federal institute for drugs and medical devices the bfarm is a federal institute within the...

Federal Institute for Drugsand Medical Devices

The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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Waivers of in-vivo BE studiesWaivers of in-vivo BE studies

Evaluation of Quality and Interchangeability of Medicinal Products

10 – 14 September 2007

Dar Es Salaam, Tanzania

Dr. Henrike Potthast; Temporary Advisor to WHO



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♦ ‚ 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…



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…the ‚sensitive‘ strength in case of non-linearity

♦ increase more than proportional:

bioequivalence testing with the highest strength

♦ increase less than proportional :

bioequivalence testing with the highest strength

cave: solubility limitations…

no data available…



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…what to do in case of…

♦ solubility limitations:

bioequivalence testing with the highest strength (or dose) even with linear kinetics

♦ no or inconclusive data on linearity available:

bioequivalence testing with the lowest and highest strength



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…MR products acc. to 5.1 of EU guidance (e.g.

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……..



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Basis for BCS-based Biowaiver Applications/Decisions

FDA - Guidance for Industry: “Waiver of in vivo bio-equivalence studies for immediate release solid oral dosage forms containing certain active moieties/active ingredients based on a Biopharmaceutics Classification System” (2000)

WHO – working document on multisource (generic) pharmaceutical products (QAS/04.093)

WHO – working document on a proposal to waive in vivo bioequivalence (QAS/04.109)

EU-guidance:“Note for Guidance on the Investigation of Bioavailability andBioequivalence” CPMP/EWP/QWP/1401/98; paragraph 5.1



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Definitions

BCS-based ‘Biowaiver’.....

.....is defined as

in vitro instead of in vivo ‘bioequivalence’ testing comparison of test and reference

....is not defined as

no equivalence test



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Definitions

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



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Definitions

acc. to the FDA guidance:

”BCS-based biowaivers are intended only for

bioequivalence studies. They do not apply to

food effect bioavailability studies or other

pharmacokinetic studies.”

(e.g., rel. bioavailability)



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BCS-based biowaiver

In vivo bioequivalence testing is generally required

but

” Such studies may be exempted if the absence of differences in the in vivo performance can be justified by satisfactory in vitro data.”

for oral immediate release dosage forms with

systemic action!



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BCS-based biowaiver

Evaluation of drug substance and

drug product

Drug substance pharmacodynamic/therapeutic aspects physicochemical aspects

Drug product in vitro dissolution



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BCS-based biowaiver

RISK assessment (see e.g. WHO QAS/04/093/rev4) sect. 9.2 and 5.1.(a))

♦ “critical use medicines” ♦ “narrow therapeutic index drugs”♦ “documented evidence for BA or BE problems♦ “scientific evidence that API polymorphs, excipients or the

manufacturing process affects BE”



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BCS-based biowaiver

Biowaiver justification

based on

”………

criteria derived from the concepts underlying

the Biopharmaceutics Classification System ......”



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BCS-based biowaiver

Biopharmaceutics Classification System (BCS)

dissolution

drug product drug substance in solution

membrane transport drug substance in the system

simplified mechanistic view of bioavailability



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BCS-based biowaiver



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Fig.1: Physicochemical properties that affect absorption (after oral administration) [H. van de Waterbeemd/ Eur J Pharm Sci 7 (1998), 1-3]

Melting point

Charge

Ionisa-tion

H-bonding

Lipophilicity

Size Shape

ChargeDistribution

Amphiphilicity

Solubility



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BCS-based biowaiver

Solubility Permeability Dissolution

Pillars of the BCS



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BCS-based biowaiver

High solubility

the highest single unit dose is completely soluble in 250 ml or less of aqueous solution at pH 1 - 6.8 (37 °C)

create a pH-solubility profile

cave: possible stability problems have to be considered

• Discussion on ‘intermediate solubility’, i.e., pH-dependent (high) solubility • Definition of low solubility?



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BCS-based biowaiver

High permeability♦ EU guidance: ”Linear and complete absorption reduces the possibility of

an IR dosage form influencing the bioavailability”

♦ FDA guidance: absolute BA >90 %♦ WHO guidance: at least 85 % absorption in humans

• Human data are preferred; in vitro data may be submitted if sufficiently justified and valid

• Definition of low permeability?



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BCS-based biowaiver



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BCS-based biowaiver

♦ ….if the fraction of the dose absorbed is the same, the human body should always do the same with the absorbed compound …Even in a disease state, this argument is still a valid statement.

[Faassen et al. Clin Pharmacokinet 43 (2004)1117]

what does the product do to the drug substance?



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BCS-based biowaiver

When are in vitro results sufficient for bioequivalence evaluation?

When is in vitro instead of in vivo bioequivalence testing scientifically justified (or even more restrictive)?

Minimizing risk by means of ‘worst case’ investigation?

Which in vitro investigations may be sufficient?



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BCS-based biowaiver

in vitro dissolution objectives

quality control justification of minor variations iviv-correlation (e.g. major variations; bridging) additional to BE studies proportionality based biowaiver BCS based biowaiver ….



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BCS-based biowaiver

in vitro dissolution prerequisites

reasonable, stability-indicating, validated methods discriminative methods reproducible methods biorelevant methods (?)

……one fits all?!



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BCS-based biowaiver

in vitro dissolution and BCS concept

meet prerequisites ensure risk minimization justify absence of difference

biorelevant?!0

2

4

6

8

10

12

14

16

18

20

0 5 10 15 20

time

%



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BCS-based biowaiver

In vitro comparison of immediate release oraldrug products (T and R)

first option: very rapidely dissolving products Not less than 85 % of labeled amount are dissolved within

15 min in each of three buffers (pH 1.2, pH 4.5 acetate buffer, pH 6.8 phosphate buffer) – no further profile comparison of T and R is required

reasonable, validated experimental conditions/methods are strongly recommended!



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BCS-based biowaiver


second option: rapidely dissolving products Not less than 85 % of labeled amount are dissolved within

30 min in each of three buffers (pH 1.2, pH 4.5 acetate buffer, pH 6.8 phosphate buffer)

reasonable, validated experimental conditions/methods are strongly recommended!



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BCS-based biowaiver

Experimental conditions:EU guidance – no specific information yetUS-FDA guidance – ‚USP‘-conditions

50 rpm (paddle) or 100 rpm (basket); 900 ml; USP buffer; 37 °C

WHO – 75 rpm (paddle) or 100 rpm (basket); 900 ml; USP buffer; 37 °C

no surfactants!



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BCS-based biowaiver


Proving similarity of dissolution profiles of T and R

e.g., using f2-test, unless similarity is obvious

(see e.g. WHO QAS/04.093 sect. 9.2 or app. 2 of the EU guidance; note prerequisites)



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BCS-based biowaiver

f2-test

acceptance value based on 10 % difference between profiles

„identical“ profiles: f2 =100

„similar“ profiles: f2 between 50 and 100 (?!)

any other reasonable/justified test possible!



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BCS-based biowaiver

Requirement: either very rapid or “similar” in vitro dissolution

how similar is ‘similar’? discussion of differences usually not appropriate



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BCS-based biowaiver

BCS based biowaiver in vitro dissolution

no iviv correlation

no biorelevant conditions (except pH)

concept to justify absence of difference!



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BCS-based biowaiver

Evaluation of excipients (e.g., large amounts, possible interactions....; e.g. Isoniazid J Pharm Sci 96 March

07: “…permeability changes due to excipient interaction cannot be detected in vitro…”)

Evaluation of manufacturing processes in relation with critical physicochemical properties



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BCS-based biowaiver

BCS-based Biowaiver for immediate release drug products containing highly soluble, highly permeable drugsubstances.

No BCS-based biowaiver for:

locally applied, systemically acting products non-oral immediate release forms with systemic action modified release products transdermal products



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BCS-based biowaiver

Provided that ......

drug solubility is high, permeability is limited, excipients do not affect kinetics, excipients do not interact ,.....



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BCS-based biowaiver

....then very rapid dissolution (e.g.>85% in 15 min) of testand reference may ensure similar product characteristics because.......absorption process is probably independent fromdissolution and almost not product related…

limited absorption kinetics due to poor drug permeability and/or gastric emptying

Biowaiver for BCS class III drugs



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BCS-based biowaiver

For drugs showing ....

‘very’ high permeability

pH-dependent solubility within the physiologically relevant pH range

.....an ‘intermediate solubility’ class is suggested

[Polli et al. J Pharm Sci 93 (2004) 1375]



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BCS-based biowaiver

pH-dependent soluble, highly permeable, weakacidic, ionizable drug compounds may be handledlike BCS class I drugs (e.g. chpt 8 in: Drug Bioavailability, van de

Waterbeemd, Lennernäs, Artursson (edts) 2003 Wiley-VCH)

in vitro dissolution requirements acc. to WHO doc at least 85% within 30 min at pH 6.8 and

f2 testing for pH 1.2 and 4.5 profiles

but no biowaiver for weak basic drugs



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BCS-based biowaiver

meaningful literature data may be used for drug substance characteristics (and excipients)

product related data must always be actually generated for the particular product



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BCS-based biowaiver

BCS-based biowaiver are not just in-vitro dissolution, but in-vitro dissolution is meant to be an important part of BCS-based biowaiver applications



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BCS-based biowaiver

THANK YOU FOR YOUR ATTENTION!

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