Application of Biopharmaceutical Classification System ... · or less of aqueous media over the pH range of 1- ... • Clinically relevant drug concentrations should be used to

Mehul Mehta AAPS Webinar 09/09/10 1

Application of Biopharmaceutical Classification System (BCS) in

Regulatory Submissions

Mehul Mehta, Ph.D.Director, DCP1

OCP, OTS, CDER, FDA


DISCLAIMER

• Views expressed are mine and do not reflect official FDA Policy.


OUTLINEI. BCS GuidanceII. Implementation:

a) CDER BCS Committeeb) Examples

III. Future ConsiderationsIV. ConclusionsV. Acknowledgements


Guidance for IndustryWaiver of In Vivo Bioavailability and

Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics

Classification System

FDA/CDERAugust 2000


I) BCS Guidancea. Central Conceptb. Biowaiversc. BCS Class 1 Requirementsd. Additional Considerations


• Observed in vivo differences in BA from two pharmaceutically equivalent solid oral products likely be due to differences in drug dissolution in vivo.

• If the in vivo dissolution of an IR solid oral dosage form is rapid in relation to gastric emptying and the drug has high permeability, BA is unlikely to be dependent on drug dissolution and GI transit time.

I. a) Central Concept


Four BCS Classes:

Class 1: HS, HPClass 2: LS, HPClass 3: HS, LPClass 4: LS, LP

I. a) Central Concept


I. b) Biowaivers• Initial in-vivo Bioavailability (BA) characterization is

required for NDAs. BCS consideration is not applicable for these studies.

• BCS consideration is applicable for waiver of bioequivalence (BE) studies in NDAs (pre- and post-approval) and ANDAs.

• The drug substance has to be BCS Class 1, the product has to be rapidly dissolving plus the test and reference formulations should be pharmaceutical equivalents and show rapid and similar dissolution.


I. c) BCS Class 1 Requirements• HS: Highest strength should be soluble in 250 ml

or less of aqueous media over the pH range of 1- 7.5.

• HP: (a) 90% or greater absolute bio, or urinary recovery, or; (b) permeability greater than the reference compound(s).

• RD: 85% in 30 minutes at pH 1, 4.5 and 6.8 each.


I. d) Additional Considerations

Permeability Methods:

• Use of nonhuman permeability test methods is limited to those drug substances that are transported by passive mechanisms.

• When a single method fails to conclusively demonstrate a permeability classification, two different methods may be advisable.



Excipients:

• Should have been used in previously approved IR solid oral dosage forms

• Quantity of excipients should be consistent with the intended function

• Large quantities of certain excipients (e.g., surfactants and sweeteners) can be an issue.



Prodrugs:

• If the prodrug drug conversion occurs post intestinal permeation, measure permeability of the prodrug;

• Otherwise, measure permeability of the drug.



BCS based waivers not applicable for:

• Narrow Therapeutic Range (NTR) drugs

• Products designed to be absorbed in the oral cavity (e.g., sublingual or buccal tablets)






II.a) CDER BCS COMMITTEEi. Formation & Objectivesii. Membershipiii. Processiv. Applications Reviewedv. Permeability determination and related

issues


II.a.i) Formation & ObjectivesFormation:• CDER BCS Committee formed in March 2004 (earlier version

was The BCS Technical Committee under the BCC)

Objectives:• Provide expert advice on all BCS review (NDA and ANDA)

issues especially those where class I claim is requested.• Serve as the point of contact for BCS related policy,

questions, interactions and clarifications within FDA and with the external constituents.

• Periodically evaluate if there is a need to consider updating the BCS guidance, based on internal and public information.


II.a.ii) Membership• Mehul Mehta (Co-Chair), OCP, OTS• Ramana Uppoor, OCP, OTS• Dakshina Chilukuri, OCP, OTS• Jayabharathi Vaidyanathan, OCP, OTS• Donna Volpe, LCP, OPS• Lawrence Yu (Co-Chair), OGD• Sam Haidar, OGD• Dale Conner, DBE1, OGD• Barbara Davit, DBE2, OGD• Tapash Ghosh (ONDQA)• Angelica Dorantes (ONDQA)• Nam Chun, Exec Sec, DBE1, OGD


Always bring this case for

discussion at the BCS committee

Reviewer can choose to bring it to the committee

(but not absolutely necessary)

YES YESNO NO

Consider bringing this to the committee

especially if it fits into BCS class I

Conclude appropriately that there are

inadequate data for BCS classification. No

further action necessary

Did the sponsor ask for BCS class I classification in this submission?

YES NO

Does reviewer feel that there are adequate data to classify the drug

into one of the BCS classes?

Does reviewer agree?

II.a.iii) Process When should one bring application to BCS Committee?


II.a.iii) Process• Primary reviewer submits the summary package to the

committee for review.• Each member has one vote• The choice is yes, no, or insufficient information for BCS

Class 1 classification; decision is by majority.• Official record of each consult is kept which consists of

the summary report, discussion, vote and outcome.• Communication back to the review team and back to the

sponsor via the review division.


II.a.iv) Applications Reviewed• The committee has met several times a year to

review submitted applications.• Forty five (45) drug products came up for evaluation.• 28/45 were classified as BCS Class 1.• 24/45 were from the New Drugs side.

– 13/24 got class 1 determination.• 21/45 were from the OGD side.

– 15/21 were classified as BCS Class 1.


BCS Cases Reviewed

NDA ANDA

24

13

21

15

0

5

10

15

20

25

Num

ber o

f cas

es

NDA ANDAAll Class I

NDA (21/45)ANDA

(24/45)


II.a.iv) Cases Reviewed• New Drugs Side:• 24 cases

– 9/24 were at the IND stage• 4 got class 1 determination and agreement on biowaivers• 2 had insufficient information• 3 were turned down

– 15/24 were at the NDA review stage• 9 got class 1 determination and related regulatory relief• 2 were turned down• 4 had insufficient information


BCS Cases Reviewed (New Drugs Side)

IND NDA

9

4

15

9

0

2

4

6

8

10

12

14

16

Num

ber o

f cas

es

IND NDAAll Class I

IND (9/24)NDA

(15/24)


II.a.iv) Cases Reviewed• Generic Drugs Side:• 21 cases

– 15 got BCS Class 1 determination– 4 were turned down– 2 had insufficient information


24

11

16

5

14

1

0

5

10

15

20

25

BCSClass Idrugs

AbsoluteBA

Massbalance

RLD label In vitroCaco-2

Ratintestinalperfusion

Note: Some drugs classified based on 2 or more methods

Num

ber o

f Dru

gs

PERMEABILITY METHODS

II.a.v) Permeability Determination


II.a.v) Permeability DeterminationGeneral Considerations:• For new drugs, in vivo human data - absolute

bioavailability and mass balance information - extremely useful for classification purposes, and are looked into ALWAYS.

• In vitro methods can be pivotal, but also play supportive role, when unanswered questions still exist from in vivo data.

• We generally have concerns in using literature information alone for BCS classification, without the underlying data for review.



Information frequently missing during review:• Stability in GIT (this information should be better

integrated when BCS classification is requested based on mass balance studies).

• Method suitability for in vitro and in-situ permeability studies.

• Information provided for absolute BA and mass balance studies is reasonably complete.


II.a.v) Permeability DeterminationDrug Stability:• Drug stability in gastrointestinal tract may be documented

using human, animal or USP simulated gastric and intestinal fluids.

• Incubation at 37ºC for 1 (gastric) or 3 (intestinal) hours.• Drug concentration measured with validated stability-

indicating assay method.• Significant degradation (> 5%) of drug may suggest

potential instability.• Stability of drug in buffers used in permeability assays (in

situ, in vitro) also of importance.



In-Vitro and in-situ permeability methods (details needed in the study report):

• Demonstrate method suitability and maintain same protocol to classify drug substance permeability.

• Standard compounds for classification and reproducibility.

• Characterize expression of active transporters and efflux mechanisms in the cell line.


II.b) Examples: Drug A

An Interesting Case (!):• During the review of the NDA of this drug,

the following was learned…...


II.b) Drug A

• In Vitro Caco-2 Permeability Study:

Concentration Permeability1.0 (µM) 0.95x10-6

50 (µM) 7.90x10 -6

• Drug X is a substrate of an efflux pump. At the concentration range studied, it was a low permeability compound.


II.b) Drug A

• Clinical Data (250 ml volume):

- Dose strength 100 mg (810 mM)- Clinical Dose 400 mg (3239 mM)- Absolute BA 98%

• Drug A is a high permeable compound.


II.b) Drug A - Conclusions• The drug is highly permeable!• Concentration dependent in-vitro permeability!• Clinically relevant drug concentrations should be used to

conduct the in vitro permeability study.

• unfortunately, the drug does not show high solubility over the require pH range and therefore, it is not BCS 1. No biowaivers considered.


II.b) Drug B1

• Formulation 1 (Generic; Test product)– Strengths 50, 100 mg

• Both strengths listed as RLD• Non-NTI drug• Appropriateness of the inactive ingredients

reviewed using the FDA Inactive Ingredient Guide (IIG).


II.b) B1: Solubility

• Definition: Highest Dose Strength (HDS) should dissolve in 250 mL of aqueous media over pH range 1 to 7.5.– HDS: 100 mg– 100 mg/250 mL: 0.4 mg/mL– If aqueous solubility > 0.4 mg/mL, the drug

substance in formulation 1 is highly soluble.


II.b) B1: SolubilityBuffer pH1.2234.656.87.48910

Solubility (mg/mL)>1000>1000>1000>1000>1000>1000>1000>1000>1000>1000


II.b) B1: Solubility

Conclusion:

• Drug substance in Formulation B1 is highly soluble.


II.b) B1: Permeability• Definition:

– Extent of absorption from the human GI tract should be > 90% of an administered dose

• Method:– In vivo intestinal perfusion studies


Drug Extent of absorption

Peff* ratio (in vivo- human intestine)

Permeability classification

Drug Substance in Formulation 1

0.99 1.07 high

Verapamil 0.95 3.6 high

Propranol 1 3.5 high

Ranitidine 0.5 0.3 low

Atenolol 0.52 0.14 low

*Peff (X 10 -4) cm/sec

II.b) B1: Permeability


II.b) B1: Permeability

Conclusion:

• Drug substance in Formulation B1 is highly permeable.


• Definition: > 85% of the labeled amount of drug substance dissolves within 30 minutes using USP Apparatus I (100 rpm) or II (50 rpm) in 900 mL of:– pH 0.1 N HCl or USP SGF without Enzymes– pH 4.5 buffer– pH 6.8 buffer or USP SIF without Enzymes

II.b) B1: Dissolution



• f2 metric calculations– If, for both Test and RLD products, > 85% of

the labeled amount of the drug dissolves in < 15 minutes in all three recommended dissolution media, f2 test is not necessary.



Time (minutes)

RLD (0.1 N HCl)

Formulation 1 (0.1 N HCl)

5 33.6 29.7 10 69.6 61.8 15 94.8 80.9 30 107.1 106.9 45 108.1 108.6 60 108.4 108.5


Dissolution Profile Comparison(Formulation 1 Vs RLD) in multi-media

0

50

100

0 20 40 60Time (min)

% D

isso

lved

F1/ 0.1F1/ 4.5F1/ 6.8R 0.1R 4.5R 6.8




• 0.1 N HCl: f2 =58.5• pH 4.5 buffer: f2 =64.9• pH 6.8 buffer: f2 =56.1



Conclusion:

• The dissolution profiles of Formulation B1 and the RLD are similar.


II.b) B1: Conclusion

• Highly Soluble• Highly Permeable• Rapidly Dissolving• Similar dissolution profiles to RLD• Both Test product (B1) and RLD are

classified as BCS Classification I. A biowaiver may be granted.


II.b) B2: Background• Formulation B2 contains the same drug

substance as in Formulation B1.

• Formulation B2 dissolution profiles are not similar to RLD.


Time (minutes)

RLD (0.1 N HCl)

Formulation 2(0.1 N HCl)

5 33.6 16.9 10 69.6 48.2 15 94.8 70.3 30 107.1 105.2 45 108.1 107.4 60 108.4 107.9

II.b) B2: Background


0

50

100

0 20 40 60Time (min)

% D

isso

lved

F2/0.1F2/4.5F2/6.8R 0.1R 4.5R 6.8

Dissolution Profile Comparison(Formulation B2 vs. RLD) in multi-media




• 0.1 N HCl: f2 =41.2• pH 4.5 buffer: f2 =31.5• pH 6.8 buffer: f2 =40.5

• Conclusion: f2 < 50 in all three media



– Highly Soluble– Highly Permeable– Rapidly dissolves, but does not have similar

dissolution profiles to RLD

• Formulation B2 fits into BCS Classification I, however...



• Since Formulation B2 dissolution profiles differ from the RLD, a bio-waiver may not be granted.

• In vivo BE studies are requested for marketing approval of Generic Formulation B2.


II.b) Drug C• Absolute BA 150 to 100 % for different dose

levels.• Reasons not clearly explained. Could be due to

assay limitations.• Mass balance study showed 84 + 12% total

radioactivity recovered, mostly as unchanged drug; excretion is urine pH dependent.

• Requested in vitro permeability study to clearly establish high permeability.






III) Future ConsiderationsBCS Class 1:• Evaluate the possibility of rational expansion of the

current BCS Class 1 limits, particularly for HP• Is the current criterion of 90% or greater permeability too

stringent? Particularly when in-vivo studies like absolute BA and mass-balance are utilized in making this assessment??– Can it be lowered to 85%?– Can it be lowered to 80%?

• Objective data needed that will provide the assurance that this new limit will safeguard against bioinequivalence


III) Future ConsiderationsBCS Class 3:• Lot of promising results published and work

ongoing (Haidar, et al, OGD research project)• Two drugs, with a 89 fold difference (1% to 89%)

in permeability can still be classified as LP!! • Objective data needed to provide the assurance

that variability in manufacturing does not lead to bioinequivalence


III) BCS NDA DATABASE• RSR proposals funded by Dr. Woodcock in 2001 and 2003

to create a database of BCS characteristics of recently approved drugs.– Solid IR oral dosage NDAs (NMEs) submitted from 1995 to 2002

surveyed for the following:• Chemical property• Formulation composition• pH-solubility profile• PK profile (Absolute BA and urinary recovery, relative BA to solution,

linearity, BE studies, metabolism, food effect studies)• Permeability assessment (methods and outcomes)• Dissolution profile

• RSR proposal funded in 2010 to update the database and utilize it for possible update of the guidance.


0 10 20 30 40 50 60 70 80 900

2

4

6

8

10

Absolute BA range for Class III* drugs

Absolute bioavailability %

Freq

uenc

y

* Includes some tentative class III drugs






1. BCS guidance is founded on sound scientific and regulatory bases.

2. CDER has created a centralized BCS evaluation process to assure consistency and transparency across all therapeutic areas and generic drugs.

3. Since the issuance of the guidance in 2000, FDA has reviewed 45 drug products of which 24 were given BCS Class 1 determination indicating wide application of the BCS principles in drug development and evaluation.

IV) Conclusions


4. In vivo studies are used and relied upon extensively for permeability classification of drug substances.

5. In vitro permeability studies can provide pivotal information. They are also very helpful many times to resolve uncertainties from in vivo data.

6. Appropriate reporting of all necessary information (e.g. GI stability, method suitability) will help timely evaluation of BCS classification submissions.

IV) Conclusions


7. Proper integration of BCS information during drug development can save time and money.

8. Updating of the BCS guidance with the goal of expanding biowaiver possibility to other classes should be undertaken using objective data and efficient process.

IV) Conclusions






CDER BCS CommitteeDr. Hong ZhaoDr. Pravin JadhavDr. Ike LeeBeth Fabian-FritschNam Chun

V) Acknowledgments


Thanks!!

Documents

Application of Biopharmaceutical Classification System ... · or less of aqueous media over the pH range of 1- ... • Clinically relevant drug concentrations should be used to