WHO Workshop on Assessment of Bioequivalence Data Addis Ababa, 31. August – 3. September 2010...

WHO Workshop on Assessment of Bioequivalence Data

Addis Ababa, 31. August – 3. September 2010

BCS-based Biowaivers

Dr. Henrike Potthast ([email protected])

WHO Workshop on Assessment Bioequivalence Data, Addis Ababa, 31. August-3.September, 2010

WHO Workshop on Assessment of Bioequivalence Data31. August – 3. September 2010, Addis Ababa

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Basis for BCS-based Biowaiver Applications/Decisions

Basis for BCS-based Biowaiver Applications/Decisions

WHO – Technical Report Series No. 937, May 2006

Annex 7: Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability

Annex 8: Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate release, solid oral dosage forms

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)

EU-guidance:“Note for Guidance on the Investigation of Bioavailability andBioequivalence” CPMP/EWP/QWP/1401/98 Rev1, Appendix 3


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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


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Bioequivalence study

– in vivo comparison using humans as dissolution models

– ‚biological quality control‘– comparative evaluation of the formulation effect

Bioequivalence therapeutic equivalence


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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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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 biowaiverBCS-based biowaiver

Evaluation of drug substance and

drug product

Drug substance

therapeutic aspects

physicochemical aspects

Drug product

in vitro dissolution


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Biowaiver justification

based on

”………criteria derived from the concepts underlying

the Biopharmaceutics Classification System ......”


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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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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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Solubility Permeability Dissolution Absorption

Pillars of the BCS


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High solubility

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

generate 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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High solubility acc. to WHO

♦ highest dose recommended by WHO (as recommended in the WHO Model List of Essential Medicines)

or

♦ highest dose strength (if not listed s.o.)

please note the differences between guidelines!


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High permeability

♦ Revised EMA guidance: extent of absorption ≥ 85 % (absolute BA or mass balance data) or ‘known absorption’

♦ FDA guidance: absolute BA >90 %

♦ WHO guidance: extent of absorption at least 85 % 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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Methods to investigate permeability

♦ PK-studies (e.g. absolute BA or mass-balance studies)

♦ Human intestinal perfusion studies

♦ Animal models

♦ Caco 2 cell lines or other suitable, validated cell lines

(in-situ or in-vitro models for passively transported APIs only)

to be noted:

the stated methods assess the fraction dose absorbed ≠ BA, which can be reduced substantially by first-pass metabolism (see e.g. Propranolol)


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Supportive data to investigate permeability:

♦ In vivo or in situ perfusion using animal models and

♦ In vitro permeation across a monolayer of cultured epithelial cells like e.g. Caco 2 or other suitable, validated cell lines

are not acceptable on a stand-alone basis

(in-situ or in-vitro models for passively transported APIs only;

negative as well as positive controls needed)


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BCS-based biowaiver


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Provided that ......

drug solubility is high,

permeability is limited,

excipients do not affect kinetics,

excipients do not interact ,.....


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....then very rapid dissolution (at least >85% in 15 min) of test

and reference may ensure similar product characteristics

because...

....absorption process is probably independent from

dissolution and not product related…

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

Biowaiver for BCS class III drugs (see WHO and revised EMA guidance)

BCS-class III?!

Fig. 1. Mean in vitro dissolution profiles of metformin for 500mg immediate-release tablet of

Glucophage® or Glucofit® in 0.1N HCI (○,●) pH 4.6 (□,■) and pH 6.8 (∆,▲) buffer solution.


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BCS-class III?!BCS-class III?!

Fig. 2. Mean in vivo plasma conentration-time profiles of metformin in 12 healthy Chinese subjects after oral

administration of a 500mg immediate-release tablet of Glucophage (○) or Glucofit (●).Fig. 2

Fig.


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Fig. 1. Comparison of mean cimetidine released-time profiles obtained from dissolution testing of cimetidine

tablets containing methacrylate copolymer and Tagamet® tablets in different media. Each value is the mean of

six observations. Data for the Tagamet® tablet were obtained from dissolution testing in 0.01N hydrovhloric acid

(HCI) and simulated intestinal fluid without pancreatin (SIFsp): (a) 0.01N HCI, pH 2; (b) phosphate buffer, pH

4.5; (c) SIFsp, pH 6.8; and (d) fasted-state simulated intestinal fluid, pH 6.5 pancreatin. Clin Pharmacokinet. Jantratid et al 2006


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Fig. 2. Comparison of mean plasma cimetidine concentration-time profiles obtained after

administration of a singel oral dose of cimetidine tablets containing methacrylyte copolymer or

Tagamet® tablets. Each point represents the mean plasma cimetidine concentration (standarderror) from 12 subjects.

Clin Pharmacokinet. Jantratid et al 2006


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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; see WHO guidance]


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“pH-dependent soluble, highly permeable, weak

acidic, ionizable drug compounds may be handled

like 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 guidance 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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According to the WHO guideline drug substances

that belong to

BCS-class 1 and 3

and some of BCS class 2 (weak acids with high permeability)

..... are in principle eligible for the BCS-based biowaiver approach


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BCS-based biowaiver approach applicable…..

pro-drugs?

effective metabolites?

instability?

polymorphic forms?

stereochemistry (enantiomer/racemate)?

wide therapeutic dose range? ..........


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RISK assessment

(see e.g. WHO guidance; 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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♦ „….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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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 to detect

possible formulation related differences?


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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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‘usual’ in vitro dissolution prerequisites

reasonable, stability-indicating, validated methods

discriminative methods

reproducible methods

biorelevant methods (?)

……one fits all?!


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in vitro dissolution and BCS concept

use of representative batches

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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In vitro comparison of immediate release oral

drug products (T and R)

first option: very rapidly 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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second option: rapidly 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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Experimental conditions:

EU guidance – usually 50 rpm (paddle) or 100 rpm (basket); 900 ml; PhEur buffer; 37 °C;

sampling schedule

US-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 or less; USP buffer; 37 °C

all: no surfactants!


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Proving similarity of dissolution profiles of T and R

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

(see e.g. WHO guidance sect. 9.2 or app. 1 of the revised EU guidance; note prerequisites)


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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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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 in-vitro dissolution

no iviv correlation

no biorelevant conditions (except pH)

concept to justify absence of difference!


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finally EXCIPIENTS Evaluation of excipients (e.g., large amounts,

possible interactions....; e.g. Isoniazid J Pharm Sci 96 March 2007: “…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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Risk assessment on EXCIPIENTS acc. to WHO

i) the excipient is present in the comparator product, or the excipient is present in a number of other products which contain the same API as the multisource drug product and which have marketing authorizations in countries participating in the International Committee on Harmonisation (ICH) or associated countries;

and

ii) the excipient is present in the multisource product in an amount similar to that in the comparator, or the excipient is present in the multisource drug product in an amount typically used for that type of dosage form.


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Excipients – generally

- Should be ‘well-known’

- Used in ‘usual amounts’

- Without relevant impact on the absorption process

Preferred for class I drugs and requested for class III: same excipients in

similar amounts as the reference

‘Critical’ excipients (e.g. surfactants, mannitol, sorbitol…)

should be qualitatively and quantitatively the same


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Summary Requirements - BCS class 1

„Dosage forms of APIs which are highly soluble, highly permeable (BCS Class 1), and are rapidly dissolving are eligible for a biowaiver based on the BCS provided:

(i) the dosage form is rapidly dissolving (as defined in section 9.1.2.2) and the dissolution profile of the multisource product is similar to that of the comparator product at pH 1.2, pH 4.5 and pH 6.8 buffer using the paddle method at 75 rpm or the basket method at 100 rpm (as described in section 9.2) and meets the criteria of dissolution profile similarity, f2 > 50 (or equivalent statistical criterion);

(ii) if both the comparator and the multisource dosage forms are very rapidly dissolving (as defined in section 9.1.2.1) the two products are deemed equivalent and a profile comparison is not necessary.“

(see WHO technical Report Series, No. 937, 2006 Annex 7 and 8)


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„Dosage forms of APIs which are highly soluble and have low permeability (BCS Class 3) are eligible for biowaivers provided all the criteria (a–d) listed in section 9.2 are met and the risk–benefit is additionally addressed in terms of extent, site and mechanism of absorption.“

Very rapidly dissolving (release of >85 % within 15 min) in standard media pH 1.2, 4.5, and 6.8; 75 rpm (paddle) or 100 rpm (basket) applies to IR products containing class III APIs.

(see WHO technical Report Series, No. 937, 2006 Annex 7 and 8)


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Summary Requirements - BCS class 3 ctd.

- criteria (a–d) listed in section 9.2:

A biowaiver based on the BCS considers:

(a) the solubility and permeability of the API (see section 9.1);

(b) the similarity of the dissolution profiles of the multisource and comparator products in pH 1.2, 4.5 and 6.8 media (see below);

(c) the excipients used in the formulation (see below); and

(d) the risks of an incorrect biowaiver decision in terms of the therapeutic index of, and clinical indications for, the API (see section 5.1 for cases where an in vivo study would be required to demonstrate bioequivalence).

(see WHO technical Report Series, No. 937, 2006 Annex 7)


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„Dosage forms of APIs with high solubility at pH 6.8 but not at pH 1.2 or 4.5 and with high permeability (by definition, some but not all BCS Class 2 compounds with weak acidic properties) are eligible for a biowaiver based on BCS provided that criteria (b), (c) and (d) described in section 9.2. are met, that the API has high permeability (i.e. the fraction absorbed is 85% or greater) and a dose:solubility ratio of 250 ml or less at pH 6.8, and that the multisource product:….



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Summary Requirements - BCS class 2 ctd…..

„is rapidly dissolving (85% in 30 minutes or less) in pH 6.8 buffer using the test procedure conforming to section 9.2;

and

(ii) the multisource product exhibits similar dissolution profiles, as determined with the f2 value or equivalent statistical evaluation, to those of the comparator product at the three pH values (pH 1.2, 4.5 and 6.8).“



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Summary Requirements - BCS class 2 ctd….

„For multisource products containing Class 2 APIs with dose:solubility ratios of 250 ml or less at pH 6.8, the excipients should additionally be critically evaluated in terms of type and amounts, e.g. of surfactants, in the formulation. Further, if the Cmax is critical to the therapeutic efficacy of the API, the risk of reaching an inappropriate biowaiver decision and its associated risks to public health and for individual patients may be deemed unacceptable.“



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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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Current recommendation for TB drugs

no BCS-based biowaiver for RMP

‘regular’ BCS-based biowaiver possible for levofloxacin and ofloxacin (“rapid dissolution”)

currently a BCS-based biowaiver is possible for isoniazid (cave: excipients!), ethambutol and pyrazinamide if the same “very rapid” dissolution (T and R) is demonstrated

see specific, currently published WHO guidance documents at: http://healthtech.who.int/pq/info_applicants/info_for_applicants_BE_studies.htm


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Current recommendation for TB drugs

however – a BCS-based biowaiver is not possible due to the comparator(!) in the case of…

Ofloxacine (since rapid dissolution is not achieved)

Ethambutol (since very rapid dissolution is not achieved)


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Current recommendation for antiretroviral drugs

a BCS-based biowaiver is possible for

♦ lamivudine♦ stavudine♦ zidovudine


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♦ „….Risk assessment: only if the risk of an incorrect biowaiver decision and an evaluation of the consequences (of an incorrect, biowaiver-based equivalence decision) in terms of public health and risks to individual patients is outweighed by the potential benefits acrued from the biowaiver approach may the biowaiver procedure be applied…“

[WHO Technical Report Series, No. 937, 2006; Annex 8]

is the concept scientifically sound?


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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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Minimize the risk by thorough and correct …

drug substance classification

In-vitro dissolution (incl. profile comparison)

demonstration that excipients are well-established (?!?) will not differ in terms of their effect on absorption will not lead to interactions that alter pharmacokinetics


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Becker C, Dressman JB, Amidon GL, Junginger HE, Kopp S, Midha KK, Shah VP, Stavchansky S, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: Pyrazinamide; J Pharm Sci. 2008 Feb 12; [Epub ahead of print]

Becker C, Dressman JB, Amidon GL, Junginger HE, Kopp S, Midha KK, Shah VP, Stavchansky S, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: ethambutol dihydrochloride; J Pharm Sci. 2008 Apr;97(4):1350-60.

Vogt M, Derendorf H, Krämer J, Junginger HE, Midha KK, Shah VP, Stavchansky S, Dressman JB, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: prednisone; J Pharm Sci. 2007 Jun;96(6):1480-9.

Becker C, Dressman JB, Amidon GL, Junginger HE, Kopp S, Midha KK, Shah VP, Stavchansky S, Barends DM; International Pharmaceutical Federation, Groupe BCS: Biowaiver monographs for immediate release solid oral dosage forms: isoniazid; J Pharm Sci. 2007 Mar;96(3):522-31.

Kalantzi L, Reppas C, Dressman JB, Amidon GL, Junginger HE, Midha KK, Shah VP, Stavchansky SA, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: acetaminophen (paracetamol); J Pharm Sci. 2006 Jan;95(1):4-14.

Potthast H, Dressman JB, Junginger HE, Midha KK, Oeser H, Shah VP, Vogelpoel H, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: ibuprofen; J Pharm Sci. 2005 Oct;94(10):2121-31.

Kortejärvi H, Yliperttula M, Dressman JB, Junginger HE, Midha KK, Shah VP, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: ranitidine hydrochloride; J Pharm Sci. 2005 Aug;94(8):1617-25.

Verbeeck RK, Junginger HE, Midha KK, Shah VP, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (BCS) literature data: chloroquine phosphate, chloroquine sulfate, and chloroquine hydrochloride; J Pharm Sci. 2005 Jul;94(7):1389-95.

……….


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THANK YOU FOR YOUR ATTENTION!

WHO Workshop on Assessment of Bioequivalence Data Addis Ababa, 31. August – 3. September 2010...

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