Lessons Learned from Approval of Generic Nasal ProductsJulie D. Suman, Ph.DPresident, Next Breath

IPAC-RS/UF Orlando Inhalation Conference: Approaches in International Regulation

March 20, 2014

ObjectivesIn Vitro Bioequivalence

Challenges

Improving probablity of success

Global regulatory requirements

What parameters are relevant?

In Vitro

In Vivo

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Approved US Generic Nasal Sprays

3Locally Acting SuspensionsLocally Acting

SolutionsSystemicSolutions

Approaches for Bioequivalence Clinical endpoint Same as a clinical studyMeasure survival rate

Pharmacodynamic (PD) endpointMore sensitive than a clinical studyMeasure lipid lowering

Pharmacokinetic (PK)

In Vitro Tests SE

NS

ITIV

TY T

O D

ETE

CT

DIF

FER

EN

CE

S

In Vitro BE Statistical Analysis Per FDA GuidanceIn Vitro Test Statistical Process

Single Actuation Content Uniformity• Drug mass per actuation

Population Bioequivalence (PBE)

Droplet Size• Dv50• Span

PBE

Spray Pattern• Ovality Ratio• Area

PBE

Plume Geometry• Width• Angle

Point Estimate

Particle Size by Microscopy N/A

Drug in Small Particles by CascadeImpaction (Sprays)

Comparison of means by PBE

Prime Reprime Point Estimate

Spray Pattern (SprayVIEW,

Proveris Scientific)

Approaches for Increasing Success for In Vitro BE

Evaluate RLD and Test during method development

Perform pre-screening studies

Avoid the temptation to compare averages and standard deviations to judge equivalence

Sample variance is factored into the PBE equation

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Droplet Size (Dv50) Method Comparison

Spray Pattern (Area) Method Comparison

Pre-BE StudiesInvestigate likely hood of a successful outcome

KEY TEST METRICS

Innovator and Generic Pumps tested with Innovator formulation

Hand study determined actuation parameters

All units acutated using Proveris Scientific platform

Droplet size (DSD) measured at beginning and end of unit life using a Malvern Spraytec

Spray pattern (SP) meaured using SprayVIEW

Plume geometry (PG) measured using SprayVIEW

Statistical analysis by population bioequivalence (PBE) and point estimates

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IN VITRO BIOEQUIVALENCE: INNOVATOR VS GENERIC RESULTS

All results show as average of 15 bottles

IN VITRO BIOEQUIVALENCE SUMMARYDSD - 3 cm DSD - 6 cm SP - 3 cm SP - 6 cm PG

Dv50 (µm) Span Dv50 (µm) Span Ovality Ratio Area (mm2) Ovality Ratio Area (mm2) Plume Angle Plume WidthInnovator Yes Yes Yes Yes Yes Yes Yes Yes Yes YesGeneric

Outcome of Population Bioequivalence (PBE) Statistics reported for Beginning of Life (BOL) and End of Life (EOL)

Average Spray Pattern ResultsDmax (mm) Dmin (mm) Ovality Ratio Area (mm2)

3 cm 6 cm 3 cm 6 cm 3 cm 6 cm 3 cm 6 cmInnovator 21.2 34.6 25.4 47.1 1.204 1.364 437.5 1297.7

Generic 21.1 35.9 24.8 43.5 1.181 1.200 418.4 1252.8

Innovator GenericSpray Angle (°) 51.0 52.0Plume Width (mm) 28.9 29.3

020406080

100120

Dv10 Dv50 Dv90

Mic

rons

Droplet Size Distribution - 3 cm

InnovatorGeneric

020406080

100120

Dv10 Dv50 Dv90

Mic

rons

Droplet Size Distribution - 6 cm

InnovatorGeneric

In Vitro BE Across Regulatory BodiesFDA Brazil (ANVISA) EMA

Droplet Size Droplet Size Droplet Size officially

Single Actuation Content Uniformity

Single Actuation Content Uniformity

Other in vitro tests appear to be used

Spray Pattern Spray PatternPrime Reprime Prime ReprimeParticle Size Number of Metered

Doses

Plume Geometry Pump DeliveryParticles < 10µm

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FDA and Brazil Generic PathwaysAgency Bioequivalence

(BE)Pharmaceutical

Equivalence (PE)

FDA In Vivo and/orIn Vitro Definition does not exist

ANVISA In Vivo In Vitro

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In VitroPlume Geometry

In Vivo Pharmacokinetics (PK)

In Vivo Clinical Endpoint

Brazil PE TestsIn Vitro Test Metric for Statistics Similarity to FDA BEContents of an actuation on the total contents of the device (single actuation content uniformity)

Mass (µg) of drug Same

Dose mass (pump delivery)

Spray weight (mg)No stats Not required

Droplet size distribution D50Span Same

Spray pattern OvalityArea Same

Number of doses CountNo stats Not required

Load and reload(prime and reprime)

Mass of drugNo statsMeet 95-105% LC

Three orientations required not oneStats required

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Which In Vitro Parameters are Relevant for BE?

Hardy, et. al. J. Pharm. Pharmacol., 1985

Initial 30 mins

Spray

1 Drop

3 Drops

Desmopressin PK Profile

0

200

400

600

800

0 100 200 300 400

minutes

Des

mop

ress

in (u

g/m

l

Spray Pumps: 100uL 200 uLNasal Drops: catheter pipet

*adapted from Harris, et al., J. Pharm. Sci. 1986

Desmopressin PD Profile

*adapted from Harris, et al., J. Pharm. Sci. 1986

0

100

200

300

400

0 100 200 300 400

minutes

Fact

or V

III

Spray Pumps: 100uL 200 uLNasal Drops: catheter pipet

Nasal Deposition and Biological Response

Harris compared plasma levels, biological response and deposition pattern of 99mTc- labelled desmopressin delivered by aqueous spray pump and nasal drops

Biological response was found to be a function of deposition pattern and clearance within the nasal cavity

Harris, et. al., Intranasal Administration of Peptides: Nasal Deposition, Biological Response & Absorption of Desmopressin. J. Pharm. Sci., 75(11) 1986

Plume Angle as a Function of Viscosity by Nasal Casts

Deposition patterns of Afrin, Ayr and Zicam (Insertion depth = 5 mm; Spray angle = 45°)

Deposition area decreases with increase in viscosity

Kundoor V, Dalby RN. Pharm Res. 2011 Aug;28(8):1895-904. Epub 2011 Apr 16.Effect of formulation- and administration-related variables on deposition pattern of nasal spray pumps evaluated using a nasal cast.

Droplet Deposition Images

Spray Pump Nasal NebulizerNasal Spray Dv50 = 70µm

Pressurized Nasal Sprays

Switch from CFC to HFA-134a

Use in patients with runny nose

Slower clearance

Deposition primarily in anterior regions for HFA due to exit velocity

020406080

100

0 10 20 30Time (minutes)

% R

etai

ned

in N

ose Nasal

pMDI

Aqueous spray pump

Redrawn from Newman, S.P. et al., J. Laryngol. Otol., 1987

Particle SizeDroplets dictates deposition pattern

What happens to the suspended drug particles?Clearance

- Mucociliary action- Physical removalDissolution and uptake

into cellsParticle size dictates

dissolution rate

- PRESENTATION TITLE - DATE21

Dissolution Modified Transwell Method*• 25 mm Transwell® system was

used. The polycarbonate membrane was replaced by glass microfiber filter eliminated the role of diffusion as the rate limiting step.

• Stirring was incorporated into the system to expedite the dissolution.

• A surfactant, like SDS, was included in the media for the in vitro dissolution of hydrophobic drugs and in order to get a dissolution rate that is comparable to the in vivo absorption.

*Guenther Hochhaus, ISAM, 2013

25 mm Transwell® system

Modified Transwell Method*• Samples were collected from the receptor compartment at specific time 

intervals and analysed for drug content.• A Weibull model was fitted to the data and the T63 for each set was 

compared.%Dissolved = 100 [1−exp−(t/T63)ßT63 ‐ Time required to dissolve 63% of the drugß ‐ Shape factor

*Guenther Hochhaus, ISAM, 2013

Fluticasone Propionate DissolutionMDI spray – DUSA tube @ 28.3 L/minNasal spray – tip @ 4-5 cm from filterDPI spray – DUSA tube @ 30 L/min

No. of replicates T63 (hours) Average amount (mcg)

FP MDI 4 16.98 99 

FP DPI 3 4.64 42.43

FP NS 4 12.94 30.21

Dv10 (µm)

Dv50 (µm)

Dv90 (µm)

% Aggregate

FP DPI 2.0 3.3 5.4 27%

FP NS 3.2 4.1 5.7 36%

Presented by Next Breath and Malvern Instruments, RDD Europe 2013

Corticosteorid DissolutionQ2

Average Beclomethasone Dipropionate (BDP) Particle Size (µm)

Formula Dv10 Dv50 Dv90

M1 0.59 3.35 17.37

M2 0.53 2.80 7.79

M3 0.50 2.13 5.29

Dissolution rate the same for all BDP particle sizes

No statistical differences in cellular uptake 

→Predict no sta s cal difference in local responseJin et al., RDD, 2010, vol 3, pp 839‐842.Benniger, Otolaryngol Head Neck Surg, 2003, vol 129, pp 739‐750.

Corticosteroid Bioavailability (%) IntranasaladministrationMometasone furoate <1Beclomethasone dipropionate 44

What leads to clinical differences?

Droplet Size

Droplet Velocity

Formulation

Particle Size

Plume Geometry?

Plume geometry (Proveris Scientific)

Nasal Spray Dv50 = 70µm

Nasal Nebulizer

Dv50 = 6µm

FDA Nasal Spray BE RequirementsLocally Acting Solution In vitro only

Systemically Acting SolutionNew guidances for Sprix

and Imitrex In vivo: if not qualitatively

(Q1) and quantitatively (Q2) the same

OR In vitro: Q1 and Q2

Suspensions In vivo

- Clinical endpoint to assess local delivery +

- Clinical endpoint to assess systemic exposure

OR- Clinical endpoint +- PK study for systemic

exposure

AND In vitro

Nasal Spray Generic Requirements

BrazilAll solution and

suspension nasal sprays

In Vitro (PE) AND

In Vivo (BE)- PK ONLY

EMA In Vitro

In Vivo - PK- PD or Clinical Endpoint

Is stepwise approach available to nasal sprays?

What In Vivo Studies are Relevant for Locally Acting Nasal Sprays?

US Locally efficacy

- Clinical endpoint or PD

Safety- Systemic exposure (PK)

BrazilPK only

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What In Vivo Studies are Relevant for Locally Acting Nasal Sprays?Pharmacodynamic studies or clinical endpoint studies to document equivalence of action at the local site is difficult because ICS have relatively flat dose-response curves on clinical endpoints” Advisory Committee for

Pharmaceutical Science and Clinical Pharmacology, FDA, CDER, July 23, 2008

Issues with PD

Less sensitive/high variability

Top of dose response curve

Is PK enough for locally acting nasal sprays?

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Slide courtesy of Günther Hocchaus

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Slide courtesy of Günther Hocchaus

ConclusionsDo your homework on in vitro tests especially spray pattern

What’s neededAdditional understanding is needed on dissolution

including technique usedCorrelations between key in vitro parameters and

in vivo performanceCan PK with or without charcoal block be used in

lieu of PD?

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Thank you for your attention!

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