Bioavailability & Bioequivalence: Regulatory perspectives in generic drug product development

Dr B Praveen Reddy Managing Director Riconpharma India Pvt Ltd Hyderabad (Subsidiary of Riconpharma LLC, NJ, USA)
2nd July 2011

Contents
Background information
Drug development process Generic drug development

Bioavailability
Concepts Factors affecting drug Absorption

Bioequivalence
Regulatory considerations Study Designs Food effect studies

BCS
Classification Bio waivers

Conclusions
07/03/11 Riconpharma India 2

Drug Approval Process

Average of 10 - 20 years and multi million USD to nurture a drug from initial discovery to market

Process:
Academic and Laboratory Research Testing done on animals

Phase 1:Drug given to a small number of healthy people to test its safety

Phase 2:Drug administered to 100 or more people with the disease that it was intended to treat

Phase 3: Rigorous testing done on larger groups of ill patients

07/03/11

Riconpharma India

NCE development timelines

10-20 years time frame 1 in 10,000 100,000 compounds see the market Very few percentage of market success
Atorvastatin (Lipitor) Ranitidine (Zantac)

07/03/11

High regulatory & ethical hurdles High R&D costs Lower effective patent terms Approved/marketed Priced high to recover costs High healthcare costs in regulated
Riconpharma India

Hatch-Waxman Amendments to FFD&C Act - 1984

Considered one of the most successful pieces of legislation ever passed Created the generic drug industry Increased availability of generics
1984 12% prescriptions were generic 2000 44% prescriptions were generic yet only 8% of revenue for prescription drugs 2008 >50% genericization

Compromise legislation to benefit both brand and generic firms

07/03/11 Riconpharma India 5

Hatch-Waxman Amendments to FFD&C Act - 1984 Allowed generic firms to rely on findings of safety and efficacy of innovator drug after expiration of patents and exclusivities (do not have to repeat expensive clinical and pre-clinical trials) Allowed patent extensions and exclusivities to innovator firms
07/03/11 Riconpharma India 6

Generics Market
Generics now account for over 50% of all prescription drugs

Americans spent over $182.7 billion dollars on prescription drugs in 2002

The average branded prescription cost four times as much as a generic drug

Generics save consumers $8 - 10 billion per 07/03/11 Riconpharma India 7 year

Generic drugs
Are safe and effective alternatives to brand name prescriptions Can help both consumers and the government reduce the cost of prescription drugs Are currently used in more than 50% of all prescriptions dispensed

07/03/11

Riconpharma India

 Same active ingredient(s) Same route of administration Same dosage form Same strength Same conditions of approved use Compared to reference listed drug (RLD) - (brand name product)
07/03/11 Riconpharma India 9

What are the requirements for a generic drug?

Generic Drug Review Process

APPLICANT ANDA
Refuse to Receive Letter Application Review

Acceptable & Complete

Y Request for Plant Inspection N

PreApproval Inspection Results OK?

Chemistry & Micro Review

Labeling Review

Bioequivalence Review N

Chem/Micro OK?

Labeling OK?

Bioequival ence OK?

proval Withheld until Results Satisfactory

Not Approvable Letter

Bio Deficiency Letter

APPROVED ANDA

Riconpharma India

10

B ra n d N a m e D ru g N D A R e q u i m e n ts re 1. 2. 3. 4. 5. 6. 7. 8. Chemistry 1. Manufacturing Controls Labeling Testing Animal Studies Clinical Studies Bioavailability

G e n e ri D ru g c A N D A R e q u i m e n ts re Chemistry 2. Manufacturing 3. Controls 4. Labeling 5. Testing 6. Bioequivalence

07/03/11

Riconpharma India

11

How do we assure the quality of generic drugs?

First 5 steps of review process are identical to NDA process Bioequivalence for complicated products is discussed with the same staff that reviewed the brand product FDA has experience with the product Scientific literature published Product is known to be safe

07/03/11

Riconpharma India

12

 Bioavailability - Basic Concepts

07/03/11

Riconpharma India

13

Bioavailability
The rate and extent of drug absorption

Conc .( mg / L )
0.0 0

Time ( h )
Riconpharma India

25

07/03/11

14

Plasma Concentration - Time Profile for a Drug Following a Single Oral Dose

Rate of drug accumulation at any time: dD BODY / dt = dD ABS / dt dD ELIM /dt Absorption Phase: dD ABS / dt > dD ELIM /dt At time of peak drug conc.: dD ABS / dt = dD ELIM /dt Post-absorption Phase: dD ABS / dt < dD ELIM /dt
07/03/11 Riconpharma India 15

The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment. This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues.

07/03/11

Riconpharma India

16

Drugs which exhibit a slow equilibration with peripheral tissues, are best described with a two compartment model

07/03/11

Riconpharma India

17

A b so rp tio n
Absorption Absorption is defined as the Drug process by which a drug proceeds Product from the site of administration to the site of measurement. Drugs are frequently administered extravascularly Drug in oral, sublingual Blood intramuscular, topical, patches, inhalation Absorption is a prerequisite for a drug to exert its pharmacologic Excretion effect (other than local effect) Several possible sites contribute to the loss
07/03/11 Riconpharma India

Distribution to Tissue and Receptor sites

Metabolism

18

Mechanisms of solute transport across membranes

passive diffusion active transport endocytosis ion-pairing filtration and bulk flow

07/03/11

Riconpharma India

19

Comparison of the Rates of Drug Absorption

A = Passive diffusion B = Active transport/

carrier mediated system

07/03/11

Riconpharma India

20

Energy Dependent Efflux Transporters ATP-binding cassette (ABC) proteins

Work against concentration gradient MDR1 (P-glycoprotein) MDR3 MRP2 (multidrug resistance associated protein, cMOAT) BSEP (bile salt export pump) BCRP (breast cancer resistance protein)

07/03/11 Riconpharma India 21

How Transporters Affect Bioavailability?

P -g l yco p ro te i s exp re sse d i n n

Intestine limit absorption low BA liver increase bile secretion low BA kidney increase secretion in urine shorten t1/2 Brain protect CNS from penetration of toxic drugs or decrease efficacy of CNS drugs Some lymphocytes drug resistance for HIV drugs

07/03/11

Riconpharma India

22

Physiological Considerations
Surface area small intestine = 200 m2 stomach = 1 m2 Permeability intestinal membrane>stomach Blood flow (for perfusion rate-limited absorption) small intestine = 1000 mL/min through intestinal capillaries stomach = 150 mL/min Gastric emptying and pH GI transit Rate of gastric emptying is a controlling step for rapid absorption

07/03/11

Riconpharma India

23

GIT

07/03/11

Riconpharma India

24

First Pass Effect

The first-pass effect is the term used for the hepatic metabolism of a pharmacological agent when it is absorbed from the gut and delivered to the liver via the portal circulation.

The greater the first-pass effect, the less the agent will reach the systemic circulation when the agent is administered orally
07/03/11 Riconpharma India

25

V o l m e o f D i b u ti n u stri o
The concentration in plasma is achieved after distribution is complete is a function of dose and extent of distribution of drug into tissues

This extent of distribution can be determined by relating the concentration obtained with a known amount of drug in the body Concentration is related to the amount by a constant, VOLUME (V)
OR

Amount (mg) = C (mg/L) * V (L) V = Amount / C V is known as Apparent Volume of distribution.

Plasma volume ~ 3 L; Extracellular water ~16 L; Total body water ~ 42 L

07/03/11

Riconpharma India

26

Volume of Distribution
Case -1 At Time zero, the drug amount in the body is the dose (500 mg) Calculated drug concentration at Time zero is 50 mg/L Then, the V = 10 L Case -2 Dose = 500 mg Calculated Concentration at time Zero is 5 mg/L Then, V = 100 L Examples: Ibuprofen: V is 10 L; Diovan17 L; Digoxin: ~500L; Chloroquin : 15000 L

07/03/11

Riconpharma India

27

Drug metabolism/Biotransformation
Liver is the main site of drug metabolism n Extrahepatic : Gut wall Intestinal Flora Lung Kidney

07/03/11

Riconpharma India

28

Drug metabolism/biotransformation
n This mainly occurs in the liver, via liver enzymes. n But it can also occur in the blood plasma or at various other places (stomach, intestines, lungs, skin, or kidneys) directly by various enzymes at those locations n In any case, these metabolites are then excreted/eliminated (more easily than would the parent molecule have been) metabolites are often smaller in size, ionized n Some drugs are excreted/eliminated in un metabolized form, as the original drug molecule

07/03/11

Riconpharma India

29

Reactions Catalysed by Drug metabolizing enzymes

Oxidative reactions ( Phase I ) dealkylation hydroxylation oxidation Deamination Conjugation reactions ( Phase II ) glucuronidation glutathione conjugation sulfation acetylation

07/03/11

Riconpharma India

30

How Drug Metabolism Affects Bioavailability?

Genetic (polymorphism in expression of enzymes in a population)

CYP2D6, CYP2C19, NAT2, etc.

Environmental (food, smoking)

Grapefruit juice (AUC and Cmax )

Drug-Drug interaction

Inhibition (AUC and Cmax ) Induction (AUC and Cmax )

Age Disease (hepatic impairment)

07/03/11

Riconpharma India

31

Excretion
n The Kidneys

This is the main excretory organ for drugs The Nephron : Glomerulus, proximal tubule, loop of Henle, distal tubule, and collecting tubule

n Drug enters the lumen of the nephron by filtration and secretion n Filtration occurs in the glomerulus; secretion is primarily restricted to the proximal tubules n Reabsorption occurs all along the nephron; Active reabsorption usually occurs in the proximal tubule n Appearance of drug in the urine is the net result of filtration, secretion, and reabsorption
07/03/11 Riconpharma India 32

Other Routes of Excretion/Elimination

n In bile (which then empties into gut, excreted in feces)

[can excrete from 5 to 95% of drug dose, esp. antibiotics]

n In sweat, saliva, tears, exhaled breath, milk, hair, nails

[as heart rate increases --- pulmonary circulation --- which then increases amounts of breath exhaled --- more drug eliminated]

n
07/03/11 Riconpharma India 33

Clearance
n Quantifies Elimination n n Is the volume of body fluid cleared per time unit (L/h, mL/min) n

07/03/11

Riconpharma India

34

Why is Clearance Important?

Clearance is the one parameter that determines the maintenance dose rate required to achieve a desired plasma conc. Dosing rate = clearance X desired plasma conc.
Riconpharma India 35

07/03/11

Area Under the Concentration Time Curve (AUC)

Concentration (Units/ml)

Time (hr) Area Under the Curve (AUC)

A quantitative measure for exposure from dosing time to time t An important parameter in PK AUC(t) and AUC(inf ) Determined by trapezoidal method AUC(inf = AUC(t) + Ct/k ) Units: Conc*t (mg/L * h) Proportional to Dose (linear PK) Accuracy of the estimate depends on frequency of sampling

07/03/11 Riconpharma India

36

C o n ce p t o f H a l Li f fe
n life = how much time it takes for blood levels of drug to decrease to half of what it was at equilibrium n There are really two kinds of life distribution life = when plasma levels fall to half what they were at equilibrium due to distribution to/storage in bodys tissue reservoirs elimination life = when plasma levels fall to half what they were at equilibrium due to drug being metabolized and eliminated n It is usually the elimination life that is used to determine dosing schedules, to decide when it is safe to put patients on a new drug

07/03/11

Riconpharma India

37

07/03/11

Riconpharma India

38

Rule of Five

5x the elimination life = time at which the drug is completely (97%) eliminated from the body 1x life - 50% of the original drug removed 2x life - 75% 3x life - 87.5% 4x life - 93.75% 5x life - 96.875%

07/03/11

Riconpharma India

39

Barriers to Oral Delivery and Systemic Exposure

Formulation Solubility Protein Binding

Permeability

First Pass Metabolism T a r g e t

Drug

Free Drug

Bound Drug

07/03/11

Gut

Liver

Systemic Circulation
Riconpharma India 40

I te ra cti n s i O ra lD ru g A b so rp ti n n o n o

07/03/11

Riconpharma India

41

Physico-Chemical Factors
Partition coefficient Ionization, pH-pKa Relationship Intrinsic solubility Polymorphism Particle Size Salt form

07/03/11

Riconpharma India

42

BA/BE - Regulatory considerations

07/03/11

Riconpharma India

43

Bioavailability (BA)
Bioavailability is defined in CFR 320.1 as: the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.

07/03/11

For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect Riconpharma India 44 the rate and extent to which the

Why BA study?
To establish dose response relationship To assess extent of drug absorption with reference to IV dosing To derive information on ADME To establish dose linearity To assess dosage form functionality To assess the performance of the formulations used in the clinical trials that provide evidence of safety and efficacy (21 CFR 320.25(d)(1)). To assess Relative BA (Bioequivalence)

07/03/11

Riconpharma India

45

Bioequivalence
Bioequivalence is defined in CFR 320.1 as: the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study
07/03/11 Riconpharma India

46

Pharmaceutical Equivalents
Drug products are considered pharmaceutical equivalents if they contain the same active ingredient(s), have the same dosage form and route of administration, and are identical in strength or concentration Equivalent products contain the same amount of ingredient in the same dosage form but may differ in characteristics, such as shape, release mechanisms, excipients and packaging
Patent challenge opportunities Freedom of research within regulatory boundaries Riconpharma India

07/03/11

47

Pharmaceutical Alternatives
Drug products are considered pharmaceutical alternatives if they contain the same therapeutic moiety, are different salts, esters, or complexes of the same moiety, are different dosage forms, or are different strengths Other pharmaceutical alternatives
Different dosage forms and strengths within a single product line by a single manufacturer Extended-release formulations when compared with immediate- or standardRiconpharma India release formulations

07/03/11

48

Therapeutic Equivalents
Drug products are considered therapeutic equivalents if they are all of the following
Pharmaceutical equivalents Bioequivalent Approved as safe and effective Adequately labeled Manufactured in compliance with current Good Manufacturing Practice regulations

Therapeutic equivalents are expected to have the same clinical effect and safety profile
07/03/11 Riconpharma India 49

Use of Bioequivalence to Determine Therapeutic Equivalency

There is a strong correlation between single-dose pharmacokinetics and therapeutic effects Single-dose pharmacokinetics are similar to steady-state pharmacokinetics Patients have a pharmacokinetic profile comparable to that of healthy volunteers A 20% to +20% difference in drug absorption of two pharmaceutical equivalent products has no significant 07/03/11 effect on therapeutic outcomes Riconpharma India

50

BE relevance in regulatory framework

1. IND/ NDA (Original product)
BE documentation can be useful during the IND or NDA approval/review period to establish links between (1) early and late clinical stage trial formulations; (2) formulations used in clinical trial and stability studies, if different; (3) clinical trial formulations and to-bemarketed drug product; (In each of the above comparison, the new formulation or new method of manufacture is the test product and the prior formulation or method of manufacture is the reference Riconpharma India 51

07/03/11

BE relevance in regulatory framework

IND/NDA (contd..) Where the test product generates plasma levels that are substantially above those of the reference product, the regulatory concern is not therapeutic failure, but the adequacy of the safety database from the test product.

Where the test product has levels that are substantially below those of the reference product, the regulatory concern becomes therapeutic efficacy

When the variability of the test product rises, 07/03/11 Riconpharma the regulatory concern India relates to both safety 52

BE relevance in regulatory framework

2. ANDAs (Generic drug products)
BE studies are a critical component of ANDA submissions. The purpose of these studies is to demonstrate BE between a pharmaceutically equivalent generic drug product and the corresponding reference listed drug (21 CFR 314.94 (a)(7)). Together with the determination of pharmaceutical equivalence, establishing BE allows a regulatory conclusion of therapeutic equivalence
Inter changeability with innovator products (equivalence ratings in Orange Book) Opened up generics market Significant reduction in healthcare costs for all Riconpharma India 53 stake holders

07/03/11

BE relevance in regulatory framework

3. Post approval changes
certain major changes in
components, composition, and/or method of manufacture after approval change in site of manufacture major change in equipment / manufacturing process

Reduces cost of approval process/ time

07/03/11

(SUPAAC-IR & MR guidance documents details the requirements of BERiconpharma India studies based on level of changes being effected)

54

Methods to document BA/BE

PK studies PD studies Order of preference Comparative clinical studies In-vitro studies
BCS class I

07/03/11

Riconpharma India

55

PK studies
This approach rests on an understanding

07/03/11

that measuring the active moiety or ingredient at the site of action is generally not possible that some relationship exists between the efficacy/safety and concentration of active moiety Riconpharma India and/or its important metabolite or 56

PK studies
To measure product quality BA and establish BE, reliance on pharmacokinetic measurements may be viewed as a bioassay that assesses release of the drug substance from the drug product into the systemic circulation.

A typical study is conducted as a crossover study.

In this type of study, clearance, volume of distribution, and absorption, as determined by physiological variables (e.g. gastric emptying, motility, pH), are assumed to have less inter occasion variability compared to the 07/03/11variability arising from formulation Riconpharma India 57

PK studies
1. Pilot BE study
small number of subjects The study can be used to validate analytical methodology, assess variability, optimize sample collection time intervals, sample size etc.,

2. Pivotal BE study
Submission to regulatory agency Conducted as per approved protocol
07/03/11 Riconpharma India 58

PK study design
Non replicate 2-way cross over design, fast/fed
IR dosage forms MR dosage forms (single/ multiple dose) More sensitive Most preferred Truncated design for drugs with long elimination half life

Replicate design
Suitable for drug products with likely high intra subject variability Requires less number of subjects Understands subject by formulation variations better More expensive

parallel design
For long half life drugs

07/03/11

Analyte: Parent/ metabolite/ pro-drug Bio analytical methods

Validated
Riconpharma India

59

PK parameters
1.Statistical treatment
1.Cmax 2.AUC 0-t 3.AUC 0-inf

2.Informative
1.Tmax 2.Kel 3.Half-life 4.Geometric/ arithmetic means of relevant PK parameters
07/03/11 Riconpharma India 60

Statistical Basis
Bioequivalence criteria
Two one-sided tests procedure Log-transformed data 90% confidence interval Significant difference is 20% (alpha is 0.05) Test (T) is not significantly less than Reference (R) Reference (R) is not significantly less than Test (T) T/R = 80/100 * 100 = 80% R/T = 100/80 * 100 = 125%
61

BE Acceptance criteria: 80.00 125.00 of 07/03/11 Riconpharma India T/R (%) for Cmax, AUC0-t, AUC0-inf at

Possible BE Results (90% CI)

80 %
07/03/11

T/R (%)

125 %
Riconpharma India 62

Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve

0 . 5 / hr

0 . 2 / hr

07/03/11

Riconpharma India

63

Rate vs extent of absorption (rate varies)

07/03/11

Riconpharma India

64

Rate vs extent of absorption (extent varies)

07/03/11

Riconpharma India

65

Formulation Variables affecting absorptive phase

Drug release
pH release profile across GIT Release mechanism Excipients Functional coatings Method of manufacture

Dosage form
Rapidly disintegrating Swelling/ muco adhesive nature

07/03/11

Riconpharma India

66

Bioequivalence: IR Products
Pharmaceutical Equivalent Products
Possible Differences Drug particle size, .. Excipients Manufacturing process Equipment Site of manufacture Batch size . Normal healthy subjects Crossover design Overnight fast Glass of water 90% CI within 80-125% of Ref. (Cmax & AUC) Reference Test

Documented Bioequivalence = Therapeutic Equivalence (Note: Generally, same dissolution spec.)

07/03/11 Riconpharma India 67

Orange Book
US FDA Official publication Approved Drug Products with Therapeutic equivalence Evaluations Reference document to healthcare professionals/ insurance/ patients Lists all approved products for US market
(NDAs, OTCs & ANDAs)

Lists approved generic drug products with suitable Therapeutic equivalence ratings
A = Substitutable B = Inequivalent, NOT Substitutable AB = Therapeutic equivalents demonstrated through appropriate BE study

Reference Listed Drugs/brand drugs identified by FDA for generic companies to compare with their proposed products Lists the strength(s) for which BE to be established, referred to as RLD RLD is usually higher strength
RLD as lower strength due to safety considerations

07/03/11

Contains patent and exclusivity information

Patent challenge opportunities
Riconpharma India

68

FDA recommendations
Individual BE study recommendations
RLD Study design Analytes Bio-waiver recommendations for lower strengths

Individual dissolution recommendations

Apparatus type, rpm Medium/ volume Recommended sampling time points
07/03/11 Riconpharma India 69

Documentation for BE
An in vivo study is generally recommended for
all solid oral dosage forms approved after 1962 and for bio problem drug products approved before 1962. (DESI products) Required for all suspension oral dosage forms

07/03/11 Riconpharma India 70

Documenting BE-Solid orals

For product quality BA and BE studies,
focus is on release of the drug substance from the drug product into the systemic circulation, a single-dose, fasting study be performed. BE studies be accompanied by in vitro dissolution profiles on all strengths of each product.
IVIVC/ relevant dissolution spec

For ANDAs,
07/03/11

BE study to be conducted between the test product and reference listed drug (RLD) using the strength(s) specified in Riconpharma India 71 Approved Drug Products with

Documenting BE-solutions
For oral solutions, elixirs, syrups, tinctures, or other solubilized forms, in vivo BA and/or BE can be waived (21 CFR 320.22(b)(3)(i)). Generally, in vivo BE studies are waived for solutions on the assumption that release of the drug substance from the drug product is self-evident and that the solutions do not contain any excipient that significantly affects drug absorption (21 CFR 320.22(b)(3)(iii)). However, there are certain excipients, such as sorbitol or mannitol, that can reduce the bioavailability of drugs with low 07/03/11intestinal permeability in amounts Riconpharma India 72

Documentation of BE
Bio-waivers
Applicable for NDAs/ ANDAs Waiver of in vivo studies for different strengths of a drug product can be granted under 320.22(d)(2) when
(1) the drug product is in the same dosage form, but in a different strength; (2) this different strength is proportionally similar in its active and inactive ingredients to the strength of the product for which the same manufacturer has conducted an appropriate in vivo study; and (3) the new strength meets an appropriate in vitro dissolution test.
07/03/11 Riconpharma India 73

Documentation of BE (contd..)
Proportionally similar means
Applicable to multiple strength drug product

All active and inactive ingredients are in exactly the same proportion between different strengths

Active and inactive ingredients are not in exactly the same proportion between different strengths as stated above, but the ratios of inactive ingredients to Riconpharma India 74 total weight of the dosage form are

07/03/11

Food effect studies

Food effect BA studies are usually conducted for
new drugs drug products during the IND period
to assess the effects of food on the rate and extent of absorption of a drug when the drug product is administered shortly after a meal (fed conditions), as compared to administration under fasting conditions.

Fed BE studies, are conducted for ANDAs

07/03/11

to demonstrate their bioequivalence to Riconpharma India the reference listed drug (RLD) under

75

Why Food effect studies?

Food can alter BA by various means, including
Delay gastric emptying Stimulate bile flow Change gastrointestinal (GI) pH Increase splanchnic blood flow Change luminal metabolism of a drug substance Physically or chemically interact with a dosage form or a drug substance
07/03/11 Riconpharma India 76

Food effect studiesExceptions

When both test product and RLD are
rapidly dissolving, have similar dissolution profiles, and contain a drug substance with high solubility and high permeability (BCS Class I) or

When the DOSAGE AND ADMINISTRATION section of the RLD label states that the product should be taken only on an empty stomach, or When the RLD label does not make any statements about the effect of food on absorption or administration
07/03/11 Riconpharma India

77

Food effect BE study

Test meal
Recommended that food-effect BA and fed BE studies be conducted using meal conditions that are expected to provide the greatest effects on GI physiology so that systemic drug availability is maximally affected. A high-fat (approximately 50 percent of total caloric content of the meal) and high-calorie (approximately 800 to 1000 calories) meal is recommended as a test meal This test meal should derive approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively.

Typical meal
two eggs fried in butter, two strips of bacon, two slices of toast with butter, four ounces of hash brown potatoes and eight ounces of whole milk.

Special studies: Apple sauce/India 07/03/11 Riconpharma beverages etc.,

78

The Biopharmaceutics Classification System ( BCS )

07/03/11

Riconpharma India

79

Purpose of the BCS guidance

Expands the regulatory application of the BCS and recommends methods for classifying drugs Explains when a waiver for in vivo bioavailability and bioequivalence studies may be requested based on the approach of BCS
Intention to minimize human exposure To simplify and expedite regulatory approval process
07/03/11 Riconpharma India 80

B i p h a rm a ce u ti C l ssi ca ti n S yste m ( B C S o cs a fi o

07/03/11

Riconpharma India

81

C l ss B o u n d a ri s a e

Drug Substance: -is considered HIGHLY SOLUBLE when the highest dose strength is soluble in < 250 ml water over a pH range of 1 to 7.5.

-is considered HIGHLY PERMEABLE when the extent of absorption in humans is determined to be > 90% of an administered dose, based on mass-balance or in comparison to an intravenous reference dose.

drug product: - is considered to be RAPIDLY DISSOLVING when > 85% of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of < 900 ml buffer solutions.

07/03/11 Riconpharma India 82

Solubility Determination

n pH-solubility profile of test drug in aqueous media with a pH range of 1 to 7.5.

n Shake-flask or titration method. n n Analysis by a validated stability-indicating assay.

n
07/03/11 Riconpharma India 83

Permeability Determination

Extent of absorption in humans:

Intestinal permeability methods:

Mass-balance pharmacokinetic studies. Absolute bioavailability studies. In vivo intestinal perfusions studies in humans. In vivo or in situ intestinal perfusion studies in animals. In vitro permeation experiments with excised human or animal intestinal tissue. In vitro permeation experiments across epithelial cell monolayers.
Riconpharma India 84

07/03/11

Determining Drug Product Dissolution Characteristics and Dissolution Profile Similarity

Dissolution testing should be carried out in USP Apparatus I at 100 rpm or Apparatus II at 50 rpm using 900 ml of the following dissolution media :

0.1N HCl or Simulated Gastric Fluid USP without enzymes a pH 4.5 buffer a pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes Simulated Gastric and Intestinal Fluids USP (with enzymes) can be used.
Riconpharma India

For capsules and tablets with gelatin coating

07/03/11

85

Dissolution Profile Similarity

n A minimum of 12 dosage units of a drug product should be evaluated to support a biowaiver request. n Samples should be collected at a sufficient number of intervals to characterize the dissolution profile of the drug product (e.g., 10, 15, 20, and 30 minutes). n When comparing the test and reference products, dissolution profiles should be compared using a similarity factor (f2). The similarity factor is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent (%) of dissolution between the two curves. . f2 = 50 * log {[1+(1/n)*t=1n (Rt - Tt)2]-05 * 100} n n Two dissolution profiles are considered similar when the f2 value is 50.

Note: When both test and reference products dissolve 85% or more of the label amount of the drug in 15 minutes using all three dissolution media recommended above, the profile comparison with an f2 test is unnecessary.
Riconpharma India 86

07/03/11

Conditions for BCS Biowaivers

Firms can request waivers of in vivo testing for Class 1 drug substances

Drug products must meet these criteria:

n Immediate-release solid oral dosage forms n Highly soluble, highly permeable drug substance n Rapid in vitro dissolution

Note: Waivers not applicable for narrow therapeutic range therapeutic range (Digoxin, Lithium, phenytoin, warfarin) drugs
Riconpharma India 87

07/03/11

Predictability of high-fat meal BCS Class

effects

by

Wu & Benet, Pharm Res, 2005 after Fleisher et al, CPK, 1999
07/03/11 Riconpharma India 88

Transport Effect on Drug Class

PK

by BCS

Wu & Benet, Pharm Res, 2005

07/03/11 Riconpharma India 89

Conclusions
BA/BE studies play a key role in regulatory approval process of
NDAs / ANDAs / Post-approval Changes

Expedites approvals Reduces cost of proving therapeutic equivalence Paves way for bio waivers
07/03/11 Riconpharma India 90

Acknowledgements
Highly thankful to research scholars/ scientists representing US FDA, Academic institutions, Pharmaceutical Industries for making available the content

07/03/11

Riconpharma India

91

Please contact for additional details: Dr B Praveen Reddy Managing Director Riconpharma India Private Limited Plot No. 113 & 114, II Floor ALEAP Industrial Estate Pragathinagar, Kukatpally Hyderabad 500 072 INDIA Ph: +91 40 20040386 (Office) +91 9652969669 (Cell) www.riconpharma.com

Thank you