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Assessment of InterchangeableMultisource Medicines

BCS-Biowaivers

Dr. Henrike Potthast ([email protected])

Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009


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Assessment of Interchangeable Multisource Medicines, Kenya, August 20092 |

Basis for BCS-based BiowaiverApplications/Decisions

WHO Technical Report Series No. 937, May 2006

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

Annex 8: Proposal to waive in vivo bioequivalence requirements for WHO

Model List of Essential Medicines immediate release, solid oral dosageforms

FDA - Guidance for Industry: Waiver of in vivo bio-equivalence studiesfor immediate release solid oral dosage forms containing certain activemoieties/active ingredients based on a Biopharmaceutics ClassificationSystem (2000)

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


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Definitions

BCS-based Biowaiver.....

.....is defined as

in vitroinstead of in vivobioequivalence testing

comparison of test and reference

....is not defined as no equivalence test


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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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Definitions

Bioavailability rate and extent at which a drug substance...becomes available in the general system (productcharacteristic!)

Bioequivalence equivalent bioavailability within pre-setacceptance ranges

Pharmaceutical equivalence Bioequivalence

Bioequivalence Therapeutic equivalence


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BCS-based biowaiver

In vivo bioequivalence testing is generally required

but

Such studies may be exempted if the absence ofdifferencesin the in vivo performance can be

justified by satisfactoryin vitro data.

for oral immediate release dosage forms withsystemic 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

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 themanufacturing process affects BE
http://upload.wikimedia.org/wikipedia/commons/d/dd/Achtung.svg


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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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Fig.1: Physicochemical properties that affect absorption (after oraladministration) [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 orless 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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BCS-based biowaiver

High permeability

EU guidance: Linear and complete absorption reduces the possibility ofan IR dosage form influencing the bioavailability

FDA guidance: absolute BA >90 %

WHO guidance: at least 85 % absorption in humans

Human dataare preferred;

in vitro data may be submitted if sufficiently justified and valid

Definition of low permeability?


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Solubility Permeability BCS classification

high high I (e.g. Propranolol)

low high II (e.g. Glibenclamide)high low III (e.g. Atenolol)

low low IV (e.g. Azathioprine)

BCS-based biowaiver


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BCS-based biowaiver

.if the fraction of the dose absorbed is the same, thehuman body should always do the same with the absorbedcompound Even in a disease state, this argument is stilla 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 bioequivalenceevaluation?

When is in vitroinstead of in vivobioequivalence 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

biorelevantmethods (?)

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 oral

drug products (T andR)

second option: rapidly dissolving products

Not less than 85 % of labeled amount are dissolved within 30 minin each of three buffers (pH 1.2, pH 4.5 acetate buffer, pH 6.8phosphate buffer)

reasonable, validated experimental conditions/methods are stronglyrecommended!


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BCS-based biowaiver

Experimental conditions:

EU guidance no specific information yet

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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BCS-based biowaiver

In vitro comparison of immediate release oral

drug products (T andR)

Proving similarity of dissolution profilesof T and R

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

(see e.g. WHO guidance sect. 9.2 or app. 2 of the current 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 justifyabsenceof difference!


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BCS-based biowaiver

Evaluation of excipients(e.g., large amounts,possible interactions....; e.g. IsoniazidJ Pharm Sci 96March 2007: permeability changes due to excipientinteraction cannot be detected in vitro)

Evaluation of manufacturing processes in relation withcritical physicochemical properties

CS


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BCS-based biowaiver

BCS-based Biowaiver for immediate release drug products

containing eligible drug substances.

No BCS-based biowaiver for:

locally applied, systemically acting products

non-oral immediate release forms with systemic action

modified release products transdermal products

BCS b d bi i


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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 ,.....

BCS b d bi i


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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/orgastric emptying

Biowaiver for BCS class III drugs (see WHO guidance)


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BCS-class III?!

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

Glucophageor Glucofit in 0.1N HCI (,) pH 4.6 (,) and pH 6.8 (,) buffer solution.

BCS class III?!


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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. 2Fig.

BCS class III?!


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BCS-class III?!

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

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

six observations. Data for the Tagamettablet 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 III?!


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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

Tagamettablets. Each point represents the mean plasma cimetidine concentration (standard

error) from 12 subjects.

Clin Pharmacokinet.

Jantratid et al 2006

BCS based biowaiver


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BCS-based biowaiver

biopharmaceutics assessment (with necessary underlying PKbackground!!) pure PK assessment

differentiation between solubility (API) and dissolution

(product performance) volume of dissolution medium (900 vs 500 ml) not relevant

(no concerns regarding hydrodynamics; recent findings); sinkconditions!

in-vitro/in-vivo relationship rather than correlation!!

slow absorptionintestinal transit about 3hs!!

BCS based biowaiver


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BCS-based biowaiver

For drugs showing ....

very high permeability

pH-dependent solubility within the physiologically relevantpH range

.....an intermediate solubilityclass is suggested

[Polli et al. J Pharm Sci 93 (2004) 1375; see WHO guidance]

BCS based biowaiver


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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,Lennerns, Artursson (edts) 2003 Wiley-VCH)

in vitrodissolution 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 biowaiver


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BCS-based biowaiver

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

product related data must alwaysbe actually generated forthe particular product

BCS based biowaiver


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BCS-based biowaiver

BCS-based biowaiver are not just in-vitrodissolution,

but in-vitrodissolution is meant to be an importantpart of BCS-based biowaiver applications

BCS-based biowaiver


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BCS-based biowaiver

Current recommendation forTBdrugs

no BCS-based biowaiver for RMP

regular BCS-based biowaiver possible for levofloxacin andofloxacin (rapid dissolution)

currently a BCS-based biowaiver is possible for isoniazid (cave:excipients!), ethambutol and pyrazinamide if the same veryrapid 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 biowaiver
http://healthtech.who.int/pq/info_applicants/info_for_applicants_BE_studies.htmhttp://healthtech.who.int/pq/info_applicants/info_for_applicants_BE_studies.htm


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ex.: Pyrazinamide [Dressman et al., 2008, unpubl.]

BCS-based biowaiver


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ex.: Pyrazinamide [Dressman et al., 2008, unpubl.]

BCS-based biowaiver


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ex.:Pyrazinamide [Dressman et al., 2008, unpubl.]

BCS-based biowaiver


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ex.: Isoniazid [Dressman et al., 2008, unpubl.]

BCS-based biowaiver


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BCS-based biowaiver


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BCS-based biowaiver


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ex.: Ethambutol [Dressman et al., 2008, unpubl.]

BCS-based biowaiver


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BCS-based biowaiver


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BCS-based biowaiver


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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; [Epubahead 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. 2008Apr;97(4):1350-60.

Vogt M, Derendorf H, Krmer 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 dosageforms: 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: Biowaivermonographs for immediate release solid oral dosage forms: ibuprofen; J Pharm Sci. 2005 Oct;94(10):2121-31.

Kortejrvi H, Yliperttula M, Dressman JB, Junginger HE, Midha KK, Shah VP, Barends DM: Biowaiver monographs forimmediate 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 biowaiver
http://www.ncbi.nlm.nih.gov/pubmed/18271031?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/17879380?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/17387693?ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/17117431?ordinalpos=6&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/17117431?ordinalpos=6&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/16307451?ordinalpos=10&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/16136567?ordinalpos=11&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/15959881?ordinalpos=12&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/15920763?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/15920763?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/15959881?ordinalpos=12&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/16136567?ordinalpos=11&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/16307451?ordinalpos=10&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/17117431?ordinalpos=6&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/17117431?ordinalpos=6&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/17387693?ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/17879380?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/18271031?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum


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