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 § DPI – for capsules devices § Nebules – lamented foil pouches is a common source
30 What Are the Sources?
Primary Packaging Components
Secondary Packaging Components
Dosing Components § pMDI actuators/spacers are typically not potential source § Nebulizers
31 “The Dose Makes the Poison.”1
No direct regulatory guidance available § Genotox Guidance - 1.5 µg/day Safety Concern Threshold (SCT) § Level below which there is negligible risk associated with the toxicity of the compound based upon dosing § Presented as a Total Daily Intake (TDI): usually in µg/day § PQRI/
1Paracelcus
32 Typical Extractables Program
Asymptotic Extractions with a minimum of three solvents § Solvents should cover polarity and pH (if applicable) range of the DP § Vigorous Extraction technique: Soxhlet, Reflux, Sonication, Microwave, etc § Don’t get TOO aggressive § Extraction data for inhalation components are expected in NDA filings.
Multiple Analytical Techniques § HPLC – Semi-Volatiles and Non-Volatiles § GC – Volatiles § ICP – For metals (USP 232/233 – ICH Q3D) § Special Case Extractables • Poly-aromatic Hydrocarbons (PAH’s) • Nitrosamines • 2-mercaptobenzothiazole
33 Leachable Method Development
Typically more complex than typical impurity methods § Complex sample preps § MS vs. UV detection Use extractables profile to aid in development § Ensures all potential leachables are monitored Quantitation limit to monitor for unknowns § 10-100X lower than typical impurity levels § Matrix interferences are typical Internal vs. External Standard Validated per ICH § Must be validated for specific drug product formulation
34 Stability Storage Configuration
Orientation used should represent possible contact § Upright and inverted typical for MDI • Sometimes sideways § Evaluate based on all possible contact orientations
Primary packaging with labels § Inks/dyes are a well known source of leachables
Secondary packaging § Required if primary packaging permeable/semi-permeable § Common source for nebules and blow-fill-seal (BFS) products
35 Leachable Stability
Leachables above reporting (AET) level § Need to be identified § Toxicological evaluations
Extractable – Leachable Correlation § Relate level of leachable to extractable level § Reduced testing possible if can control at extractable testing • Extractable level of 30 µg equates to 2 µg leachable
36 PMDI Case study 1
pMDI device: § Polymer lined canister § Metering valve (5 different materials) § 1.1 ug/canister reporting level
Extraction of components resulted in 150 identified extractables
Analysis of aged samples demonstrated 75 leachables above reporting level § 2 of the found leachables were not detected in original extraction study § Instituted 5 control methods required for release and stability testing
37 Conclusions
§ Inhalation testing can be challenging § Performance aspects of the testing presents challenges not typically encountered with other dosage forms § Requires understanding variables in order to develop robust method • Do early in the process § Method used should be targeted to your specific drug product • Technique used for one does not automatically mean it is the best for a different product § E&L for inhalation is the most challenging of any dosage form and often one of the most problematic of any test
38 Contact Us
Please send any additional questions to
Wayland Rushing at [email protected]
Web site: https://www.eurofinsus.com/bpt
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