Bioequivalence of Oral Generic Product with An Alternate Administration

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Grant Quinn
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1 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 1

2 Disclaimer & Disclosure The following presentation reflects the opinions of the author and does not necessarily represent the official position of the US-FDA 2

3 Agenda Background Current BE recommendation In vitro NG tube testing Common deficiencies in ANDA submissions Summary and conclusion 3

4 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 4

5 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 5

6 Feeding Tube 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. NG tube: Size: 5-18F Material: polyurethane, silicone, Tygon G tube Size: 14-28F J tube Size: 14-18F 1 French unit=0.33 mm 6

7 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) 7

8 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

9 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

10 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

11 Draft Guidance with NG Tube Testing Lansoprazole DR Capsule Esomeprazole Strontium DR Capsule Esomeprazole Magnesium DR Capsule 11

12 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. 12

13 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

14 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) 14

15 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 15

16 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 16

17 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

18 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

19 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) 19

20 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 20

21 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

22 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 22

23 Questions/Comments 23

Proton Pump Inhibitors

Market DC Proton Pump Inhibitors Override(s) Prior Authorization Quantity Limit** Approval Duration Preferred PPI: No Prior Authorization required Preferred PPI quantity override: Lifetime Non-Preferred