WHO Prequalification Programme June 2007 BCS-Based Biowaiver Monographs Prof. Dr. Jennifer Dressman & Corina Becker Johann Wolfgang Goethe University Frankfurt

WHO Prequalification Programme June 2007

BCS-Based Biowaiver Monographs

Prof. Dr. Jennifer Dressman & Corina Becker

Johann Wolfgang Goethe University

Frankfurt am Main, Germany

Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceutics Classification

Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceutics Classification


The WHO Biowaiver ProcedureThe WHO Biowaiver Procedure

Scope Simplified approval for IR generic solid oral products

AdvantageDemonstration of BE by in vitro instead of in vivo PK

Studies

Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms. Technical Report Series, No 937, 40th Report, Annex 8 of WHO Expert committee on specifications for pharmaceutical preparations


The Biowaiver Monographs I.The Biowaiver Monographs I.

An initiative of the Federation Internationale Pharmaceutique (FIP).

The aim is to summarize all data from the literature relevant to the decision as to whether dissolution can be used as a surrogate for PK to show bioequivalance.

The biowaiver procedure can be used to demonstrate bioequivalence after a product has been scaled-up, in the approval of a new, multisource product of an existing API, and in continued approval of products for which there has been a change in composition and/or manufacturing procedure.


The Biowaiver Monographs II.The Biowaiver Monographs II.

The approach includes all factors considered in the WHO Document: „Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms.” Technical Report Series, No 937, 40th Report, Annex 8 of WHO Expert committee on specifications for pharmaceutical preparations

Where criteria vary among various regions (US, EU), these are also addressed.

A recommendation is given about whether the biowaiver procedure can be utilized, or if bioequivalence should rather be tested with a pharmacokinetic comparison.


lBiowaiver

Criteria

Biowaiver

Criteria

Biowaiver

BCS

Risks Therapeutic Index Indication

Dissolution

Interactions with Food and Excipients BA/BE Studies


Literature studies on bioequivalence of existing products

Literature and laboratory data comparing dissolution of existing products

Determinations of Permeability e.g. BAabs, urinary excretion, Caco-2 studies

Therapeutic indications, therapeutic index, types and severity of toxic effects observed.

Physicochemical properties, especially solubility at 37°C between pH 1.2 and 6.8, but also pKa, logP, polymorphism, solvates and saltsIf necessary,

additionaly solubility and dissolution studies are run with the pure API

The Biowaiver MonographWhat is taken into consideration?The Biowaiver Monograph

What is taken into consideration?

Interactions with food and excipients


I

Highly permeable

The Biopharmaceutics Classification

System The Biopharmaceutics Classification

System

II

Highly soluble

III IV

Poorly permeable

Poorly soluble

U.S. Department of Health and Human Services Food and Drug Administration Center for Evaluation and Research (CDER). 2000. Guidances for industry: Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a Biopharmaceutics Classification System


Solubility

BCS Criteria according to WHOBCS Criteria according to WHO

BCS

Dose/Solubility ratio ≤ 250 ml

in 3 aqueous media pH 1.2 – 6.8

37°C

Absorption ≥ 85 %

Human absolute BA or mass balance studies

alternatives are intestinal perfusion and tissue permeation studies

Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms. Technical Report Series, No 937, 40th Report, Annex 8 of WHO Expert committee on specifications for pharmaceutical preparations

]/[

][][/

)(max

mlmgSolubility

mgDmlSD

EMLratio

Permeability


Case Example: PyrazinamideCase Example: Pyrazinamide

One of the four main APIs used in treatment of Tubercolosis

Its highly specific action against mycobacterium tuberculosis in an acid environment contributes important sterilizing activity to the standard chemotherapy

The most common, serious adverse effect is liver damage, which occurs in 15% of patients at doses just above the therapeutic range.

N

NNH2

O


Solubility of PyrazinamideSolubility of Pyrazinamide

in compendial buffers pH 1.2 – 6.8 at 37°C,equilibrium solubility after 24 hours

0

2

4

6

8

10

12

14

16

18

20

So

lub

ilit

y [

mg

/ml]

SGFsp pH 1.2 Phosphate buffer pH 4.5 SIFsp pH 6.8

D/S ratio17.6 ml

D/S ratio18.6 ml

D/S ratio18.0 ml

Highlysoluble


34% Urinary recovery of a oral dose after 24 h, 40% after 48 h Ellard GA 1969. Absorption, metabolism and excretion of pyrazinamide in man. Tubercle 50(2):144-158.

Urinary recovery of 73% after 72 h 0- 4% fecal recovery Lacroix C, Hoang TP, Nouveau J, Guyonnaud C, Laine G, Duwoos H, Lafont O 1989. Pharmacokinetics of pyrazinamide and its metabolites in healthy subjects. Eur J Clin Pharmacol 36(4):395-400.

Pyrazinamide is actively reabsorbed in the kidney Weiner IM, Tinker JP 1972. Pharmacology of pyrazinamide: metabolic and renal function studies related to the mechanism of drug-induced urate retention. J Pharmacol Exp Ther 180(2):411-434.

Kasim et al. BCS III Kasim NA, Whitehouse M, Ramachandran C, Bermejo M, Lennernas H, Hussain AS, Junginger HE, Stavchansky SA, Midha KK, Shah VP, Amidon GL 2004. Molecular properties of WHO essential drugs and provisional biopharmaceutical classification. Mol Pharm 1(1):85-96.

Lindenberg et al. BCS III Lindenberg M, Kopp S, Dressman JB 2004. Classification of orally administered drugs on the World Health Organization Model list of Essential Medicines according to the biopharmaceutics classification system. Eur J Pharm Biopharm 58(2):265-278.

WHO Guideline für bioequivalence BCS III/I WHO 2006. Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms. Technical Report Series, No 937, 40th Report, Annex 8 of WHO Expert committee on specifications for pharmaceutical preparations.

Permeability of PyrazinamidePermeability of Pyrazinamide

„Poorlypermeable“


Dissolution of existing products, literature studies of Bioequivalence

Dissolution of existing products, literature studies of Bioequivalence

No cases of bioINequivalence reported in the literature

Products on German market have similar dissolution profiles

0

20

40

60

80

100

120

0 10 20 30

time [min]

% d

isso

lved

“Very rapidly dissolving” 400 mg pure substance Pyrafat®

Pyrazinamide “Lederle”


BCS Class (II, III, IV)

narrow therapeutic index

„critical“ indication

Risk of abuse

slow and incomplete dissolution

„Food effects“ or interaction with excipients

published bioinequivalence

Biowaiver

BCS Class I (II, III)

wide therapeutic index

„uncritical“ indication

no risk of abuse

„rapid“ or „very rapid“ dissolution

no reported interaction with food or excipients

BE- Studies

Evaluation of the collected Information

Evaluation of the collected Information


Biowaiver Recommendation for Pyrazinamide

Biowaiver Recommendation for Pyrazinamide

Biowaiver Only with specific requirements for monitoring hepatic function

Solubility Permeability

Dissolution Risks

0

20

40

60

80

100

120

0 10 20 30

time [min]

% d

isso

lved

Solubility > 20 mg/ml

D/s ratio400mg

< 20 ml

BCS ClassIII

0

2

4

6

8

10

12

14

16

18

20

“Very rapidly dissolving” 400 mg pure substance Pyrafat®

Pyrazinamide “Lederle”

73% Urinary excretion after 72h

no recovery in the feces

Dose-proportional absorption in range 200 – 3600 mg

Indication: Long-term treatment of TB

Toxicity: Hepatoxicity

Monitoring of hepatic function

Inhibition of urate excretion (gout)


Summary of biowaivers for first line anti-TB drugs

Summary of biowaivers for first line anti-TB drugs

APISolubilityPermeabilityBCSBiowaiverConstraintsBE Test

Isoniazid

(Biowaiver monograph published)

highborderlineIII/IYESOnly if the formulation does not contain reducing sugars.

Otherwise a PK study should be run

In vitro

(in vivo)

Ethambutol • 2 HCl

(Biowaiver monograph published)

highlowIII(YES)Narrow therapeutic index, due to impairment of vision. Should only be biowaived in jurisdictions where visual monitoring can be guaranteed

In vivo

(in vitro)

PyrazinamidehighborderlineIII/I(YES)Narrow therapeutic index, due to impairment of liver function. Should only be biowaived in jurisdictions where liver function monitoring can be guaranteed

In vivo

(in vitro)

RifampicinborderlinehighII/INOInstability, poor wettability, polymorphism, several reported cases of bioinequivalence

In vivo


Biowaiver Monographs already availableBiowaiver Monographs already available

Acetaminophen (Paracetamol)

Amitriptyline

Atenolol

Chloroquine

Cimetidine

Ethambutol

Ibuprofen

Isoniazid

Prednisolone

Prednisone

Propanolol

Ranitidine

Verapamil

www.fip.org/bcs


Many thanks to the team of co-authorsMany thanks to the team of co-authors

Dirk Barends (rivm Holland), Chief Editor

Jennifer Dressman (University of Frankfurt), Co-Editor

Gordon Amidon

Vinod Shah

Kamal Midha

Solomon Stavchansky

Sabine Kopp (WHO)

Hans Junginger…………………………and the many first authors who give their time and expertise to the project!

Documents

WHO Prequalification Programme June 2007 BCS-Based Biowaiver Monographs Prof. Dr. Jennifer Dressman & Corina Becker Johann Wolfgang Goethe University Frankfurt