BA/BE Overview: Continuing Equivalence Erika Stippler, Ph.D.

Drug Release The Rate Limiting Step

Modern Biopharmaceutics, G.L. Amidon, M. Bermejo 2003

BCS Concept

Published by Amidon and co-workers 1995 Biopharmaceutics Classification System is a

scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability

The aim is to optimize the development of oral dosage forms relying only on rate limiting factors for absorption

Class Solubility Permeability I High High II Low High III High Low IV Low Low

Solubility directly influences the dissolution behavior of oral dosage forms in gastrointestinal tract

Biopharmaceutical Drug Classification System (BCS)

Volume of water (ml) required to dissolve the highest dose strength at pH 1.2 - 8

1 10 100 1000 10000 100000 0.01

0.1

1.0

10 I

III

II

IV

Dissolution likely to be rate limiting

Gastric emptying determines on-set of

absorption

Absorption might be: - incomplete - sensitive to certain excipients

Generally problem molecules

Hum

an P

erm

eabi

lity

Biopharmaceutics Classification System

Dissolution Testing Requirements for in vitro BE

FDA EMA WHO

Apparatus USP App. 1 USP App. 2

Basket Paddle

Basket Paddle

Dissolution media

0.1 N HCl or SGF Buffer pH 4.5 Buffer pH 6.8 or SIF

Buffer pH 1.0 or SGF Buffer pH 4.5 Buffer pH 6.8 of SIF

Buffer pH 1.2 Buffer pH 4.5 Buffer pH 6.8

Use of enzymes is allowed in case of gelatin capsules or gelatin coated tablets

Absolutely no addition of surfactant or enzymes is allowed

Int. Ph. Buffers are preferred

Volume 900 ml 900 ml or less 900 ml or less

Temperature

37C 0.5C 37C 1C 37C

Agitation

Basket: 100 rpm Paddle: 50 rpm alternatives to be justified

Basket: 100 rpm Paddle: 50 rpm

Basket: 100 rpm Paddle: 75 rpm

Sampling time 10, 15, 20, 30 min 10, 15, 20, 30, 45 min 10, 15, 20, 30, 45, 60 min

Sample # 12 12 12

Requirements f2 50 50 f2 100 50 f2 100

Dissolution Characteristics of IR Drug Products

FDA EMA WHO

Very rapidly dissolving

No definition 85%of the labeled amount dissolves in 15 min

85%of the labeled amount dissolves in 15 min or less

Rapidly dissolving

85%of the labeled amount dissolves in 30 min

No definition

85%of the labeled amount dissolves in 30 min

Similarly dissolving (EMA)

No definition

85%of the labeled amount dissolves between 15 and 30 min

No definition

Test conditions Paddle at 50 rpm or Basket at 100 rpm in 900 ml or less of 0.1N HCl or SGF Buffer pH 4.5 Buffer pH 6.8 or SIF

Paddle at 50 rpm or Basket at 100 rpm in 900 ml or less of 0.1N HCl or SGF Buffer pH 4.5 Buffer pH 6.8 or SIF

Paddle at 75 rpm or Basket at 100 rpm in 900 ml or less of Buffer pH 1.2 Buffer pH 4.5 Buffer pH 6.8

FDA-Requirements for BCS-based Biowaiver

Immediate release drug products only BCS-Class I drug substance Rapidly dissolving IR drug product Test and reference drug product are pharmaceutically equivalent Test and reference drug product exhibit similar dissolution profiles

Exclusions IR drug products considered not to have a narrow therapeutic index Products designed to be absorbed in the oral cavity

EMA-Requirements for BCS-based Biowaiver

Restricted for immediate release drug products considered not to have a narrow therapeutic index Case I

Same drug substance BCS-Class I or different salt both BCS-Class I either very rapid or rapid in vitro dissolution Same excipients in similar amounts Similarity of dissolution profiles

Case II Same drug substance BCS-Class III very rapid in vitro dissolution Same excipients in very similar amounts Similarity of dissolution profiles

WHO-Requirements for BCS-based Biowaiver

WHO Model List of Essential Medicines immediate release solid oral dosage forms Case 1

BCS-Class I drugs very rapidly dissolving drug products (both test and reference) rapidly dissolving drug products for which similarity of dissolution profiles was

demonstrated Case 2

BCS-Class III drugs very rapid in vitro dissolution Same composition regarding excipients in both test and reference

WHO-Requirements for BCS-based Biowaiver

WHO Model List of Essential Medicines immediate release solid oral dosage forms Case 3

BCS-Class II compounds with weak acid properties (high solubility at pH 6.8 but not at pH 1.2 or 4.5 and with high permeability)

rapidly dissolving in pH 6.8 (both test and reference) similar of dissolution profiles for both test and reference product in all three

buffer media (pH 1.2, 4.5, and 6.8) Careful examination of type and amount of surfactant in the formulation

Dosage Form Performance Test - Dissolution

To label a drug product as Bioequivalent test results must be compared with an appropriate comparator

About 70% of orally administered immediate release essential medicines (WHO List) are highly soluble drug products

Using dissolution criteria as safe haven base, it is possible to develop drug products with acceptable performance, as in MC

There will be always instances where dissolution it self may not be sufficient, and may require clinical or bioequivalent study

Medicines Compendium, General Chapter

NEW CONCEPT for drug product performance Non-solution orally administered immediate release drug products A partial solution for well-behaved IR drug products Creates a default characterization for most IR drug products Linked to the BCS classification of the drug substance

Details MC General Chapter

Determine the Solubility of the Drug Substance Aqueous media at pH 1.2 and pH 6.8 Maximum unit dose in 250 mL media Room temperature, gentle stirring High or low solubility

Determine Dissolution Conditions 4 cases possible Conduct dissolution tests

Dissolution Cases according to MC GC

High solubility in both pH 1.2 and 6.8 Conduct dissolution according to USP-NF in each pH 1.2 and 6.8 App. 1@100 rpm or App. 2@50 rpm in 900 mL Q=85% in 30 minutes

High solubility in pH 1.2 only Conduct dissolution according to USP-NF in pH 1.2 App. 1@100 rpm or App. 2@50 rpm in 900 mL Q=85% in 15 minutes

High solubility in pH 6.8 only Conduct dissolution according to USP-NF in pH 6.8 App. 1@100 rpm or App. 2@50 rpm in 900 mL Q=85% in 15 minutes

Low solubility in both pH values Product specific development needed Suggestions on surfactant usage could be included

Products that meet the acceptance criteria may be considered: To perform optimally or To be optimally available for in vivo absorption

Products that do not meet the acceptance criteria are not necessarily bad products, require additional studies (i.e. in vivo studies) to demonstrate proper

performance

API with high solubility over the entire pH range formulated in rapidly dissolving solid oral dosage forms can be considered optimally bioavailable (OBA)

no need for a reference product to evaluate performance

Evaluation of Drug Product Performance

17

Pharmaceutically equivalence

Highly soluble drug substance (API)

Then optimally bioavailable (OBA) All O-BA are also BE No comparator product; no comparison studies Registration only No regulatory review Periodic inspection to assure conformity Label OBA

What Would This Further Look Like?

Slide Number 1BA/BE Overview: Continuing EquivalenceDrug Release The Rate Limiting StepBCS ConceptBiopharmaceutical Drug Classification System (BCS)Biopharmaceutics Classification SystemDissolution Testing Requirements for in vitro BEDissolution Characteristics of IR Drug ProductsFDA-Requirements for BCS-based Biowaiver EMA-Requirements for BCS-based Biowaiver WHO-Requirements for BCS-based Biowaiver WHO-Requirements for BCS-based Biowaiver Dosage Form Performance Test - DissolutionMedicines Compendium, General Chapter Details MC General Chapter Dissolution Cases according to MC GC Evaluation of Drug Product PerformanceWhat Would This Further Look Like?Slide Number 19Slide Number 20