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WHO Workshop on Assessment of Bioequivalence Data Addis Ababa, 31. August – 3. September 2010 BCS-based Biowaivers PowerPoint Presentation
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WHO Workshop on Assessment of Bioequivalence Data Addis Ababa, 31. August – 3. September 2010 BCS-based Biowaivers . Dr. Henrike Potthast (henrike.potthast@bfarm.de). WHO Workshop on Assessment Bioequivalence Data, Addis Ababa, 31. August-3.September, 2010.

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slide1

WHO Workshop on Assessment of Bioequivalence Data

  • Addis Ababa, 31. August – 3. September 2010
  • BCS-based Biowaivers

Dr. Henrike Potthast(henrike.potthast@bfarm.de)

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

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
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
definitions1
Definitions
  • Bioequivalence study
    • in vivo comparison using humans as dissolution models
    • ‚biological quality control‘
    • comparative evaluation of the formulation effect
  • Bioequivalence therapeutic equivalence
definitions2
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

definitions3
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)

bcs based biowaiver
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!
bcs based biowaiver1
BCS-based biowaiver

Evaluation of drug substance and

drug product

Drug substance

  • therapeutic aspects
  • physicochemical aspects

Drug product

  • in vitro dissolution
bcs based biowaiver2
BCS-based biowaiver

Biowaiver justification

based on

”………criteria derived from the concepts underlying

the Biopharmaceutics Classification System ......”

bcs based biowaiver3
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

slide11

Melting point

Charge

Solubility

Size

Shape

Ionisa-tion

H-bonding

Charge

Distribution

Lipophilicity

Amphiphilicity

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

bcs based biowaiver4
BCS-based biowaiver

Pillars of the BCS

SolubilityPermeabilityDissolution

Absorption

bcs based biowaiver5
BCS-based biowaiver

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?
bcs based biowaiver6
BCS-based biowaiver

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!
bcs based biowaiver7
BCS-based biowaiver

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?
bcs based biowaiver8
BCS-based biowaiver

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)

bcs based biowaiver9
BCS-based biowaiver

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)

bcs based biowaiver10
BCS-based biowaiver

Provided that ......

drug solubility is high,

  • permeability is limited,
  • excipients do not affect kinetics,
  • excipients do not interact ,.....
bcs based biowaiver11
BCS-based biowaiver

....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

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.

bcs class iii1
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.

Fig. 2

bcs class iii2
BCS-class III?!

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

bcs class iii3
BCS-class III?!

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 (standard

error) from 12 subjects.

Clin Pharmacokinet. Jantratid et al 2006

bcs based biowaiver12
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; see WHO guidance]

bcs based biowaiver13
BCS-based biowaiver

“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
bcs based biowaiver14
BCS-based biowaiver

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

bcs based biowaiver15
BCS-based biowaiver

BCS-based biowaiver approach applicable…..

  • pro-drugs?
  • effective metabolites?
  • instability?
  • polymorphic forms?
  • stereochemistry (enantiomer/racemate)?
  • wide therapeutic dose range? ..........
bcs based biowaiver16
BCS-based biowaiver

RISKassessment

(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”
bcs based biowaiver17
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?

bcs based biowaiver18
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 to detect possible formulation related differences?
bcs based biowaiver19
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
  • ….
bcs based biowaiver20
BCS-based biowaiver

‘usual’ in vitro dissolution prerequisites

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

……one fits all?!

bcs based biowaiver21
BCS-based biowaiver

in vitro dissolution and BCS concept

  • use of representative batches
  • meet prerequisites
  • ensure risk minimization
  • justify absence of difference
  • biorelevant?!
bcs based biowaiver22
BCS-based biowaiver

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!
bcs based biowaiver23
BCS-based biowaiver

In vitro comparison of immediate release oral

drug products (T and R)

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!
bcs based biowaiver24
BCS-based biowaiver

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!
bcs based biowaiver25
BCS-based biowaiver

In vitro comparison of immediate release oral

drug products (T and R)

  • 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)

bcs based biowaiver26
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!
bcs based biowaiver27
BCS-based biowaiver
  • requirement: either “very rapid” or “similar” in vitro dissolution
    • how similar is ‘similar’?
    • discussion of differences usually not appropriate
bcs based biowaiver28
BCS-based biowaiver

BCS-based biowaiver in-vitro dissolution

  • no iviv correlation
  • no biorelevant conditions (except pH)
  • concept to justify absence of difference!
bcs based biowaiver29
BCS-based biowaiver

finally EXCIPIENTS

  • Evaluation of excipients(e.g., large amounts, possible interactions....; e.g. IsoniazidJ 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
bcs based biowaiver30
BCS-based biowaiver

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.
bcs based biowaiver31
BCS-based biowaiver

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

bcs based biowaiver32
BCS-based biowaiver

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)

bcs based biowaiver33
BCS-based biowaiver

Summary Requirements - BCS class 3

  • „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)

bcs based biowaiver34
BCS-based biowaiver

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)

bcs based biowaiver35
BCS-based biowaiver

Summary Requirements - BCS class 2

  • „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:….

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

bcs based biowaiver36
BCS-based biowaiver

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).“

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

bcs based biowaiver37
BCS-based biowaiver

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.“

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

bcs based biowaiver38
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
bcs based biowaiver39
BCS-based biowaiver
  • 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
bcs based biowaiver40
BCS-based biowaiver
  • 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)
bcs based biowaiver41
BCS-based biowaiver
  • Current recommendation for antiretroviral drugs

a BCS-based biowaiver is possible for

♦ lamivudine

♦ stavudine

♦ zidovudine

bcs based biowaiver42
BCS-based biowaiver

♦„….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?

bcs based biowaiver43
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
bcs based biowaiver44
BCS-based biowaiver

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
bcs based biowaiver45
BCS-based biowaiver
  • 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.

……….

bcs based biowaiver46
BCS-based biowaiver

THANK YOU FOR YOUR ATTENTION!