Bundesinstitut für Arzneimittel und Medizinprodukte Pt WHO-consultant 1 WHO Training Workshop on Pharmaceutical Quality, Good Manufacturing Practice &

Bundesinstitut für Arzneimittel und Medizinprodukte

Pt WHO-consultant 1

WHOTraining Workshop on Pharmaceutical Training Workshop on Pharmaceutical

Quality, Good Manufacturing Practice & Quality, Good Manufacturing Practice & BioequivalenceBioequivalence

BiowaiverBiowaiver

Kiev, October 3-7, 2005

Dr. H. Potthast ([email protected])


Pt WHO-consultant 2

Basis for Biowaiver Basis for Biowaiver Applications/DecisionsApplications/Decisions

Note for Guidance on the Investigation of Bioavailability and Bioequivalence” CPMP/EWP/QWP/1401/98; paragraph 5.1

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)

Current scientific discussion


Pt WHO-consultant 3

Definitions 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


Pt WHO-consultant 4

Biowaiver - Multiple StrengthsBiowaiver - Multiple Strengths

♦ For IR oral dosage forms one BE study using (usually) the highest strength may be sufficient for all strengths if…

♦ same manufacturer and process♦ linear drug input (if this is not the case…..)♦ same qualitative composition of different strengths♦ same ratio between active substance and excipients, or same

excipients in case of low concentration (less than 5 %) ♦ similar in vitro dissolution

(see e.g. 5.4 of EU guidance)

also valid for MR products acc. e.g. to 5.1 of EU guidance CPMP/EWP/280/96


Pt WHO-consultant 5

Biowaiver - Multiple StrengthsBiowaiver - Multiple Strengths

♦ in case of non-linear pharmacokinetics…

♦ …if AUC increases more than proportional, in vivo BE testing at least of the highest dose strength

♦ …if AUC increases less than proportional, in vivo BE testing at least of the lowest dose strength

♦ …in case of insufficient or no information, in vivo BE testing

at least of the lowest and highest dose strength


Pt WHO-consultant 6

Biowaiver – Test vs ReferenceBiowaiver – Test vs Reference

‘Biowaiver’.....

.....is defined as

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

....is not defined as

no bioequivalence test


Pt WHO-consultant 7

Definitions 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)


Pt WHO-consultant 8

EU Note for Guidance....EU Note for Guidance....

In vivo bioequivalence testing is generally required but acc. to paragr. 4.2 and 5.1:

” 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!


Pt WHO-consultant 9

EU Note for Guidance....EU Note for Guidance....

Biowaiver justification

paragr. 5.1.1:

”This section .........takes into consideration

criteria derived from the concepts underlying

the Biopharmaceutics Classification System ......”


Pt WHO-consultant 10

BCS based BiowaiverBCS based Biowaiver

Evaluation of drug substance and

drug product

Drug substance pharmacodynamic/therapeutic aspects physicochemical aspects

Drug product in vitro dissolution



Drug Substance Characteristics IDrug Substance Characteristics I

EU NfG paragr. 5.1.1

a)i “Risk of therapeutic failure or adverse drug reactions” (e.g., narrow therapeutic index drugs)

examples: Theophylline, Carbamazepine

b)ii “Risk of bioinequivalence” (i.e., bioavailability problems are evident)examples: Ciclosporine, Glibenclamide



Drug Substance Characteristics IIDrug Substance Characteristics II

Biopharmaceutics Classification System (BCS)

dissolution

drug product drug substance in solution

membrane transport drug substance in the system

simplified mechanistic view of bioavailability



BCS AssumptionBCS Assumption

♦ ….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?



BCS AssumptionBCS Assumption

Solubility Permeability Dissolution

Pillars of the BCS



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



Drug Substance Characteristics IIIDrug Substance Characteristics III

High solubility (acc. to BCS)

the highest single unit dose is completely soluble in

250 ml of aqueous solution at pH 1-8 (37 °C)

recommended investigations at pH 1, 4.6, 6.8 and pkacave: possible stability problems have to be considered

• Discussion on ‘intermediate solubility’, i.e.,

pH-dependent (high) solubility • Definition of low solubility?



Drug Substance Characteristics IVDrug Substance Characteristics IV

High permeability (acc. to BCS)

EU guidance: ”Linear and complete absorption reduces the possibility of an IR dosage form influencing the bioavailability”

• FDA guidance: absolute BA >90 %• Human data are preferred; in vitro data may be

submitted if sufficiently justified and valid• Definition of low permeability?



Drug Substance Characteristics IVDrug Substance Characteristics IV

♦ Methods to determine permeability

Non-clinical methods♦ Cell cultures (eg CaCo-2)♦ Animal studies (everted rat gut)

Clinical methods♦ Intestinal perfusion

(Loc-I-gut system)♦ Absolute bioavailability

(mass balance)



Fig.2: Relation of human permeability and absorption [R. Löbenberg, G.L.Amidon/ Eur J Pharm Biopharm 50 (2000), 3-12]



Drug Substance Characteristics VDrug Substance Characteristics V

”More factors affect bioavailability when

absorption is slow or incomplete than when it is

rapid and complete,hence, slow or incomplete

absorption often leads to variable therapeutic

responses.” [Turner et al. Pharm Res 21(2004)68]

“Dynamic character of the dissolution/uptake

process” [Rinaki et al. Pharm Res 21 (2004) 1567]



Drug Substance Characteristics VIDrug Substance Characteristics VI

Absorption Bioavailability

but...

High bioavailability High absorption

Low bioavailability (not necessarily) Low

absorption



Drug Substance Characteristics VIIDrug Substance Characteristics VII



Drug Substance Characteristics VIIIDrug Substance Characteristics VIII

Additional aspects to be considered: prodrugs effective metabolites instability polymorphic forms stereochemistry (enantiomer/racemate) wide therapeutic dose range ..........



BCS ConceptBCS Concept

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?



Drug PRODUCT characteristics IDrug PRODUCT characteristics I

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

Not less than 85 % of labeled amount are dissolved within 15 min in each of three buffers (pH 1 – 8) – no further comparison of T and R is required

Proving similarity of dissolution profiles of T and R e.g., using f2-test, unless similarity is obvious

(see app. 2 of the EU guidance; note prerequisites)

reasonable experimental conditions/methods are strongly recommended!



Drug product characteristics IIDrug product characteristics II

Evaluation of excipients (e.g., large amounts, possible interactions....)

Evaluation of manufacturing processes in relation with critical physicochemical properties



EU/FDA GuidanceEU/FDA Guidance

Biowaiver for immediate release drug products containing highly soluble, highly permeable drugsubstances only.

No biowaiver for:

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

action modified release products transdermal products



Biowaiver Extensions ?!Biowaiver Extensions ?!

Provided that ......

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




....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 not product related…

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

Biowaiver for BCS class III drugs (e.g. Atenolol)?!




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]




„pH-dependant soluble, highly permeable, weakacidic, ionizable drug compounds may be handledlike BCS class I drugs“ (quotation)

Current discussions on in vitro dissolution requirements?!

Probably no biowaiver for weak basic drugs (personal communication)




„BDDCS - Biopharmaceutics Drug Disposition Classification System“

“Consideration of elimination criteria may expand number of class 1 drugs eligible for a waiver of in vivo BE studies and provide predictability of drug disposition profiles for classes 2, 3, and 4 compounds.”

(Wu et al., Pharm Res 22 (2005) 11)



Biowaiver Documentation IBiowaiver Documentation I

Evaluation of possible therapeutic risks related to bio(in)equivalence

Discussion of relevant pharmacokinetic characteristics e.g.: therapeutic range

metabolism

kinetic linearity

‘absorption window’

variability....



Biowaiver Documentation IIBiowaiver Documentation II

Physicochemical characterisation of

the drug substance

solubility permeability/absorption stability

Documentation of analytical method validation



Biowaiver Documentation IIIBiowaiver Documentation III

Evaluation of product characteristics

comparison of in vitro dissolution of test

and reference evaluation of excipients evaluation manufacturing process

Documentation of analytical method validation



Biowaiver Documentation IVBiowaiver Documentation IV

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

product related data (incl. in vitro dissolution) must always be actually generated for the particular product



Biowaiver ApplicationBiowaiver Application

for generic drug applications

variations

development/new drug products (e.g., bridging studies, pilot BA batch vs

production batch)



BiowaiverBiowaiver

THANK YOU FOR YOUR ATTENTION!

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Bundesinstitut für Arzneimittel und Medizinprodukte Pt WHO-consultant 1 WHO Training Workshop on Pharmaceutical Quality, Good Manufacturing Practice &