In-depth Characterizations of OINDPs from R&D to Regulatory Submission

©Gateway Analytical LLC. 2015
In-depth Characterizations of OINDPs
from R&D to Regulatory Submission
Join Gateway Analytical and Next Breath scientists as they discuss the value of
drug product development for nasal sprays.
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About Us
Gateway Analytical is a full service analytical testing laboratory that features specialized
expertise in particulate identification. We provide detailed analysis to characterize and identify
particulate while providing extended customer support to help identify the source of
contaminates.
Next Breath, a member of AptarGroup, is a cGMP specialty Contract Research Organization (CRO)
with analytical expertise for pharmaceutical, biotechnology, and consumer health product
development focused on pulmonary, nasal, topical and ophthalmic delivery systems.
Collaborative Expert Support:
– Reduced risk of clinical trials
– Mitigation of device failure
– Meet deadlines to get products to market
– Advance bioequivalence studies

About the OINDP Webinar Series
Gateway Analytical and Next Breath have partnered to present a webinar
series to provide a comprehensive review of their in-house analytical
technologies, GMP methods, and specialized expertise.
2016 Presentation Topics in our OINDP Webinar Series:
– Characterization of MDIs from R&D to Regulatory
Submission
– Characterization of DPIs from R&D to Regulatory
Submission
– Injectable Drug Products – CMC Requirements and
Forensic Analysis

Meet Today’s Presenters
Oksana Olkhovyk, PhD
Sr. Scientist
Gateway Analytical
olkhovyko@gatewayanalytical.com
Julie Suman, PhD
Co-Founder & President
Next Breath, LLC
julie.suman@nextbreath.net

Outline of Today's Webinar
• Utilization of ISPS to support formulation development, API and
excipient selection
• Linking particle size to bioequivalence
• Pre Bioequivalence studies
• Techniques and methods for identification of foreign particulates
• Stability studies FAQ
• Abbreviated new drug application - Common deficiencies
• Q&A Session

OINDPs Formulations
The most critical attributes: raw materials testing,
reproducibility of the drug dose and drug particle size
distribution
.

How Can Chemically Specific Imaging
Gives the Details for Bioequivalence?

Specifications for the Active Ingredients in
OINDPs that Can be Obtained with ISPS:
 Particle size distribution
 Particle morphology
 Solvates and hydrates
 Crystalline forms
 Polymorphs
 Amorphous forms
Optical microscopy is the method used for release and stability data
submission for evaluation of:
• Drug substance particle size
• Presence of large particles
• Degree and extend of agglomerate
• Crystal grows
• Foreign particular matter
Limitations of optical microscopy : subjective; does not distinguish
between chemical compounds

Reverse Engineering
Deformulation

API/Excipients selection
• Raw materials testing-comparison with
innovator product
• API/Excipient compatibility studies
• Vendor/manufacturer/lot-to lot variability
analysis
• Polymorphic form confirmation
• Purity analysis

Instrumentation / Equipment for API/Excipients selection
• Optical Microscopy
• Chemical Imaging
– Raman Chemical Imaging
– Fluorescence Chemical Imaging
– Visible Chemical Imaging
– NIR Chemical Imaging
• Raman Spectroscopy
• EDS-Scanning Electron Microscopy
• Fourier Transform Infrared
Spectroscopy
• Wet Chemistry
• Specialized Sample Preparation
– Digital Sample Documentation
– Microtoming Service
– Vacuum Filtration
– Class 5 ISO Certified Preparation
Environment

Identification and Sizing of Drug and
Agglomerated Drug Particles
in Pharmaceutical Formulations
RCI technique has the potential to
address the FDA’s requirement for
direct measurement of drug
particle size distribution and
extent of agglomerates in nasal
spray suspensions, by validated
RCI technique as qualitative and
semi-quantitative method for
examination of drug and
aggregated drug particle size
distribution for formulations
containing suspending agents*.
*In FDA, “Draft Guidance for Industry
Bioavailability and Bioequivalence Studies
for Nasal Aerosols and Nasal Sprays for
Local Action,” for suspension products,
drug particle size distribution and extent of
agglomerates should be characterized in
spray or aerosol formulation prior to
actuation, and in spray following the
actuation to characterize the potential
influence of the device on
deagglomeration.

ISPS Batch Comparison
Budesonide in Rhinocort Aqua (Raw Data)
0
0.2
0.4
0.6
0.8
1
1 2 3 4 5 6 7 8 9 10 11 12 13 14
NormalizedFrequency
Maximum Chord, μm
Batch1 PSD
Batch 2 PSD
Statistic Batch 1 Batch2
Total Particles 1060 1408
D10 (µm) 2.1 2.1
D50 (µm) 3.5 3.6
D90 (µm) 7.0 7.1
Standard Deviation (µm) 2.3 2.5
BFR/RCI Fusion (Batch #1) BFR/RCI Fusion (Batch #2)
Batch comparison
results in passing of a
Kolmogorov-Smirnov
test for non-normal
distributions

Nasal Spray Suspensions:
Temperature Stability Study
A
100µm
B
A
B
100µm100µm
A
B
°
Commercial
Nasal Spray
A
B
100µm
-20 ° C
Nasal Spray
60 ° C
Nasal Spray
Room Temperature
Nasal Spray
Chemically Specific Analysis of OINDP: Differentiation of Drug Particle Agglomeration by Raman
Chemical Imaging, Olkhovyk O, Ngo D, Doub WH, Respiratory Drug Delivery 2014. Volume 2, 2014: 423-
426.

Sample
ID
Total
#
%
Agglomerates
API-API/
API-
Excipient
Primary Particles API-API
Agglomerates
API-Excipient
Agglomerates
D50 STD Mean D50 STD Mean D50 STD Mean
RT NS 103 14/15 3.3 1.0 3.5 3.6 1.4 4.2 3.7 1.0 3.9
-20 °C NS 131 10/11 3.4 1.2 3.7 4.0 1.7 4.5 3.6 0.8 3.8
60°C NS 105 9/19 3.4 1.2 3.6 5.3 1.6 4.7 3.9 1.2 4.1
Commercia
l NS
261 23/25 3.8 1.3 4.0 4.8 1.6 5.3 4.2 1.2 4.4

0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0
5
10
15
20
25
30
35
40
45
1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8 8.5 9 More
Frequency
Equivalent Circular Diameter, µm
RT NS
-20 °C NS
60°C NS
Commercial NS
Cumulative %
Cumulative %
Cumulative %
Cumulative %

Polymorph Identification of Drug
Particles in Orally Inhaled and
Nasal Drug Products

particles in OINDP
• Increasing demand in Polymorph ID of drug particles in nasal spray
suspensions and cream/ ointments products due to the FDA
regulations related to reporting and confirming Polymorphic form
of the drug particles in finished product “Section 505(j) of the Act
specifies that an ANDA must contain, among other things,
information to show that the active ingredient in the generic drug
product is the "same as" that of the RLD” *
*Guidance for Industry ANDAs: Pharmaceutical Solid Polymorphism Chemistry, Manufacturing, and Controls Information U.S. Department of Health and
Human Services; FDA , (CDER) July 2007;
**Upon demonstration of in-vivo bioequivalence between the generic drug product16 and the reference listed drug (RLD),17 in-vitro dissolution testing is
then used to assess the lot-to-lot quality of the generic drug product. Drug product dissolution testing frequently provides a suitable means to
identify and control the quality of the product from both the bioavailability and physical (stability) perspectives. In particular, inadvertent changes to
the polymorphic form that may affect drug product BA/BE can often be detected by drug product dissolution testing.

particles by RCI
• As part of ISPS services GA offers Polymorph
Identification of Drug particles in nasal spray
suspensions, creams, gels, ointments by RCI, as
qualitative and semi-quantitative method for
examination of drug Polymorph ID
• The method is based on already validated ISPS
for nasal spray suspensions

Polymorph Identification of Drug particles
• Raman spectroscopy is used to create Raman spectral library (reference spectra) of the pure form
of the drug substance confirm Polymorph Form of drug substance supplied in powdered form and
compare the positions of Raman peaks to reported in literature Raman spectra for the Polymorph
form of the Drug substance
• Reference Polymorph Raman spectra is used to confirm the polymorph of Drug particles in
suspensions as compared to pure component
• Manual particles selection-spectral acquisition and comparison by analyst for number of particles
specified per customer request (10 or more)
0
0.05
0.1
0.15
0.2
600 800 1000 1200 1400 1600 1800
Scaled Intensity, a. u.
Raman Shift, cm-1
PARTICLE RAMAN SPECTRUM
DRUGPURE COMPONENTRAMANSPECTRUM

Method Validation

GA Process for Addressing
the Method Validation
• For most of the routine analyses Gateway
Analytical uses USP methods
• For using RCI for ISPS, we perform the
following steps:
– Phase I – Write Validation Protocol
– Phase II – Implement Validation Protocol
– Phase III – Provide Data to Establish Bio-
Equivalency

Phase I – Writing validation protocol
• Required by FDA to have a written method
and validation protocol plan
• To set pre-determined acceptance criteria
• To receive client input and acceptance of the
plan for the validation study

Phase II – Implementation of Validation Protocol
cGMP Validation Study Conclusions
• The following can be demonstrated by
implementing Validation protocol:
– Suitability and reliability of the Falcon II Raman
Chemical Imaging System for ISPS analysis
– Suitability and reliability of the RCI method for ISPS
analysis
– Ability to accurately and precisely prepare and analyze
a Generic and Innovator Nasal Spray Suspension
– Establish similarity of Generic nasal spray suspension
to the Innovator product based on statistically
significant number of drug particles PSD

NIST- traceable PSMS Stand-Alone and
Agglomerates Identification and Sizing for accuracy
and precision determination
Representative Raman White Light (RWL) Image (A); Binary Mask-Processed RCI image
(B) and RWL/RCI fusion Image of 5μm sizes PSMS (false colored in green)
• RCI-based approach to identify and accurately size agglomerated particles can be easily challenged and
verified for the sizing precision and accuracy on NIST- traceable sizing standards such as Polystyrene
Microspheres (PSMS) of same sizes
• Current example features 2 stand-alone 5 μm PSMS and 1 agglomerated 5 and 5 μm PSMS. Max chord of
agglomerate should be a 10 μm
A B C
10μm
5μm
5μm

Phase III – Provide Data to Establish
Bio-Equivalency
• Final BE step includes ISPS analysis of 60 samples (30
generic and 30 innovator)
– to support the submission of this validated method for
review by the FDA
• Raman Chemical Imaging for ISPS offers an objective
evaluation of API particle size in complex matrices like
nasal spray suspensions
• Statistical analysis of brand vs generic products based
on the for PSD sameness assure confidence prior
submissions
• Expert support during FDA reviews/evaluations

Poll Question #1
• What part of R&D you outsource the most?
• A: Raw materials testing
• B: API PSD analysis
• C: Stability testing

Linking Particle Size to
Bioequivalence
Rate of dissolution will potentially
affect local activity and extent of absorption
.

Linking Particle Size to Bioequivalence

FDA Approaches for Bioequivalence
• Clinical endpoint
– Same as a clinical study
– Measure survival rate
• Pharmacodynamic (PD) endpoint
– More sensitive than a clinical study
– Measure lipid lowering
• Pharmacokinetic (PK)
• In Vitro Tests
SENSITIVTYTODETECTDIFFERENCES

FDA Nasal Spray BE Requirements
• Locally Acting Solution
– In vitro only
• Systemically Acting Solution
– New guidance's for Sprix,
NasalFent 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

In Vitro BE Statistical Analysis Per FDA Guidance
In 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)

Approaches for Increasing Success for In Vitro BE
(IVBE)
• 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

Droplet Size (Dv50) Method Comparison
Test
RLD

Spray Pattern (Area) Method Comparison
Test
RLD

Pre Bioequivalence Studies
Investigate likelihood of a successful outcome
.

Pre-BE Studies
• KEY TEST METRICS
– Innovator and generic pumps tested with innovator formulation
– Hand study determined actuation parameters
– All units actuated using Proveris Scientific platform
– Droplet size (DSD) measured at beginning and end of unit life using a
Malvern Spraytec
– Spray pattern (SP) measured using SprayVIEW
– Plume geometry (PG) measured using SprayVIEW
– Statistical analysis by population bioequivalence (PBE) and point
estimates

IN VITRO BIOEQUIVALENCE: INNOVATOR VS GENERIC
• RESULTS
– All results show as average of 15 bottles
• IVBE SUMMARY
DSD - 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 Width
Innovator
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Generic
Outcome of Population Bioequivalence (PBE) Statistics reported for Beginning of Life (BOL) and End of Life (EOL)
Average Spray Pattern Results
Dmax (mm) Dmin (mm) Ovality Ratio Area (mm2)
3 cm 6 cm 3 cm 6 cm 3 cm 6 cm 3 cm 6 cm
Innovator 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 Generic
Spray Angle (°) 51.0 52.0
Plume Width (mm) 28.9 29.3
0
20
40
60
80
100
120
Dv10 Dv50 Dv90
Microns
Droplet Size Distribution - 3 cm
Innovator
Generic
0
20
40
60
80
100
120
Dv10 Dv50 Dv90
Microns
Droplet Size Distribution - 6 cm
Innovator
Generic

Preparing for In Vitro Bioequivalence
• Validation with using Reference Drug Product
– Consider incorporating test product
• Blinding and randomization
• Flexibility in BE protocol
– Statistical justification to add additional units
• Coordinate IVBE with stability
– Release testing performed with IVBE

FDA CMC Specifications for Nasal Sprays
• Appearance
• Identification
• Assay
• Impurities and degradation
products
• Particulate matter
• Microbial limits
• Net content
• Leachables
• Weight loss on stability
• pH, osmolality, viscosity
• Pump delivery
• Spray content uniformity
• Spray pattern
• Plume geometry
• Droplet size distribution
• Particle size distribution
Release Testing
Stability
Support IND or NDA
Refer to CMC guidance—not all tests
required on stability

One Time CMC Studies—Nasal Sprays
• Cascade Impaction
– If for BE, not a CMC study
• Robustness
– Drop & Vibration Testing
– Cleaning
• Temperature Cycling
• Photostability
• Tail-off
• Effect of Dosing Orientation
• Prime/Reprime Studies
– Two orientations required
– If for BE, one orientation for BE,
second for CMC purposes
Short stack Andersen
Cascade Impactor

• R&D stability
–Duration variable
• Registration stability
–Three batches
–Stored in two orientations
• Upright and inverted
• Upright and horizontal
–Duration 2 to 3 years
–Total number of nasal spray
units tests: 12,000 – 20,000 units
Stability Studies

Stability & Release
• Recommend including spray pattern in stability programs
• Release strategies (US persective)
– Spray pattern and droplet size
• Test 10 bottles x 1 spray per batch, report results on 10
sprays
OR
• Test 3 bottles x 3 sprays, report average for each bottle
• Foreign particulate matter
• Techniques are advancing

Poll Question #2
• Do you include spray pattern in your stability
programs?
– Yes
– No
– Not Sure

Contamination
Code of Federal Regulations, ICH Guidelines
“The undesired introduction of impurities of a chemical or
microbiological nature, or of foreign matter, into or onto a raw
material, intermediate, or API during production, sampling,
packaging or repackaging, storage or transport.”

“The undesired introduction of impurities of a chemical or
microbiological nature, or of foreign matter…”
What kind of contaminations appear?
• Contamination can involve different types of
failures, such as contamination related to
particulate OR sterility
• Sterile = related to the presence of
microorganisms
• Particulate = related to the presence of foreign
particles

“…into or onto a raw material, intermediate, or API…”
Where do contaminants appear?
• Contaminants in the final formulation may be
introduced from various sources
• OINDP are combination products of drug
formulation and device
• Drug(s)
• Excipient(s)
• Container Closure System

 The pursuit of quality in all aspects of service and all service
offerings is critical to the results, interpretation and defense
of analytical data.
 Testing under cGMP conditions
 Validation of methods
 Validation of instrumentation
 Traceable reference standards
 Training, proficiency testing
Quality Control
 How do you use a validated method or process when the
sample is unknown?

Sample Preparation
• Collection of emitted dose in particulate free
environment
• Dissolution of API
• Dissolution of Excipients

Preparation of Filter – Automated Raman
Gold Coated Polycarbonate Filter Filtration Preparation
• Low blanks
• Cleanroom manufactured
• System integrated
• High sensitivity
• No background signal for ID

Commonly Found Sources of Particulate
Contamination
• Stainless Steel
• Human/Animal Hairs
• Paint
• Glass (delamination)
• Rubber (stoppers)
• Polymers
• Insects
• Silicone Products
• Teflon
• Synthetic Fibers
• Natural Fibers
• Labels
• Burned Material
• Paper Products
• Metals
• Environment

Single Particle Explorer SPE-Is
raman.ID + Metal.ID system
Fast ID robot:
Image Analysis @ 2 µm
Particle Count, Size and Shape
Image Directed Spectroscopy
Chemical Structure ID @ 2µm (Raman)
 1-60s/Particle
Statistically meaningful results,
fully compliant

An Overview of Database Entries
• Active ingredients and additives
• Water and gases
• Production machines
• Filling process and equipment
• Surroundings
• Personnel and clothing
• Cleaning process
• Containers and seals

Foreign Particulate Matter in MDIs and DPIs

0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0
50
100
150
200
2 10 20 30 40 50 60 70 80 90 100 150 200 500 1000More
Frequency
Size, µm
Sample 1
Sample 2
Cumulative %
Cumulative %Sample 1
Sample 2
Comparison of FPM in MDI Samples

Size Distribution (non-cumulative) of Found and Measured Particles –Sample1
Number Size Distribution [µm]
- - >=2.00 >=10.00 >=25.00 >=50.00 >=100.00 >=1000.00
Analyzed 500 204 71 86 104 35 0
Titanium(IV)oxide,
Anatase
1 0 0 0 1 0 0
Polystyrene 335 117 40 65 88 26 0
Polyethylene 13 8 2 1 2 0 0
Polyamide 70 25 22 14 8 1 0
Poly(acrylonitrile) 3 2 0 0 1 0 0
Nitrocellulose 2 2 0 0 0 0 0
Nitrate Sodium 1 1 0 0 0 0 0
Fluorescence 63 43 6 4 4 5 0
Filling material 2 1 0 0 0 1 0
Fiber 1 0 1 0 0 0 0
Cellulose 9 5 0 2 0 2 0
All Particles 3376 2071 868 298 104 35 0
Size Distribution (non-cumulative) of Found and Measured Particles –Sample2
Number Size Distribution [µm]
- - >=2.00 >=10.00 >=25.00 >=50.00 >=100.00 >=1000.00
Analyzed 500 157 43 256 41 3 0
White Petroleum Jelly 1 1 0 0 0 0 0
Titanium(IV)oxide,
Anatase
2 0 0 1 1 0 0
Sulfate Calcium 1 0 0 1 0 0 0
Polystyrene 313 61 31 189 34 0 0
Polyethylene 5 0 1 3 1 0 0
Polyamide 58 3 4 49 2 0 0
Clothing 1 0 0 1 0 0 0
Fluorescence 94 80 8 4 2 2 0
Fiber 8 5 1 2 0 0 0
Storage bags 2 1 0 1 0 0 0
Cellulose Acetate 1 0 0 1 0 0 0
Cellulose 6 0 0 4 1 1 0
All Particles 4077 2863 906 264 41 3 0

How Does Combined Raman/LIBS
Compare to Other Technologies?
• Particle size is important factor
– LIBS not applicable to 2-10 micron range
– CCSEM may be applicable as complimentary
technique
• Fast analysis
– Manual confirmation often required for large
fluorescent populations
• General characterization of population
• Cost effective for overall population evaluation

Achieving BA/BE for OINDPs
Relying on our expertise and knowledge for
in-depth characterization of the nasal product will:
– Assist with establishing BA/BE of OINDP prior to
clinical trials
– Assist with BE submissions of OINDPs
– Help identify product failure root causes
– Assist in process control
– Improve product quality
– Get to the market first!

Poll Question #3
• Do you need to do foreign particulate analysis
for your product?
• A: Yes
• B: No

USA: Abbreviated New Drug
Application Common Deficiencies
• Case #1: Multiple actuations were used in the
spray pattern testing and the average of
multiple actuations was used to conduct PBE
analysis
• Recommendation: As per the Draft Nasal
Guidance, one single spray should be used for
the spray pattern determination test
Source – Orlando Inhalation Conference: Approaches in International Regulation
Orlando, FL, March 20, 2014 – FDA OGD

• How many retention samples should be reserved for
each site of in vivo and in vitro BE studies of NS?
• If the BE studies are conducted at one site: at least 50
units for each batch of Test & RLD, including placebos
(if applicable)
• If the BE studies are conducted at multiple sites: at
least 50 units for each batch of test and RLD
• The FDA will ask to see retained samples during Pre-
approval Inspection (PIA)
• Not specified in EMA and HC

• What are FDA’s expectations for plume
height? The automated systems (Sprayview
and ADSA) cannot calculate an actual plume
height.
• Currently, plume height data is submitted as
supporting evidence only. FDA does not set
specific criteria for plume height evaluation.

• The sponsor used water (or test product) to
conduct the validation studies for IVBE
• FDA recommends the use of reference drug
product to conduct the validation studies for
IVBE

It’s Time for the Q&A Session

Contact Us & Follow-up
For more information on our services or upcoming webinar events:
www.gatewayanalytical.com
www.nextbreath.net
Contact Information
Oksana Olkhovyk, PhD
Sr. Scientist
Gateway Analytical
olkhovyko@gatewayanalytical.com
Tel: 724-443-1900 x102
Julie Suman, PhD
Co-Founder & President
Next Breath
julie.suman@nextbreath.net
Tel: 410-455-5909
Paige Cohen
Sales Development Associate
cohenp@gatewayanalytical.com
Tel: 724-443-1900 x129

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In-depth Characterizations of OINDPs from R&D to Regulatory Submission

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