Pira International Conference Extractables Testing for Pumps and Valves Francois Billard, M.S. Laboratory Manager, Valois of America October 2006

USP Requirements Pump or Valve = Container Biological Reactivity Test, in Vitro Biological Reactivity Test, in Vivo Elastomeric Closures for Injections Containers – Plastics

Guidances Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products Chemistry, Manufacturing and Controls Documentation (October 1998) Nasal Spray and Inhalation Solution, Suspension and Drug Products - Chemistry, Manufacturing and Controls Documentation (July 2002) IPAC-RS (International Pharmaceutical Aerosol Consortium on Regulation and Science) offers GMP guidelines for suppliers of OINDP components Future guidance may be based on “PQRI Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products” (2007?)

FDA Requirements Specifications and analytical methods should exist for the primary packaging components for: Extractables Degradation products Unknown foreign substances

Why Control Extractables? Extractables can migrate into the drug product during normal storage (Leachables) and affect product quality and safety to the patient Guarantee the consistency of the device components in terms of: –composition (additives …) –constant levels of extractables Guarantee that the process is under control

Extractables Definition PQRI definition: “Extractables are compounds that can be extracted from Orally Inhaled Nasal Drug Products (OINDP) device components or surfaces of the OINDP container/closure system in the presence of an appropriate solvent(s) and/or condition(s)”

Pump Drawing Ferrule Sealing Gasket Stem Gasket Stem Pre-Compression Spring Piston Spring Cap Return Spring Spring Support Floating Gasket Body Diptube

Valve Drawing 2 nd STEM GASKET BODY UPPER STEM FERRULE LOWER STEM DOSAGE CHAMBER NECK GASKET 1 st STEM GASKET RING SPRING

Components Valves or nasal pumps may contain over 12 components: Stem, turret, thread, piston, spring cap, spring support, body, dip tube, ring (thermoplastics) Neck, stem and floating gaskets (elastomers) Ferrule, precompression spring, spring (metals) Note: Other components are added to the device and include: actuator, insert (pumps), spacer (valves) and container (glass, metal or plastic)

Thermoplastic Materials Polyethylene (PE) Polypropylene (PP) Polybutylene Terephthalate (PBT) Polyacetal / Polyoxymethylene (POM) Polyamide (Nylon)

Potential Extractables from Plastics Chemical additives (antioxidants, stabilizers, plasticizers) Degradation products from additives and polymers By-products from polymerization Residual products from polymerization (oligomers, monomers)

Gasket Materials Butadiene Acrylonitrile Elastomer Polychloroprene Elastomer Butyl Elastomer Ethylene Propylene Diene Monomer (EPDM) Elastomer Thermoplastic Elastomers (TPE)

Main Ingredients in a Rubber Formulation TYPEPRODUCTSFUNCTIONS Elastomer (Raw Material) Nitrile, EPDM, Butyl, Polychloroprene Seal FillersSilica, Aluminum silicate, Carbon black Improve mechanical properties Processing aidsFatty acid / WaxImprove process AntioxidantPhenols / PhosphitesImprove the ageing of the rubber PlasticizerPhtalate Aromatics, paraffinics, naphtenic oils Reduce cost and hardness, improve process Curing agentPeroxide Sulfur Tridimensional structure

Potential Extractables from Elastomers By-products from polymerization (e.g. PNA’s, Nitrosamines, fatty acids, semi-volatiles) Residual products from polymerization (e.g. monomer) Chemical additives such as processing aids (e.g. fatty acids), antioxidants (e.g. semi-volatiles) Degradation products from additives Secondary reaction products from curing (or vulcanization) process (e.g. peroxide)

Metals Stainless steel Aluminum Potential Extractables: Residual cleaning agents Organic surface residues (e.g. oils)

Other Potential Sources of Extractables Processing aids used during assembly process on machinery or component Mould release agents Lubricants Adhesive, glue, ink from labels or secondary packaging

Material Selection Chemical/physical compatibility with drug formulation Mechanical properties => device performance Sealing properties & moisture permeability Regulatory status & extractable profile

Selection of Plastic Materials All plastic materials must be in compliance with existing regulations and pharmacopeia (e.g. relevant 21 CFR chapters) The materials selected from established suppliers should be pharmaceutical or medical grades whenever possible

Selection of Elastomer Materials Regulatory: Elastomer ingredients must comply with existing regulations and pharmacopeia (e.g. relevant 21 CFR chapters). Mechanical: Swelling (potential for swelling if strong affinity with propellant mixture) Mechanical properties + retention of mechanical properties throughout product shelf life (valve shelf life combined with filled inhaler shelf life)

Selection of Elastomer Materials (Cont.) Elastomer materials should be as “clean as possible”: Minimize use of carbon black (known carcinogenic) by using inorganic fillers (e.g. silica) Eliminate plasticizers by using a continuous curing process Preferably use “clean” pharmaceutical grades of gaskets obtained through different treatments (e.g. ethanol extraction) Extractables: elimination of toxics extracts (e.g. PNAs, Nitrosamines)

Controlled Extraction Studies Controlled extraction studies are performed to characterize the extractables profiles. They are done in 3 steps: 1) Obtain as much information as possible from suppliers on the composition of the raw materials and on the manufacturing process 2) Select extraction conditions using multiple solvents (with varying polarities) and extraction techniques. 3) Use of appropriate analytical techniques (with appropriate sensitivity).

Typical Method Grind sample Weigh sample Extract sample in a solvent using very aggressive conditions to maximize extractables levels Collect extract Concentrate extract Reconstitute extract into a fixed volume of mobile phase Analyze extract

Solvents of various polarities Methylene chloride Water Isopropanol Hexane Ethanol (MDI’s) Etc…

Extraction Parameters Sample preparation: grinding, compression (film) Extraction techniques: accelerated solvent extractor, microwave, reflux, soxhlet, sonication Extraction Volume, Time and Temperature Evaporation step

Analytical Techniques UV-spectrophotometry (e.g. formaldehyde) HPLC-UV (plastics and fatty acid quantification) HPLC-ELS (non-chromophoric analytes) HPLC-MS (identification and quantification) GC-FID (semi-volatiles quantification) GC-MS (identification and quantification) GC-NPD (e.g. acrylonitrile) GC-TEA (e.g. nitrosamines) Atomic Spectroscopy (Absorption)

Controlled Extraction Studies Extraction techniques should be optimized to maximize extract levels Analytical methods should be validated to meet ICH and FDA Guidelines

Routine Extractables Testing A systematic control of extractables should be performed for the critical components (or the raw material provided that a correlation can be established between the two). The extraction and analytical methods should be based on the controlled extraction studies: The extraction should be done using very aggressive conditions (solvent, technique) to maximize extracts levels. The analytical method should be validated and the sensitivity appropriate.

Example: Routine Extractables Testing on Plastics The analysis of extractables in plastics is done by reverse phase HPLC-UV. Example of additives investigated: Irganox 1010 Irganox 1076 Irganox 245 Irganox 259 BHT Irgafos 168 Oleamide

Routine Extractables - Plastics A calibration solution contains all the tested additives. Extraction procedure: Samples are ground to a fine powder (can be done from plastic beads or molded components) Extraction is done under reflux using suitable solvent identified for each type of material (e.g. Methylene Chloride, Chloroform, etc) The procedure is optimized so that the extractable levels measured is representative of the RM composition.

Extractables Specifications Specifications are established for each material based on:  Extractables profiles from multiple lots of raw material  Extractables profiles from molded components (try to correlate levels in the components to the corresponding lots of raw material)  Limits are set for each extractable  A specification (reporting limit) is also set for unknowns at the LOQ of the method

Conclusion Timeline and Cost for Extractables and Leachables programs depends mainly on: Choice of packaging materials Extracting power of formulation Cooperation with device supplier Making the right choice of materials and starting the program early enough are key factors in minimizing costs and duration

Questions ?