Regulatory Requirements For BE: Evaluation of Quality and Interchangeability of Medicinal Products

Federal Institute for Drugs
and Medical Devices
Regulatory Requirements for BE
Evaluation of Quality and

Interchangeability of Medicinal Products
10 – 14 September 2007
Dar Es Salaam, Tanzania
Dr. Henrike Potthast; Temporary Advisor to WHO
1
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
and Medical Devices

 EU “Note for Guidance on the Investigation of
Bioavailability and Bioequivalence” CPMP/EWP/QWP/1401/98
 FDA - Guidance for Industry: “Bioavailability and Bioequivalence Studies

for Orally Administered Drug Products – General Considerations” (Oct.
2000) – and related guidances
 WHO – Multisource (generic) pharmaceutical products: Guidelines on

registration requirements to establish interchangeability (2005)
 CN – Guidance for Industry; Conduct and analysis of bioavailability and

bioequivalence studies – Part A: Oral dosage formulations used for
systemic effects (1992)
 ….and others
2
and Medical Devices
 Bioavailability – rate and extent at which a drug

substance... becomes available in the general system
(product characteristic!)
 Bioequivalence – equivalent bioavailability within pre-set

acceptance ranges
 Pharmaceutical equivalence  Bioequivalence
 Bioequivalence  Therapeutic equivalence

3
and Medical Devices
 Bioequivalence Studies
 in vivo comparison of products by means of volunteers

serving as “in-vivo dissolution model”
 ‘biological quality control’
comparison of product characteristics in order to ensure

therapeutic equivalence
4
and Medical Devices
 Immediate and Modified Release Dosage

Forms
BE is generally required and can be investigated by

means of
♦ pharmacokinetic (BE) studies (preferred as most sensitive)

♦ comparative pharmacodynamic studies
♦ comparative clinical trials
♦ comparative in vitro trials
5
and Medical Devices
 Immediate Release (IR) Dosage Forms
 possible BE exemptions
♦ aqueous solution (incl. syrups, elixirs, but no suspensions)

♦ gases
♦ aqueous otic or ophthalmic products (contg. the same actives and
excipients)
♦ nebulizer inhalation products or nasal sprays (contg. the same actives

and excipients)
6
and Medical Devices
Particularity for IR dosage forms
‘BCS-based Biowaiver’.....
.....which is defined as
 in vitro instead of in vivo bioequivalence testing
 comparison of test and reference
....is not defined as
 no equivalence testing
cave: different recommendations in WHO, EU, and FDA!
7
and Medical Devices

 Bioequivalence for Immediate Release Dosage Forms
by means of…
 …the ‘parent’ drug substance within a single dose 2-period

crossover design is usually appropriate
 note – special cases

♦ dose- or time-dependent kinetics
♦ specific food recommendations in the SPC
♦ active metabolites
♦ pro-drugs
♦ enantiomers……
8
and Medical Devices
 Modified Release (MR) Dosage Forms
 controlled (extended, sustained) release

 delayed release
♦ single unit formulations
♦ multiple unit formulations
9
and Medical Devices
 Modified Release (MR) Dosage Forms
generally BE under specific conditions
♦ single dose study (fasting)

♦ multiple dose study (steady state conditions – EU, not FDA)
♦ food-effect study (“dose-dumping” under high-fat
conditions; note: FDA guidance on ‘Food-Effect Bioavailability and
Fed Bioequivalence Studies’, CDER; December 2002)
10
and Medical Devices
♦ ‚ If a product concerns several strengths…‘

(see e.g. 5.4 EU guidance)
♦ bioequivalence proven for one strength

♦ same manufacturer and manufacturing process
♦ linear drug input (if this is not the case…..)
♦ same qualitative composition of different strengths (WHO)
♦ same ratio between active substance and excipients, or same excipients
in case of low concentration (less than 5 % API)
♦ similar in vitro dissolution (WHO)
 see also guidance for MR products, 5.1 of EU guidance

CPMP/EWP/280/96…
11
and Medical Devices

 …MR products acc. to 5.1 of EU guidance
(CPMP/EWP/280/96)…however, there is a possibility for
♦ single-unit forms:
single dose study in the fasted state for every
strength, multiple dose study may be waived for lower
strengths
♦ multiple-unit forms:
single and multiple dose studies may be waived for
lower strengths in case of identical beeds or pellets
cave: in vitro dissolution studies……..
12
and Medical Devices
♦ Comparative in vitro dissolution ….
♦ complementary to BE studies (see e.g. 3.7 EU guidance)

♦ comparison of reference products
♦ in vitro/in vivo correlation (only level A for BE decision)
♦ ‚biowaiver‘ – dose proportionality
♦ ‚biowaiver‘ – BCS concept
♦ batch release and other ‚quality issues‘….
13
and Medical Devices
 Fixed combination products
 in vivo comparison vs appropriate comparator combination

(or separate comparator products in specific cases)
 general testing criteria apply to all active components
bioequivalence criteria apply to all active components
14
and Medical Devices
 Bioequivalence for transdermal therapeutic systems

(TTS)
 BE by means of single and multiple dose studies

 performing a replicate design study is advisable (investigation
of subject by formulation interaction)
 ‘BE’ regarding local tolerability
 dose proportionality issue: thorough in vitro release testing
and exact proportionality (partial effective surface area!)
15
and Medical Devices
 Bioequivalence for topical dosage forms

without systemic action
EU/WHO  usually therapeutic studies necessary

(therapeutic equivalence, safety and tolerability usually not possible by means
of blood sampling and PK data)
FDA  usually therapeutic studies necessary (specific

FDA guidance for corticosteroids…..)
 possibilities are e.g. skin stripping, microdialysis, NIR…
16
and Medical Devices
♦ ..inhalatives… metered dose inhalers…(locally

acting)
♦ usually therapeutic studies necessary

♦ in some cases PK studies for safety reasons
♦ in some cases PK studies in addition to in-vitro (‚quality‘ -
deposition characteristics e.g. FPD)
♦ usually in patients
 EU guidances: CPMP/EWP/4151/00 ref. to 75/318/EEC – Council Regulation No

594/91), CPMP/EWP/2922/01, and CPMP/EWP/239/95
 FDA: ‚Critical Path Opportunities for Generic Drugs‘ May 1, 2007
17
and Medical Devices
THANK YOU FOR YOUR

ATTENTION
18

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Federal Institute for Drugs

and Medical Devices

Regulatory Requirements for BE

Evaluation of Quality and

Dr. Henrike Potthast; Temporary Advisor to WHO

Regulatory Requirements for BE

 FDA - Guidance for Industry: “Bioavailability and Bioequivalence Studies

 WHO – Multisource (generic) pharmaceutical products: Guidelines on

 CN – Guidance for Industry; Conduct and analysis of bioavailability and

Regulatory Requirements for BE

 Bioavailability – rate and extent at which a drug

 Bioequivalence – equivalent bioavailability within pre-set

 Pharmaceutical equivalence  Bioequivalence

 Bioequivalence  Therapeutic equivalence

Regulatory Requirements for BE

 in vivo comparison of products by means of volunteers

 ‘biological quality control’

comparison of product characteristics in order to ensure

Regulatory Requirements for BE

 Immediate and Modified Release Dosage

BE is generally required and can be investigated by

♦ pharmacokinetic (BE) studies (preferred as most sensitive)

Regulatory Requirements for BE

 Immediate Release (IR) Dosage Forms

♦ aqueous solution (incl. syrups, elixirs, but no suspensions)

♦ nebulizer inhalation products or nasal sprays (contg. the same actives

Regulatory Requirements for BE

Particularity for IR dosage forms

Regulatory Requirements for BE

 …the ‘parent’ drug substance within a single dose 2-period

 note – special cases

Regulatory Requirements for BE

 Modified Release (MR) Dosage Forms

 controlled (extended, sustained) release

♦ single unit formulations

♦ multiple unit formulations

Regulatory Requirements for BE

 Modified Release (MR) Dosage Forms

generally BE under specific conditions

♦ single dose study (fasting)

Regulatory Requirements for BE

♦ ‚ If a product concerns several strengths…‘

♦ bioequivalence proven for one strength

 see also guidance for MR products, 5.1 of EU guidance

Regulatory Requirements for BE

Regulatory Requirements for BE

♦ Comparative in vitro dissolution ….

♦ complementary to BE studies (see e.g. 3.7 EU guidance)

Regulatory Requirements for BE

 Fixed combination products

 in vivo comparison vs appropriate comparator combination

 general testing criteria apply to all active components

bioequivalence criteria apply to all active components

Regulatory Requirements for BE

 Bioequivalence for transdermal therapeutic systems

 BE by means of single and multiple dose studies

Regulatory Requirements for BE

 Bioequivalence for topical dosage forms

EU/WHO  usually therapeutic studies necessary

FDA  usually therapeutic studies necessary (specific

 possibilities are e.g. skin stripping, microdialysis, NIR…

Regulatory Requirements for BE

♦ ..inhalatives… metered dose inhalers…(locally