Analytical Challenges in Implementing Effective QC/Stability testing of 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 (pMDI or simply MDI) • HFA propellant Driven § Dry Inhaler (DPI) • Patient driven § • Aerosolizes for constant delivery § Nasal Spray • or powder delivery to nasal cavity

3 Regulatory Guidance

FDA Guidances § Guidance for Container Closure Systems for Packaging Human and Biologics (1999) § Reviewers Guidance for , Metered Dose , Spacers and Actuators (1993) § Metered Dose Inhalers (MDI) and Dry Powder Inhalers (DPI) (revised 2018) § Nasal Spray and Inhalers , , 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 — 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 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 – , 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/ recommends 0.15 µg/day for inhalation products § Only applies to unknowns

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 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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