Best Practices for OINDP Pharmaceutical Development Programs Leachables and Extractables II. OINDP Container Closure Systems PQRI Leachables & Extractables Working Group PQRI Training Course April 12-13, 2007 Chicago
Container Closure System Components Primary Packaging Components,, which are or may be in direct contact with the dosage form. These include: containers (e.g., ampules,, vials, bottles), container liners, closures (e.g., screw caps, stoppers, metering valves), closure liners, stopper overseals,, container inner seals, administration ports, overwraps,, etc. Secondary Packaging Components,, which are not or will not be in direct contact with the dosage form. These include container labels, administration accessories, shipping containers, etc. Note that even though secondary packaging components are not in direct contact with the drug product, they may still contribute leachables under certain conditions. April 2007 PQRI Training Course 2
Critical Components Critical components of an OINDP container closure system are defined as those that contact either the patient or the formulation, components that affect the mechanics of the overall performance of the device, or any necessary secondary protective packaging. April 2007 PQRI Training Course 3
MDI Critical Components Dose metering valve Metering chamber Stem(s) Seals/gaskets Sealing rings Canister Coated? Mouthpiece/actuator MDI Schematic Provided by Bespak Europe April 2007 PQRI Training Course 4
OINDP Container Closure System Components April 2007 PQRI Training Course 5
DPI Images provided by Bespak Europe and Pfizer April 2007 PQRI Training Course 6
DPI Critical Components ARCHaler Drug reservoir Air in Dose metering arc Note that the ARCHaler is a complete fabrication. Any resemblance to any existing drug product or container closure system is purely coincidental. April 2007 PQRI Training Course 7
What are some potential sources for leachables and extractables? Chemical additives present in individual elastomeric/polymeric container closure system components, including contaminants in such s additives (e.g. PAHs and N-nitrosamines). N Monomers and higher molecular weight oligomers derived from incomplete polymerization reactions. Migrants from secondary packaging components, such as inks and label adhesives. Surface residues, such as heavy oils and degreasing agents on the surfaces of metal canisters and containers. Chemical additives on the surfaces of container closure system component fabrication machinery, such as mould release agents, antistatic and antislip agents, etc. Chemical entities from the storage environment (i.e., very secondary packaging components), such as volatiles from cardboard shipping containers or plastic storage bags. April 2007 PQRI Training Course 8
What is an Additive???? Additives are Ingredients Incorporated into the Polymer to Stabilize or Enhance its Performance Stabilizers Maintain the Polymer s Original Properties Strength Flexibility Toughness Modifiers Change or Improve Polymers Performance Performance Additives (Slips, Anti-Stats) Pigments Fillers April 2007 PQRI Training Course 9
Polymer Degradation Physical Characterisitics Inherent Stability Molecular Structure Polymerization Process Catalysts/Co-Catalysts/ResidueCatalysts/Residue Finishing Steps April 2007 PQRI Training Course 10
Processing Concerns Polymer Degradation Temperature Shear Exposure Duration End Use Concerns Intended Usage Life Environmental Exposures Improved High Temperature Stabilization April 2007 PQRI Training Course 11
Examples of Chemical Additives CH 3 CH CH 3 CH 3 H O HOOC CH 3 H O P O April 2007 PQRI Training Course 12
What s in a name? Abundance 3200000 TIC: 08190305.D 3000000 2800000 2600000 Abietic acid 2400000 2200000 2000000 1800000 1600000 1400000 1200000 1000000 800000 600000 400000 200000 Time--> 0 5.00 10.00 15.00 20.00 25.00 30.00 April 2007 PQRI Training Course 13
Stabilizer Classes Melt Processing Phosphites Hindered Phenols Process Stabilization / Base Stabilization Long-term Thermal Hindered Phenols Hindered Amines Thermal Stabilizers Light Stabilizers Radical Traps UV Absorbers Excited State Quenchers Light Stabilization Package April 2007 PQRI Training Course 14
Degradation and Stabilization R-H (Polymer) Melt Processing Energy (UV Light, Heat) Catalyst Residues React with primary antioxidants to yield inactive products (ROH and H 2 0) RO + OH Cycle II R Cycle I Oxygen ROO Path of Degradation Path of Stabilization R + ROOH Reacts with secondary antioxidants to yield inactive products (ROH) R Alkyl radical RO Alkoxy radical ROO Peroxy radical ROOH Hydroperoxide Reacts with primary antioxidants April 2007 PQRI Training Course 15
Extractables and Leachables Challenge Stabilization is a dynamic process Many additives will transform and/or degrade during use. Transformation and degradation products must be considered along with the intact additives as potential leachables and extractables. Unexpected Additives May also be Present in the Polymer April 2007 PQRI Training Course 16
Stabilizers Auto-oxidation oxidation can be suppressed by the use of radical scavengers (CH 3 C OH OH C(CH 3 Most polyolefins contain one or more antioxidants at levels of 0.05 0.10% Primary antioxidants are generally radical scavengers or H-donorsH i.e. hindered phenols such as BHT, Irganox 1010, or Irganox 1076 Long-term protection for the polymer Secondary antioxidants are typically hydroperoxide decomposers i.e. trivalent phosphorus compounds such as Irgafos 168 Process stabilization (protects the primary AO against decomposition during processing) CH 3 CH 3 Irganox 2246 O O P O Irgafos 168 April 2007 PQRI Training Course 17
Additive Chemistry O Hydroperoxide (ROOH) O O P O O P O O Irgafos 168 April 2007 PQRI Training Course 18
Reaction of Hindered Phenol with Singlet Oxygen (CH 3 C O OH C(CH 3 (CH 3 C O O C(CH 3 C H 3 OOH CH 3 C H 3 OOH H 3 C OOH OH OH (CH 3 C C(CH 3 O OH (CH 3 C C(CH 3 (CH 3 C OH OH C(CH 3 1 O 2 CH 2 OCH 3 CH 3 C H 3 OOH CH 2 OCH 3 CH 3 CH 3 OH OH O OH (CH 3 C C(CH 3 (CH 3 C C(CH 3 C H 3 OH CH 3 CH 2 OCH 3 CH 2 OCH 3 O O (CH 3 C C(CH 3 H 3 C OH H 3 C OH April 2007 PQRI Training Course 19
Stabilization Systems Along The Value Chain MARKETS Monomer Manufacturing Polymer Manufacturing Synthesis Extrusion Masterbatchers Converters End Products Polymer Recycling R Process Chemicals Polymerization Regulators Storage Stabilizers Antioxidants Processing Stabilizers (Light stabilizers) Light Stabilizers (AO/Proc. stabilizers) Additives for Plastics Recycling PRODUCTS April 2007 PQRI Training Course 20
Masterbatchers and Converters Polymer Concentrate -Stabilizers -Pigments -Antistats Polymer Often Contains a Base Stabilization Package April 2007 PQRI Training Course 21
Raw Materials Supply Chain April 2007 PQRI Training Course 22
Raw Materials - Supply Chain April 2007 PQRI Training Course 23
Component Fabrication Moulding machine Image provided by Bespak Europe Extruder Image Provided by Ciba April 2007 PQRI Training Course 24
Deep Drawing Process deepdrawing tool metal rolls Images provided by Presspart April 2007 PQRI Training Course 25
Deep Drawing Process finished canisters Images provided by Presspart degreasing process April 2007 PQRI Training Course 26
Information Required The elastomeric/polymeric or other material constituting the principal structure of the component (e.g., High Density Polyethylene, Ethylene-Propylene Propylene-Diene rubber, stainless steel, etc.) The polymerization/cross-linking/curing linking/curing process, or processes, for the component base polymer, including any chemical additives employed. The compounding/fabrication process, or processes, including any additives designed to assist in compounding/fabrication. All individual chemical additives/ingredients in the component, including the composition and chemistry of each individual additive. ive. Any cleaning/washing processes for finished components, including knowledge of cleaning, washing, or other agents. The storage/shipping environment for both components and drug product, if the potential for environmental leaching exists. April 2007 PQRI Training Course 27
Rubber Formulation A (Sulfur Cured) Ingredient % CALCINED CLAY 8.96 BLANC FIXE (barium sulfate) 25.80 CREPE 38.22 BROWN SUB MB 16.84 1722 MB 2.11 ZINC OXIDE 4.04 2, 2 METHYLENE-BIS (6-TERTIARY BUTYL-4-ETHYL PHENOL) 0.56 COUMARONE-INDENE RESIN 1.12 PARAFFIN 1.12 TETRAMETHYLTHIURAM MONOSULFIDE 0.11 ZINC 2-MERCAPTOBENZOTHIAZOLE2 0.29 SULFUR 0.84 April 2007 PQRI Training Course 28
What do we know? Carbon black is a known source of PAHs and has also been shown to be involved in N-nitrosamine N formation in rubber ( special cases ). Thiurams are known precursors of N-nitrosamines. N 2-Mercaptobenzothiazole is a known special case. Paraffin and Coumarone-indene resin are natural product materials and are likely complex mixtures of related structures. Individual additives are likely GC-able. April 2007 PQRI Training Course 29
Sulfur Cured Rubber Extractables Profile by GC/MS Abundance TIC: 02210302.D 1.2e+07 1.15e+07 1.1e+07 1.05e+07 1e+07 9500000 9000000 8500000 8000000 7500000 7000000 6500000 6000000 5500000 5000000 4500000 4000000 3500000 3000000 2500000 2000000 1500000 1000000 500000 0 5.00 10.00 15.00 20.00 25.00 30.00 35.00 Time--> April 2007 PQRI Training Course 30
Polypropylene Formulation Ingredient wt % Primary Stabilizers Tetrakis (methylene(3,5-di di-t-butyl- 4-hydroxyhydrocinnamate)) methane Irganox 1010 (Ciba) 0.08 wt% Anox 20 (Great Lakes) Secondary Stabilizers Bis(2,4-di di-t-butylphenyl)pentaerythritol diphosphite Ultranox 626 (GE) 0.05 wt% April 2007 PQRI Training Course 31
Polypropylene Formulation Ingredient % Corrosion Inhibitors Calcium Stearate 114-50 (Ferro) 0.03-0.4 wt% Antistatic Vegetable oil derived 90% alpha monoglycerides (soybean) Pationic 901 (Patco( Patco) Dimodan HS-KA (Danisco( Danisco) 0.3 wt% Nucleating Agents 3,4 -dimethyl dibenzylidene sorbitol Millad 3988 (Milliken) 0.2 wt% April 2007 PQRI Training Course 32
What do we know? Polypropylene is known to contain many soluble oligomers. Individual additives will likely require analysis by HPLC based methods. Individual additives could be both chemically complex and have complex degradation chemistries. No reason to suspect the presence of special cases April 2007 PQRI Training Course 33
Polypropylene Extractables Profile by LC/UV/MS Reflux PP Disc/CH2Cl2 03270311 4 280 nm 10.55 ANALOG 100 5.22e5 12 20.92 % 2 5.34 0 % 3 8.44 9 18.90 33.92 03270311 8 Scan AP- 18.36 TIC 100 11 1.27e7 20.25 3 3.17 5.02 8.55 4 10.64 7 16.02 9 5 10 13.50 6 12 34.01 25.63 31.38 40.31 37.86 44.91 0 5.00 10.00 15.00 20.00 25.00 30.00 35.00 40.00 Time April 2007 PQRI Training Course 34
Summary of PQRI Recommendations The pharmaceutical development team should obtain all available information on the composition and manufacturing/fabrication processes for each component type to the extent possible, and determine which components are critical, before beginning extractables and leachables studies on a given OINDP and its associated container/closure system components. Component formulation should inform component selection. Risk Assessment should be performed during the selection of components and materials. Extractables testing, including Controlled Extraction Studies and the development and validation of Routine extractables testing methods, should be accomplished for all critical OINDP components. April 2007 PQRI Training Course 35