BCS

Biopharmaceutics Classification System (BCS):

Biopharmaceutics Classification System (BCS) Presented By: GUIDED BY: Amisha Shah Dr. Shital Bariya 10MPH101

INTRODUCTION:

INTRODUCTION The Biopharmaceutics Classification System is a guide for predicting the intestinal drug absorption provided by the U.S. Food and Drug Administration . The fundamental basis for the BCS was established by Dr. Gordon Amidon who was presented with a Distinguished Science Award at the August 2006 International Pharmaceutical Federation (FIP) congress in Salvador, Brazil . Continue……

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The biopharmaceutical classification system was developed primarily in the context of immediate release (IR) solid oral dosage forms. It is the scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability . The interest in this classification system is largely because of its application in early drug development and then in the management of product change through its life cycle. It was first introduced into regulatory decision-making process in the guidance document on Immediate Release Solid Oral Dosage Forms: Scale Up And Post Approval Changes .

Parameters:

Parameters This system restricts the prediction using the parameters solubility and intestinal permeability . The solubility classification is based on a United States Pharmacopoeia (USP) aperture. The intestinal permeability classification is based on a comparison to the intravenous injection .

Biopharmaceutics Classification System:

Biopharmaceutics Classification System

BCS System:

BCS System Class I - High Permeability, High Solubility Example: Metoprolol Those compounds are well absorbed and their absorption rate is usually higher than excretion. Class II - High Permeability, Low Solubility Example: Glibenclamide The bioavailability of these products is limited by their solvation rate. A correlation between the in vivo bioavailability and the in vitro solvation can be found. continue……..

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Class III - Low Permeability, High Solubility Example: Cimetidine The absorption is limited by the permeation rate but the drug is solvated very fast. If the formulation does not change the permeability or gastro-intestinal duration time, then class I criteria can be applied. Class IV - Low Permeability, Low Solubility Example: Hydrochlorothiazide These compounds have a poor bioavailability . Usually they are not well absorbed over the intestinal mucosa and a high variability is expected.

CLASSIFICATION PARAMETERS:

CLASSIFICATION PARAMETERS Solubility Permeability Dissolution Pillars of the BCS

CLASSIFICATION PARAMETER:

CLASSIFICATION PARAMETER Solubility Permeability Dissolution

CLASS BOUNDARIES:

CLASS BOUNDARIES Solubility class boundaries - It is based on the highest dose strength of an immediate release product. A drug is considered highly soluble when the highest dose strength is soluble in 250ml or less of aqueous media over the ph range of 1 to 7.5. The volume estimate of 250ml is derived from typical bioequivalence study protocols that prescribe administration of a drug product to fasting human volunteers with a glass of water. 2. Permeability class boundaries- It is based indirectly on the extent of absorption of a drug substance in humans and directly on the measurement of rates of mass transfer across human intestinal membrane. A drug substance is considered highly permeable when the extent of absorption in humans is determined to be 90 % or more of the administered dose based on a mass-balance determination or in comparison to and intravenous dose. Continue……

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3. Dissolution class boundaries- An immediate release products is considered rapidly dissolving when no less than 85% of the labeled amount of the drug substance dissolve within 30 minutes using USP Dissolution Apparatus 1 at 100 RPM or Apparatus 2 at 50 RPM in a volume of 900ml or less in following media,) 0.1 N HCl or simulated gastric fluid or pH 4.5 buffer and pH 6.8 buffer or simulated intestinal fluid.

CLASS BOUNDARIES OBJECTIVE:

CLASS BOUNDARIES OBJECTIVE

Applications of BCS in oral drug delivery technology :

Applications of BCS in oral drug delivery technology The major challenge in development of drug delivery system for class I drugs is to achieve a target release profile associated with a particular pharmcokinetic and/or pharmacodynamic profile. Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug. The systems that are developed for class II drugs are based on micronisation , lyophilization , addition of surfactants, formulation as emulsions and microemulsions systems, use of complexing agents like cyclodextrins .

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Class III drugs require the technologies that address to fundamental limitations of absolute or regional permeability. Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days. Class IV drugs present a major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral with the formulation containing solubility enhancers.

The benefits of knowing the BCS category of a compound :

The benefits of knowing the BCS category of a compound It can save both time and money—if the immediate -release, orally administered drug meets specific criteria, the FDA will grant a waiver for expensive and time-consuming bio-equivalence studies. The aim of the BCS is to provide a regulatory tool for the replacement of certain BE studies by conducting accurate in vitro dissolution tests. continue…… 15

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BCS has been developed primarily for regulatory applications, but it has also several other applications in both the pre-clinical and clinical drug development processes and has gained wide recognition within the research-based industry. This classification is associated with drug dissolution and absorption model, which identifies the key parameters controlling drug absorption as a set of dimensionless numbers. 16

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BCS based Biowaiver:

BCS based Biowaiver Evaluation of drug substance and drug product Drug substance pharmacodynamic /therapeutic aspects physicochemical aspects Drug product in vitro dissolution

BCS Based Biowaivers Evaluation:

BCS Based Biowaivers Evaluation Drug Substance Solubility Permeability High High Drug Product Dissolution Very Rapid Low Low Rapid Slow

Drug Substance Characteristics I:

Drug Substance Characteristics I “ Risk of therapeutic failure or adverse drug reactions” ( e.g., narrow therapeutic index drugs) examples : Theophylline , Carbamazepine b) “Risk of bioinequivalence ” ( i.e., bioavailability problems are evident) examples : Ciclosporine , Glibenclamide

Drug Substance Characteristics II:

Drug Substance Characteristics II Biopharmaceutics Classification System (BCS) dissolution drug product  drug substance in solution membrane transport  drug substance in the system simplified mechanistic view of bioavailability

Drug Substance Characteristics III:

Drug Substance Characteristics III High solubility the highest single unit dose is completely soluble in 250 ml of aqueous solution at pH 1-8 (37 °C) recommended investigations at pH 1, 4.6, 6.8 and pka cave: possible stability problems have to be considered Discussion on ‘intermediate solubility’, i.e., pH-dependent (high) solubility

Drug Substance Characteristics III:

Drug Substance Characteristics III ♦ Methods to determine solubility 1.pH-solubility profile of test drug in aqueous media at 37 ± 1 o C with a pH range of 1 to 7.5. 2.Shake-flask or titration method. continue…..

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The number of pH conditions for a solubility determination can be based on the ionization characteristics of the test drug substance.e.g . when the pKa of the drug is in the range of 3-5, solubility should be determined at pH = p Ka, pH = p Ka +1, pH = pKa-1, and at pH = 1 and 7.5. A minimum of three replicate determinations of solubility in each pH condition is recommended. . Standard buffer solutions described in the USP are considered appropriate for use in solubility studies . continue….. 24

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Methods other than the traditional shake-flask method, such as acid or base titration methods, can also be used with justification to support the ability of such methods to predict equilibrium solubility of the test drug substance. Concentration of the drug substance in selected buffers (or pH conditions) should be determined using a validated stability-indicating assay that can distinguish the drug substance from its degradation products.

Drug Substance Characteristics IV:

Drug Substance Characteristics IV High permeability EU guidance: ” Linear and complete absorption reduces the possibility of an IR dosage form influencing the bioavailability” FDA guidance: absolute BA >90 % Human data are preferred; in vitro data may be submitted if sufficiently justified and valid

Drug Substance Characteristics IV:

Drug Substance Characteristics IV ♦ Methods to determine permeability Non-clinical methods Cell cultures (eg CaCo-2) Animal studies (everted rat gut) Clinical methods Intestinal perfusion (Loc-I-gut system) Absolute bioavailability (mass balance)

Drug Substance Characteristics V:

Drug Substance Characteristics V ” More factors affect bioavailability when absorption is slow or incomplete than when it is rapid and complete,hence , slow or incomplete absorption often leads to variable therapeutic responses .”

Drug Substance Characteristics VI:

Drug Substance Characteristics VI Absorption  Bioavailability but... High bioavailability  High absorption Low bioavailability  (not necessarily) Low absorption

BCS Assumption:

BCS Assumption ♦ ….if the fraction of the dose absorbed is the same, the human body should always do the same with the absorbed compound …Even in a disease state, this argument is still a valid statement.  what does the product do to the drug substance?

Drug PRODUCT characteristics I:

Drug PRODUCT characteristics I In vitro comparison of immediate release oral drug products ( T and R ) Not less than 85 % of labeled amount are dissolved within 15 min in each of three buffers (pH 1 – 8) – no further comparison of T and R is required Proving similarity of dissolution profiles of T and R e.g., using f2-test, unless similarity is obvious reasonable experimental conditions/methods are strongly recommended!

Dissolution Test (BCS):

Dissolution Test (BCS) Multisource (test) and Comparator (reference) product - Paddle method at 75 rpm or Basket method at 100 rpm - Dissolution profile in pH 1.2, 4.5 and 6.8 - Similarity f 2 > 50 continue…..

Dissolution Characteristics - Test Results:

Dissolution Characteristics - Test Results Very rapidly dissolving – 85% in 15 min Rapidly dissolving – 85% in 30 min Slowly dissolving – more than 30 min for 85% dissolution For biowaivers , multisource and comparator (T and R) products must have similar dissolution profile in all 3 media – pH 1.2, 4.5 & 6.8.

Drug product characteristics II:

Drug product characteristics II Evaluation of excipients (e.g., large amounts, possible interactions....) Evaluation of manufacturing processes in relation with critical physicochemical properties.

EU/FDA Guidance:

EU/FDA Guidance Biowaiver for immediate release drug products containing highly soluble , highly permeable drug substances only . No biowaiver for: locally applied, systemically acting products non-oral immediate release forms with systemic action modified release products transdermal products

Conclusions:

Conclusions BCS principles provide a reasonable approach for testing and approving drug product quality. BCS applications for Class 2 and 3 are challenging, but at the same time provides opportunities for lowering regulatory burden with scientific rational. BCS also provides an avenue to predict drug disposition, transport, absorption, elimination.

BDDCS - Biopharmaceutical Drug Disposition Classification System :

BDDCS - Biopharmaceutical Drug Disposition Classification System BDDCS is a modification of the FDA’s Biopharmaceutics Classification System. BDDCS was developed to address DDIs and transporter-enzyme interplay, thereby providing a road map for designing preclinical and Phase 1 clinical studies.

BDDCS-CHART:

BDDCS-CHART

CLASSIFICATION:

CLASSIFICATION Class 1 (High solubility, high permeability): The high permeability/high solubility of such compounds allows high concentrations in the gut to saturate any transporter, both efflux and absorptive. Efflux transporters may have, however measurable effect on the penetration of the compounds through the blood-brain barrier. If the systemic concentration of the compounds is lower, transporters may overcome the effect of the high passive permeability of the compound. These compounds can also be involved in transporter mediated drug-drug interactions . continue…..

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Class 2 (Low solubility, high permeability) : These high permeability compounds will pass through the gut membranes and uptake transporters will have no effect on absorption. However, the low solubility will limit the concentration at the enterocytes , thereby preventing saturation of the efflux transporters. Consequently, efflux transporters will affect the extent of oral bioavailability and the rate of absorption of Class 2 compounds. continue…..

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Class 3 (High solubility, low permeability): For Class 3 compounds, the drug availability will be sufficient in the gut lumen due to good solubility, but an uptake transporter will be necessary to overcome the poor permeability of these compounds. Apical efflux transporters may also be important for the absorption of such compounds when sufficient penetration is achieved via an uptake transporter. Class 4 (Low solubility, low permeability): Due to the low permeability and low solubility of these compounds both uptake and efflux transporters play an important role in the oral bioavailability of Class 4 compounds.

ADVANTAGES:

ADVANTAGES A major advantage of BDDCS is that drugs can generally be correctly classified without running expensive and time consuming permeability studies in humans. At this time, BDDCS may not be sufficient for the regulatory agencies, but it gives scientists a roadmap for predicting drug disposition and drug-drug interaction characteristics very early and with little additional expense.

BCS VS BDDCS:

BCS VS BDDCS Class 1 Metabolism Class 2 Metabolism Class 3 Renal & Biliary Elimination of Unchanged Drug Class 4 Renal & Biliary Elimination of Unchanged Drug High Solubility Low Solubility Permeability Permeability High Low

What are the Implications of this Strong Correlation between Permeability and Metabolism?:

What are the Implications of this Strong Correlation between Permeability and Metabolism? If you know the intestinal absorption of an NME, you can predict whether the major route of elimination of the NME will be metabolism. Note that the permeability parameter does not predict the ability for the NME to enter the liver/ hepatocytes (since a number of non-metabolized Classes 3 & 4 compounds will be excreted in the bile), but rather the access to the metabolic enzymes within the hepatocytes .

REFERENCES:

REFERENCES www.fda.gov/cder/guidance www.pharmainfo.net Bddcs from solvo biotechnology http://www.solvo.jp/Solvo%20Solutions/Biopharmaceutical%20Drug%20Disposition%20Classification%20System.html http://www.eufeps.org/document/BA_BE_presentations/Benet_Leslie_Z.pdf William Addicks , Application of the Biopharmaceutical Classification System at a Generic Pharmaceutical Company. Mylan Laboratories Inc.