Bioequivalence of Oral

Generic Product with An

Alternate Administration

Minglei Cui, Ph.D.

CDR, U.S. Public Health Service

Division of Bioequivalence 2

Office of Generic Drugs

CDER/FDA

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Disclaimer & Disclosure

• The following presentation reflects the opinions

of the author and does not necessarily represent

the official position of the US-FDA

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Agenda

• Background

• Current BE recommendation

• In vitro NG tube testing

• Common deficiencies in ANDA submissions

• Summary and conclusion

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Bioequivalence • Bioequivalence means the absence of a

significant difference in the rate and extent to which the active ingredient becomes available at the site of drug action (21 CFR

320.1)

• Bioequivalence studies compare formulation performance (because the active ingredient is identical)

• Products with equivalent performance will produce the same effect when used in the same patients

Bioequivalence of Drugs with

Alternate Administration

• In vivo measurement of active moiety or

moieties in biologic fluid

– “Pharmacokinetic (PK) study” (fasting and fed)

• In vivo or vitro comparison

– Bioequivalence and substitutability need to be

established for all types of alternate administration

(e.g. tube delivery) for which the RLD is approved

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A feeding tube is a medical device used to provide nutrition or medication to

patients who cannot obtain nutrition or medication by swallowing. They are

classified according to the site of insertion, such as Nasogastric (NG) tube,

Gastrostomy (G) tube, and Jejunal (J) tube.

Size: 5-18F

Material: polyurethane, silicone, Tygon

Size: 14-28F

Size: 14-18F

Feeding Tube

NG tube:

G tube

J tube

1 French unit=0.33 mm

Drugs with Approval for NG tube

Administration • PPI Drug

– Prevacid (Lansoprazole) Delayed-Release Capsules

– Prevacid SoluTab (Lansoprazole) Delayed-Release Orally

Disintegrating Tablets

– Nexium (Esomeprazole) Delayed-Release Capsules

– Esomeprazole Strontium Delayed-Release Capsules

– Dexilant (Dexlansoprazole) Delayed-Release Capsule

– Nexium (Esomeprazole) for Delayed-Release Oral Suspension

– Prilosec (Omeprazole) for Delayed-Release Oral Suspension

– Zegerid (Omeprazole/Sodium Bicarbonate) for Oral Suspension

– Protonix (Pantoprazole) For Delayed-Release Oral Suspension

• Non PPI drug (e.g. Morphine Sulfate MR Capsule;

Xarelto® (Rivaroxaban) Tablets)

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Substitutability Concern for Drug Products

with Alternate Administration

• Adverse event complaints for Lansoprazole

delayed-release ODT

– FDA received adverse reports

– A generic lansoprazole ODT clogged and blocked

feeding tubes

• FDA issued a letter to health professional on

4/15/2011

• This product was voluntarily withdrawn from

distribution

QbD Approach For Product With

NG Tube Administration

• Formulation and process design of the generic to

reduce potential risk

– Particle/granule size

– Surface characteristics (e.g. Integrity of coating material)

– Total mass

– Excipients (e.g. insoluble excipient)

• In vitro testing to support labeled tube administration

• Demonstration of robustness of in vitro testing

– Different tube material

– Tube size

– Length 9

OGD’s Current Thinking

• In vitro testing should be requested if a product

is a solid oral dosage form and contains

instructions for NG tube administration in the

RLD labeling

• The specific in vitro testing requirements may be

different for individual drug products:

– Instruct slightly different based on product’s label

and/or formulation characteristic of the RLD

– Waive the in vitro testing for BCS Class I Immediate

Release dosage form

Draft Guidance with NG Tube Testing

• Lansoprazole DR Capsule

• Esomeprazole Strontium DR Capsule

• Esomeprazole Magnesium DR Capsule

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Labeled Alternative Administration

• NEXIUM® (Esomeprazole magnesium) DR Capsules

– Empty the intact granules into syringe and mixed with 50 mL of

water

– Attach the syringe to a nasogastric tube and deliver the contents

through the nasogastric tube into the stomach

– The mixture must be used immediately after preparation.

– Product can be used for infant patient (less than 1 year old)

• PREVACID® (LANSOPRAZOLE) DR Capsules

– Nasogastric Tube (≥16 French)

– Mix intact granules into 40 mL of apple juice. DO NOT USE

OTHER LIQUIDS.

– Inject through the nasogastric tube into the stomach.

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In Vitro NG Tube Testing

• FDA-recommended in vitro NG tube testing

– Sedimentation testing

– Particle size distribution study

– Recovery testing

– Comparative acid resistance stability testing

• Variation of the testing conditions per labeling

– Medium (water or apple juice)

– Pre-soaking time

– Tube size (8 or 16 French)

– Tube material 13

In Vitro NG Tube Testing (Cont.)

• Integrity of enteric coating in water

– Water with different pH (pH 5.5, 6.5, and 7.5)

– 0 and 15 min (esomeprazole, immediate

delivery)

• Robustness of in vitro testing

– Different size and material (requested by

CMC)

– Different media and holding position

(requested by CMC)

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Sedimentation Testing

• Determine sedimentation depth (volume of sediment) of

granule dispersion

– Testing medium and pretreatment time will vary based on the

labeling

• Photo results and qualitative description

– Whether particle aggregation or adhesion was observed

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Particle Size Distribution Study

• Important factor to predict the tendency of the drug

product to clog feeding tubes

• Surface properties of the granule particles may influence

– Interaction between granules and surface of the enteral tube

– Interaction between granules and oral syringe

– Among the granules as aggregation.

• Comparison of D10, D50, D90 and D-span of particle

size between the test and RLD products

• The results will be considered together with

– Recovery study

– Acid Resistance Study

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Recovery Study • Measure the percentage of drug substance

recovered at the tube exit relative to the initial dose.

• Determine the integrity of the granule enteric

coating

– All media (e.g. different pH of water)

– All pre-soaking time required per labeling

• Identify other inherent formulation problems

affecting NG tube administration – Granule size, insoluble ingredients, surface properties of the granule

• The recovery of the test and reference product

needs to be comparable

Acid Resistance Study • Integrity of the granule enteric coating

– Media (water in different pH or apple juice)

– Different pre-treatment time

• Acid resistance testing after recovery

– Through a combination of oral syringe and 8 or 16 F

NG tube.

• The Acid Resistance of the test and reference

products should to be comparable

– The amount released: NMT 10% of the labeled drug

– The test product releases same or less than the RLD 18

Common Deficiencies

• Formulation issues

– Particle size > that of the RLD

– Contains insoluble ingredient

– Surface properties of the granule particles (aggregation

and stick to the NG tube)

• Failed recovery study

– Large particle size of the generic product

– Tube size according to labeling (8 fr for pediatric use)

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Common Deficiencies • Failed Acid Resistance testing

– Integrity of coating in water with various pre-soaking time

– NMT 10% release in acid

– If release, test product release ≤ the RLD

– Measure from remaining granule if drug substance is acid

labile

• Testing method and other issues – Used Sieve or other methods can not provide D10, D50, D90 ,

and D-span for Particle size analysis

– PH of water before and after granule dispersion, testing date,

tube material

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Summary and Conclusions

• QbD approach for generic product design with alternate

administration

• Currently FDA-recommended in vitro testing for PPI

products

– Purpose

– Method

– Analysis

• Common deficiencies for submissions that we received

• The generic product must demonstrate Bioequivalence

after oral and NG tube administration

Acknowledgments

• John Peters, MD.

• Ethan Stier, Ph.D.

• Xiaojian Jiang, Ph.D.

• Hongling Zhang

• Ping Ren, Ph.D.

• Joan Zhao, Ph.D.

• Li Xia, Ph.D.

• Om Anand, Ph.D.

• Chitra Mahadevan, Pharm D

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Questions/Comments

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