Developing Droplet Size Test Methods in Nasal Sprays Products: How can the stable phase of the spray be selected and identified reliably?

Transcription

1 Developing Droplet Size Test Methods in Nasal Sprays Products: How can the stable phase of the spray be selected and identified reliably? Guillaume BROUET, Valois SAS

2 Background Spray Characterization has become a standard test to perform on Nasal Spray products and devices New approaches towards the analysis of droplet size have been proposed by the regulatory agency (Food and Drug Administration) New equipments have been made available (software & hardware) and now provide new opportunities to optimize test methods

3 Nasal spray devices Multi-dose spray pumps Mechanical type device Are used to dispense usually aqueous based formulations Dispense typically l Produce droplets typically in the m range Produce a very small number of fine (< 10 m) droplets

4 Nasal actuator technology Swirl chamber External insert technology Internal insert technology

5 Other factors that influence spray characteristics Pressure Density Viscosity Surface tension Spray angle Drop size Velocity

6 Spray characterization Clinical relevance? Process control tool for components Relevant parameter to control?

7 Spray Characterization Tests Test Apparatus Results Droplet size distribution Laser diffraction instrument Representative diameters Plume Geometry - Laser light sheet - High speed video Spray pattern - Specific stand (w or wo TLC plate) - Laser sheet - Spray cone angle ( ), - Plume shape - Pattern shape (circularity) - Pattern size

8 Droplet Size Testing Characterizes droplets emitted by Nasal Spray Devices Typically requires use of an automatic actuating machine: Pneumatic Electrical Can be performed to measure Geometric diameter (laser diffraction) Aerodynamic diameter (impaction technique)

9 Droplet Size Testing Critical parameters for Laser Diffraction Test: Selection of actuation machine Position of the nozzle with respect to the laser/lens Orientation of the nozzle Instrument set-up /parameters Use of an exhaust system

10 Laser diffraction apparatus set-up % Transmission (% T) is defined as the % of laser light that does not get diffracted %T Represents density of droplets in the measurement zone

11 Representative diameters Diameters typically calculated from a volume based distribution: D(v, 0.1); units in m droplet diameter such that 10% of the total liquid volume consists of droplets of smaller diameter D(v, 0.5); units in m droplet diameter such that 50% of the total liquid volume consists of droplets of smaller diameter D(v, 0.9); units in m droplet diameter such that 90% of the total liquid volume consists of droplets of smaller diameter

12 Typical spray profile for a 50 l pump (generated with the Spraytec from Malvern Instruments) % Transmission Formation phase Stable phase Dissipation phase

13 Typical droplet size distribution Equadel 120 l (Valois latest nasal spray) actuated at high speed using an NSP machine from InnovaSystems: Volume (%) Volume (%) Dose time: 10 msec Force: 60 N Diameter (µm) Diametre des Particules (µm.) D(v, 0.1) D(v, 0.5) D(v, 0.9) Mean SD

14 FDA requirement for Droplet Size Testing The sponsor s protocol would state the criterion selecting the region of the plateau at which droplet size data will be determined (e.g. the average of all scans over the entire plateau, the data of a single scan only at minimum % transmission or the average of a specified number of scans around this % transmission) Ref: BA & BE studies for nasal aerosol and nasal sprays for local action, April 2003

15 FDA requirement for Droplet Size Testing Identification of the stable phase of the spray: Technique Advantage Disadvantage Manual selection Selection of a transmission window Selection of a time window Enables selection of the largest number of scans (large sampling) - Easy to put in place - Eliminates subjectivity - Eliminates subjectivity - Strictly complies with FDA guidance document Subjective and not practical in a QC environment May lead to eliminating valid data (scans) Requires a good understanding of duration of the stable phase

16 Understanding the duration of (the stable phase of) the spray May potentially be influenced by: Delivered volume Choice of automatic actuating machine Actuation speed Liquid type Transmission window selected Laser diffraction instrument set-up

17 1/ Selection of transmission window Objective: Reduce variability & better select the stable phase of spray Position of the cut-off transmission window (e.g. 85%)

18 1/ Selection of transmission window Reduce cut-off %T and evaluate impact on variability of D(v, 0.9) (most sensitive and variable diameter) Evolution of D90 as a function of cut off T% VP3 pump tested with water (manual actuation) Microns 180,0 160,0 140,0 120,0 100,0 80,0 60,0 40,0 20,0 0,0 Mean D(v, 0.9) S.D (D(v, 0.9) Test at 93% T Test at 90% T Test at 85% T Test at 80% T Test at 75% T

19 1/ Selection of transmission window Disadvantage: potential for reducing the size of the sample Number of measurements Number of measurements taken at different transmission filters VP3 pump tested with water (manual actuation) % transmission nombre de mesure 80% nombre de mesure 85% nombre de mesure 93%

20 1/ Selection of transmission window Evaluation of the # of scans measured through multiple pump lots (VP3 pumps tested with water and manually actuated): 60 # of scans measured at 85% cut-off 50 # of scans Lot #

21 2/ Selection of a time window Influence of the delivered volume and spray cone angle: 1) Delivered volume: Analysis of VP7 50 l and 100 l pumps actuated manually: Recording of the duration of the spray Recording of the representative diameters 2) Spray cone angle: Analysis of VP3 100 l pumps using CB18 actuators that produce narrow vs. wide spray cone angle Recording of the duration of the spray Recording of the representative diameters

22 2/ Selection of a time window In all experiments conducted, the stable phase of the spray is selected manually as shown below: Stable portion (manually selection)

23 Influence of delivered volume Impact on spray duration and droplet size: (manual actuation) Influence of delivered volume on spray duration and droplet size # of scans # of scans D(v, 0.5) VP7/ 50 VP7/ 100

24 Influence of spray cone angle Impact on spray duration and droplet size: (manual actuation) Influence of spray cone angle on spray duration and droplet size # of scans # of scans D(v, 0.5) 50 0 VP3 narrow angle VP3 wide angle

25 Selection of a time window Influence of the use of an automatic actuating machine: Analysis of a VP7/50 pump actuated manually or using the NSx from Image Therm Engineering or the mighty runt from InnovaSystems: Actuation machine None (manual) NSx (electrical) NSx (electrical) NSx (electrical) NSx (electrical) Mighty Runt (pneumatic) Mighty Runt (pneumatic) Mighty Runt (pneumatic) Parameters N/A 40 mm /sec 60 mm/sec 70 mm/sec 80 mm/sec 4 Kg, 0.2 sec 5 Kg, 0.3 sec 6 Kg, 0.3 sec

26 Influence of actuation parameters VP7/50 (pre-compression) pump Duration of the stable phase of the spray (n = 3) # of scans Manual NSx 40 mm/sec NSx 60 mm/sec NSx 70 mm/sec NSx 80 mm/sec Mighty Runt 4 KG, 0.2 sec Mighty Runt 5 KG, 0.3 sec Mighty Runt 6 KG, 0.3 sec

27 Influence of actuation parameters VP7/50 (pre-compression) pump Influence of actuation profile on D(v, 0.5) D(v, 0.5) ( m) Manual NSx 40 mm/sec NSx 60 mm/sec NSx 70 mm/sec NSx 80 mm/sec Mighty Runt 4 KG, 0.2 sec Mighty Runt 5 KG, 0.3 sec Mighty Runt 6 KG, 0.3 sec

28 Preliminary conclusion The stable phase of the spray appears to be primarily affected by: Delivered volume (no surprise) Actuation speed for electrical automatic actuating machine The influence of spray cone angle and actuation parameters on a pneumatic machine do not appear to be very significant

29 Influence of actuation parameters Case of the Equadel pump: user/patient independent by design Less influence of actuation parameter is expected with Equadel Spray performance as well as spray duration are expected to be user / actuation profile independent Appropriate selection of a time window in Droplet Size Measurement likely to be facilitated when device to be used is less user dependent

30 Equadel: : Design and principle of function 8 mm 7.5 mm 1.5 mm Pre-Compression and Compression From 0 to ~ 30 N Spray ~ 30 N

31 20 Droplet size measured with Equadel at different actuation speeds (water data): Volume (%) Volume (%) Volume (%) Volume (%) Diametre des Particules (µm.) Diameter (µm) D(v, 0.1) D(v, 0.5) D(v, 0.9) Mean SD High Speed Actuation Dose time: 10 msec Force: 60 N Diameter (µm) Diametre des Particules (µm.) D(v, 0.1) D(v, 0.5) D(v, 0.9) Mean SD Low Speed Actuation Dose time: 30 msec Force: 30 N 10 0

32 Spray performance of Equadel at different actuation speeds Plume geometry testing (measurement of spray cone angle) at different actuation speeds: 25 mm/s 35mm /s 50 mm/s 60 mm/s Machine type NSX (ITE) Acceleration: 1000mm/s² Hold time :0.3s Camera CCD 500 image/s Product: Water

33 Influence of actuation parameters (Equadel 120 l) Duration of the stable phase of the spray (n=3) # of scans Manual NSx 40 mm/sec NSx 60 mm/sec NSx 80 mm/sec Mighty Runt 4 KG, 0.2 sec Mighty Runt 5 KG, 0.3 sec Mighty Runt 6 KG, 0.3 sec

34 Conclusion The understanding of the time profile is critical when developing a robust droplet size test method This profile can be affected by a number of parameters among which the most critical (actuation speed and delivered volume) should be easy to control when running batch release testing The selection of a time window should therefore be appropriate when designing such a method The sensitivity/variability of the time profile will depend on the type of device used

35 Acknowledgements Paul Kippax, Malvern Instruments Julie Suman, Next Breath LLC.