Regulatory Response to BCS in JapanRegulatory Response to BCS in Japan

Nobuo Aoyagi, Ph.D.National Institute of Health Sciences

Harmonization, Globalization and Innovation in PharmaceuticalScience and Technology, September 26, 2005

日本薬剤学会創立２０周年記念シンポジウム

BCS : 日本における行政の対応

In pharmaceutical regulation, it isIn pharmaceutical regulation, it isimportant to reduce burdensome testsimportant to reduce burdensome testswhile efficacy and safety are ensuredwhile efficacy and safety are ensuredmaximally.maximally.

In bioequivalence (BE) tests, humanIn bioequivalence (BE) tests, humantests should be reduced as much astests should be reduced as much aspossible where dissolution test may bepossible where dissolution test may beused as a surrogate. Butused as a surrogate. But……

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FlufenamicFlufenamic acid acidcapsulecapsule

IndomethacinIndomethacincapsulecapsule pH 7.2

Paddle at 120 rpmPaddle at 120 rpm Serum concentrationSerum concentration

pH 7.6

Kaniwa,Int.J.Cl.Pharm.Ter.Tox.,21, 56, 1983

Aoyagi, Int.J.Cl.Pharm.Ter.Tox.,23, 529, 1985

OutlineOutline

•• Concept of BCSConcept of BCS•• BE Test in JapanBE Test in Japan•• Reason for Reason for NotNot using BCS using BCS•• ConclusionConclusion

Unreliable in vitro/in vivo correlation (IVIVC)Unreliable in vitro/in vivo correlation (IVIVC)

Mechanistic analysis of drug absorption

Limit the use of dissolution test as a surrogate forhuman test in BA/BE studies

Other approaches are neededOther approaches are neededwithout relying on IVIVC alonewithout relying on IVIVC alone

Class 4Class 4Low solubility (LS)Low solubility (LS)Low permeability (LP)Low permeability (LP)

Class 3Class 3High solubility (HS)High solubility (HS)Low permeability (LP)Low permeability (LP)

Class 2Class 2Low solubility (LS)Low solubility (LS)High permeability (HP)High permeability (HP)

Class 1Class 1High solubility (HS)High solubility (HS)High permeability (HP)High permeability (HP)

Perm

eabi

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Perm

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Low

Low

Hig

hH

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HighHigh LowLowSolubilitySolubility

Biopharmaceutics Classification System (BCS)Biopharmaceutics Classification System (BCS)

HS : Highest dose is soluble in <250 ml (pH 1–7.5).HP : Extent of absorption is ≥ 90 %.

BCSBCS GI absorption GI absorption IVIVCIVIVCClass 1 Class 1 Gastric emptying-limitedGastric emptying-limited Not expectedNot expected (HS / HP)(HS / HP) if dissolution is rapidif dissolution is rapidClass 2 Class 2 Dissolution-limitedDissolution-limited ExpectedExpected (LS / HP)(LS / HP)

Class 3 Class 3 Permeability-limitedPermeability-limited Not expectedNot expected (HS / LP) (HS / LP)

Class 4 Class 4 Dissolution orDissolution or ? ? (LS / LP)(LS / LP) permeability-limitedpermeability-limited

Rate limiting step in gastrointestinal (GI) absorptionRate limiting step in gastrointestinal (GI) absorption

IVIVC : in vitro/in vivo correlationIVIVC : in vitro/in vivo correlation

Great Contribution of BCS inGreat Contribution of BCS inPharmaceutical RegulationPharmaceutical Regulation

•• Enable the use of dissolution test forEnable the use of dissolution test forBiowaiver Biowaiver of minor change inof minor change informulation & manufacturing in U.S.A.formulation & manufacturing in U.S.A.

•• Currently being used for Currently being used for biowaiver biowaiver ofofmulti-source products in WHO Guidelinemulti-source products in WHO Guideline

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Normal subject AchlorhydricsubjectCinnarizineCinnarizine

capsulescapsules

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Morihara, Biol.Pharm.Bull., 24, 313,2001Age (year)Age (year)

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Ogata, Int.J.Pharm.29, 113, 1986

•• BE test for whom and in whom ?BE test for whom and in whom ?•• How to assure BE in normal and How to assure BE in normal and achorhydricachorhydric

subjects? Can we require BE tests in both groups?subjects? Can we require BE tests in both groups?•• Is dissolution testing truly of no use for BEIs dissolution testing truly of no use for BE

assessment ?assessment ?

Need to clarify why in vitro/in vivoNeed to clarify why in vitro/in vivocorrelations are unreliablecorrelations are unreliable

pH 3.1- 6.7pH 3.1- 6.7ContractionContraction<3 - 30 mmHg<3 - 30 mmHg

pH 1.2 - 7.6pH 1.2 - 7.6Fluid volume 5 - 200 mlFluid volume 5 - 200 ml

Fluid volumeFluid volume10 - 20 ml10 - 20 ml

pH 5.2 - 6.0pH 5.2 - 6.0Bile acidBile acid0 0 –– 17 17 mMmMFlow rateFlow rate0 - 2 ml/min0 - 2 ml/min

50 rpm

pH 1.2pH 1.2900 ml900 ml

In Vivo : DynamicIn Vivo : Dynamic In Vitro : StaticIn Vitro : Static

Predictable ?Predictable ?

Intersubject variability

Based on current understanding of GI physiologyand learned knowledge, discriminativedissolution tests should be established that areable to discriminate Bioinequivalent products.

What is the discriminative dissolution tests ?

To predict in vivo performance, dissolution testmust be done under various conditions (differentpH, ionic strength, agitation etc).

Is there simpler approach ?Is there simpler approach ?

Not suitable for BE test Not suitable for BE test

IR productsIR products•• Low mechanical stress (e.g. Paddle method)Low mechanical stress (e.g. Paddle method)•• Low agitation (e.g. 50 rpm)Low agitation (e.g. 50 rpm)•• Multiple pHs in a physiological pH rangeMultiple pHs in a physiological pH range•• No surfactantNo surfactant

CR productsCR products•• Low andLow and highhigh mechanical stress (Paddle andmechanical stress (Paddle and

Disintegration apparatus)Disintegration apparatus)•• Low and Low and high high agitation (50 and 200 rpm)agitation (50 and 200 rpm)•• Multiple pHs in a physiological pH rangeMultiple pHs in a physiological pH range•• Low and Low and high high concentrations of surfactantconcentrations of surfactant•• Low and Low and high high ionic strengthionic strength

Discriminative dissolution test

especially under vigorous conditions

No dose-dumpingNo dose-dumping

Dose-dumpingDose-dumping

Dissolution Test for IR productsDissolution Test for IR products

Acidic drug Basic drug Coated product Neutral drug

50 rpm pH 1.2 pH 1.2 pH 1.2 pH 5.5-6.5 pH 3.0-5.0 pH 3.0-5.0 pH 6.8-7.5 pH 6.8 pH 6.8 Water Water Water

100 rpm A discriminative pH between pH 1.2 – 7.5

Paddle methodPaddle method

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Paddle, 50 rpmPaddle, 50 rpm Predicted LevelPredicted Level

ConvolutionConvolution

Similar dissolutionSimilar dissolution at all pHs by at all pHs bydiscriminative in vitro testsdiscriminative in vitro tests

Likely bioequivalentLikely bioequivalent without withoutsubject-formulation interactionsubject-formulation interaction

No need of strict human studyNo need of strict human study(decrease of sample size or waiver of(decrease of sample size or waiver of

human study)human study)

Different dissolutionsDifferent dissolutions under one under oneof conditionsof conditions

They may not be bio-They may not be bio-inequivalentinequivalentinin some types of subjectssome types of subjects

Strict human studyStrict human study using discriminative using discriminativesubjects such as achlorhydric subjectsubjects such as achlorhydric subject

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Ogata. Int.J.Pharm.Ther.Tox.23, 277, 1985.

Use of Dissolution Test in BE AssessmentUse of Dissolution Test in BE Assessment

1. Generic drug1. Generic drug•• Exemption from 90 % confidence interval (C.I.)Exemption from 90 % confidence interval (C.I.)

If dissolutions are similar, test products will beIf dissolutions are similar, test products will beapproved even if 90 % C.I. of Cmax or AUC isapproved even if 90 % C.I. of Cmax or AUC isout of 80 - 125 %.out of 80 - 125 %.

•• Strict human test using specific subjectsStrict human test using specific subjectsIf dissolutions differ at pH 6.8, achlorhydricIf dissolutions differ at pH 6.8, achlorhydricsubjects are required in human test.subjects are required in human test.

2. Minor change in formulation and different strengths2. Minor change in formulation and different strengthsIf dissolutions are similarIf dissolutions are similar, human test can be , human test can be

exempted for all drugs.exempted for all drugs.

BCS was not introduced in our BE tests, althoughwe discussed its advantage and disadvantage.

Why ?

The reason will be shown in following slides.

Dissolution indigestive tract

Bioavailability

FormulationManufacturing

FormulationManufacturing

Bioavailability

Reference product Test product

Dissolution indigestive tract

Identical

Same

Same

Dissolution indigestive tract

Bioavailability

FormulationManufacturing

FormulationManufacturing

Bioavailability

Reference product Test product

Dissolution indigestive tract

Differ

Differ

Differ

Solubility and permeability are not directly relatedto difference in BA

Reason 1

Solubility and permeability are notimmediate causes for Bioinequivalencewhich is mainly caused by differences informulation & manufacturing.

Reason 2

In U.S.A., BCS is employed to increase the useof dissolution test for Biowaiver in minor changein formulation & manufacturing while it willdecrease the use in Japan, if introduced, wheremultimedia dissolution tests are extensivelyapplied (BCS does not give merits).

BE can be assured by theBE can be assured by themultimedia test without relyingmultimedia test without relyingon BCS?on BCS?

BE of most IR products will be assured

•• Strict requirement using specific subjectsStrict requirement using specific subjectsif dissolutions differif dissolutions differ

•• Waiver of 90 % confidence intervalWaiver of 90 % confidence intervalif dissolutions are similarif dissolutions are similar

To produce generic products showingTo produce generic products showingcomparable in vitro dissolutionscomparable in vitro dissolutions

Consequently compel

Most generic companieshave enough capability

Accumulation of in vitro and in vivo data in genericAccumulation of in vitro and in vivo data in genericcompanies (1997-2005)companies (1997-2005)

Q : All your products,Q : All your products,showing similar dissolution,showing similar dissolution,passed human BE test ?passed human BE test ?

Passed(73 %)

Q : Percentage ofQ : Percentage offailed products / totalfailed products / total

Failed(27 %)

Questionaire Survey to Generic Companies (n=14)March, 2005

< 5 %(All companies)

Failure ratio of human BE test < 1.4 % (= 27 × 5 %)

Question to failedcompanies

Multimedia dissolution tests used inJapan function well to ensure BE evenfor generic IR products which differ frominnovator products in formulation andmanufacturing.

U.S.A.U.S.A. JapanJapanBCS BCS For all drugsFor all drugsClass 1 : 0.1N Class 1 : 0.1N HClHCl Multi-media (Multi-media ( pH 1.2,pH 1.2,Class 2Class 2 : : Compendial Compendial mediummedium pH 3-6, pH6.8, Water) pH 3-6, pH6.8, Water)Class 3Class 3 : Multi-media (0.1N : Multi-media (0.1N HClHCl, ,

pH 4.5, pH 6.5, pH7.5) pH 4.5, pH 6.5, pH7.5)Class 4Class 4 : (Human test) : (Human test)

Test Medium of Dissolution tests for Minor ChangesTest Medium of Dissolution tests for Minor Changesin Excipients (Level 2 in USA = Level C in Japan)in Excipients (Level 2 in USA = Level C in Japan)

BCS Simplifydissolution medium

Multiple PHs are necessaryto ensure BE in normal andachlorhydric subjects and tocheck formulation effects

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Ogata, Int.J.Cl.Pharm.Ther.Tox. 24, 279, 1986

MetronidazoleMetronidazole (Class 1) : sugar coated tablets (Class 1) : sugar coated tablets

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Diazepam (Class 1) : plain tabletsDiazepam (Class 1) : plain tabletsOgata. Int.J.Pharm.Ther.Tox., 23, 277 (1985)

Reasons for Not using BCS• Solubility and permeability are properties of drugs but

not properties of formulation & manufacturing that causeBioinequivalence.

• BCS is used to increase the use of dissolution test in USAwhile it will decrease the use in Japan where dissolutiontests are extensively applied (BCS does not give merits).

• BE of most IR products will be assured by the multimediadissolution test used in Japan which does not need BCS.

• BCS is employed to simplify dissolution tests in U.S.A. butcan’t be in Japan. Multimedia test is needed when effectsof excipients on dissolution and BE assurance in normaland achlorhydric subjects are considered.

• Permeability is still not known for many drugs, making itdifficult to use BCS in our regulation because regulatoryequivalence tests can’t be shown for such drugs.

Disadvantage of dissolution testDisadvantage of dissolution test•• Difficult to emulate in vivo condition completelyDifficult to emulate in vivo condition completely

due to our limited understanding of gastrointestinaldue to our limited understanding of gastrointestinal(GI) variables affecting dissolution.(GI) variables affecting dissolution.

•• Difficult to assess Difficult to assess excipientexcipient’’ss effect on permeability effect on permeability•• Difficult to assess GI transition of drug productsDifficult to assess GI transition of drug products

which affects dissolution.which affects dissolution.•• Artificial sink condition (large fluid volume,Artificial sink condition (large fluid volume,

addition of surfactant)addition of surfactant)

Difficult to predict in vivo performance of someproducts containing low solubility drugs and somemodified release products.

Use of BCS as a Risk FactorUse of BCS as a Risk FactorBCS is currently not employed in Japan, which,BCS is currently not employed in Japan, which,however, should be used as a risk factor whenhowever, should be used as a risk factor whendissolution test is expanded to dissolution test is expanded to ““BiowaiverBiowaiver”” for formajor changes in formulation and manufacturingmajor changes in formulation and manufacturingand even for generic products, when theand even for generic products, when thedisadvantages of dissolution tests are considered.disadvantages of dissolution tests are considered.

By the combination use of dissolution test andBy the combination use of dissolution test andBCS, significant bio-BCS, significant bio-inequivalenceinequivalence problems will problems willbe avoided, leading to the reduction of patientbe avoided, leading to the reduction of patient’’s risks risk(Immediate application of dissolution test for all(Immediate application of dissolution test for allclasses of drugs is risky).classes of drugs is risky).

Risk Factors to be Considered for Risk Factors to be Considered for BiowaiverBiowaiver

LowLow High High

BCSBCS Class 1Class 1 Class 4Class 4

Dosage formDosage form SimpleSimple ComplicatedComplicatedDrug releaseDrug release IRIR CRCRTherapeutic windowTherapeutic window WideWide NarrowNarrowDiseasesDiseases NonseriousNonserious SeriousSeriousAdverse effectAdverse effect MildMild SevereSevereElimination half lifeElimination half life LongLong ShortShort

RiskRisk

• Give a theoretical bases for usingdissolution tests BCS (U.S.A)

• Increase the reliability of dissolutiontest by improving the test

Multimedia test (Japan)

To use dissolution test for biowaiver

Conclusion Conclusion

• BCS enables the use of dissolution test for biowaiver inUSA, which, however, is not used in Japan with severalreasons (extensive use of dissolution tests in Japan,solubility & permeability are not immediate causes ofbioinequvalence).

• When use of dissolution tests is expanded to biowaiverfor major changes in formulation & manufacturing andfor generics, BCS should be considered as a risk factor.

• BCS will contribute to develop predictable new drugsand to decrease meaningless IVIVC studies.

• Considering inter-subject difference in gastrointestinalphysiology, it is important to establish dissolution teststhat are able to ensure BE in various subjects.