the bcs and biowaiver - pqri · the bcs and biowaivers a global overview raimar löbenberg, phd ......

The BCS and Biowaivers a Global Overview

Raimar Löbenberg, PhD Professor Director Drug Development and Innovation Centre

Outline Biowaivers

Post Office

Insured package? Just sign this Waiver…..

o Biowaivers o SUPAC

o Fixed Dose combinations o IVIVC o BCS EMA, FDA, WHO

o New FDA Guidance o Example of three drugs in the Americas o Amoxicillin: challenge & harmonization

How it started…

Fundamental 1

Only what is dissolved can be absorbed

Fundamental 2

Only what is absorbed can be studied in vivo

IVIVC 1997 Bio-

waiver

BCS Classification I-IV IR/ER Dosage Forms

BCS Biowaiver 2000

SUPAC 1995/ 1997 Level 1/2/3 Changes

Level A Correlation

FDA-EMA-WHO

Design Space

Bioequivalence

Reference Product

Test Product

Bioequivalent

Bioequivalence Study

Not Bioequivalent

Pharmaceutical Equivalent

Establishing Therapeutic Equivalence using Biowaivers and In Vitro Similarity

Establishing Therapeutic Equivalence using Bioequivalence studies

In Vitro Similarity

Interchangeability

How the BCS changed drug regulations

15-02-12

Level 1/2/3 Changes

Definition of Level • Level 1 changes are those that are unlikely to

have any detectable impact on formulation quality and performance.

• Level 2 changes are those that could have a significant impact on formulation quality and performance.

• Level 3 changes are those that are likely to have a significant impact on formulation quality and performance.

Level 1/2 Changes Filler ±5% 10% Disintegrant

Starch ±3% 6% Other ±1% 2%

Binder ±0.5% 1% Lubricant

Calcium (Ca) or Magnesium (Mg) Stearate ±0.25% 0.5% Other ±1% 2%

Glidant Talc ±1% 2% Other ±0.1% 0.2%

Film Coat ±1% 2%

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).

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.

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.

Health Canada Post-Notice of Compliance (NOC) Changes: Quality Document 2016

Health Canada

• These percentages are based on the assumption that the drug substance in the product is formulated to 100.0% of label/potency. The total additive effect of all excipient changes should be not more than 5.0%.

• Multi-functional Excipients: If an excipient provides multiple functions (e.g., microcrystalline cellulose as a filler and as a disintegrant), then the most conservative recommended range should be applied (e.g., ±3.0% for microcrystalline cellulose should be applied in this example). If a wider range is proposed, scientific justification, including supporting data to demonstrate that the wider range will not affect the other function of the excipient should be provided.

Fixed Combination Drug Products

Fixed combination drug products contain two or more drug substances in a single dosage form.

Both actives in a single compartment

Each active in a separate compartment (multilayer tablets, tablet in tablet)

How can the proportionality be assessed? For single compartment –what is the role of the 2nd active? For separate compartments – based on compartment or as a whole dosage unit?

From: Emilija Fredro-Kumbaradzi, Apotex Inc. Presented CSPS workshop 2015, Ottawa

Regulatory aspects Canada “Bioequivalence of proportional formulations “(1996): – does not cover proportionality of combinations (yet we have approvals granted)

US “Draft Guidance BA and BE Submitted in NDAs or INDs” (2014):

Bilayer tablets are considered to be one formulation even though they consist of two separate layers with different compositions. In assessing the proportional similarity of the different strengths, all components of both layers should be proportionally similar (whole tablet). Exceptions to the above definitions may be possible if adequate justification is provided.

EU “Guideline for the investigation of the bioequivalence”(2010): The conditions regarding proportional composition should be fulfilled for all active substances of fixed combinations. When considering the amount of each active substance in a fixed combination the other active substance(s) can be considered as excipients. In the case of bilayer tablets, each layer may be considered independently

Proportionality of fixed drug combinations

Single compartment

Do we consider second active as an excipient? If so, what is the “role” of the second active ?

What is the “% change” of the second active?

Total additive effect of % change (active + excipient)?

As “Whole tab” – all other strengths qualify for biowaiver

Ingredient Bio strength strength 2 strength 3 strength 4 % diff from bio strength

% w/w whole tab

% w/w each layer

% w/w whole tab

% w/w each layer

% w/w whole tab

% w/w each layer

% w/w whole tab

% w/w each layer As whole tab Each layer

LAYER 1 Active 1 1.6 3 1.8 3.5 5.8 11.7 5.8 11.7 - - Disintegrant 0.7 1.3 0.7 1.4 0.7 1.4 0.7 1.4 0-0.1 Filler 2 50.3 94.1 46.7 93.4 42.6 85.3 42.6 85.3 -0.7 to -8.8% Dye 0.02 0.05 0.02 0.05 0.02 0.05 0.02 0.05 0 Lubricant 0.7 1.3 0.7 1.4 0.7 1.4 0.7 1.4 0-0.1 Glidant 0.1 0.2 0.1 0.2 0.1 0.2 0.1 0.2 0

Total layer 1 53.5 100 50 100 50 100 50 100 LAYER 2

Active 2 10.2 22 5.5 11 9.2 18.3 4.6 9.2 - - Disintegrant 8.6 18.5 8.6 17.2 8.6 17.2 8.6 17.2 1.3 Filler 1 23.3 50 23.3 46.5 23.3 46.5 23.3 46.5 3.5 Filler 2 3.6 7.7 11.8 23.6 8.2 16.3 12.7 25.5 +8.6 to+17.8% Lubricant 0.7 1.5 0.7 1.4 0.7 1.4 0.7 1.4 0-0.1 Glidant 0.1 0.2 0.1 0.2 0.1 0.2 0.1 0.2 0

Total layer 2 46.5 100 50 100 50 100 50 100 Total: 100 100 100 100

Total disintegrant 9.3 9.3 9.3 9.3 0 Total lubricant 1.4 1.4 1.4 1.4 0 Total glidant 0.2 0.2 0.2 0.2 0 Total filler 1 23.3 23.3 23.3 23.3 0 Total filler 2 53.9 58.5 50.8 55.4 -3.1 to +4.6% Total %difference

(max) 4.6% 9.0%(layer 1) 22.7%(layer 2)

Separate compartments

Ingredient Strength 1 Bio strength %difference

% w/w whole tab

% w/w each layer

% w/w whole tab

% w/w each layer As whole tab Each Layer

LAYER 1 Active 1 42.33 77.16 47.71 77.16 - -

Release modifying agent 1 6.77 12.35 7.63 12.35 0.86 0

Release modifying agent 2 3.39 6.173 3.82 6.173 0.43 0 Binder 1.69 3.086 1.91 3.086 0.22 0 Glidant 0.17 0.309 0.19 0.309 0.02 0 Glidant 0.25 0.463 0.29 0.463 0.03 0 Lubricant 0.25 0.463 0.29 0.463 0.03 0

TOTAL LAYER 1: 100.0 100.0 LAYER 2

Active 2.51 5.55 2.12 5.55 - - Diluent 39.45 87.375 33.35 87.375 6.1 0 pH modifier 2.71 6.0 2.29 6.0 0.42 0 Dye 0.03 0.075 0.03 0.075 0 0 Lubricant 0.45 1.0 0.38 1.0 0.07 0

TOTAL LAYER 2: 100.0 100.0 Total % difference: 100.0 - 100.0 - 8.2%

As “individual layer” – the lower strength qualifies for a biowaiver

Separate compartments

Options? Actives in a single compartment Define % variability of second active and total % change for

proportionality assessment Actives in separate compartments Assessing the proportionality as a whole tab or as

individual compartments may result in different interpretation of formulation proportionality and feasibility of biowaiver justification. Each approach, in combination with adequate in vitro

dissolution similarity, should be considered supportive of biowaiver justification.

IVIVC 1997 Bio-

waiver

BCS Biowaiver 2000

Level A Correlation

FDA-EMA-WHO

Design Space

FDA defines IVIVC

“A predictive mathematical model describing the relationship between an in vitro property of a dosage form (usually the rate and extent of drug dissolution or release) and a relevant in vivo response, e.g., plasma drug concentration or amount of drug absorbed”

Level A • A correlation of this type is generally linear and

represents a point-to-point relationship between in vitro dissolution and the in vivo input rate (e.g., the in vivo dissolution of the drug from the dosage form).

• In a linear correlation, the in vitro dissolution and in vivo input curves may be directly superimposable or may be made to be superimposable by the use of a scaling factor.

• Nonlinear correlations (uncommon) may also be appropriate

• Alternative approaches to developing a Level A IVIVC are possible

• United States Pharmacopoeia. • Guidance for industry, extended release oral dosage forms: development, evaluation and application of an in vitro/in vivo

correlation. FDA, CDER, 1997.

Deconvolution-based IVIVC methods

Journal of Controlled Release 72 (2001) 127–132 Regulatory perspectives on in vitro (dissolution) / in vivo (bioavailability) correlations Venkata Ramana S. Uppoor

• These methods are two-stage modeling procedures

• In the first stage, a deconvolution

method is used to estimate the time course of in-vivo absorption (fraction absorbed fabs vs time t).

• In the second stage, the in-vivo absorption (or release) time profile obtained in this first stage is plotted vs. the time course of the in-vitro dissolution profile.

• Usually a point-to-point relationship is established between the in-vivo and in-vitro parameters of the same time point (e.g., in-vivo fraction absorbed fabs vs in-vitro fraction dissolved fdis);

• Linear or sigmoidal curves

Convolution-based IVIVC methods • Convolution-based IVIVC methods are one-

stage modeling approaches, and they directly relate the time course of the in-vivo measured plasma concentration to the time profile of the in-vitro dissolution.

• integral or differential equations

Gillespie 1997; Modi et al 2000; Veng-Pedersen et al 2000; Balan et al 2001; O’Hara et al 2001; Pitsiu et al 2001; Gomeni et al 2002

Drug Description • pKa = 3.1 and 5.7 Basic and Acetic • logP = 7.01, highly lipophilic • >99% bound to plasma proteins • Oral bioavailability variable 58-70%

(Cheng, et al 1996)

Flow-through protocol (like Apparatus 4) & Paddle

Designed to simulate passage of a drug through the GIT 1-SGF-SLS(0.25%) for 15 min 2-Biorelevant media pH 6.5 for 75 min 3-Biorelevant media pH 7.5 for 60 min 4-Biorelevant media, pH 5.0 for 30 min 5-Entire fluid flow per sampling interval collected 6-A sample was taken and analyzed Test time 180 min

Dissolution Profiles

1. Fast and complete dissolution in 10 min H2O-0.25% SLS. 2. Incomplete dissolution in biorelevant media (89, 77 and 69%) in FaSSIF 500-100

RPM, FaSSIF-900 & FaSSIF-500-75 RPM 3. SIF and Phosphate buffer <10%, and insignificant in blank FaSSIF 4. Insignificant difference between 500 and 900 mL at 75 RPM

Simulations Results

1. AUC from Flow through, FaSSIF-500 mL-100 RPM, FaSSIF-900 ml, 75 RPM and H2O-0.25% SLS are not significantly different from observed mean value (p>0.05)

2. Cmax from H2O-0.25% SLS is significantly different from observed mean value (p<0.05

Dynamic dissolution testing using the flow through cell seems to be a powerful

tool to establish in vitro/in vivo correlations for poorly soluble drugs as

input function into GastroPlus.

In most cases the goals of QC versus R&D approaches make it necessary to design two different dissolution protocols. An over-discriminatory test

might be suitable for QC purposes to detect even small production deviations. However, such a test is not desirable for the prediction of the in vivo performance of drug product. Here dissolution testing should be a sensitive and a reliable predictor of bioavailability (Siewert et al., 2003).

Dissolution testing is used here as a predictive tool for the in vivo performance of a drug product. This requires that the in vitro and in vivo dissolution behavior of a dosage form be either similar or have a scalable

relationship to each other (Siewert et al., 2003).

IVIVC 1997 Bio-

waiver

BCS Biowaiver

Level A Correlation

FDA–EMA-WHO

Design Space

BCS Definitions (FDA 2000)

“highly soluble” highest marketed dose strength is soluble in 250 ml of aqueous media over a pH range of 1–7.5 at 37°C

“highly permeable” when the extent of absorption

in humans is determined to be greater or equal to 90% of an administered dose based on a mass balance determination or in comparison to an intravenous reference dose

Volume of water (ml) required to dissolve the highest dose strength at pH 1.2 – 7.5

1 10 100 1000 10000 100000 0.01

II Dissolution likely

to be “rate limiting”

I >90% Gastric emptying

determines on-set of absorption

Generally “problem” molecules

BCS Yesterday FDA

Absorption might be: incomplete

sensitive to certain excipients

May 2015 BCS Revision 1 FDA • NEW:

– permeability 85% – Class 3 drugs – 500 mL medium only ??? Why not 750 mL ??? 3-times the solubility?

• Dissolution • An IR drug product is considered rapidly dissolving when 85 percent

or more of the labeled amount of the drug substance dissolves within 30 minutes, using United States Pharmacopeia (USP) Apparatus I at 100 rpm (or Apparatus II at 50 rpm or at 75 rpm when appropriately justified (see

• section III.C.)) in a volume of 500 mL or less in each of the following media: (1) 0.1 N HCl or Simulated Gastric Fluid USP without enzymes; (2) a pH 4.5 buffer; and (3) a pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes.

Volume of water (ml) required to dissolve the highest dose strength at pH 1.2 – 7.5 / 6.8

1 10 100 1000 10000 100000 0.01

I >90/85% Gastric emptying

BCS Today FDA

Absorption might be: - incomplete - sensitive to certain excipients

1 10 100 1000 10000 100000 0.01

BCS Tomorrow FDA

Absorption might be: - incomplete - sensitive to certain excipients

REPLACING DISSOLUTION WITH DISINTEGRATION For drug products in both BCS classes 1 and 3, USP disintegration testing can be used in lieu of the dissolution test if the product is shown to meet a dissolution specification of Q=80% in 15 minutes. For drug products that meet this criterion, the USP disintegration test, which requires the product to completely disintegrate within 5 minutes (via USP apparatus in 0.01M HCl), may serve as a surrogate for routine release and stability dissolution testing. However, the approved dissolution method should be retained as the primary method and the approved disintegration method as an alternate method. Note that to support post-approval changes for which dissolution testing would be typically be needed, you should use the approved dissolution method.

IR: When no deliberate effort has been made to modify the drug substance release rate

2010 European Medicines Agency

London, 20 January 2010 Doc. Ref.: CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **

COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP)

GUIDELINE ON THE INVESTIGATION OF BIOEQUIVALENCE

DISCUSSION IN THE JOINT EFFICACY AND QUALITY WORKING GROUP

December 1997 E October 1998

very rapid (> 85 % within 15 min) similarly rapid (85 % within 30 min ) excipients that might affect bioavailability are qualitatively and quantitatively the same…other excipients are qualitatively the same and quantitatively very similar Fixed Combinations (FCs) BCS-based biowaiver are applicable for immediate release FC products if all active substances belong to BCS-class I or III

3/22/2017 46

Volume of water (ml) required to dissolve the highest Therapeutic dose at pH 1.2 – 6.8

1 10 100 1000 10000 100000 0.01

Absorption might be:

- incomplete - sensitive to certain excipients

BCS Today EMA & Canada

1 10 100 1000 10000 100000 0.01

Dissolution likely to be “rate limiting”

BCS 2006- 2015 WHO

II-B II-C II-A

Solubility in the relevant GI Segment The “High Solubility” Definition of the Current FDA

Guidance on Biopharmaceutical Classification System May Be Too Strict for Acidic Drugs” (Yazdanian et al 2004)

Based on the current definition of solubility, 15 of the 18 acidic NSAIDs in this study will be classified as Class II compounds as the solubility criteria applies to the entire pH range of 1.2 to 7.4, although the low solubility criteria does not hold true over the entire pH range. Whence, of the 18 acidic drugs, 15 can be classified as

Class I based on the pH 7.4 solubility alone. This finding is intriguing because these drugs exhibit Class I behavior as their absorption does not seem to be dissolution or solubility limited.

Recommendation: Acetic Drugs pH 5.0 – 7.4

2015 guidance

• Very rapid, Rapid, Not rapid In vitro equivalence testing based on dose- proportionality of formulations • where the amount of the API in the dosage form

is relatively low (up to 10 mg per dosage unit or not more than 5% of the weight of the dosage form), the total weight of the dosage form remains similar for all strengths.

• E.g. capsule Time points: 5, 10, 15, 20, 30, 45, 60

Dose / Volume Problem

• unless justified by the absence of sink conditions. If the different strengths of the test product do not show similar dissolution profiles owing to the absence of sink conditions in any of the above media, this should be substantiated by showing similar dissolution profiles when testing the same dose per vessel (e.g. two tablets of 5 mg versus one tablet of 10 mg) or by showing the same behaviour in the comparator product.

0 20 40 60

Time (min)

Flagyl SIF

Flagyl 250 mg USA (Pfizer)

0 20 40 60

Time (min)

Flagyl SGF

CPP Flagyl 250 mg USA

0 20 40 60

Time (min)

Flagyl pH 4.5

Flagyl 250 mg USA (Pfizer)

Delayed-release tablets and capsules

• a lower strength can be granted a biowaiver if it exhibits similar dissolution profiles, f2≥50, in the recommended test condition for delayed-release product, e.g. dissolution test in acid medium (pH 1.2) for 2 hours followed by dissolution in pH 6.8. When evaluating proportionality in composition, it is recommended to consider the proportionality of gastro-resistant coating with respect to the surface area (not to core weight) to have the same gastro-resistance (mg/cm2).

Extended-release tablets and capsules • have the same API-release mechanism,

• lower strengths in the series can be granted a biowaiver if they exhibit similar dissolution three different pH buffers (between pH 1.2 and 7.5) and the QC media by the recommended test method.

• For extended-release tablets with an osmotic pump release mechanism, OR beaded capsules where different strengths have been achieved solely by means of adjusting the number of beads one recommended test condition is sufficient for a biowaiver based on dose-proportionality of formulation.

In vitro equivalence testing for non-oral dosage forms

• Suspensions • Nasal drops/spray • Pressurized metered dose inhalers • Topical gels • Otic/ophthalmic suspensions • Locally acting in the GI tract

Volume of water (ml) required to dissolve the highest Therapeutic dose at pH 1.2 – 6.8

1 10 100 1000 10000 100000 0.01

BCS 2015 WHO

1 10 100 1000 10000 100000 0.01

Gastric emptying determines on-set of absorption

Absorption might be: - incomplete - sensitive to

certain excipients

Generally “problem” molecules H

y BCS Today JP

3/22/2017 59

1 10 100 1000 10000 100000 0.01

Gastric emptying determines on-set of absorption

Absorption might be: - incomplete - sensitive to

certain excipients

Generally “problem” molecules H

y BDDCS BCS Biowaiver Scientific Status

3/22/2017 61

IV-A IV-C

II-B II-A II-C

Biowaiver Case Study in the Americas • 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

Orange Book 2007: Amoxicillin RLD

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

3/22/2017 63

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.

Orange Book – finding a RS

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

Orange Book Today (RLD vs. RS)

Active Ingredient: AMOXICILLIN Proprietary Name: AMOXICILLIN Dosage Form; Route of Administration: TABLET; ORAL Strength: 875MG Reference Listed Drug: No TE Code: AB Application Number: A065056 Product Number: 002 Reference Standard: Yes Approval Date: Sep 18, 2000 Applicant Holder Full Name: TEVA PHARMACEUTICALS USA INC Marketing Status: Prescription

Study Design and Considerations

3/22/2017 66

Test Product and CPP

Evaluate Release

Profile

Perform dissolution test n=6

F2 test evaluation between the test

product and the CPP

Less than 85% release in 15 min

n < 12

No further evaluation

More than 85% release in 15 min

n < 12

n = 12

Equivalence Decision

3/22/2017 67

Zidovudine’s

footprint

Zidovudine

3/22/2017 69

Amoxicillin Classification

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”

3/22/2017 72

Amoxicillin Chile

Amoxicillin Peru

Dissolution behavior of 250-mg amoxicillin products marketed in China

Summary Amoxicillin

• 12 generics and the CPP (US product 500 mg) were tested

• 9 generics failed In Vitro equivalence (IVE) criteria according to WHO guidelines

3/22/2017 77

Flagyl

Metronidazole Argentina

Mexico

Brazil – different strengths be careful with wrong conclusions!

3/22/2017 82

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.

Let’s test the Amoxicillin Classification Globally according to TODAY’s Guidances

500 mg = 185 mL

750 mg = 277 mL

875 mg = 324 mL >90% FDA 89% BA Solubility Bioavailability

Acknowledgements

• Faculty of Pharmacy University of Alberta

• Drug Development and Innovation Centre

3/22/2017 86

Arthur Okumo Marie DiMaso Merck Nadia Boch- Chacra University of Sao Paulo Roger Williams USP Erika Stippler USP Vinod Shah USP

the bcs and biowaiver - pqri · the bcs and biowaivers a global overview raimar löbenberg, phd ......

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