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7.Inhalation Testing

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7.Inhalation Testing Analytical Challenges in Implementing Effective QC/Stability testing of Inhalation Drug Products Wayland Rushing, Ph.D. Director, Scientific Affairs Eurofins BioPharma Product Testing www.Eurofins.com Inhalation Overview Delivery of one or more drug products to the lungs or nasal mucosa Benefits: § Directly targets the lungs § Rapid onset of drug action • Quick absorption into bloodstream § Low doses required § Fewer side effects 2 Drug/Device Combination Devices Orally Inhaled and Nasal Drug Products (OINDP) § Metered Dose Inhaler (pMDI or simply MDI) • HFA propellant Driven § Dry Powder Inhaler (DPI) • Patient driven § Nebulizer • Aerosolizes solutions for constant delivery § Nasal Spray • Liquid or powder delivery to nasal cavity 3 Regulatory Guidance FDA Guidances § Guidance for Container Closure Systems for Packaging Human Drugs and Biologics (1999) § Reviewers Guidance for Nebulizers, Metered Dose Inhalers, Spacers and Actuators (1993) § Metered Dose Inhalers (MDI) and Dry Powder Inhalers (DPI) (revised 2018) § Nasal Spray and Inhalers Solution, Suspension, and Spray Drug Products (2002) § Drug Products Packaged in Semipermeable Container Closure Systems (2002) USP Chapters § USP <5>: Inhalation and Nasal Drug Products—General Information and Product Quality Tests § USP <601>: Inhalation and Nasal Drug Products: Aerosols, Sprays, and Powders— Performance Quality Tests § USP <1602>: Spacers and Valved Holding Chambers Used with Inhalation Aerosols— Characterization Tests § USP <1664.1>: Orally Inhaled and Nasal Drug Products 4 Revise 2018 FDA Guidance – CQA’s § Delivered drug purity CQAs: • Impurities and degradants of the drug substance and excipients • Foreign particulate matter • Leachables § Targeted delivered dose (product strength) CQAs: • Assay • Metered dose • Net content 5 Revise 2018 FDA Guidance – CQA’s § Aerodynamic Performance CQAs (MDI): • Delivered dose • Particle size distribution • Spray pattern • Moisture content • Net content • Device constituent part CQAs • Drug substance CQAs 6 Typical Inhalation Tests § Appearance § Particle/Droplet size distribution § DS/DP impurities § Content uniformity § Foreign particulate matter § Through-Life uniformity § Leachables § Water content § Ethanol content § Spray pattern § Elemental impurities Component testing: § Total can assay § Dimensional testing § Dose delivery § Extractables testing § Fill weight § Leakage rate § Valve delivery 7 Analytical Method Challenges § Chemical Tests • Sample preparation challenges • Low active present • Low quantitation levels (Leachables) § Performance Tests • Device specific requirements – Custom fittings – Custom designs § Human Factors • Training • Reproducibility • Robustness 8 Sample Preparation - pMDI How to sample inside the canister? § Frozen sampling • Freezing down the canister with Nitrogen • Allowing to thaw and then rinsing § Venting • Using a venting tool to pierce the canister to slowly allow propellant to vent 9 Case Study – Venting vs. Thawing Frozen Vented Imp A 1.5 ND Imp B 2 0.3 Imp C 1.1 1.2 Imp D 0.75 0.8 The vented sample preparation resulted in Imp A and B being lost due to volatilization. Could be controlled with slower venting but variable results. 10 Sample Preparation - Chemical Multiple Sampling Techniques § De-crimping Can • De-crimping can lead to contamination – Shredding valve – Metal contamination • De-crimpers are notoriously problematic § Cutting Can • Use a tube cutter after can is vented/frozen to open • Metal contamination • Allows for easy sample retrieval 11 Case Study - Leachables Replicate Decrimping Cut 1 10 12 2 20 10 3 10 11 Source of variance was found that silicone was residing within the valve, not coming into contact with the product during normal storage, but sampling technique artificially increased the results. 12 Foreign Particulate Matter Required test, but USP and guidance documents do no dictate technique or specifications How to perform testing will depend on a number of factors: § Formulation components § pMDI vs. DPI vs. Nebules § Therapeutic site § Formulation state (i.e. powder, solutions, suspensions) 13 Foreign Particulate Matter What are your particles § Identify the range of particles § Numerous techniques possible • Raman microscopy • FTIR microscopy • SEM-EDX Identification of the particles § Toxicological evaluation § Source Identification and possible control 14 Foreign Particulate Matter Sampling Technique § Sample extraction • Collected from formulation – Formulation dissolved in solvent if needed – Finding the appropriate solvent can prove challenging • Pros – Relatively easy to implement – Can be more reproducible – less prone to error § Delivered dose • Collected from “delivered” product – “Real world” sample – Modified DDU method (i.e. actuated, nebulized, etc) • Requires specialized equipment • Higher sKill set – More prone to analyst errors 15 Foreign Particulate Matter Analysis Technique § Light Obscuration • Particle counting – similar to USP <788> • Pros – Common instrumentation – Preferred technique § Microscopy • Sample collected on filter paper • Automated analysis vs manual – Automated requires specialized equipment and software • Can have higher errors at the lower particle size range 16 Droplet Size Distribution § Laser Diffraction • Measures droplet sizes by laser diffraction in aerosol • Technique recommended by FDA guidance for Nasal Sprays and aerosol delivery systems for BE § Impaction • Determines droplet size based on aerodynamic performance in relation to varying filter sizes • Preferred method for pMDI and DPI 17 Aerodynamic Particle Size Distribution Andersen Cascade Impactor (ACI) § Historical technique Next Generation Cascade Impactor (NGI) § Newest design – most popular for new devices 18 Variables of the Methods § Flow rate § # of actuations § Flow profile § Wall loss § Adaptor § Recovery techniques § Actuation angle § Environmental conditions § Actuation speed § Plate coating § Actuation timing § Sample analysis technique § Actuation force § Actuation hold § Shaking technique § Priming 19 “Breadth” Timing § Comparison of flow timing 4.5s vs 6.5s § Formulation dependent Component/ 4.5 6.5 Stage Stem (Valve) 5.44 3.74 Actuator/Spacer 69.37 61.48 Throat 5.80 3.17 Jet (Stage 0) 0.02 0.04 Plate 0 0.98 0.81 Plate 1 0.65 0.58 Plate 2 0.59 0.75 Plate 3 3.02 3.41 Plate 4 11.75 15.30 Plate 5 22.28 29.75 Plate 6 10.47 14.41 Plate 7 4.81 5.56 Filter 2.40 4.71 Total Flunisolide hemihydrate PAST 62.77 78.49 Actuator (µg) Total Flunisolide 137.58 143.71 hemihydrate (µg) % µg for components 87.1 93.2 < 4.7 µm 20 Actuation Angle § Adaptor allows for minor altering of angle § Critical parameters for analyst training and periodic checking Off angle Correct angle Stem (Valve) 2.14 3.74 Actuator/Spacer 64.37 61.48 Throat 40.46 3.17 Jet (Stage 0) 0.08 0.04 Plate 0 0.79 0.81 Plate 1 0.53 0.58 Plate 2 0.63 0.75 Plate 3 1.12 3.41 Plate 4 5.08 15.3 Plate 5 12.72 27.75 Plate 6 8.13 14.41 Plate 7 2.31 5.56 Filter 1.71 4.71 Total Flunisolide hemihydrate PAST 73.56 76.49 Actuator (µg) Total Flunisolide 140.07 141.71 hemihydrate (µg) 21 Delivered Dose Uniformity (DDU) Delivered/Emitted dose • Total amount of drug delivered by the device to the patient • Uniformity measured between devices and through-life • Performed by using DUSA1 • Dosage Unit Sampling Apparatus 1Image from Copley Scientific, Quality Solutions for Inhaler Testing, Page 19 22 DDU Method Variables § Adaptor § Actuation speed § Actuation timing § Shaking technique § Priming § Recovery techniques § Sample analysis technique 23 DDU Common Issues § Tube deformations § Incomplete sealing § Blowback 24 Spray Pattern Device is placed a known distance from a measuring methodology § Measures the spray’s pattern as it emerges from the device § Optical methodology • Uses laser/optics to measure the spray pattern as emitted • Requires highly specialized equipment § TLC plate • Product sprayed onto TLC place • Dye/Fluorescence used to determine properties • Preferred method for NDA filings 25 Spray Pattern § Drying Time • Variance between 10 to 30 minutes • Too short leads to false measurements • Solvent interference § Developing Solutions • Staining techniques can often react with drug product • can obscure fine details 26 Extractable vs. Leachable Degradant § An impurity resulting from a chemical change in the drug substance…(ICH Q3B) Extractable Extractable § Compounds which under aggressive laboratory conditions can migrate our of materials Leachable Leachable § Normally a subset of extractables § Compounds which migrate into the drug product Extractable ≠ Leachable § Extractables don’t always leach § Leachables don’t always extract 27 Best Practices/Compendia PQRI § Safety Thresholds and Best Practices for Extractables and Leachables in Orally inhaled and Nasal Drug Products (September 2006) USP § <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems § <1664> Assessment of Drug Product Leachables Associated with the Pharmaceutical Packaging/Delivery System § <1664.1> Orally Inhaled and Nasal Drug Products FDA § Metered Dose Inhalers (MDI) and Dry Powder Inhalers (DPI) (revised 2018) • Qualitative and Quantitative extractables data on components • Data for leachables 28 What Are the Sources? Primary Packaging Components § pMDI – Canister, Valve § DPI – Capsule, Foil pouches, Reservoir § Nasal Sprays – Housing, Stopper § Nebules – Bottle, BFS 29 What Are the Sources? Primary Packaging Components Secondary Packaging Components § pMDI – rarely ever considered §
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