BCS Classification by thilak0505

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									 Biopharmaceutic Classification System
                (BCS)


       C.V.S. Subrahmanyam
               Principal
Gokaraju Rangaraju College of Pharmacy
             Hyderabad



Grcp
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CVS                          m/
 Biopharmaceutic Classification System
                (BCS)
           Objectives of this session
The participant shall be able to:
       - Explain the concept of BCS
       - Define the parameter
       - Determine the parameters – How to




Grcp
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CVS                              m/
 Biopharmaceutic Classification System
                (BCS)
Abbreviations
  IVIVC : In vitro and in vivo correlations
  IR : Immediate release
  BE: Bioequivalence
   HS: High solubility
   LS: Low solubility
   HP: High permeability
   LP: Low permeability
   D:S: Dose solubility ratio
   BA: Bioavailability
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CVS                              m/
 Biopharmaceutic Classification System
                (BCS)
Abbreviations
  T and R: Test and reference
  CV : Coefficient of variance
  NDAs: New drug applications
  RD: Rapid dissolving
  ANDAs: Abbreviated new drug applications
  INDAs: Investigational new drug
            applications



Grcp
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CVS                            m/
 Biopharmaceutic Classification System
It is a framework for classifying drug substances
       based on the aqueous solubility and
      permeability
It is a drug classification scheme that provides
      a basis for establishing IVIVC
It is a drug development tool to justify
       ‘biowaiver’ in conjunction with dissolution
      of the drug product
 It is a drug classification scheme that provides
        a basis for designing the dosage form

Grcp
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 CVS                              m/
 Biopharmaceutic Classification System
It is based on solubility and permeability of the
       drug substance and dissolution of the drug
      product, i.e., dosage form
It also takes into consideration
    - Gastric pH, gastric fluid volume and gastric
         emptying time
       - Intestinal pH, intestinal fluid volume,
         intestinal transit time and permeability




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 CVS                               m/
 Biopharmaceutic Classification System
To recommend a class of IR solid oral dosage
       forms for which BE may be assessed based
     solely on the in vitro dissolution test
To recommend methods to permit classification
       according to dosage form dissolution and
       the solubility and permeability
    characteristics of a drug
Guidance: Waiver of in vivo BE studies for IR
       solid oral dosage forms based on a
       biopharmaceutic classification system
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 CVS                              m/
 Biopharmaceutic Classification System
         View on Bioequivalence
If two drug products, containing the same
       drug, have same concentration-time
       profiles at the intestinal membrane
       surface, then they will have the same rate
       and extent of absorption
      Same in vitro dissolution profiles under all
          luminal conditions
      Formulation components do not affect the
           membrane permeability and/or
           intestinal transit
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CVS                                m/
  Biopharmaceutic Classification System
Solubility and permeability are the properties
        of a drug substance whereas dissolution is
        the property of a drug product
 Dissolution is dependent upon the drug
         substance solubility, drug product
         formulation and dissolution test
         methodology




 Grcp
                    http://pharmacystuffforu.blogspot.co
  CVS                               m/
 Biopharmaceutic Classification System
      System                             Drug absorption
Absorption of oral drug product is dependent
       upon
       Solubility of drug substance: - HS, - LS
       Intestinal permeability of the drug
            substance: - HP, - LP
       Dissolution of the dosage form:
            - Rapid, - slow



Grcp
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CVS                                m/
               Biopharmaceutic Classification System
               Class I HS/HP              Class II LS/HP
               RLB: Gastric emptying      RLB: Dissolution
               IVIVC: Yes                 IVIVC: Yes
Permeability




               Eg: Verapamil,             Eg: Ketoprofen, naproxine,
               propranolol, metoprolol    carbamazepine
               Class III HS/LP            Class IV LS/LP
               RLB: Permeability          RLB: various factors
               IVIVC: No                  IVIVC: may be
               Eg: Ranitidine,            Eg: Furosemide,
               cimetidine,                hydrochlorthiazide

                      0                  250        10,000
        Grcp          Vol. of Aq buffer added to dissolve
                              http://pharmacystuffforu.blogspot.co
          CVS         the highest unit dose, pH 1-8
                                              m/
 Biopharmaceutic Classification System
                 Solubility
Solubility is defined terms of dose solubility,
     highest dose strength, solubility in 250 ml
    of aqueous medium, pH 1.0 to 7.5
  Highly soluble when the highest dose
        strength is soluble in 250 ml of or less
        of aqueous media over the pH range of
       1.0 to 7.5
    The volume estimate of 250 ml is derived
          from the typical BE study protocols
     A drug product is administered to fasting
Grcp      human volunteers with a glass (about
          8 ounces) of water
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 Biopharmaceutic Classification System
               Solubility
What are the solubility criteria?
Guidance: Dose: solubility ratio > 250 ml
                over the range pH 1-8
                              dose (mg)
 Dose: solubility ratio =
                          solubility (mg/ml)
A dose : solubility ratio > 250 ml indicates that
       the whole dose is unlikely to be dissolved
       under sink conditions in the GIT under
       fasted state conditions

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CVS                               m/
  Biopharmaceutic Classification System
 Considerations for application of the dose:
                  solubility ratio:
• Early in development the dose is often unknown
• Compounds with low doses may be incorrectly
  classified into class I/III (eg: digoxin)
• Only pH and volume effects are considered:
   Some compounds may be inappropriately
   classified into Class II/IV
 Alternative Criterion: Very few substances
      with solubility >100 g/ml exhibit
        dissolution problems in vivo
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  CVS                              m/
 Biopharmaceutic Classification System
               Solubility
BCS Application to development of New Drug
       Entities
                  Dissolution                  Stabi Perme     First
                                               lity  ability   pass
Favourbale        >100 g/ml
Unfavourable <100 g/ml
 Determine the solubility in various biorelevant
       media


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 CVS                                m/
  Biopharmaceutic Classification System
               Solubility
BCS Application to development of New Drug
     Entitites
Determine the solubility in various biorelevant
    media
D:S<250 ml       D:S-250 to                             D:S>1000 ml
                 1000 ml                      Formulation
Confirm with
biorelevant    Simple                         requires expertise
dissolution    approach, Eg                   and creativity.
test           microniza-                     Compare candidate
               tion may                       formulation with
               suffice                        biorelevant
 Grcp                                         dissolution test
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  CVS                            m/
 Biopharmaceutic Classification System
 Examples of Class I and III
Class I
Paracetamol 14.5 mg/ml, Neutral, 85-90% bio
Metoprolol   1 g/ml (tartrate salt), pKa 9.7
             ( weak base), Close to 100% bio
 Class III
 Acyclovir   1.3 mg/ml, Neutral, Ca 20% bio




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 CVS                            m/
 Biopharmaceutic Classification System
 Examples of poorly soluble compounds
      (Class II and IV)
Weak acids
   Mefenamic acid 0.5 g/ml  pKa 4.3
   Troglitazone      2 g/ml 6.1
   Glibenclazmide <0.1 g/ml 5.3
Neutral compounds
   Danazol       1.0 g/ml
      Atovoquone          0.1 g/ml                        pKa 9
      Sanfetrinem         0.18 g/ml

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CVS                                 m/
 Biopharmaceutic Classification System
 Examples of poorly soluble compounds
     (Class II and IV)
Weak bases
 Ketoconazole     4.7 g/ml pKa 2.9, 6.5
 Dipyridamole     7.5 g/ml 6.4
 Albendazole      1.0 g/ml 2.68, 11.83




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CVS                            m/
 Biopharmaceutic Classification System
                Permeability
Permeability is defined in terms of human
       permeability, absorbable bioavailability
       (comparison with intravenous dose) or in
     terms of jejunum permeability
It is concerned with the fraction of dose
     absorbed, not systemic bioavailability
Highly permeable when the extent of the
       drug absorption in human is > 90% of
    an administered dose (compared to i.v.)
  90% of an administered dose is recovered in
Grcp      urine. Single method is sufficient
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CVS                               m/
  Biopharmaceutic Classification System
               Permeability
 When single method fails, two different
      methods may be advisable
Chemical structure and certain physicochemical
        attributes (eg: partition coefficient in
        suitable systems) can provide useful
        information about its permeability
        characteristics




 Grcp
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  CVS                                m/
 Biopharmaceutic Classification System
          Permeability Studies
Pharmacokinetic studies in humans:
- Mass balance studies
It involves the use of unlabeled, stable isotope
       or a radiolabeled drug substance for
     measuring extent of absorption
- Absolute bioavailability studies
 90% or more bioavailability is considered
  Additional data on drug stability in GIT is
       not necessary


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CVS                              m/
 Biopharmaceutic Classification System
             Permeability Studies
  Intestinal permeability studies
- In vivo intestinal perfusion studies in humans
- In vivo or in situ per perfusion studies in
    animals (eg: rats)
-In vitro permeation studies using excised
    human or intestinal tissue
 -In vitro permeation studies across monolayer
    of cultured epithelial cells (for passively
    transported drugs)
  All these methods are considered appropriate
        for passively transported drugs
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 CVS                             m/
 Biopharmaceutic Classification System
        Permeability Studies
Pharmacokinetic studies on dose linearity or
       proportionality may provide useful
       information for evaluating the
       relevance of observed in vitro efflux of
     a drug
Careful considerations should be given the
     limitation of in vitro models




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CVS                               m/
 Biopharmaceutic Classification System
          Dissolution method
Dissolution depends on:
       - Drug substance
       - Drug formulation
       - Dissolution methodology
            * Test apparatus
           * Agitation
           * Dissolution media




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CVS                            m/
       Biopharmaceutic Classification System
                       Extent of absorption vs.
                     Human jejunal permeability

                      Metoprolol
Percent absorbed




                                                                    D glucose
                                       L dopa
                                                               Naproxane

                         Terbutalin

                   Atenolol




Grcp                           Permeability
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   CVS                                        m/
 Biopharmaceutic Classification System
          Dissolution method
Scheme for developing a dissolution test
  1. Determine the category according to BCS
  2. Choose an appropriate medium
  3. Choose an appropriate apparatus
  4. Hydrodynamic considerations
  5. De-aeration of medium
  6. Duration of test




Grcp
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CVS                            m/
 Biopharmaceutic Classification System
Scheme for developing a dissolution test
Basket method at 100 rpm
Peddle method at 50 rpm
 - 500- 900 ml of dissolution medium at 37 C
      - 0.1 N HCl or SGF, without enzyme
      - pH 4.5 buffer
    - pH 6.8 bugger or SIF without enzyme
Drug product is ‘rapidly dissolving’, when
    dissolution is  85% in  30 minutes in
       all three media


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CVS                              m/
 Biopharmaceutic Classification System
   Scheme for developing a dissolution test
2. Choose an appropriate medium
       Class I                           Class II
* Simple medium                   * SGF plus surfactant
   Eg: SGFsp, SIFsp               * FaSSIFA
* Avoid water                     * FeSSIFA
                                  * Ensure® Plus
      Class III                          Class IV
* See Class I                     * See Class II
  A. Substitute with appropriate buffer/
Grcp surfactant combination for quality control
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CVS                               m/
 Biopharmaceutic Classification System
   Scheme for developing a dissolution test
3. Choice of apparatus
  * USP II for immediate release dosage forms
4. Hydrodynamics
     * 50 to 70 rpm usually OK
     * “ coning”    100 rpm or “peak vessel”
     * Use a sinker if necessary (capsules)
5. Deaeration of medium
      • Case by case (chemical or physical
        reasons must be individually assessed)

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CVS                               m/
 Biopharmaceutic Classification System
   Scheme for developing a dissolution test
6. Duration of test
     Class I, III – 15 to 30 minutes, single
             point for QC
       Class II – upto 4 hours, multipoint
       Class IV – take into account sites of
                        absorption




Grcp
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CVS                               m/
               Biopharmaceutic Classification System
               Class I HS/HP              Class II LS/HP
               RLB: Gastric emptying      RLB: Dissolution
               IVIVC: Yes                 IVIVC: Yes
Permeability




               Eg: Verapamil,             Eg: Ketoprofen, naproxine,
               propranolol, metoprolol    carbamazepine
               Class III HS/LP            Class IV LS/LP
               RLB: Permeability          RLB: various factors
               IVIVC: No                  IVIVC: may be
               Eg: Ranitidine,            Eg: Furosemide,
               cimetidine,                hydrochlorthiazide

                      0                  250        10,000
        Grcp          Vol. of Aq buffer added to dissolve
                              http://pharmacystuffforu.blogspot.co
          CVS         the highest unit dose, pH 1-8
                                              m/
Biopharmaceutic Classification System
Dissolution Guidance Waiver of in vivo BA & BE
     for IR drug products based on BCS
Describes the criteria for biowaibver of
      immediate release solid oral dosage
      forms
 - Highly soluble (highest dose soluble in 250
    ml in water over pH range of 1-8)
 - Highly permeable (Extent of absorption
    greater than 90%) and
  - Rapidly dissolving (Basket 100 rpm or
      paddle 50 rpm in 900 ml of 0.1 N HCl,
Grcp pH 4.45 buffer and pH 6.8 buffer)
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CVS                             m/
 Biopharmaceutic Classification System
For a waiver of BE, test and reference
       products should exhibit similar
       dissolution profiles




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CVS                               m/
 Biopharmaceutic Classification System
       BCS- based Biowaiver for Class 1 Drug
 products (HS and HP) with Rapid dissolution
• Dissolution test using 12 units (capsules or
      tablets) with appropriate sampling intervals
      to generate a dissolution profile, eg: 10, 15,
   20 and 30 minutes
• With T and R products, compare dissolution
   profile using similarity factor, f2
 • Use mean data to calculate f2, CV should not
      be more than 20% at the earlier time points
      (eg: 10 minutes) and similar to and 10%
Grcp
      at other three points
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CVS                                     m/
 Biopharmaceutic Classification System
       BCS- based Biowaivers for Class 1 Drug
 products (HS and HP) with Rapid dissolution
• Only one (1) data point after 85% in 15
      minutes dissolution in all three
   recommended media
• Two profiles (T and R products) are
   considered similar when f2 value is  50
      under all three dissolution test conditions
 • When dissolution is 85% minutes, profile
      comparison is not needed

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CVS                                m/
 Biopharmaceutic Classification System
Similarity factor
 Similarity is a measurement in percent (%) of
       dissolution between the two curves
f2 = 5.0 *log {[1 + (1/n)t-1n(Rt – Tt2)]-0.5*100}
It is logarithmic reciprocal square root
       transformation of the sum of squared
    error
 Two dissolution profiles are considered
       similar when the f2 value is 50%


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CVS                             m/
 Biopharmaceutic Classification System
          BCS- based Biowaivers
BCS- based biowaivers for HS/HP/rapidly
     dissolving drug products
BCS- based biowaivers are intended only for
       bioequivalance studies for
       pharmaceutically equivalent drug
   products
NDAs
 BE studies between to-be-marketed
       formulation and clinical trial formulation

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CVS                              m/
 Biopharmaceutic Classification System
              BCS- based Biowaivers
ANDAs
  -The reference product should belong to
          BCS Class 1
       - Profile comparison between T and R
      product
Post approval changes
   - Profile comparison between pre-change
         and post-change products
  Define what constitutes a major change
          to the formulation to address the
Grcp      potential physiological issues
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CVS                               m/
 Biopharmaceutic Classification System
               BCS- based Biowaivers
             Class 1 drug products
       * Highly soluble drug substances
       * Highly permeable drug substances
       * Rapidly dissolving drug product




Grcp
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CVS                               m/
 Biopharmaceutic Classification System
                    Extension ?
        Descri       Current          Future
Class
         ption   requirement       extensions?
  I     HS/HP Dissolution Bio-
        /RD    profile     waiver

  I     HS/HP Dissolution BE      Extend
               profile                  study          dissolution time
                                                       to 45 to 60 min?
                                                       Biowavier
  II    LS/HP Dissolution BE                           Biowaiver
               profile with study
               surfactant

Grcp
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CVS                             m/
 Biopharmaceutic Classification System
                      Extension ?
      Descrip   Current                                  Future
Class
      tion      requirement                              extensions?
 III HS/LP/     Dissolution BE                           Biowaiver
      RD        profile      study
 III HS/LP      Dissolution BE
                profile      study
 IV    LS/LP    Dissolution BE
                profile with study
                surfactant



Grcp
                  http://pharmacystuffforu.blogspot.co
 CVS                              m/
 Biopharmaceutic Classification System
             Issues to be solved
Is the BCS safe?
Should biowaivers be limited to class I drugs,
    or could we extent them to other classes?
 What about controlled release dosage forms?
 How early in the development process can
       we apply the BCS principles or should
       the same cut off values be applied to
       developing both new drug products and
       SUPAC applications?

Grcp
                http://pharmacystuffforu.blogspot.co
CVS                             m/
 Biopharmaceutic Classification System
                  Summary
 BCS is a bench mark in the regulation of
      bioequivalence of oral products
If two drug products yield the same
       concentration profile along the GIT, they
     will result in the same plasma profile
Dissolution data can surrogate for PK data to
       demonstrate bioequivalence of two drug
       products



Grcp
                  http://pharmacystuffforu.blogspot.co
CVS                               m/
 Biopharmaceutic Classification System




Grcp
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CVS                          m/

								
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