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

©Gateway Analytical LLC. 2015©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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©Gateway Analytical LLC. 2015

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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, PhDSr. Scientist

Gateway [email protected]

Julie Suman, PhDCo-Founder & President

Next Breath, [email protected]


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 ImagingGives 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 ComparisonBudesonide in Rhinocort Aqua (Raw Data)

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

0.2

0.4

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0.8

1

Batch1 PSDBatch 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

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

100µm

\\LAB_FALCON_TOTO\Dropbox\Users\Olkhovyk\LS-13-0611\RT\RT_ROI2

100µm

A

B

°

CommercialNasal Spray

AB

100µm

- 20 ° CNasal Spray

60 ° CNasal Spray

Room TemperatureNasal 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 4.1Commercia

l NS261 23/25 3.8 1.3 4.0 4.8 1.6 5.3 4.2 1.2 4.4



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 More0

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0%

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RT NS

-20 °C NS

60°C NS

Commercial NS

Cumulative %

Cumulative %

Cumulative %

Cumulative %

Equivalent Circular Diameter, µm

Freq

uenc

y


Polymorph Identification of Drug Particles in Orally Inhaled and

Nasal Drug Products


Polymorph Identification of Drug 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.


Polymorph Identification of Drug 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

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0.15

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600 800 1000 1200 1400 1600 1800

Scaled Intensity, a. u.

Raman Shift, cm - 1

PARTICLE RAMAN SPECTRUM

DRUG PURE COMPONENT RAMAN SPECTRUM


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

SE

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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

exposureAND– In vitro


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 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 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

Dv10 Dv50 Dv900

20

40

60

80

100

Droplet Size Distribution - 3 cm

InnovatorGeneric

Mic

rons

Dv10 Dv50 Dv900

20406080

100120

Droplet Size Distribution - 6 cm

InnovatorGeneric

Mic

rons


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 TestingStability

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


ContaminationCode 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 drugformulation 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


2 10 20 30 40 50 60 70 80 90 100 150 200 500 1000

More

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50

100

150

200

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10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Sample 1

Sample 2

Cumulative %

Cumulative %

Size, µm

Freq

uenc

ySample 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 RegulationOrlando, 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 Source – Orlando Inhalation Conference: Approaches in International Regulation

Orlando, FL, March 20, 2014 – FDA OGD



• 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, PhDSr. ScientistGateway [email protected]: 724-443-1900 x102

Julie Suman, PhDCo-Founder & PresidentNext [email protected]: 410-455-5909

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

http://www.gatewayanalytical.com/

http://www.nextbreath.net/

mailto:[email protected]




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