BA.BE-Regulatory perspectives by praveen reddy

Bioavailability & Bioequivalence:Regulatory perspectives in generic

drug product development

Dr B Praveen ReddyManaging Director

Riconpharma India Pvt LtdHyderabad

(Subsidiary of Riconpharma LLC, NJ, USA)

2nd July 2011

04/09/2023 Riconpharma India 2

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


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

– FDA Review – Approval/Disapproval


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)

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


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


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


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 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


What are the requirements for a generic drug?

• 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)

Riconpharma India 10

Generic Drug Review Process

Bioequivalence Review

Labeling ReviewChemistry & Micro Review

Request for Plant Inspection

APPLICANT

ANDA

Acceptable & Complete

Application Review

N Chem/Micro

OK?

Labeling

OK?Bioequivalence

OK?

PreApprovalInspection Results

OK?

Not Approvable Letter

Approval Withheld until Results Satisfactory

Bio Deficiency Letter

APPROVED ANDA

NN N

N

Y Y Y

Y

Y

Refuse to Receive Letter


Brand Name Drug Generic DrugNDA Requirements ANDA Requirements

1. Chemistry 1. Chemistry2. Manufacturing 2. Manufacturing3. Controls 3. Controls4. Labeling 4. Labeling5. Testing 5. Testing6. Animal Studies7. Clinical Studies 6. Bioequivalence8. Bioavailability


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


• Bioavailability - Basic Concepts


Bioavailability

• The rate and extent of drug absorptionCo

nc.(m

g/L)

Time (h)0 25

0.0


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

Rate of drug accumulation at any time: dDBODY/dt= dDABS/dt - dDELIM/dt

Absorption Phase:dDABS/dt > dDELIM/dt

At time of peak drug conc.:dDABS/dt = dDELIM/dt

Post-absorption Phase:dDABS/dt < dDELIM/dt


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.


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


Absorption is defined as the process by which a drug proceeds from the site of administration to the site of measurement.

Drugs are frequently administered extravascularly oral, sublingual intramuscular, topical, patches,

inhalation Absorption is a

prerequisite for a drug to exert it’s pharmacologic effect (other than local effect)

Several possible sites contribute to the loss

Drug Product

Drug in Blood

Distribution to Tissue and

Receptor sites

MetabolismExcretion

Absorption

Absorption


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

Mechanisms of solute transport across membranes


A = Passive diffusionB = Active transport/ carrier mediated system

Comparison of the Rates of Drug Absorption


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

Work against concentration gradientMDR1 (P-glycoprotein)MDR3MRP2 (multidrug resistance

associated protein, cMOAT)BSEP (bile salt export pump)BCRP (breast cancer resistance

protein)


How Transporters Affect Bioavailability?

P-glycoproteins expressed in Intestine limit absorption low BA liver increase bile secretion low BAkidney increase secretion in urine shorten t1/2

Brain protect CNS from penetration of toxic

drugs or decrease efficacy of CNS drugsSome lymphocytes drug resistance for HIV drugs


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

Physiological Considerations


GIT


• 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

First Pass Effect


Volume of Distribution 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)

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

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


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; Diovan 17 L; Digoxin: ~500L; Chloroquin: 15000 L


Drug metabolism/Biotransformation

Liver is the main site of drug metabolism

Extrahepatic:Gut wallIntestinal FloraLungKidney


Drug metabolism/biotransformation

This mainly occurs in the liver, via liver enzymes. 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

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

Some drugs are excreted/eliminated in un-metabolized form, as the original drug molecule


Reactions Catalysed by Drug metabolizing enzymes

Oxidative reactions (Phase I)dealkylationhydroxylationoxidation Deamination

Conjugation reactions (Phase II)glucuronidationglutathione conjugationsulfationacetylation


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)

How Drug Metabolism Affects Bioavailability?


Excretion The Kidneys

This is the main excretory organ for drugsThe Nephron: Glomerulus, proximal

tubule, loop of Henle, distal tubule, and collecting tubule

Drug enters the lumen of the nephron by filtration and secretion

Filtration occurs in the glomerulus; secretion is primarily restricted to the proximal tubules

Reabsorption occurs all along the nephron; Active reabsorption usually occurs in the proximal tubule

Appearance of drug in the urine is the net result of filtration, secretion, and reabsorption


Other Routes of Excretion/Elimination

In bile (which then empties into gut, excreted in feces)[can excrete from 5 to 95% of drug dose, esp. antibiotics]

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]


Clearance

Quantifies Elimination

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


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.


Area Under the Concentration – Time 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

0.01

0.1

1

10

0 5 10 15 20

Time (hr)

Con

cen

trati

on

(U

nit

s/m

l)

Area Under the Curve (AUC)


Concept of “Half Life” ½ life = how much time it takes for blood levels of drug to decrease

to half of what it was at equilibrium There are really two kinds of ½ life…

“distribution” ½ life = when plasma levels fall to half what they were at equilibrium due to distribution to/storage in body’s tissue reservoirs

“elimination” ½ life = when plasma levels fall to half what they were at equilibrium due to drug being metabolized and eliminated

It is usually the elimination ½ life that is used to determine dosing schedules, to decide when it is safe to put patients on a new drug



“Rule of Five”

5x the elimination ½ life = time at which the drug is “completely” (97%) eliminated from the body 1x ½ life - 50% of the original drug removed2x ½ life - 75%3x ½ life - 87.5%4x ½ life - 93.75%5x ½ life - 96.875%


Barriers to Oral Delivery and Systemic Exposure

Drug Free Drug

Bound Drug

Target

Systemic CirculationGut Liver

FormulationSolubility

Permeability

First Pass Metabolism

Protein Binding


Interactions in Oral Drug Absorption


Physico-Chemical Factors

Partition coefficient

Ionization, pH-pKa Relationship

Intrinsic solubility

Polymorphism

Particle Size

Salt form


BA/BE - Regulatory considerations


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.

– For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.


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)


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”


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


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 standard-release formulations


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


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 effect on therapeutic outcomes


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-be-marketed 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 product)



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, the regulatory concern relates to both safety and efficacy



• 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 stake holders



• 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(SUPAAC-IR & MR guidance documents details the requirements

of BE studies based on level of changes being effected)


Methods to document BA/BE

– PK studies– PD studies– Comparative clinical studies– In-vitro studies

• BCS class I

Order of preference


PK studies

• This approach rests on an understanding

– 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 and/or its important metabolite or metabolites in the systemic circulation.


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 variability arising from formulation performance


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


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

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

– Validated– LC MS-MS


PK parameters

1. Statistical treatment1. Cmax2. AUC 0-t3. AUC 0-inf

2. Informative1. Tmax2. Kel3. Half-life4. Geometric/ arithmetic means of relevant PK

parameters


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%

• BE Acceptance criteria: 80.00 – 125.00 of T/R (%) for Cmax, AUC0-t, AUC0-inf at 90% CI


Possible BE Results (90% CI)

T/R (%)80% 125%


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

0.5/hr

0.2/hr


Rate vs extent of absorption (rate varies)


Rate vs extent of absorption (extent varies)


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


Bioequivalence: IR Products

Reference Test

Pharmaceutical EquivalentProducts

Possible Differences

Drug particle size, ..

Excipients

Manufacturing process

Equipment

Site of manufacture

Batch size ….

Documented Bioequivalence= Therapeutic Equivalence

(Note: Generally, same dissolution spec.)

Normal healthy subjectsCrossover design

Overnight fastGlass of water

90% CI within 80-125%of Ref. (Cmax & AUC)


“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

– (NDA’s, OTC’s & ANDA’s)• 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• Contains patent and exclusivity information

– Patent challenge opportunities


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


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


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, – BE study to be conducted between the test product and

reference listed drug (RLD) using the strength(s) specified in Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book)


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 intestinal permeability in amounts sometimes used in oral liquid dosage forms


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.


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 total weight of the dosage form are within the limits defined by the SUPAC-IR and SUPAC-MR guidances


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 – to demonstrate their bioequivalence to the reference

listed drug (RLD) under fed conditions


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


Food effect studies- Exceptions

• 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


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/ beverages etc.,


The Biopharmaceutics Classification System (BCS)


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


Biopharmaceutics Classification System (BCS)


Class Boundaries

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.


Solubility Determination

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

Shake-flask or titration method.

Analysis by a validated stability-indicating assay.


Permeability Determination

Extent of absorption in humans: Mass-balance pharmacokinetic studies. Absolute bioavailability studies.

Intestinal permeability methods: 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.


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 enzymesa pH 4.5 buffera pH 6.8 buffer or Simulated Intestinal

Fluid USP without enzymes

For capsules and tablets with gelatin coatingSimulated Gastric and Intestinal Fluids USP

(with enzymes) can be used.


Dissolution Profile Similarity

A minimum of 12 dosage units of a drug product should be evaluated to support a biowaiver request.

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).

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]-0.5 * 100}

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.


Conditions for BCS Bio-waivers

Firms can request waivers of in vivo testing for Class 1 drug substances Drug products must meet these criteria: Immediate-release solid oral dosage formsHighly soluble, highly permeable drug

substanceRapid in vitro dissolution

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


Predictability of high-fat meal effects by BCS Class

Wu & Benet, Pharm Res, 2005 after Fleisher et al, CPK, 1999


Wu & Benet, Pharm Res, 2005

Transport Effect on Drug PK by BCS Class


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


Acknowledgements

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

Thank you ……

Please contact for additional details:

Dr B Praveen ReddyManaging Director

Riconpharma India Private LimitedPlot No. 113 & 114, II FloorALEAP Industrial EstatePragathinagar, KukatpallyHyderabad 500 072 INDIAPh: +91 40 20040386 (Office) +91 9652969669 (Cell)www.riconpharma.com

http://www.riconpharma.com/

BA.BE-Regulatory perspectives by praveen reddy

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