CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-450
`
`CLINICAL PHARMACOLOGY AND
`
`BIOPHARMACEUTICS REVIEW! S 2
`
`
`
`

`

`CLINICAL PHARMACOLOGYIBIOPHARMACEUTICS REVIEW
`
`DRUG: Zomig ® (Zolmitriptan)
`NDA: 21-450
`
`PRIMARY REVIEWER: Andre Jackson
`TYPE: NDA Amendment
`
`FORMULATION: Nasal Spray
`APPLICANT: Astra Zeneca
`
`STRENGTH: 0.5 , 2.5 , 5.0 mg
`SUBMISSION DATE: Nov 11, 2002
`
`INDICATION: Migraine Headache
`Generic Name: Zolmitriptan
`SIKDDY IUEEDHDMIHEP
`
`The firm has submitted an amendment to their NDA 21-450 to address
`
`
`5.0 mg nasal
`deficiencies in the in vitro data for their
`sprays. There was no new data in the submission only the firm's re—
`interpretation of the previously submitted data.
`
`The major points made were:
`1.The firm takes exception to the particle size distribution data at the -‘—‘
`'—-n———“——————*"—*———*”-—————————— . They state that --r is the
`industry standard. At the present time this can not be confirmed. Literature
`for the '————-*. pump used in their studies recommend standard operating
`procedures for testing droplet size distribution (BSD) by
`fl.————————’
`when using the *
`._————-——~——--—*—
`(the most common brand, at least in
`
`the US).
`7
`(for a unit dose system. and for two multidose pumps)
`W The problem i s
`that the firm did not use an —-—._..—«
`so it is difficult to
`validate their argument.
`
`2.The firm also contends that differences in span measurements would not
`
`effect the delivery of the spray since they maintain a routine specification
`that not more than
`of droplets below »—-——are contained in the product.
`I: W:
`
`3.The firm also argues that plume geometry and spray pattern are also not
`meaningful since the limited volume of the nasal cavity does not allow the
`plume to fully develop. This may also be true, but spray pattern and plume
`geometry analysis are current in vitro requirements for nasal sprays.
`
`Therefore the arguments presented by the firm provide no compelling new
`evidence to support the in vitro equivalence of the commercial device to the
`clinical device.
`
`Andre Jackson
`
`RD/FT Initialed by Raman Baweja, Ph.D.
`CcNDA 21450, RFD—120, HFD—BGO{Jackson,Baweja,Mehta), Central Documents Room
`(Biopharm—CDR)
`
`
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`mummnmnuMu—mmoafln—tmnmn-n———
`
`Andre Jackson
`12/2/02 12:22:43 PM
`BIOPHARMACEUTICS
`
`Raman Baweja
`12/2/02 02:31:12 PM
`BIOPHARMACEUTICS
`
`Mums :4
`
`{m magma
`
`

`

`
`
`CLINICAL PHARMACOLOGYIBIOPHARMACEUTICS REVIEW
`
`DRUG: Zomig ® (Zolmitriptan)
`NDA: 21-450
`
`PRIMARY REVIEWER: Andre Jackson
`TYPE: NDA Amendment
`
`
`FORMULATION: Nasal Spray
`APPLICANT: Astra Zeneca
`
`INDICATION: Migraine Headache
`Generic Name: Zolmitriptan
`1.EXECUTIVE SUMMARY
`
`, 5.0 mg
`STRENGTH: '
`SUBMISSION DATES: 2-27—02
`9-26—02
`
`10-9-02
`
`The firm conducted a double—blind placebo, double-dummy parallel group multi—center
`trial to compare the efficacy and two open—label safety studies with Zomig nasal spray in
`subjects with migraine headaches.
`
`Zomig nasal spray is a unit dose system designed to deliver zolmitriptan to the nasal cavity.
`
`The sponsor changed the outer body of the clinical trial nasal spray device used to deliver
`zolmitriptan to the nasal cavity. These changes included a safety feature to prevent removal of
`the filled vial and a thumb push was added to ease firing. The bioequivalence of the clinical
`device and commercial device will be determined based upon in vitro performance of these two
`devices.
`
`This Clinical Pharmacologleiopharmaceutics review will evaluate whether the applicant has
`adequately demonstrated in vitro that the commercial device is bioequivalent to the clinical
`device.
`
`In vitro product performance data was determined based upon the following in vitro tests:
`1.Dose or spray content uniformity
`
`2.Droplet size distribution
`3.Particle size distribution
`
`'4.Drug and aggregate particle size density
`5.3pray pattern(Dmax, Dmin, Ovality)
`6.Plume geometry
`
`Bioequivalence was based upon the ratio of geometric means (Testheference) being within the
`
`interval of -——"-"'
`The following in vitro tests had ratios for geometric means that
`exceeded the limits of
`.. These were:
`
`I_e;_s_t_
`Median Diameter
`Median Diameter
`Span
`Span
`Dmin
`Dmax
`Plume Geometry-Length
`
`Dose Size
`0.5 mg droplet size
`2.5 mg droplet size
`0.5 mg droplet size
`2.5 mg droplet size
`0.5 mg spray pattern
`0.5 mg spray pattern
`5.0 mg
`
`

`

`
`
`Plume Geometry-Spray Angle
`
`5.0 mg
`
`Appears This Way
`On Original
`
`1
`
`Based upon these findings the Office of Clinical Pharmacology and Biopharmaceutics (OCPB)
`recommends that the clinical and commercial devices are deemed not to be bioequivalent.
`
`1.1 Recommendation: The in vitro product performance studies provided in this study
`amendment to the Division of Neuropharmacological Drug Products does not provide in vitro
`evidence supporting the bioequivalence of the to be marketed commercial nasal spray device to
`the clinical Zomig nasal spray device. This submission is not acceptable from the OCPB
`perspective.
`
`Please see comments to the firm on pages 33 and 34 and forward these to the sponsor.
`
`APPEL‘ZETF? we: we
`GEE .°;"'rn-,s.
`=9
`list-1:";
`,
`
`

`

`TABLE OF CONTENTS
`
`
`1.
`
`EXECUTIVE SUMMARY
`
`1.1 RECOMMENDATIONS
`
`2. INTRODUCTION AND BACKGROUND
`
`3. Current Submission
`
`4.CLINICAL PHARMACOLOGY QUESTION BASED REVIEW
`
`4.1 GENERAL ATTRIBUTES
`
`4.2 FORMULATION COMPARISON
`
`4.3 SPRAY DEVICE COMPONENT SPECIFICATIONS
`
`4.4 ANALYTICAL METHODS FOR ZOMIG
`
`4.5 UNIFORMITY OF DOSAGE UNITS
`
`4.6 PARTICLE SIZE
`4.5.1 MEDIAN DROPLET SIZE
`4.6.2 SPAN
`
`4.8 SPRAY PATTERN
`
`4.9 PLUME GEOMETRY
`
`4.10 CONCLUSIONS
`
`5.COMMENTS TO THE FIRM
`
`6.APPENDIX 1
`
`7.APPENDIX 2
`
`7.1 OCPB FILING AND REVIEW FORM
`
`8-9
`
`9-10
`
`10-12
`
`1 2
`12
`1 6
`
`20
`
`22
`
`30
`
`32
`
`33
`
`36
`
`45
`
`55
`
`

`

`
`
`2. Introduction and Background:
`Zolmitriptan ( ZOMIG®) is a selective 5-HT1B/1D receptor agonist for the acute treatment
`of migraine. The efficacy and safety of the conventional oral tablet formulation of zolmitriptan
`has been demonstrated, and this formulation is indicated for the acute treatment of migraine with
`or without aura in adults (NDA 20-768, approved 25 November 1997). In addition, an orally
`disintegrating tablet (ZOMIG-ZMT®) has been developed, which dissolves rapidly in the mouth
`and is swallowed with the patient’s saliva, obviating the need for access to water or other fluids
`(NDA 21—231, approved 13 February 2001).
`
`The ongoing development of zolmitriptan has identified intranasal delivery as a clinically
`desirable additional method of drug administration for migraine sufferers. Drug absorption
`directly across the nasal mucosa allows rapid access into the systemic circulation, which would
`result in the intranasally absorbed proportion of a zolmitriptan dose initially avoiding the first-
`pass metabolism undergone by oral formulations of zolmitriptan. Consequently, compared to
`oral delivery, zolmitriptan nasal spray has the potential to provide faster onset of action and more
`rapid relief of migraine symptoms. Furthermore, intranasal administration offers effective
`delivery of zolmitriptan for patients affected by migraine-related gastric stasis, nausea or
`vomiting (any of which can limit or delay absorption of oral medication), and for patients with
`an aversion to swallowing tablets.
`
`AstraZeneca has developed an alternative formulation, ZOMIG Nasal Spray, to provide a non-
`oral route of dosing that may be particularly useful in patients who experience nausea (a
`In
`common symptom associated with migraine) or other difficulties with oral formulations.
`addition, intranasal dosing offers the potential for rapid absorption of drug, and possibly faster
`onset of migraine relief, compared with oral dosing.
`
`The clinical pharmacology of zolmitriptan after oral administration has been well characterized
`in the previous NDA submission for the conventional oral tablet formulation (NDA 20-768,
`approved 25 November 1997). Studies conducted for the nasal spray NDA were therefore
`complementary to previous studies with the oral tablet, and were designed to select an
`appropriate formulation of the nasal spray, define the absorption characteristics of zolmitriptan
`after intranasal dosing, and confirm the similarity of distribution, metabolism and elimination of
`zolmitriptan after oral and intranasai dosing. This document summarizes all available
`information on the pharmacokinetics of zolmitriptan nasal spray, and refers to relevant data on
`the phannacokinetics of oral zolmitriptan. It was shown after the administration of single and
`multiple doses (0.5, 1, 2.5 and 5 mg) of the clinical intranasal formulation that the
`pharmacokinetics are dose proportional. A second study showed that zolmitriptan was primarily
`distributed to the nasoPharynx region. A third study indicated that the absorption and
`distribution of zolmitriptan was identical after a single dose of either zolmitriptan 5 mg nasal
`Spray 30 minutes after a single dose of intranasal xylometazoline{ --- weight/volume solution),
`or zolmitriptan 5 mg nasal spray alone. Together these data comprise the normal components of
`a new drug application (NDA).
`
`

`

`Briefly, the pharmacokinetics, metabolism and elimination profiles of zolmitriptan when taken
`orally or intranasally are similar. This suggests that prescribing information relating to drug-drug
`interactions and drug-demographic interactions for ZOMIG oral tablet is equally relevant for
`ZOMIG Nasal Spray. The rapid intranasal absorption of zolmitriptan afier intranasal
`administration indicates that ZOMIG Nasal Spray should have a faster onset of action with
`earlier relief of migraine symptoms than the ZOMIG oral tablet.
`
`3.0URRENT SUBMISSION-
`
`The objective of this study was to generate data to confirm the in vitro bioequivalence (BE) of
`ZOMIG Nasal Spray delivered via 2 nasal Spray devices - the clinical trial device, used during
`the initial dose-finding efficacy study (Trial 31 NIL/0077) for ZOMIG Nasal Spray, and the
`commercial device which is the device proposed for commercialization.
`
`ZOMIG Nasal Spray is a unit dose system designed to deliver zolmitriptan to the nasal cavity.
`The device proposed for commercialization '(‘commercial’ device) is comprised of a clear neutral
`
`USP Type 1 glass vial sealed with a
`' rubber stopper, assembled into a vial holder and
`an actuation device. The solution is contained within the glass vial. A protection cap is fitted
`over the device.
`
`Both ‘clinical trial’ and ‘commercial’ devices are identical with respect to device firing
`mechanism and contact materials, however the appearance of the outer body of the ‘commereial’
`device has been modified to incorporate a safety feature preventing removal of the filled vial. A
`thumb push has also been added to ease firing and the protection cap has been designed to
`prevent actuation of the device prior to patient use. An exploded diagram illustrating both
`devices is shown in Figure 1.
`
`APPEARS Tl-llS WAY
`0N GEiGlivlill.
`
`

`

`
`
`Figure 1
`
`Exploded View of clinical trial device and commercial device
`
`______——-— @ Prat-dicecap
`
`L__——_.
`
`N“
`
`3
`3
`
`%
`
`Noodlen.
`Mi.
`
`swim
`
`Inch
`
`fi
`m
`“HI mg Vialhold-r
`@ umpush
`
`K
`
`\
`5"”__"‘
`
`-
`
`Clinical trial device
`
`Commercial device
`
`In-vitro equivalence testing was performed according to the Center for Drug Evaluation and
`Research (CDER) document: Guidance for Industry, ‘Bioavailability and Bioequivalence Studies
`for Nasal Aerosols and Nasal Sprays for Local Action’, June 1999. ZOMIG Nasal Spray is a
`unit dose rather than a multi-dose system, and as such not all tests described in the guidance are
`
`

`

`
`
`.
`appiicable. Testing on ZOMIG Nasal Spray 5 mg‘ r/F’ _
`
`consistent with the CDER Draft Guidance, are described
`“-—--""—""“‘
`
`u
`
`M
`u
`u
`
`4. CLINICAL PHARMACOLOGY QUESTION BASED REVIEW
`
`4.1 General Attributes
`
`Equivalence of Clinical and Commercial Spray Devices
`
`4.2 What were the formulations for the Clinical and Commercial Spray Devices?
`
`The quantitative composition of the formulations for the clinical and commercial lots used in
`ZOMIG Nasal Spray 5, ""
`mg are identical (see Table l to Table 3).
`
`Table 1
`Quantitative composition of ZOMIG Nasal Spray 5 mg used in clinical
`and commercial lots
`
`
`Ingredient
`Quantity (mg per nominal
`Function
`
`100 u! dose)
`
`Zolmitriptan
`
`Citric acid. anhydrous
`D.
`.
`.
`theme sodium phosphate
`Purified water
`
`Nitrogen
`
`5.0
`
`_
`
`7
`
`‘
`
`3
`
`E 7
`
`j
`
`
`
`Drug substance
`
`_.-
`L
`" '
`
`t/
`
`3
`
`3
`
`Table 2
`Quantitative composition of Zomig Nasal Spray 2.5 mg used in clinical
`
`and commercial lots-__——|
`
`
`Ingredient
`Quantity (mg per nominal
`Function
`100 pl dose)
`
`
`Zolmitriptan
`Citric acid. anhydrous
`'Dibasic sodium phosphate C
`3
`'
`i
`Purified water
`
`Nitrogen E E j
`
`2.5
`"
`
`
`
`j
`
`'
`
`
`
`Drug substance
`' " '
`l
`C
`
`J
`
`

`

`Table 3
`Quantitative composition of ZOMIG Nasal Spray 0.5 mg used in
`clinical and commercial lots
`
`
`ingredient
`
`Quantity (mg per nominal
`[00 pl dose)
`
`Function
`
`Zolmitriptan
`
`0.5
`
`Drug substance
`
`Citric acid, anhydrous
`Dibasic sodium phosphate
`Purified water W
`
`1/
`
`1
`
`J
`_.—-——-—--——-—"—“_'—-—-——-—.
`Water for injection'
`
`
`Nitrogen , - ‘L’,_
`Solvent used in batch PHIIOBZBI‘DS.
`
`4.3 What were the specifications for the components for the Clinical and Commercial
`Spray Devices?
`
`The specifications for all the internai components for the clinical and commercial devices are
`identical. Individual specifications for each of the components are shown (see Table 4 to
`Table 7).
`
`
`
` Table 4 Specification for vial
`
`Test
`
`Appearance
`Material
`Height (mm)
`
`Specification
`
`Clear glass vial. free from any critical defects
`Clem Type 1 (USP) neutral glass
`19.5 10.5
`
`
`
`Intemal body diameter (mm) 5.0 :tO.
`
`The vial is regarded as the metered chamber volume for ZOMIG Nasal Spray
`
`
`
` Table 5 Specification for rubber stopper
`
`Test
`Appearance
`Material
`
`Rib diameter (mm)
`
`Height (mm)
`
`Diaphragm thickness (mm)
`
`Specific gravity
`
`_
`
`Specification
`Black rubber stopper, free from any critical defects
`-—-—--
`Type l (USP) . ..—-— ‘ rubber
`
`5.300 10.075
`
`6.0 :l:0.l
`
`_.0 10.
`
`\
`
`
`
`Hardness (Shore A) -—._.-
`
`

`

`
`
`
`
`Table 6 Specification for vial holder sub-assemblyWan—"W
`
`Test
`Specification
`
`Appearance
`
`Material
`
`Plastic vial holder with thumb push attached“, free from
`any critical defects
`M
`
`Break ring diameter (min)
`Actuation force (N)
`
`l4.0 10.]
`“5‘
`
`The thumb push attachment is for the commercial device
`
`A.
`
`Table 7
`Specification for actuator sub-assembly
`
`
`
`Test
`Specification
`
`Appearance
`
`Plastic actuator sub-assembly. free from any critical
`defects
`
`Material
`
`Body/needlciigi ail—T"
`Needle; .—______
`Orifice diameter (mm) 0.3l 31105
`
`
`
`t
`
`Both clinical and commercial devices have the same specifications for the actuation force but it
`is highly likely that any combination of manuai actuation differences and batch to batch
`variation of the break ring (which appears to be part of a pre—compression mechanism) could
`result
`in large variation in the median dropiet size of particles delivered from study to study with
`different lots of the spray device.
`
`4.4 Was a properly validated analytical method used for the analysis of the in vitro
`
`content uniformity and '
`data?
`
`AFPEf‘flS HHS to?
`Oh! F”
`
`

`

`Linearity
`
`Linearity of zolmitriptan peak area response versus zolmitriptan content has been
`demonstrated over the rangr -—'_—-'-T"1 (see Table 9).
`
`
`
` Table 9 Droplet size by——-._.-___ - linearity of zolmitriptan
`
`Zolmitriptan concentration (ugh!!!)
`' " *1
`
`.1
`E
`A 1
`
`Peak area
`
`f
`/““
`
`-...
`
`
`The linearity data was from: _f“ however, the firm claimed a sensitivity of
`
`*r-‘E‘ curve data {
`_
`needs to be supplied by the firm to support their claim.
`The current data submitted by the firm does not support the ’ r-fi
`LOQ claimed by the firm
`for their assay.
`
`
`
`4.5 Was the uniformity of the dosage units consistent with the % label claim for the
`clinical and commercial spray devices?
`
`Dose content uniformity was performed as a single test per device; the firm did not conduct
`‘through container iife’ testing as described in the CDER Draft Guidance because ZOMIG Nasai
`Spray is a unit dose system.
`
`Assay (mg/mi) and uniformity of dosage units (% label claim) for the reference and test batches
`of ZOMIG Nasal Spray 5 mg and ZOMIG Nasal Spray 0.5 mg are shown, see Table 6 and Table
`7.
`
`niformi of dosa_e units % label claim for ZOMIG Nasal S u ra 5 in
`
`
`
`
`atch number
`
`
`
`
`
`
`lO
`
`”1598/32
`'/1598/31
`l1598/20I1Il'1598/36
`l1598/19
`—___——
`- M
`I-
`_——
`_
`—-—
`———
`_
`—
`
`
`
`-
`
`itcomets 100ul __-E
`
`
`
`niformi of dosa_e units (% label claim — —
`
`

`

`_ ‘-
`— \
`
`_
`
`7
`
`— Mil“
`—
`
`i “a
`
`__——_
`
`— L
`1101 101
`
`g’“
`, __ WW #:7‘
`101
`
`101
`
`104
`
`9
`
`Ratio of Geometric mean (Test/Reference) for the ‘—- batches = 4.61/4.615:l .0
`
`niformi of dosae units % label claim for ZOMIG Nasal Sra
`_I 1 —--—_
`———_-—_
`_-H10323/95 1-11598116
`I'll631/O6 1-11593133
`111598115
`m__———__
`—_—_———
`"'
`
`
`
`
`
`
`
`
`
`
`
`-—
`
`___——_
`———_-——
`__——___
`
`- nit comets lOOul
`
`
`
`nifonni of dos _e units % label claim
`
`ll
`
`
`
`
`

`

`
`
`
`
`EE__—__
`Ratio of Geometric means (Test/Reference) for the t -’ catches = 4.62/4.62:1.0
`
`CONCLUSION
`
`The test and reference formulations both exhibit acceptable content uniformity. The ratios of
`geometric mean values for the """—0.5 mg and “—35 mg dose lots are within the acceptable
`ratio of ——--—'"-
`'
`
`4.6 Do the summary parameters for the particle size distribution data collected with the
`«-—-—~———--""'
`.. support bioequivalence between the clinical and commercial
`spray devices?
`4.6.1 Median Droplet Size
`
`Laser diffraction is a non-aerodynamic optical method of droplet sizing which measures the
`geometric size of droplets in flight. Laser instrumentation provides plots of obscuration( optical
`concentration) or per cent transmission and droplet size distribution over the entire life of a
`single spray.
`
`Summary data for median droplet size for the 3 doses 5 mg, 2.5 mg and 0.5 mg are presented
`
`for the 3 distances from the Laser beam \
`_ which represent different stages
`of plume formation after actuation. Data is presented for between and within lot % CV for the 3
`lots '«édevices per lot) at the different distances (N=30) that were tested. Summary statistics
`are presented for the ratio of geometric means and the F-test comparison of variances. The
`median diameter, ---'- l “- of the particles, referred to the volume, have a diameter 5
`indicated value. Units are in um.) is presented in the following tables.
`
`12
`
`
`
`

`

`
`
`5 MG DROPLET SIZE BY LASER DIFFRACTION DATA
`
`13
`
`—-———-,‘ 30.5))
`,--——. (iota
`
`Product
`
`Distance
`
`(cm)
`
`Ref
`
`Test
`
`Within lot % CV (n=10)
`
`Mean
`n=30
`
`87.16
`68.62
`52.59
`85.61
`72.55
`52.88
`
`Total
`% CV
`
`'1
`[-
`f—H
`
`._.__.r
`
`., L.
`
`J
`
`Mean of log
`n=30
`
`Between lot
`% CV
`
`__
`
`1.924
`1.814
`1.708
`1.914
`1.847
`
`1.707
`
`W —-_'—-_.‘
`
`'1
`
`J
`
`‘I
`
`J
`
`7
`
`.3
`
`r’
`
`L
`5..
`
`1’; '
`
`‘ "1
`
`L.
`
`A
`
`.
`
`Lot
`1"‘1
`
`u R
`
`ange
`
`h L
`
`ul
`
`Range
`
`Arithmetic mean
`
`Geometric mean
`
`Product
`
`Ref
`
`Test
`
`T/R ratios
`
`Distance (cm)
`
`0.982
`1.0573
`1.0055
`
`F—test comparison of variances
`
`Distance (cm)
`
`F~ratio
`
`1.23
`
`1.23
`1.50
`
`’
`
`;
`
`0.977
`1.078
`0-997
`
`P—value
`
`0.257
`0.253
`0.141
`
`

`

`2.5 MG DROPLET SIZE BY LASER DIFFRACTION DATA
`
`~'—-"*- 05))
`.s__data
`
`Product
`
`Distance
`(cm)
`
`Ref
`
`Test
`
`Within lot % CV (n=10)
`
`Product
`
`Ref
`
`Lot
`
`1—1
`
`Mean
`n=30
`
`66.75
`51.05 ,
`45.12
`
`65.29
`48.84
`39.81
`
`Total
`% CV
`
`F‘fi
`——-*-—'~
`
`fl
`
`,
`
`Mean of log
`n=30
`
`Between lot
`% CV
`
`‘1
`1/
`1 .8079
`1.7001 W
`1.6457
`
`1.8039 f
`1.6783
`1
`1.5985
`—’
`
`1,
`
`____,_———__________‘3 K
`
`T-
`
`‘7
`
`l
`I
`
`x.) fl
`
`Test
`
`T/R ratios
`
`Range
`m
`
`J
`R
`
`ange
`
`L
`
`c__..——-—-————-—__\
`
`Distance (cm)
`
`Arithmetic mean
`
`Geometric mean
`
`0.9781
`0.9567
`0.8823
`
`Jest comparison of variances
`
`Distance (cm)
`
`F—ratio
`
`3'
`
`1.22
`1.36
`8.73
`
`*TIR ratio outside '
`
`0.9908
`0.9510
`0.8970*
`
`P~value
`
`0.298
`0.209
`4.8E-8
`
`

`

`
`
`0.5 MG DROPLET SIZE BY LASER DIFFRACTION DATA
`
`15
`
`Mean
`n=30
`
`84.71
`60.86
`51.45
`
`70.09
`54.24
`
`43.18
`
`Total
`% CV
`
`Mean of log
`n=30
`
`Between lot
`% CV
`
`r H ' '
`
`'1
`
`1.8627
`1.7585
`1.6877
`
`-—-—'—
`
`..
`
`1.83 76 J
`1.7298
`
`L,
`
`J
`
`1.6335
`
`‘
`
`'.0.5))
`
` ‘
`
`c__._data
`
`Product
`
`Distance
`(cm)
`
`Ref
`
`Test
`
`Within lot % CV (n=10)
`
`Product
`
`Lot
`
`-\-__._..—-—-—--*
`
`-—"'—""
`
`—-—-—-——--""
`
`Ref
`
`Test
`
`TI’R ratios
`
`V“?
`
`LJ
`
`Range
`(“'1
`
`x.»
`
`.
`Range
`
`V
`
`1"
`
`fl
`
`\___._.—--—--—"""
`
`7
`
`“1
`
`Distance (cm)
`
`Arithmetic mean
`
`Geometric mean
`
`0.8274
`0.8912
`0.8393
`
`F-test comparison of variances
`
`Distance (cm)
`
`F—ratio
`
`22.65
`0.15
`22.35
`
`*TIR ratio outside --—
`
`0.9438
`0.9361
`0.8827*
`
`P—value
`
`2.8E-13
`0.999
`3.3E—13
`
`
`
`

`

`4.6.2 Span \
`
`Summary data for particle size span for the 3 doses 5 mg, 2.5 mg and 0.5 mg are presented for
`
`the 3 distances from the Laser beam \
`'
`which represent different stages of
`plume formation after actuation. Data is presented for between and within lot % CV for the 3
`lots ’—- devices per tot) at the different distances (N=30) that were tested. Summary statistics
`are presented for the ratio of geometric means and the F—test comparison of variances.
`-—'-
`
`f-
`
`it???§:2$ “”3 WAY
`“wan“ : =1; 9.
`{Jig UiitGEaA.-:L
`
`16
`
`|
`
`

`

`Span 5 mg Dose
`
`Span
`Span data
`
`Product
`
`Ref
`
`Test
`
`‘
`
`Within lot % CV (n=10)
`
`Distance
`(cm)
`
`Mean
`n=30
`
`Total
`% CV
`
`Mean of log
`n=30
`
`Between lot
`% CV
`
`'
`
`’1
`
`5.91
`2.61
`2.19 f -
`
`7.24
`2.32
`2.24
`
`L;
`
`A
`
`j
`
`r
`
`0.757
`0.378
`0.295
`0.84
`0.341 \
`0.302
`L
`J
`
`Product
`
`Ref
`
`Test
`
`Lot
`
`1'"
`
`U
`
`,_____—-—v-'— /
`
`r
`
`‘1
`
`r
`
`7
`
`.
`
`’
`
`rF-‘H
`
`
`
`T
`
`'1
`
`
`Range k
`""
`
`W— ,
`
`L.
`
`.1
`
`L
`
`.1
`
`1..
`
`.1
`
`w R
`
`ange
`
`TIR ratios
`
`Distance (cm)
`
`Arithmetic mean
`
`Geometric mean
`
`‘1
`1.
`1
`
`1.2258
`0.8897
`1.0256
`F-twt comparison of variances
`
`Distance (cm)
`
`F-ratio
`
`1.40
`1.70
`1 .59
`
`
`
`l.2106**
`0.9183
`1.0162
`
`_
`
`Pavalue
`
`0. 1 85
`0.079
`0. 109
`
`but not considered pivotal due to the close —-- distance
`*‘TIR ratio outside
`from the laser beam which does not give plume sufficient time to form and results in
`highly variable data
`
`
`
`17
`
`

`

`Span 2.5 mg Dose
`Span data
`
`Product
`
`Distance
`(cm)
`
`Mean
`n=30
`
`Total
`% CV
`
`Mean of log
`n=30
`
`Between lot
`% CV
`
`Ref
`
`Test
`
`E
`
`m
`
`‘-
`-
`Within lot % CV (n=10)
`
`5.71
`2.66
`2.03
`8.97
`5.16
`1.50
`
`Product
`
`Lot
`
`1"
`
`1'
`1
`
`
`.___,
`
`L.
`
`.1
`
`0.7343
`0.3887
`0.2444
`0.9474
`0.6503
`0.1666
`
`T—
`
`—1
`
`._____‘
`J
`
`L
`
`‘1
`
`J
`
`Ref
`
`Test
`
`T/R ratios
`
`b1 . a
`,
`
`.
`
`-
`
`Range
`r“:
`_/'
`u...‘
`
`Range
`
`L
`
`‘—_————————*\“
`
`Distance (cm)
`
`I Arithmetic mean
`
`Geometric mean
`
`__,.
`
`1.5711
`
`1.9424
`/ .
`0.7388
`_
`F-test comparison of variances
`
`Distance (cm)
`
`F-ratio
`
`-.._
`
`.
`‘ V
`
`1.80
`4.19
`16.99
`
`*TIR ratio outside
`
`
`
`1.6334**
`
`1.8264*
`0.8360*
`
`P—value
`
`0.06
`0.0001
`1.2E—11
`
`'listance
`"TIR ratio outside ‘ —4- but not considered pivotal due to the close E'-
`from the laser beam which does not give plume sufficient time to form and results in
`highly variable data
`
`18
`
`

`

`Span 0.5 mg Dose
`Span data
`
`Product
`
`Distance
`(em)
`
`Mean
`n=30
`
`Total
`% CV
`
`Mean of log
`n=30
`
`Between let
`% CV
`
`Ref
`
`Test
`
`Within lot % CV (n=10)
`
`7.13
`2.17
`1.97
`8.37
`3.82
`1.75
`
`"1
`r
`f!“
`
`—-—---*
`
`1..
`
`0.834
`0.32
`0.236
`0.917
`0.516
`0.224
`
`I—
`
`“7
`
`“*3
`-——/
`
`L
`
`4
`
`Lot
`t—i
`
`LJ
`Range
`
`Product
`
`Ref
`
`Test
`
`T/R ratios
`
`*1 w
`
`LI
`Range
`
`L.
`
`—~
`
`—-1
`
`'-—-——--
`
`T"
`
`—.—_—-—__-—————'—-‘-\
`
`“1
`
`J.
`
`Distance (cm)
`
`Arithmetic mean
`
`Geometric mean
`
`1.1733
`1.7632
`
`0.8884
`I
`F-test comparison of variances
`
`Distance (cm)
`
`F-ratio
`
`2.18
`10.69
`3.41
`
`1.2106“
`1.5704*
`
`0.9727
`
`P—value
`
`0.02
`4.2E—9
`0.0007
`
`*TIR ratio outside “—7-—
`a distance
`**TIR ratio outside x but not considered pivotal due to the close t—-
`from the laser beam which does not give plume sufficient time to form and results in
`highly variable data
`
`19
`
`

`

`CONCLUSION
`
`The following testlreference geometric mean ratios related to particle size exceeded _
`‘-—_
`
`M
`Median Diameter
`Median Diameter
`Span
`Span
`Span
`
`Dose Size
`0.5 mg droplet size@
`2.5 mg droplet size@I ._.
`0.5 mg droplet size@,I ,
`2.5 mg droplet size@i
`2.5 mg droplet size@
`
`Based upon these results, the firm has failed to demonstrate that the commercial
`product is bioequivalent to the clinical product based upon median particle size diameter
`and particle span.
`
`4.7 Do the summary data for the -~————----————-———-———- indicate that the
`clinical device and the commercial device result in the same deposition pattern
`within the '
`‘-—-———--—"’
`?
`
`.._.—_-——-—-—-"'““—' measures aerodynamic
`The sizing of droplets or particles by
`diameter based upon i c—-—-—~1, an important factorIn the deposition of drug in the nasal
`passage.
`
`hi)?i.» reap Tic-“n “’5‘;
`“it L::...;.‘-r.1!5
`
`20
`
`

`

`
`
`5 MG DROPLET SIZE BY‘ _ ——"—‘———"—_ DATA
`
`f A data
`
`
`Mean n=9
`
`Total % cv Mean of log n=9
`
`Between lot % cv
`
`Product
`
`Distance
`(micron)
`WW
`2.55
`i
`0.404
`
`Te“
`
`0.34
`
`0.13
`
`0.13
`
`0.04
`
`0.02
`
`95-33
`
`2.58
`
`0.31
`
`0.11
`
`0-12
`
`0.03
`
`'
`
`;
`
`1
`
`‘
`
`_0_473
`
`-0.904
`
`41896
`
`-1.38
`
`—1.699
`
`1.986
`
`0.395
`
`41.518
`
`-0.966
`
`-0.956
`
`1512
`
`
`RA
`0.02
`4 L.‘
`-l .699
`Within lot "A: cv (n=3)
`m
`
`
`Product
`Lot
`
`
`Ref
`
`- r—1
`
`r—
`
`71
`
`fl
`
`Ln}
`Range
`M "
`
`A
`
`Test
`
`. Ln:
`
`Range L J
`
`P/fi
`
`.v
`h
`fly??? a? 3:155" 1519wa
`K r
`
`21
`
`

`

` TIR ratios
`
`Size (micron)
`
`Arithmetic mean
`
`Geometric mean
`
`i
`
`[
`
`_ L—J
`
`1.0003
`1.0118
`
`0.9118
`
`0.8462
`
`0.923]
`
`0.75
`
`1.0
`
`1.0002
`0.9802
`
`0.8999
`
`0.8682
`
`0.8706
`
`0.7688
`
`1.0
`
`F—test comparison of variances
`
`Size (micron)
`
`F-ratio
`
`M
`
`‘ LJ
`
`8.39
`6.87
`
`4.21
`
`4.48
`
`9.88
`0
`
`0
`
`‘
`
`Pavalne
`
`7.6E-8
`7.3E—7
`
`0.0001
`
`6.2E—5
`
`LIE—8
`1.0
`
`1.0
`
`The 0.76 ratio at -". um is not considered pivotal since ’-~.. of the applied dose was
`recovered in the ;.——. for the“‘- for the clinical and commercial spray devices.
`
`CONCLUSION
`
`The data for the 5 mg spray indicates that for the _.. and particles --‘ and larger, the
`commercial and clinical devices arebioequivalent. Recovery data indicated that ._.... of the
`applied dose was recovered in the f—‘for the.
`for the clinical and commercial spray
`devices
`.—————-—-—-—-——-——-——-—-———-——..______.—-———-——-—-"-——“———_.
`-_——-
`
`4.8 Does the comparative spray pattern summary data for the clinical device and the
`commercial device support the bioequivalence of the two products.
`
`22
`
`

`

`or
`Spray pattern studies characterize the spray either during the spray prior to ' ~..___,
`following ———-..,
`L on an appropriate target such as thin-layer chromatography. The test is
`done at different distances from the TLC plate. Spray pattern analysis allows for comparison of
`shapes, measurement of area or maximum diameter‘(Dmax), minimum diameter (Dmin), and
`ovality ( Dmaxlein).
`
`‘fl‘fiif‘fim h
`At”? Li':§g{;
`;“ 5f m .H
`Uffi ‘3“:Cér! “2'
`
`23
`
`

`

`5 MG SPRAY PATTERN DATA
`
`Ovality ratio
`
`Ovality ratio data
`
`
`Product
`
`Distance
`(cm)
`
`Ref
`
`Test
`
`2
`3
`
`4
`
`2
`
`3
`
`Mean
`n=30
`
`1.06
`1.067
`
`1.083
`
`1.07
`
`1.07
`
`Totai
`% cv
`
`1"“
`
`Mean of log
`n=30
`
`Between lot
`% cv
`
`F1
`
`0025
`0.028
`
`0.034
`
`0.029
`
`0.029
`
`
`4
`‘
`1.07
`t_J
`Within lot 9/. cv (n=10)
`‘
`
`
`U
`
`0.027
`
`Product
`
`Lot
`
`=:_____._______.
`
`Test
`
`k.)
`
`Range
`‘——7
`
`L...J
`
`Range
`L__;
`‘u—J
`1. J
`TIR ratios
`
`
`Geometric mean
`Arithmetic mean
`. Distance (cm)
`.
`1.0093
`1.0094
`1.4x
`1.0021
`1.0028
`I1 /‘
`
`0.935 0.984
`'
`
`F—test comparison of variances
`
`
`7 Distance (cm)
`F-ratio
`Pwvalue
`
`:
`
`.1.“-
`
`‘
`
`1.03
`
`0.416
`
`1 v
`2.14
`0.022
`1.37
`0.201
`'
`
`
`$5.111: Rum:
`APPE 1‘
`
`35*}‘121fl' 1..
`1
`.11
`..
`0:11 D 111.1“;
`
`

`

`Dmax
`
`D“, data
`
`
`Product
`Distance
`Mean
`Total
`Mean of log
`Between lot
`
`(em)
`n=30
`% cv
`n=30
`% cv
`
`1
`
`Ref
`
`Test
`
`3.17
`3.81
`
`4.93
`
`3.23
`
`3.96
`
`1—
`
`7
`
`0.493
`0.577
`
`0.686
`
`0.507
`
`0.594
`
`'r
`
`1
`
`
`
`JI.4.90 ._.l 0.686 L.
`
`
`
`
`
`
`
`
`
`Within lot % cv (n=10)
`Product
`Lot
`( —-——;—’————-—-\
`
`Ref
`
`fl
`
`1'
`
`<1
`
`i“
`
`1
`
`r
`
`'3
`
`u R
`
`ange
`h
`
`L.
`
`Test
`
`
`Range
`L—
`1
`L.
`TIP. ratios
`
`
`.L
`
`L.
`
`A
`
`
`Distance (cm)
`Arithmetic mean
`Geometric mean
`
`1.0189
`
`1.0393
`
`1.0198
`
`1.0399
`
`
`
`0.995] 0.9984
`
`F—tect comparison of variances
`
`' D
`
`istance (cm)
`
`F—ratio
`
`P—‘value
`
`I .08
`
`L03
`
`0.416
`
`0.464
`
`
`
`1.39 0.191
`
`
`
`25
`
`

`

`Dmin
`
`Dmin data
`
`
`Distance
`(cm)
`
`'1
`
`Product
`
`Ref
`
`Test
`
`Mean
`n=30
`
`2.99
`3.59
`
`4.56
`
`3.00
`
`Total
`'/o cv
`
`rfi
`
`Mean of log
`n=30
`
`Between lot
`o/o cv
`
`m
`
`0.473
`0.551
`
`0.654
`
`0.475
`
`0.566
`3.72
`!
`0.656
`U
`4.58
`L“,
`
`Within lot % cv(n=10)
`
`
`'
`
`1’1
`
`W7
`
`t“!
`
`-—-"
`
`1"“!
`
`Product
`
`Ref
`
`Test
`
`Lot
`
`11
`
`LJ
`
`Range
`N
`
`L;
`
`
`Range
`w
`L.)
`a .
`,
`TIR ratios
`
`
`
`Distance (cm)
`Arithmetic mean
`Geometric mean
`
`{1
`
`1.0033
`1.0362
`
`1.0065
`1.0359
`
`
`{1
`1.0044
`1.0051
`F—test comparison of variances
`
`
`
`Distance (cm)
`F-ratio
`.
`P—vaiue
`
`11
`
`1.51
`1.06
`
`0.137
`0.438
`
`1.14
`0.360
`
`.
`
`U
`
`H“ 1'; 3-} §
`m .
`
`w
`“a ;?--?”‘ My
`
`26
`
`

`

`
`
`0.5 MG SPRAY PATTERN DATA
`
`Ovality ratio
`
`Ovality ratio
`
`
`Product
`
`Distance
`(cm)
`
`Ref
`
`:1
`
`Test
`
`Mean
`n=30
`
`1.06
`1.04
`
`1.10
`
`1.08
`
`1.11
`
`Total
`% cv
`
`1
`
`‘
`
`Mean of log
`n=30
`
`Between lot
`% cv
`
`1""!
`
`0.0243
`0.0149
`
`0.039
`
`0.0338
`
`0.0438
`
`1)
`
`1.08
`L.)
`0.0318
`.
`,
`Within lot % cv (n=10)
`
`
`Product
`
`Ref
`
`Test
`
`Lot fl
`
`1""
`
`'1‘
`
`"1
`
`1
`
`Range
`
`M
`
`/<’-——%
`-
`
`L——+’
`
`Range
`L.
`J,
`TIR ratios
`
`
`‘_____________w
`
`Distance (cm)
`
`Arithmetic mean
`
`Geometric mean
`
`Er‘l
`
`1.0217
`
`1.0704
`
`_
`
`1.0222
`
`1.0681r
`
`31»)
`0.9872
`0.9337
`
`
`
`F-test comparison of variances
`
`
`Distance (cm)
`F-rutio
`P—value
`
`in
`‘
`
`0.94
`2.62
`
`0.566
`0.006
`
`
`
`. 0 0.002 3.06
`
`
`
`27
`
`

`

`Total
`% CV
`
`”—1
`
`1...!
`
`Mean of log
`n=30
`
`Between lot
`% CV
`
`0.4748
`0.5527
`0.6164
`0.5043
`0.6102
`
`0.6896
`
`fl
`
`.
`'
`
`,__J
`
`
`
`.1
`
`Distance
`
`(cm)
`
`Dmax
`Product
`
`Ref
`
`Test
`
`Within lot % CV (n=10)
`
`Product
`
`Lot
`
`Ref
`
`Test
`
`.
`TfR ratios
`
`'51
`
`1....)
`
`Range
`fl
`
`1...:
`
`Range
`
`Mean
`n=30
`
`3.00
`3.61
`4.19
`3.20
`4.09
`4.92
`
`r
`
`L.
`
`Distance (cm)
`
`Arithmetic mean
`
`Geometric mean
`
`-
`
`-(
`
`1.0666
`
`1.1347
`
`1.1735
`
`F-test comparison of variances
`
`Distance (cm)
`
`F—ratio
`
`i
`
`1.90
`i .81
`2.08
`
`*TIR ratio outside
`
`“—-
`
`1.0703
`1.1416*
`1.1836“
`
`P—value
`
`0.045
`0.057
`0.027
`
`28
`
`

`

`2-81
`3.41
`3-85
`
`2.96
`3.71
`
`4.54
`
`r ‘ _ '
`
`Dmin
`
`Product
`
`Ref
`
`Test
`
`:
`
`.
`
`‘
`
`_
`.
`.
`Wlthln lot % CV (n=10)
`
`Lot
`
`1""?
`
`L...£
`
`Range
`
`M L
`
`...)
`Range
`
`Product
`
`Ref
`
`Test
`
`TIR ratios
`
`‘L.
`
`.
`
`.
`
`J
`
`1
`
`5
`
`Distance (cm)
`
`Arithmetic mean
`
`Geometric mean
`
`I
`
`1.0556
`
`1.088]
`
`1.1784
`
`r-test comparison of variances
`
`Distance (cm)
`
`F~ratio
`
`0.79
`0.67
`0.65
`
`*TIR ratio outside " ,'__...—-
`
`CONCLUSION
`
`1.0573
`
`1.0927
`
`1.1874*
`
`P—value
`
`0.732
`0.859
`0.870
`
`Distance
`(cm)
`
`Mean
`n=30
`
`Mean of log
`n=30
`
`Between lot
`% CV
`
`Total
`% CV
`
`fl
`
`‘
`
`c._.J
`
`0.4457
`0.5282
`0.5788
`
`0.4699
`0.5667
`
`0.6534
`
`__________,__
`
`r—\
`
`L._J
`
`"]
`
`

`

`
`
`The spray pattern data for the 5 mg dosage strength is acceptable. For the 0.5 mg dose, the
`Dmin and Dmax Testheference geometric means ratios exceed the 5-— Iimit at the
`”—
`distance. At the -/ ‘ distance Dmin and Ovality were within the established limits.
`
`4.9 Does the comparative plume geometry summary data for the 0“ degree and 90"
`angles for the clinical device and the commercial device support the bioequivalence
`of the two products.
`
`5 MG PLUME GEOMETRY DATA
`
`Overall cv with raw data
`
`
`Total cv
`spray
`angle
`
`{‘1
`
`Product Degree
`
`Position Mean
`width
`
`
`Total cv Mean
`width
`length
`
`Total cv Mean
`length
`spray
`angle
`
`R
`R
`
`R
`
`T
`
`T
`
`T
`
`R
`
`R
`
`R
`
`T
`
`T
`
`0
`0
`
`0
`
`0
`
`0
`
`0
`
`90
`
`90
`
`90
`
`90
`
`90
`
`Begin
`Middle
`
`End
`
`Begin
`
`Middle
`
`End
`
`Begin
`
`Middle
`
`End
`
`Begin
`
`Middle
`
`99.41
`113.32
`
`126.87
`
`97.38
`
`118.11
`
`I 19.73
`
`99.40
`
`106.07
`
`122.03
`
`97.48
`
`108.52
`
`f‘fi
`
`167.93 F"
`231.27
`
`283.67
`
`137.13
`
`185.67
`
`208.27
`
`170.93
`
`228.60
`
`285.67
`
`144.00
`
`173.27
`
`54.07
`48.67
`
`43.00
`
`60.40
`
`5 I .47
`
`28.27
`
`50.13
`
`45.80
`
`39.00
`
`58.13
`
`47.33
`
`
`T
`90
`End
`115.13
`1“,
`200.20
`I \._1
`29.40 v _
`R
`Clinical.
`T
`Commercna]
`
`
`
`:| J; .4: «gulmtma
`
`3O
`
`

`

`Mean of log 10 of data
`
`
`Product Degree
`
`Position Mean of log width Mean of leg length Mean of log spray
`angle
`
`R
`
`R
`
`R
`
`T
`
`T
`
`T
`
`R
`
`R
`
`R
`
`T
`
`T
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`90
`
`90
`
`90
`
`90
`
`90
`
`Begin
`
`Middle
`
`End
`
`Begin
`
`Middle
`
`End
`
`Begin
`
`Middle
`
`End
`
`Begin
`
`Middle
`
`1.993
`
`2.052
`
`2.101
`
`1.984
`
`2.070
`
`2.075
`
`1.991
`
`2.022
`
`2.084
`
`1.985
`
`2.031
`
`2.221
`
`2.361
`
`2.451
`
`2.131
`
`2.264
`
`2.313
`
`2.226
`
`2.356
`
`2.454
`
`2.152
`
`2.230
`
`1.721
`
`1.675
`
`1.618
`
`1.773
`
`1.689
`
`1.428
`
`1.678
`
`1.645
`
`1.573
`
`1.756
`
`1.648
`
`T
`90
`End
`2.058
`2.290
`1.430
`
`R
`Clinical.
`'1‘
`Commercial.
`
`n0 “UH” ‘
`A 1‘5? in
`{Jill Ulisfliw '~
`
`_
`
`

`

`
`
`T/R ratios raw mean
`
`‘ Degree
`
`Position
`
`TIR arithmetic mean
`width
`
`TIR arithmetic mean
`length
`
`TfR arithmetic mean
`spray angle
`
`0
`0
`0
`90
`90
`90
`
`Begin
`Middle
`End
`Begin
`Middle
`End
`
`0.9795
`1.0422
`0.9437
`0.9807
`1.0231
`0.9435
`
`0.8166
`0.8028
`0.7342
`0.8424
`0.7579
`0.7008
`
`1.1171
`1.0575
`0.6574
`1.1596
`1.0335
`0.7538
`
`TIR ratios log data
`
`Degree
`
`Position
`
`TIR geometric mean
`width
`
`T/R geometric mean
`length
`
`T/R geometric mean
`spray angle
`
`0
`0
`0
`90
`90
`90
`
`Begin
`Middle
`End
`Begin
`Middle
`End
`
`0.9799
`1.0420
`0.9419
`0.9870
`1.0208
`0.9434
`
`0.8140*
`0.7999*
`0.7279*
`0.8442*
`0.7490*
`0.6853*
`
`1 . 1285*
`1.0330
`0.6462*
`1.1946*
`1.0067
`07180“
`
`*TfR ratio is less than or greater than ‘-————
`
`CONCLUSION
`
`The plume geometry data for the 5 mg nasal spray indicates that the TesUReference geometric
`means are outside of the acceptable limits. The firm should submit plume geometry data on the
`0.5 mg dosage strength.
`
`4.10.0verall Conclusions:
`
`The in vitro results for the following tests comparing the c