Bioequivalence in the Americas using the WHO guidelines

Outline: Biowaivers Introduction Biowaivers Globally Drug Performance Testing Snap shot in the Americas Zidovudine Amoxicillin Metronidazole Conclusions

What is a BIOWAIVER? In a Biowaiver -based submission the Sponsor tests bioequivalence with in vitro dissolution instead of a pharmacokinetic study The method can be applied to approval of Generics, approval of products at lower doses and for scale-up and post-approval changes (FDA), also known as Variations (EMA), in the manufacture.

In vitro vs. in vivo Dissolution

BCS Classification I-IV IR/ER Dosage Forms SUPAC 1995/ 1997 Level 1/2/3 Changes IVIVC 1997 BCS Biowaiver 2000 Level A Correlation BSC Class 1 EMA - WHO Biowaiver QbD Design Space 4/1/2013 5

How the BCS changed drug regulations 4/1/2013 7

Dissolution Documentation Case A: High Permeability, High Solubility Drugs Dissolution of 85% in 15 minutes in 900 ml of 0.1N HCl. If a drug product fails to meet this criterion, the applicant should perform the tests described for Case B or C (below). 4/1/2013 8

Dissolutions Documentation Case B: Low Permeability, High Solubility Drugs Multi-point dissolution profile should be performed in the application/compendial medium at 15, 30, 45, 60 and 120 minutes or until an asymptote is reached. The dissolution profile of the proposed and currently used product formulations should be similar. 4/1/2013 9

Dissolutions Documentation Case C: High Permeability, Low Solubility Drugs Multi-point dissolution profiles should be performed in water, 0.1 N HCl, and USP buffer media at ph 4.5, 6.5, and 7.5 Adequate sampling should be performed at 15, 30, 45, 60, and 120 minutes until either 90% of drug from the drug product is dissolved or an asymptote is reached. profile of the proposed and currently used product formulations should be similar. 4/1/2013 10

SUPAC Level of Change Test Product and CPP F2 test evaluation between the test product and the CPP Equivalence Decision Perform dissolution test n=12 Evaluate Release Profile 4/1/2013 11

4/1/2013 13

BCS and Quality by Design Product Quality Implementation Lifecycle Initiative (PQLI) Quality by Design is a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding based on sound science and quality risk management. ICH Q8 Pharmaceutical Development ICH Q9 Quality Risk Management ICH Q10 Quality Systems FDA Pharmaceutical cgmps for the 21st Century - A Risk-Based Approach. Final Report 4/1/2013 15

BCS Today FDA 10 I Gastric emptying determines on-set of absorption II Dissolution likely to be rate limiting Human Permeability 1.0 0.1 III Absorption might be: - incomplete - sensitive to certain excipients IV Generally problem molecules 0.01 1 10 100 1000 10000 100000 Volume of water (ml) required to dissolve the highest dose strength at ph 1.2 7.5 4/1/2013 17

BCS Today EMA 10 I Gastric emptying determines on-set of absorption II Dissolution likely to be rate limiting Human Permeability 1.0 0.1 III Absorption might be: - incomplete - sensitive to certain excipients IV Generally problem molecules 0.01 1 10 100 1000 10000 100000 Volume of water (ml) required to dissolve the highest dose strength at ph 1.2 6.8 4/1/2013 18

BCS Today WHO 10 I Gastric emptying determines on-set of absorption II-A II-B Dissolution likely to be rate limiting II-C Human Permeability 1.0 0.1 III Absorption might be: - incomplete - sensitive to certain excipients IV Generally problem molecules 0.01 1 10 100 1000 10000 100000 Volume of water (ml) required to dissolve the highest dose strength at ph 1.2 6.8 4/1/2013 19

BDDCS BCS Scientific Status Poor Metabolism Extensive Metabolism Human Permeability 0.01 10 I 1.0 0.1 Gastric emptying determines on-set of absorption III Absorption might be: - incomplete - sensitive to certain excipients II-A IV-A II-B Dissolution likely to be rate limiting IV-B Generally problem molecules 1 10 100 1000 10000 100000 Volume of water (ml) required to dissolve the highest dose strength at ph 1.2 6.8 II-C IV-C 4/1/2013 20

BCS Today JP 10 I Gastric emptying determines on-set of absorption II Dissolution likely to be rate limiting Human Permeability 1.0 0.1 III Absorption might be: - incomplete - sensitive to certain excipients IV Generally problem molecules 0.01 1 10 100 1000 10000 100000 4/1/2013 21 5

WHO EXPERT COMMITTEE ON SPECIFICATIONS FOR PHARMACEUTICAL PREPARATIONS The dissolution testing is now emerging as a surrogate equivalence test for certain categories of orally administered pharmaceutical products. For these products (typically solid oral dosage forms containing APIs with suitable properties) a comparative in vitro dissolution profile Similarity can be used to document equivalence of a multisource generic with a comparator product. 4/1/2013 22

WHO Guide On the basis of solubility and permeability of the API, and dissolution characteristics of the dosage form, the BCS approach provides an opportunity to waive in vivo pharmacokinetic bioequivalence testing for certain categories of immediaterelease drug products. 4/1/2013 23

BCS Classification I, IIA, III IR Dosage Forms Pharmaceutical Equivalence WHO Biowaiver In vitro Equivalence BCS Biowaiver Generic Drug Approval

Study Introduction The study was designed to investigate in vitro dissolution differences between BCS class 1 drugs sold in the Americas. The products were compared to US products The US-RLD was identified and if appropriate an alternative comparator pharmaceutical product (CPP) was chosen A study protocol was developed for three drugs Zidovudine Amoxicillin Metronidazole 25

Orange Book: Amoxicillin No BE RDL Name & Dosage Form Route & Dose Manufacturer 050754 AB No AMOXICILLIN TABLET; ORAL 500MG AMOXIL GLAXOSMITHKLINE 050754 AB Yes AMOXICILLIN TABLET; ORAL 875MG AMOXIL GLAXOSMITHKLINE 065228 AB No AMOXICILLIN TABLET; ORAL 500MG AMOXICILLIN SANDOZ 065228 AB No AMOXICILLIN TABLET; ORAL 875MG AMOXICILLIN SANDOZ A Drug products that FDA considers to be therapeutically equivalent to other pharmaceutically equivalent products, i.e., drug products for which: (1) there are no known or suspected bioequivalence problems. These are designated AA, AN, AO, AP, or AT, depending on the dosage form; or (2) actual or potential bioequivalence problems have been resolved with adequate in vivo and/or in vitro evidence supporting bioequivalence. These are designated AB. 4/1/2013 26

What do you do if the Innovator is not available? In the case that no innovator product can be identified within the context of (i) (iii) above, the choice of the comparator must be made carefully and must be comprehensively justified by the applicant. The most important selection criteria in order of preference are: approval in ICH- and associated countries; prequalified by WHO; extensive documented use in clinical trials reported in peerreviewed scientific journals; and long and unproblematic period of postmarket surveillance ( well selected comparator ) 4/1/2013 27

Orange BOOK Search results from the "OB_Rx" table for query on "065228." Active Ingredient: AMOXICILLIN Dosage Form;Route: TABLET; ORAL Proprietary Name: AMOXICILLIN Applicant: SANDOZ Strength: 500MG Application Number: 065228 Product Number: 001 Approval Date: Jul 13, 2005 Reference Listed Drug No RX/OTC/DISCN: RX TE Code: AB Patent and Exclusivity Info for this product: View 28

Study Design and Considerations Test Product and CPP F2 test evaluation between the test product and the CPP Equivalence Decision n = 12 No further evaluation Perform dissolution test n=6 n < 12 Evaluate Release Profile More than 85% release in 15 min n < 12 Less than 85% release in 15 min 4/1/2013 29

Analytical Method Method Mode: LC Detector: UV 265 nm Column: RP-8 Water : ACN mixture (72:28) Flow rate: 1 ml/min Injection size: 10 µl Dissolution Apparatus 2 : 75 rpm Time: 10, 15, 20, 30, 45, 60 min Media: SGF, ph 4.5, SIF Low concentration 4/1/2013 30

Zidovudine 31

Amoxicillin Analytical Development USP Tablets 230 nm Low concentration High concentration 4/1/2013 32 Analytical assay HPLC 219 nm RP 18 Column 1 ml/min Acetonitrile : Buffer, ph 5.0 Dissolution Apparatus 2 : 75 rpm Time: 10, 15, 20, 30, 45, 60 min Media: SGF, ph 4.5, SIF

Commentary 500 mg is a common dose use in Europe and several countries in South America 875 mg is the strength of the US-RLD. 4/1/2013 33

Amoxicillin Classification Solubility 1 g / 370 ml 875 mg = 324 ml 750 mg = 277 ml 500 mg = 185 ml Bioavailability 89% BA >90% FDA 34

Amoxicillin Argentina

Sandoz Clarifies: amoxicillin tablets marketed in Argentina were developed as generic medical products for the European Union (EU) market based on the company s bioequivalence study CPA 45/97. In this study the bioavailability of the generic medicinal product OSPAMOX 750 mg FCT, batch 95362 (Biochemie GmbH, Austria) was compared with the reference medicinal product CLAMOXYL 750-mg tablets, batch 96D15/32335 (SmithKline-Beechem Pharma GmbH, Germany). Because the 90% confidence intervals for the primary bioequivalence parameters were within the pre-specified limits of 80% 125%, the study demonstrated the bioequivalence of the tested formulations 4/1/2013 36

Therapeutic Equivalence RLD/CPP Pharmaceutical Equivalent YES In vitro Similarity YES Generic NO NO Establishing Therapeutic Equivalence using biowaivers and IVS Bioequivalence Study NO YES Establishing Therapeutic Equivalence using BE studies Not Bioequivalent Therapeutic Equivalent

Amoxicillin Chile

Amoxicillin Peru

Summary Amoxicillin 12 generics and the CPP (US product 500 mg) were tested 9 generics failed In Vitro similarity criteria according to WHO guidelines 40

Analytical Method Method Mode: LC Detector: UV 228 nm Column: RP-8 Water : ACN mixture (66:34) Flow rate: 1 ml/min Injection size: 10 µl Dissolution Apparatus 2: 75 rpm Time: 10, 15, 20, 30, 45, 60 min Media: SGF, ph 4.5, SIF 4/1/2013 41

Flagyl

Metronidazole Argentina

Mexico

Publication At times, identifying a CPP in one of the selected markets proved difficult. The study demonstrates that products sold across national markets may not be bioequivalent. When coupled with the challenge of identifying a CPP in different countries, the results of this study suggest the value of an international CPP as well as increased use of BCS approaches as means of either documenting bioequivalence or signaling the need for further in vivo studies. Because of increased movement of medicines across national borders, practitioners and patients would benefit from these approaches.

Conclusions The BCS changed the way we look at drugs The BCS is the mechanistic base for modern oral drug development and can be used as Risk management tool in early drug development Risk management tool clinical development The BCS is the scientific foundation for Biowaivers Generic drugs can be approved using Biowaivers however, the products on the market were not developed according to the BCS Insufficient comparator products exist for some essential drugs (Innovator is discontinued) Need for global comparator standards 4/1/2013 47

Acknowledgements Faculty of Pharmacy University of Alberta Drug Development and Innovation Centre Nadia Chacra Roger Williams Erika Stippler Vinod Shah University of Sao Paulo USP USP USP 4/1/2013 48