gateway webinar: strategies for biowaiver application for generic nasal sprays 102416

©Gateway Analytical, LLC 2016. All Rights Reserved.

Strategies for Biowaiver Application for Generic Nasal Sprays

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Date: October 27, 2016Start Time: 2:00 p.m. EDT (U.S & Canada)

Duration: 45 min. + Q&A time


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About Gateway Analytical

cGMP-compliant | FDA Registered & Inspected | ISO 17025 & ISO 9001

Standard five day turnaround and available one day turnaround!

Gateway Analytical is the innovative analytical testing laboratory that businesses around the world trust to provide solutions for their most challenging foreign particulate analysis, foreign particulate identification and materials analysis needs. Gateway’s expert scientists, specialized testing techniques and comprehensive analysis methods allow the company to deliver the fast, accurate and reliable results that customers in the pharmaceutical, materials and medical device industries demand. www.gatewayanalytical.com

http://www.gatewayanalytical.com/


About Next Breath

Next Breath, a member of the AptarGroup, is a full service laboratory specializing in analytical testing of a range of drug delivery systems from early stage to commercialization. They provide comprehensive solutions to the drug product development process from formulation development to CMC support for generics and new product submissions to regulatory agencies worldwide.

www.nextbreath.net


Meet Today’s Presenters

David ExlinePresident

Gateway [email protected]

David Exline has more than 20 years of experience in the areas of managing and administering analytical laboratories and consulting services. As the president of Gateway Analytical, he oversees the company’s day-to-day operations, business growth and service areas.

David has specific expertise in applying chemical imaging methods such as Raman, UV-Vis and NIR techniques to solve the most difficult pharmaceutical and material science problems for Gateway customers. David is adept in numerous pharmaceutical-related services and testing methods including: materials characterization, particulate contamination analysis, particle sizing and high-resolution microscopy.


Meet Today’s Presenters

Julie SumanPresidentNext Breath

[email protected]

Dr. Julie D. Suman is co-founder and President of Next Breath, LLC, a contract research organization dedicated to the development and analytical testing of nasal and inhalation delivery systems. Dr. Suman directs the research division that supports product development and regulatory submissions for North American and International Clients in the pharmaceutical, biotechnology and medical device markets. Dr. Suman holds a B.S. in Pharmacy from Duquesne University (1996) and a Ph.D. in Pharmaceutical Sciences from the University of Maryland, Baltimore (2002). She is a co-editor for Respiratory Drug Delivery Proceedings, an international symposium, and an adjunct assistant professor at the University of Maryland, School of Pharmacy in Baltimore, Maryland. She is also an Affiliate Assistant Professor in the Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University. Dr. Suman is the Past-Chair of the AAPS Inhalation Technology Focus Group. She is also a licensed Maryland pharmacist. Dr. Suman has published her research in peer-reviewed journals and has been presented during podium sessions at international meetings, the FDA Visiting Professor Lecture Series and has been an invited speaker at ANVISA in Brazil. Dr. Suman’s doctoral research, which focused on the relationship between in vitro tests for nasal sprays and in vivo deposition, has been recognized for excellence by a research award presented at the International Society for Aerosols in Medicine, 2001. In 2008, Dr. Suman received an award from the Greater Baltimore Committee for Entrepreneurial Spirit.


Outline of Today's Webinar• Overview of bioequivalence

• Intro to biowaiver concept

• Raman spectroscopy overview

• Techniques for biowaiver and data interpretation

• Biowaiver and in vitro bioequivalence strategies

• Q&A session

8 ©Gateway Analytical, LLC 2016. All Rights Reserved.

Overview of Bioequivalence


Global Regulatory Perspectives: Generics• FDA and Brazil (ANVISA) have issued guidances for bioequivalence

(BE) of nasal and pulmonary drug products• Europe (EMA) had issued a BE guidance on pulmonary products• China regulatory approaches increasing• Different approaches to bioequivalence

• EMA applies step-wise approach to BE• FDA applies weight of evidence• Brazil appears to follow FDA approach new details Nov 2016• Required tests and statistical approaches vary between regions


• Generally defined as the same rate and extent of absorption as the Reference Drug Product

• EU, US, Brazil and Canada all require bioequivalence

• Common goal: Determine the effectiveness of the proposed generic’s active ingredient[s] at the primary site of action

• Requirements for chemical “sameness” of the active- and non-active ingredients vary among regions

• In U.S., formulations are expected to be quantitatively and qualitatively the same (within 5% of reference drug)

• FDA recommends device designs be as close as possible in all critical dimensions to those of the reference product

Definition of Bioequivalence


FDA Approach for Bioequivalence • Clinical endpoint

• Same as a clinical study• Measures survival rate

• Pharmacodynamic (PD) endpoint• More sensitive than a clinical study• Measures lipid lowering

• Pharmacokinetic (PK)• In vitro tests• Nasal and respiratory drug products place special emphasis

on in vitro tests for ANDA applications

SE

NS

ITIV

TY T

O D

ETE

CT

DIF

FER

EN

CE

S


FDA Nasal Spray BE Requirements

• Locally Acting Solution• In vitro only

• Systemically Acting Solution• New guidances for Sprix, NasalFent,

Imitrex, etc.• In vivo: if not qualitatively (Q1) and

quantitatively (Q2) the sameOR• 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• Particle size removed for

mometasone BUT biowaivers possible


In Vitro BE Statistical Analysis Per FDA GuidanceNasal Spray ExampleIn 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 Cascade Impaction (Sprays) Comparison of means by PBE

Prime Reprime Point Estimate

Spray Pattern (SprayVIEW, Proveris

Scientific)


Introduction to Biowaiver Concept

©Gateway Analytical, LLC 2016. All Rights Reserved.15

Biowaiver• Typically considered a waiver of clinical

bioequivalence studies• Commonly used for oral solid dosage forms as

classified by the BCS (biopharmaceutics classification system)

• In 2016, FDA accepted data using Raman spectroscopy in lieu of a clinical endpoint study for mometasone nasal spray


Linking Particle Size to Bioequivalence• Rate of dissolution will potentially

affect local activity and extent of absorption

• Impacts local effect• Impacts bioequivalence• Ingredient-specific particle size

techniques objectively quantify API particle size and can differentiate API-API and API-excipient agglomerates

16


Raman Spectroscopy Overview


Raman Spectroscopy• Complimentary technique to FTIR• Also based on molecular vibrations• Based on scattering, rather than absorption, of light• Raman a useful technique for:

• Information about chemical structures, crystalline structure, polymorphisms, no sample prep, layered samples, inclusions in glass, minerals analysis, thin layer on a substrate


• Inelastic scattering phenomenon

• Laser based technique• Probes energy of

molecular vibrations - provides a “molecular fingerprint” Stokes

Scattering (III) h(-)

h

RayleighScattering (II) h

Anti-StokesScattering (I)

h(+)

LASER

Raman Spectroscopy Principle


Raman Spectra are specific

400 800 1200 1600 2000 2400 2800 3200 3600Raman shift (cm-1)

Offs

et R

aman

inte

nsity

methyl salicylate

diethyl malonate

triethyl phosphate

dimethyl methylphosphonate

Advantages• Little to no sample preparation• Small amount of sample required• Operates in ‘reflectance’ mode• Diverse experimental conditions (fiber optics &

microprobes)• Suitable for in situ monitoring (no vacuum

required)• Glass optics including fiber optics and fiberscopes• Usually nondestructive and noninvasive• Suitable for aqueous, gaseous and solid samples• Inorganic and organic material analysis• Water not an interference

Disadvantages• Moderate sensitivity (0.1-1 wt%)• Fluorescence interference (can be minimized)

Raman Spectroscopy Principle


Techniques for Biowaiver and Data Interpretation


Specialized Analysis - Automated Raman Spectroscopy with Raman/LIBS Overview


RESULT: Cellulose [Paper] RANK: 882, S/N

Sample Number- - >=10 >=25 >=50 >=100

batch1 48 42 5 0 1batch1 93 84 5 2 2batch2 43 34 3 2 4batch2 18 16 0 1 1batch3 234 221 9 3 1batch3 216 188 18 4 6batch4 47 46 1 0 0batch4 44 41 3 0 0

Size Distribution [µm]

Particle Sizing, Counting and Identification


• The Rap.ID Single Particle Explorer (SPE) • Combines optical microscopy (with automated counting/sizing software

and algorithm) with automated Raman analysis• Allows for the counting and sizing of an entire population of particles• Plus Raman characterization of a specific set of those particles

• Typically up to 500 particles• Particles are randomly chosen based on input criteria

• SPE has been primarily utilized for foreign particulate matter investigations of a population of particles and wear debris studies

• MDIs, DPIs, catheter sets, and other medical devices

SPE Capabilities


• New studies allow for analysis of the drug products themselves• Studies have been performed on MDIs, DPIs, nasal sprays,

lotions/ointments/gels• Types of analyses:

• API-specific particle size distribution• Polymorphism studies• Agglomerate analysis of APIs

SPE Capabilities


• Every product type is unique• Analysis success is dependent on many

factors:• If the instrument can “see” the particles of

interest• How Raman active API is• Overwhelming signal from excipients• API concentration

• Perform method development for every project

• GMP-compliant analysis

What we “see”

What instrument software “sees”

SPE Capabilities


SPE Capabilities


• Data obtained from analysis of nasal spray• One API

API-specific Particle Size Distribution


Size Distribution (non-cumulative) of Found and Measured Particles

Number Size Distribution [µm]

- - >=2.00 >=5.00 >=10.00 >=25.00 >=50.00 >=100.00

Analyzed 500 203 256 38 2 1 0

UnidentifiedExcipient 373 191 174 8 0 0 0

Albuterol 127 12 82 30 2 1 0

All Particles 15024 6070 7852 1055 40 7 0

• Data obtained from analysis of an aerosol-based meter dosed inhaler

• One API

API-specific Particle Size Distribution


• Collect reference spectra from each polymorph • Must have both/all forms• Must be Raman active material• Only 785nm laser on SPE

• Build customer-specific database for subsequent searching• Prep and run sample on aluminum-coated slide

• Database can automatically identify APIs, including different polymorphisms

• All spectra manually confirmed as correct type

Polymorphism Studies


• Confirm/reject whether agglomerate by viewing 50x images collected by instrument during analysis

• Single API particles and agglomerates can then be classified separately• All agglomerates will be rejected with this method

• No way to identify API or excipient agglomerate via images

• Analysis can also be performed in “verification mode”• Allows analyst the ability to relocate all identified API particles manually• Perform additional manual Raman

• This allows API-API agglomerates or API-excipient agglomerates to be determined• Perform manual sizing of the different parts of agglomerate• Very time intensive; costly to customer

Agglomerate Analysis


• Manual relocation of an agglomerated particle for further Raman analysis

• Determined to be an API-excipient agglomerate

Agglomerate Analysis


FLONASE™: Size Distribution (non-cumulative) of API Particles


- - >=2.00 >=3.00 >=4.00 >=5.00 >=6.00 >=7.00 >=8.00 >=9.00 >=10.00 >=25.00

Fluticasone Propionate 137 53 44 29 8 1 2 0 0 0 0

Agglomerates 46 0 2 13 13 6 4 6 1 1 0

Total API 183 53 46 42 21 7 6 6 1 1 0

API Particle Sizing Results for Innovator Nasal Spray (Flonase™)

GENERIC: Size Distribution (non-cumulative) of API Particles


- - >=2.00 >=3.00 >=4.00 >=5.00 >=6.00 >=7.00 >=8.00 >=9.00 >=10.00 >=25.00

Fluticasone Propionate 102 31 19 23 19 2 2 0 0 0 0

Agglomerates 36 0 0 5 11 11 2 5 0 2 0

Total API 138 31 19 28 30 13 4 5 0 2 0

API Particle Sizing Results for Generic Nasal Spray (Equate)

API-specific PSD and Agglomerate Analysis


Innovator(Flonase™) Generic (Equate)

D10 2.2 2.2

D50 3.2 3.6

D90 4.8 5.5

Min 2.1 2.1

Max 7.7 7.6

Mean 3.41 3.80

API PSD statistics; Single Particles Only

API-specific PSD Results and Histogram


0

5000

10000

15000

20000

25000

30000

400 800 1200 1600 2000 2400 2800 3200Raman shift (cm-1)

Inte

nsity

Brightfield Image

• Sample comprised of six ingredients (one API, five excipients)• Bulk Raman spectrum an average representation of the sample• Minor constituents masked in bulk, average measurement

Average Raman Spectrum

Conventional Spectroscopy of Nasal Spray Suspension


• Chemical imaging reveals properties of individual ingredients within complex mixtures• Pure pixel spectra measurable• Material identification and ingredient specific morphologies can be detected

Pure Component Raman Spectra

API Raman Image/Brightfield Image Raman Shift (cm-1)

Offs

et In

tens

ity

EXCIPIENT #5

API

EXCIPIENT #1

EXCIPIENT #4

EXCIPIENT #3

EXCIPIENT #2

1657 cm-1

1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000

36

Raman Chemical Imaging of Nasal Spray Suspension


What is Chemical Imaging?Hyperspectral Imaging for the chemical analysis of materials

Why Chemical Imaging?• Rapid• Non-contact & nondestructive• High information content

Image Contrast Based on Composition, Structure & Concentration

Massively Parallel Spectroscopy

x

y21

3n-1

lXI1,J1

XI2,J2

4

Optical Imaging of multiple components in formulated nasal spray

0.0

0.4

0.8

1.2

600 1200 1800 2400 3000Raman Shift (wavenumbers)

• Spectroscopy provides fingerprint for the material• Enables ID of trace materials in complex

backgrounds

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

0

10

20

30

40

50

60

70

80

Max Chord (µ)

Tota

l Par

ticle

s

D50 = 3.23 µ, Total Particles 383D50 = 5.10 µ, Total Particles 118

BudesonidePotassium Sorbate


Nasal Spray API CharacterizationRaman Chemical Imaging ISPS Process

5. Data processing 6. Statistical analysis

2. Raman dispersive spectroscopy

1648 cm-1

Offs

et In

tens

ity

1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000Raman Shift (cm-1)

EDTA

BUDESONIDE (API)

POTASSIUM SORBATE

AVICELDEXTROSE

POLYSORBATE 801657 cm-1

4. Brightfield Imaging & RCI

1. Cosmic Filter

2. Bias Correction

3. Vector Normalization

4. API Peak Frame extraction

5. Gaussian Filter

6. Brightfield Guided Binarization

7. Boundary Particles Removed

Total Particles 313

Median ± std. dev. 3.5 ± 3.1 µm

D50 3.5 µm

D90 8.5 µm

3. Optimize spectral range for Raman Chemical Imaging

0

10

20

30

40

50

60

2 4 6 8 10 12 14 16 18Max Chord (µm)

Freq

uenc

y

1. Sample preparation

Pure components

Formulated product


ISPS Batch ComparisonBudesonide in Rhinocort Aqua

• Provides a fundamental understanding of API particles in the presence of undissolved excipients in the formulation

• Can be used to study• Ingredient-specific particle size• Shape• Aggregation• Dispersion characteristics

• Sample types include• OINDPs• Semi-solid creams, ointments & gels• Transdermal drug delivery systems.

39

BFR/RCI Fusion (Batch #1)

BFR/RCI Fusion (Batch #2)

1 2 3 4 5 6 7 8 9 10 11 12 13 140

0.10.20.30.40.50.60.70.80.9

1 Batch1 PSD Batch 2 PSD

Maximum Chord, μm

Nor

mal

ized

Fre

quen

cy

Statistic Batch 1 Batch2Total Particles 1060 1408

D10 (µm) 2.1 2.1D50 (µm) 3.5 3.6D90 (µm) 7.0 7.1

Standard Deviation (µm) 2.3 2.5


Biowaiver and In Vitro Bioequivalence Strategies


• Phase 1• Method feasibility to confirm API can be positively

identified• Pure component analysis• Product analysis

• Optional formulation confirmation• Confirm API source• Presence of polymorphs

• Phase 2• Raman spectroscopy analysis of test and RLD

The Path Forward


• Phase 2 Continued• Utilize result to prepare for meeting with FDA

• Agree on analysis process• Agree on validation procedure

• Next Breath and Gateway support available for FDA meeting

• Phase 3• Validate Raman spectroscopy method• Perform BE study on RLD and test by SPE• Perform remaining in vitro BE studies

The Path Forward


It’s Time for the Q&A Session


Contact Us and Follow-up

Get insights from our blog:www.gatewayanalytical.com/blog

Contact InformationDavid ExlinePresidentGateway [email protected]: 724-443-1900 x106

Julie SumanPresidentNext [email protected]: 412-983-1634

Paige CohenBusiness Development [email protected]: 724-443-1900 x129

Angus MillerGlobal Marketing [email protected]: 724-443-1900 x132

@GatewayTweets

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