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Bioequivalence biowaiver and ivivc studies 2014 new

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Bioequivalence biowaiver and ivivc studies 2014 new

  1. 1. 1
  2. 2. BIOEQUIVALENCE “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.” 2 CDER U.S. Food & Drug Administration
  3. 3. What are Pharmaceutical Equivalents Drug Products in identical dosage form that contains the same active ingredients i.e. the same salt or ester are of the same dosage form use the same route of administration identical in strength or concentration same amount of active ingredient meet the same or compendial or other applicable standards They may differ in characteristics such as shape, scoring configuration, release mechanisms, packaging, excipients (including color, flavours, preservatives), expiration time and within certain limits labeling. 3
  4. 4. What are Pharmaceutical alternatives Drug product that contain the same therapeutic moiety but as different salts, ester, or complexes. For e.g. Tetracycline hydrochloride or tetracycline phosphate equivalent to 250 mg tetracycline base. Different dosage form and strength within a product line by a single manufacturer for eg. an extended release and standard immediate release. Tablet and capsule containing the same active ingredient in the same dosage strength. 4
  5. 5. Reasons for Bioequivalence Study To prove that Generic Drug Products are bioequivalent to innovators/marketed drug product (Reference Listed Drugs). Change in formulations i.e. from capsule to tablets. Change in any process or manufacturing site (In few cases) To determine the efficacy and safety from the bioequivalence data. 5
  6. 6. APPROACHES TO DETERMINE BIOEQUIVALENCE In vivo measurement of active moiety in biological fluid  Plasma Drug Concentration  Cmax, Tmax and AUC  Urinary Drug Excretion  Ae, Ae/t, t Acute Pharmacodynamic effect  Dose-Response Curve (Skin Blanching-Topical cortico steroids, Force Expiratory Volume- Inhaled Bronchodilators) Clinical Observations  Well controlled Clinical Trials to establish efficacy and safety In vitro Studies  Comparative Drug Release/Dissolution Studies (f2 test)  IVIVC studies  In vitro biomarker/in vitro binding studies 6
  7. 7. IN-VIVO BIOEQUIVALENCE STUDY DESIGN CROSS OVER STUDY SINGLE DOSE, TWO WAY CROSS OVER- FASTED SINGLE DOSE, TWO WAY CROSS OVER- FED SINGLE DOSE REPLICATE DESIGN (Highly variable drugs) MULTIPLE DOSE TWO WAY CROSS OVER-FASTED (Less Sensitive, Non Linear Kinetic) PARALLEL GROUP STUDY SINGLE DOSE, PARALLEL, FASTED (Long Elimination Half Life Drugs) CLINICAL END POINT STUDY 7
  8. 8. COMPONENTSOF BIOEQUIVALENCESTUDY PROTOCOL CLINICAL PHASE Title Principal Invesitgator/Project Number Study Objective and Design Drug Products, Dosage Regimen, Sample Collection Schedule Study Population Subjects, Selection, Inclusion/Exclusion criteria Ethical Considerations IRB, Informed consent Clinical Procedures Drug Administration and Sampling ANALYTICAL PHASE Analytical Method Validation Sensitivity, specificity, selectivity accuracy, precision, recovery, stability etc Sample Analysis PK parameters such as Cmax, Tmax, AUC, Rate constants etc. Statistical Analysis ANOVA, Two one sided test etc. 8
  9. 9. IMPORTANT CONSIDERATION IN BIOEQUIVALENCE STUDY  Objectives  Why, Is there any requirement.  Benefit-Risk and ethical consideration with regard to testing in humans  Basic Guiding Principle “Do not do unnecessary human research”  Nature of Reference Material and the dosage form tested  Study type  Usually Single Dose, Randomized Cross Over (Occasionally Parallel)  Volunteers Selection  Healthy based on clinical examination and lab test  Male or Female (Usually Male)  Age group 18-45 years  Same Average weight group within 10% of the ideal body weight  No other medication at least 1 weak prior to study  Non alcoholic/non smokers  Should sign informed consent containing detailed information about the study including risks and right to withdraw at anytime 9
  10. 10. Sample size  Depends on the variability in the PK parameters  At least 12 (Ideally 24) Sample Type  Usually Blood, Plasma/serum  Urine in some cases if required Sample Collection schedule  Test/Reference Dosage form with 250 ml of water from subjects in an overnight fast condition  First sample immediately before dose administration (Just before zero time).  Fasting conditions till 2-4 hrs of the first dose  At least 10 blood Samples (5-10 ml) upto 7th elimination half lives.  Three samples from absorption phase, three from distribution, and four from elimination phase 10
  11. 11. Sample Analysis  Chromatographic (LC-UV, LC-PDA, LC-MS recommended)  Validated method i.e. sensitivity, specificity, accuracy, precision and recovery etc should be done prior to study.  Method should be sensitive enough to analyze the drug in trace levels (usually less than 100 ng/ml is required for analytical methods)  Stability determination of the frozen storage of the study samples Pharmacokinetic Analysis  Non compartmental method  Cmax, Tmax, AUC0-t and AUC0- 11
  12. 12. Statistical Analysis  Analysis of Variance (ANOVA) explaining different sources of errors in the calculated PK parameters such as  Sequence effect (Order effect)  Subject nested in sequence  Period Effect (phase effect)  Treatment Effect (Product Effect)  Two one sided t test to test BE  Calculation of 90% Confidence Interval for the ratio (or difference) of the average log- transformed pharmacokinetic parameters for the test and reference products  Log transformed Cmax and Tmax as these parameters are not normally distributed (Log transformed values are normally distributed-log normal distribution)  90% CI for the ratio of the average log transformed AUC and Cmax should fall within the BE limit of 80-125%. 12
  13. 13. NEED TO REDUCE OUR RELIANCE ON IN VIVO BE STUDIES – BE THEME FOR 21ST CENTURY Ethical reasons  21 CFR 320.25(a) “… no unnecessary human research should be done.”  Science continues to provide new methods to identify and eliminate unnecessary in vivo BE studies Focus on prevention - “building quality into products” - “right first time” Time and cost of drug development and review 13
  14. 14. BIOWAIVERS Termed as In-vitro Bioequivalence Studies Means in vivo bioavailability and/or bioequivalence studies may be waived off Instead of conducting expensive and time consuming in vivo studies, an in vitro dissolution test could be adopted as the surrogate basis for the decision as to whether the two pharmaceutical products are equivalent. 14
  15. 15. PD studies clinical studies in vitro methods Different Approach for Establishing Equivalence Standard: in vivo BE studies 15
  16. 16. HISTORICAL BACKGROUND IN THE DEVELOPMENT OF DISSOLUTION AS A PROGNOSTIC TOOL FOR ORAL DRUG ABSORPTION  In 1985, Amidon and co-workers, using a Pseudoequilibrium Model where solubility and dose were taken into account for the estimation of the absorption potential (AP) of a drug.  Quantitative version of the Absorption potential concept was published which enabled the estimation of the fraction of dose absorbed as a function of AP (Macheras and Symillides, 1989).  Microscopic model publish in 1993 based on mass balance considerations can be considered as a landmark in the history of oral drug absorption since it revealed the three fundamental parameters, namely, dissolution, absorption and dose numbers (Oh et al, 1993) 16
  17. 17. Amidon et al. in 1995 published a revolutionary paper in Pharmaceutical Research i.e. A theoretical basis for a Biopharmaceutic drug classification—the correlation of in-vitro drug product dissolution and in-vivo bioavailability. Classifying drugs on the basis of BCS Dressman et al in 1998 established correlations between in vitro dissolution and in vivo absorption using artificial fluids, simulated gastric and intestinal fluids both in fasted and fed conditions. (i.e. BIO-RELEVENT Dissolution mediums). FDA acknowledges Amidon et al 1995 BCS system with the guidance documents. “FDA, 2000. Guidance for Industry,Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms based on a Biopharmaceutics Classification System. FDA/CDER”. 17
  18. 18. BIOPHARMACEUTICS CLASSIFICATION SYSTEM CLASS I HIGH SOLUBILITY HIGH PERMEABILITY CLASS II LOW SOLUBILITY HIGH PERMEABILITY CLASS III HIGH SOLUBILITY LOW PERMEABILITY CLASS IV LOW SOLUBILITY LOW PERMEABILITY 18
  19. 19. HIGH SOLUBLE  A 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. 250 ml: derived from typical BE study protocols that prescribe the administration of a drug product to fasting human volunteers with a glass (approximately 250 ml) water Relevance of pH 1-7.5 i.e. Physiological pH range from stomach (Dissolution) to small intestine –Duodenum to Ileum (Dissolution and Absorption). Solubility can be determined by  pH-solubility profile of test drug at 37oC in aqueous media with a pH range of 1 to 7.5  Shake-flask or titration method  Analysis by validated stability-indicating assay 19
  20. 20. HIGH PERMEABLE  A drug substance 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.  Permeability can be determined by Pharmacokinetic studies in humans:  Mass-balance 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 (Caco2 cell) 20
  21. 21. 21
  22. 22. 22
  23. 23. BCS Class I Drug IR solid Oral Dosage Forms Stable Drugs in G I Tract Drug must not have narrow therapeutic Index Drug is designed not to be absorbed in the oral cavity FDA approved safe excipients FDA BCS Class I, Class II (weak acid), Class III (rapidly dissolving) IR solid Oral Dosage Forms Extended Release, Delayed Release (Dose Proportionality Formulations) Drug must not have narrow therapeutic Index Well established safe and approved excipients WHO 23 DISSOLUTION BASED BIOWAIVERS
  24. 24. BCS GUIDANCE FOR DRUG PRODUCT PERFORMANCE  BCS CLASS I-VERY RAPIDLY DISSOLVING  When no less than 85% of the drug dissolves within 15 minutes using  USP Dissolution Apparatus I at 100 rpm or Apparatus II at 50-75 rpm  In a volume of 900 ml or less in each of the following medium  0.1 N HCl or simulated gastric juice  pH 4.5 and 6.8 phosphate buffers or simulated intestinal juice  No further profile comparison of Test (T) and Reference (R) product is required 24
  25. 25.  BCS CLASS I – RAPIDLY DISSOLVING  When no less than 85% of the drug dissolves within 30 minutes using  USP Dissolution Apparatus I at 100 rpm or Apparatus II at 50-75 rpm  In a volume of 900 ml or less in each of the following medium  0.1 N HCl or simulated gastric juice  pH 4.5 and 6.8 phosphate buffers or simulated intestinal juice  Proving similarity of dissolution profiles of T and R e.g., using f2-test  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) 25
  26. 26. When comparing the test and reference products, dissolution profiles should be compared using a similarity factor 𝑓2 𝑓2 = 50 × log 1 + 1 𝑛 𝑗−1 𝑛 𝑅𝑗 − 𝑇𝑗 2 −0.5 × 100 Two dissolution profiles are considered similar when the 𝑓2 value is ≥50. 26
  27. 27. 27
  28. 28. BCS CLASS II DRUGS Weakly Acidic Drugs Dose: solubility ratio of 250 ml or less at pH 6.8 Multisource product is rapidly dissolving (no less than 85% in pH 6.8 in 30 minutes) Dissolution profile is similar to that of the comparator product at pH 1.2, 4.5 and 6.8 28
  29. 29. BCS CLASS III DRUGS Multisource and comparator product are very rapidly dissolving (no less than 85% in 15 minutes at pH 1.2, 4.5 and 6.8) Note: FDA has not allowed Dissolution based biowaivers for Class II and Class III (VERY CONSERVATIVE said by WHO) 29
  30. 30. BCS IVIVC BIOWAIVER S COMPOSITION PROPORTIONALI TY 30
  31. 31. BCS (Dissolution based) Class I-Very Rapidly Dissolving, Rapidly Dissolving Class II-Weak Acid, HS in pH 6.8 Class III-Very Rapid Dissolving IVIVC Composition Proportionality BIOWAIVER S Level A Level B Level C Multiple Level C • API and Excipient are same qualitatively and quantitatively. • Same manufacturing process 31
  32. 32. IN-VITRO IN-VIVO CORRELATIONS (IVIVC) Correlations between an in-vitro property of dosage form and a relevant in-vivo response In-vitro property is the rate and extent of drug dissolution In-vivo response is the amount of drug absorbed or the plasma concentration time profile Based on developing and optimizing the conditions of in vitro dissolution testing procedures for a particular formulation that can predict the in vivo performance of that formulation 32
  33. 33. LEVEL A • Point to Point Correlations between in vitro input rate and in vivo out put rate • Highest level • Most informative • Regulatory Support LEVEL B • Using the Principle of statistical moment theory • Mean in vitro dissolution Time (MDT) compared to Mean in vivo Dissolution time (MRT) • Single integrated parameter and no point to point correlations • No Regulatory Support so no importance LEVEL C • A single point correlations between an in vitro dissolution parameter (eg. Time to release 50% of the drug T50 and an in vivo parameter (eg. Cmax and AUC) • Does not reflect complete in vivo plasma conc time profile • Not very useful for regulatory support. • Use for earlier formulation development MULTIPLE LEVEL C • Extension of single point Level C • Relates several in vivo parameter to in vitro parameters related to drug release at several time point of Dissolution profiles • Useful like Level A 33 LEVEL OF CORRELATIONS
  34. 34. 34 LEVEL A LEVEL B LEVEL C
  35. 35. IVIVC Level A Development of Formulations Slow Intermediate Fast In Vitro Dissolution Data 12 individual dosage form in each lot Adequate sampling Point 0.1MHCl, pH 4.5 and6.8 buffers, Biorelevant mediums <10% CV for the mean dissolution profiles In Vivo PK Data Cross over or Parallel 12-36 subjects Reference IR Formulation (Solution/suspension/tablets) or IV also included 35
  36. 36. 36 In Vitro Dissolution Data In Vivo PK Data 0 20 40 60 80 100 0 10 20 30 40 Cp (ng/ml) Time (h) In vivo vs. In vitro absorbed Deconvolution Convolution
  37. 37. DECONVOLUTION • Two Step Process In vivo profile transformed to in vitro dissolution profile (Output to Input) • Wagner Nelson (1 comp) • Loo Reigelman (2 Comp) • Numerical Deconvolution Model Fitting of In vitro/in vivo Dissolution Curves • Weibull Model • 𝒎 = 𝟏 − 𝒆𝒙𝒑 − 𝒕−𝒕 𝒊 𝜷 𝜶 Time Scaling • 𝑿 𝒗𝒊𝒗𝒐 = 𝑿 𝒗𝒊𝒕𝒓𝒐(𝒃 𝟐 × 𝒕) • Where 𝒃 𝟐 = 𝜶 𝒊𝒏 𝒗𝒊𝒕𝒓𝒐 𝜶 𝒊𝒏 𝒗𝒊𝒗𝒐 37 STEP BY STEP DECONVOLUTION IVIVC
  38. 38. CONVOLUTION • Single Step Process In vitro profile transformed to in vivo Time Plasma conc profile (Input to Output) • Unit Impulse Response • 𝑪 𝒕 = 𝟎 ∞ 𝑪 𝜹 𝒕 − 𝒖 𝑿 𝒗𝒊𝒕𝒓𝒐 𝒖 𝒅𝒖 In vivo/In vitro Time plasma conc profile • Cmax and AUC calculated from both In vitro and In vivo Data. • % 𝑷𝑬 = 𝑶𝒃𝒔 𝒗𝒂𝒍𝒖𝒆−𝑷𝒓𝒆𝒅 𝒗𝒂𝒍𝒖𝒆 𝑶𝒃𝒔𝒆𝒓𝒗𝒆𝒅 × 𝟏𝟎𝟎 38
  39. 39. 39 IVIVC MODEL PREDICTABILITY (VALIDATION) For Cmax: For AUC: Acceptance criteria: According to FDA guidance • ≤15% for absolute prediction error (%P.E.) of each formulation. • ≤ 10% for mean absolute prediction error (%P.E.)
  40. 40. BCS CLASSIFICATION AND EXPECTED IVIVC FOR IMMEDIATE RELEASE PRODUCTS CLASS SOLUBILITY PERMEABILITY IVIVC I HIGH HIGH POSSIBLE (IF DISSOLUTION IS RATE LIMITING II LOW HIGH EXPECTED III HIGH LOW LITTLE OR NO IVIVC IV LOW LOW LITTLE OR NO IVIVC 40
  41. 41. SOFTWARES FOR BE, BIOWAIVERS AND IVIVC STUDIES Phoenix Winnonlin (Certara) Gastro Plus, IVIVC Plus and DDD Plus (Simulation–Plus) IVIVC for R DD Solver (Excel Add in) Equiv Test (Statcon) Kinetica (Thomson) 41
  42. 42. IVIVC PACKAGE FROM SIMULATION PLUS 42
  43. 43. IVIVC FROM R PACKAGES 43
  44. 44. IVIVC TOOLKIT FROM PHOENIX 44
  45. 45. RESEARCH SCOPE AND BENEFITS More than 400 manufacturing units involved in Generic Manufacturing Bioequivalence required for many products  Areas covered  Pharmacokinetics  Pharmacodynamics  Chromatographic method development and validation  Understanding Statistical Techniques Dissolution based biowaivers, an alternative for in vivo BE can be performed within the regulatory framework IVIVC, another alternative in which a surrogate dissolution medium can be developed  Areas Covered  Developing New Formulations  Optimization Techniques  Development and understanding of new and existing dissolution mediums  Development and understanding of new and existing mathematical dissolution models 45
  46. 46. Proper use of these methods leads to Safe Cost effective Less Time consuming Optimized Quality Product 46

Notes de l'éditeur


  • Clinical observations:

    Well controlled clinical trials in humans establish safety and effectiveness of drug products and may be used to determine the bioavailability . However the clinical trial approach is the least accurate least sensitive to bioavailability differences and most variable. The highly variable clinical response requires the use of a large population which increase the study cost and requires a longer time to complete compared to other approaches for determination of bioequivalence. The FDA considers this approach only when analytical methods and pharmacodynamics effects are not available to permit use of other recommended approaches.

    The use of in vitro biomarkers and in vitro binding studies has been proposed to establish bioequivalence. For example cholestyramine resin is a basic quartenary ammonium exchange resin that is hydrophilic, insoluble in water and not absorbed in the G I tract. The bioequivalence of cholestyramine is performed by equilibrium and kinetic binding studies of the resin to bile acids and salts.
  • The numbers of volunteers required for the BE study depends on the variability in the pharmacokinetic parameters of the drug, the acceptable significance level (=0.05) and the acceptable deviation level between product compared (±20%). Since the variation in the pharmacokinetic parameters for most drug is <30% CV, the number of volunteers needed for most drug is 24. Drug with high variability in their PK parameters requires large number of volunteers

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