complex Multi-Laminate System Source: rning-center/basicfundamentals-oflabeling/label-construction 16

17 Shipping, Storage, and Environmental??? Contaminants?????? Not Well Characterized Surprises!!! 17

18 How much time do we spend focusing on leachables from secondary packaging and the environment? Vibranium??? How much confidence do we have in the materials that are used to construct our shield? 18

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), 19

20 Copolymers PQRI PDP E&L Workshop April 18-19,

21 Reasons for Crystallization Structural Regularity with Little Branching Key - Lock principle: e.g. different types of PP or PE Molten phase Compact, rdered Morphology Solid phase 21 PQRI PDP E&L Workshop April 18-19,

22 What Type of Polypropylene? Density of [g/cm 3 ]; Crystallinity up to 70%, Mp: 160 C C; Polymerization with Ti/Al, Cr or Metallocene-catalyst; Less stable against UV-light then PE; good chemical resistance. homo-pp: isotactic n * highest crystallinity syndiotactic n * atactic n most transparent The tacticity is determined because of the catalyst which is used for the polymerization copo-pp: raco block * n m * 22

23 Useful Polymer Information Polymer Type Homopolymer, Copolymer, Blend, etc. T g and/or T m Molecular Weight Distribution Monomers and ligomers % Crystallinity Density Raw Materials Any Chemicals of Concern Impacts the Migration Rate of Leachables! PQRI PDP E&L Workshop April 18-19,

24 Polymer Properties Highly rganized Polymers Structural Regularity with Little Branching HDPE LDPE Higher % Crystallinity Higher Density Greater T g and T m More Rigid Better Barrier Properties Less Prone to Leachables or Contaminants 24

25 Labels Leachables Risk Glass is an Impermeable Barrier No Leachables Risk Polymers are Semi-Permeable Barriers PET > PP > HDPE > LDPE Homopolymers better than Copolymers PET Has Excellent Barrier Properties Maintains Carbonation PQRI PDP E&L Workshop April 18-19,

26 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 PQRI PDP E&L Workshop April 18-19,

27 Extractables Profile for Plastic and Rubber Monomers or ligomers from Incomplete Polymerization Stabilizers Stabilizer - Transformation and Degradation Products Lubricants / Surface Modifiers Plasticizers Specialty Additives Fillers PNAs Rubber Curing Agents Nitrosamines Mercaptobenzothiazoles 5.00 Abundance TIC: D 1.2e e e e+07 1e Time--> Courtesy of PQRI PQRI PDP E&L Workshop April 18-19,

28 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 PQRI PDP E&L Workshop April 18-19,