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Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceutics Classification. BCS-Based Biowaiver Monographs Prof. Dr. Jennifer Dressman & Corina Becker Johann Wolfgang Goethe University Frankfurt am Main, Germany. The WHO Biowaiver Procedure.

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Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceutics Classification

BCS-Based Biowaiver Monographs

Prof. Dr.Jennifer Dressman & Corina Becker

Johann Wolfgang Goethe University

Frankfurt am Main, Germany

the who biowaiver procedure
The WHO Biowaiver Procedure

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

Scope

  • Simplified approval for IR generic solid oral products

Demonstration of BE by in vitro instead of in vivo PK Studies

Advantage

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.
biowaiver criteria
BiowaiverCriteria
  • l

BCS

Biowaiver

  • Risks
  • Therapeutic

Index

  • Indication

Dissolution

  • Interactions with

Food and

Excipients

  • BA/BE Studies
slide6

The Biowaiver MonographWhat is taken into consideration?

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

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

Literature and laboratory data comparing dissolution of existing products

Determinations of Permeability

e.g. BAabs, urinary excretion, Caco-2 studies

Literature studies on bioequivalence of existing products

Interactions with food and excipients

the biopharmaceutics classification system
The Biopharmaceutics Classification System

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

Highly permeable

II

I

Highly soluble

Poorly soluble

III

IV

Poorly permeable

bcs criteria according to who
BCS Criteria according to WHO

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

Solubility

  • 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

BCS

case example pyrazinamide
Case 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.
solubility of pyrazinamide
Solubility of Pyrazinamide
  • in compendial buffers pH 1.2 – 6.8 at 37°C,equilibrium solubility after 24 hours

Highly

soluble

D/S ratio

17.6 ml

D/S ratio

18.6 ml

D/S ratio

18.0 ml

permeability of pyrazinamide
Permeability of Pyrazinamide
  • 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.

„Poorly

permeable“

dissolution of existing products literature studies of bioequivalence
Dissolution of existing products, literature studies of Bioequivalence

120

100

80

60

% dissolved

40

20

0

0

10

20

30

time [min]

  • No cases of bioINequivalence reported in the literature
  • Products on German market have similar dissolution profiles
  • “Very rapidly
  • dissolving”
  • 400 mg pure substance
  • Pyrafat®
  • Pyrazinamide “Lederle”
evaluation of the collected information
Evaluation of the collected Information
  • 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
  • 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

-

Biowaiver

+

biowaiver recommendation for pyrazinamide
Biowaiver Recommendation for Pyrazinamide

20

18

16

14

12

10

8

6

4

2

0

120

100

80

% dissolved

60

40

20

0

0

10

20

30

time [min]

BCS

Class

Solubility

Permeability

III

  • 73% Urinary excretion after

72h

  • no recovery in the feces
  • Dose-proportional absorption

in range 200 – 3600 mg

Solubility

> 20 mg/ml

D/s ratio

< 20 ml

400mg

Biowaiver

Only withspecific requirements

for monitoring hepatic function

  • Indication: Long-term

treatment of TB

  • Toxicity: Hepatoxicity
  • Monitoring of hepatic function
  • Inhibition of urate excretion

(gout)

  • “Very rapidly
  • dissolving”
  • 400 mg pure substance
  • Pyrafat®
  • Pyrazinamide “Lederle”

Dissolution

Risks

biowaiver monographs already available
Biowaiver Monographs already available
  • Isoniazid
  • Prednisolone
  • Prednisone
  • Propanolol
  • Ranitidine
  • Verapamil
  • Acetaminophen (Paracetamol)
  • Amitriptyline
  • Atenolol
  • Chloroquine
  • Cimetidine
  • Ethambutol
  • Ibuprofen

www.fip.org/bcs

many thanks to the team of co authors
Many 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!