New guidance on Bioequivalence

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“Drug Regulations” is a non profit organization which provides free online resource to the Pharmaceutical Professional.
Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals.

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New guidance on Bioequivalence

  1. 1. This presentation is compiled by “ Drug Regulations” a non profit organization which provides free online resource to the Pharmaceutical Professional. Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals. 12/11/2013 1
  2. 2. This presentation is compiled by “ Drug Regulations” from freely available resources like the FDA on the World wide web.  “Drug Regulations” is a non profit organization which provides free online resource to the Pharmaceutical Professional.  Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals.  Drug Regulations : Online Resource for Latest Information 12/11/2013 2
  3. 3.  Main focus of ANDA application ◦ Bioequivalence of Generic products to RLD ◦ The FD&C Act requirement for BE  The rate and extent of absorption of the drug do not show a significant difference from the rate and extent of absorption of the listed drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses... Drug Regulations : Online Resource for Latest Information 12/11/2013 3
  4. 4.  Focus of BE studies for most products ◦ Release of the drug substance from the drug product into the systemic circulation. ◦ Comparison of the systemic exposure profile of a Generic drug product to that of the RLD. Drug Regulations : Online Resource for Latest Information 12/11/2013 4
  5. 5.  Use “the most accurate, sensitive, and reproducible approach available among those set forth” to demonstrate BE. ◦ ( 21 CFR 320.24(b)).  Use of in vivo and/or in vitro methods acceptable to establish BE. (21 CFR 320.24) Drug Regulations : Online Resource for Latest Information 12/11/2013 5
  6. 6.  Descending order of preference ◦ Pharmacokinetic ◦ Pharmacodynamic ◦ Clinical ◦ In vitro studies. Drug Regulations : Online Resource for Latest Information 12/11/2013 6
  7. 7.  Statutory definition of BE ◦ Expressed in terms of rate and extent of absorption of the active ingredient or moiety ◦ Emphasizes the use of pharmacokinetic endpoints ◦ Endpoints determined in biological matrix, such as blood, plasma, and/or serum, ◦ Indicates release of the drug substance from the drug product into the systemic circulation. Drug Regulations : Online Resource for Latest Information 12/11/2013 7
  8. 8.  Statutory definition of BE ◦ Frequently relies on pharmacokinetic endpoints  C max  (peak plasma concentration) and  AUC  (area under the plasma concentration time curve)  Reflective of rate and extent of absorption Drug Regulations : Online Resource for Latest Information 12/11/2013 8
  9. 9.  Use measurement of urinary excretion if serial measurements of the drug or its metabolites in plasma, serum, or blood cannot be accomplished. Drug Regulations : Online Resource for Latest Information 12/11/2013 9
  10. 10.  Applicant may conduct a pilot study ◦ Conducted before full BE study ◦ Carried out in a small number of subjects ◦ Used to  Validate analytical methodology  Assess variability  Optimize sample collection time intervals  Provide other information. Drug Regulations : Online Resource for Latest Information 12/11/2013 10
  11. 11.  FDA recommends an approach given in slides to follow : ◦ For both replicate and nonreplicate in vivo pharmacokinetic BE studies, ◦ Elements can be adjusted for certain drug substances and drug products. Drug Regulations : Online Resource for Latest Information 12/11/2013 11
  12. 12.  Study conduct: ◦ Administer the test or RLD products with about 8 ounces (240 mL) of water ◦ Use appropriate number of subjects ◦ Use fasting conditions, unless the study is a fed BE study. Drug Regulations : Online Resource for Latest Information 12/11/2013 12
  13. 13.  Study conduct: ◦ Fed Treatments:  Subjects should have an overnight fast of at least 10 hours  Start the recommended meal 30 minutes before administration of the drug product  Study subjects should eat this meal in 30 minutes or less  Administer the drug product 30 minutes after start of the meal.  Use 8 fluid ounces (240 mL) of water for administration. Drug Regulations : Online Resource for Latest Information 12/11/2013 13
  14. 14.  Study conduct: ◦ Do not allow food for at least 4 hours post dose. ◦ Allow Water as desired except for 1 hour before and after drug administration. ◦ Give subjects standardized meals ◦ Schedule meals at the same time in each period of the study. Drug Regulations : Online Resource for Latest Information 12/11/2013 14
  15. 15.  Study conduct: ◦ Administer highest-marketed strength as a single unit. ◦ If warranted to achieve sufficient bio-analytical sensitivity, multiple units of the highest strength can be administered, provided the total single dose remains within the labelled dose range and the total dose is safe for administration to the study subjects. Drug Regulations : Online Resource for Latest Information 12/11/2013 15
  16. 16.  Study conduct: ◦ Separate each treatment with an adequate washout period  e.g., more than five half-lives of the moieties to be measured. Drug Regulations : Online Resource for Latest Information 12/11/2013 16
  17. 17.  Study conduct: ◦ State the lot numbers of both test and RLD products and the expiration date for the RLD product. ◦ The assayed drug content of the test product batch should not differ from the RLD product by more than +/- 5 percent. ◦ Include a statement of the composition of the test product ◦ Include a side-by-side comparison of the compositions of test and RLD products ◦ Retain the test and RLD products for five years. (21 CFR 320.63) Drug Regulations : Online Resource for Latest Information 12/11/2013 17
  18. 18.  Study conduct: ◦ Before and during each study phase  Allow subjects to have water as desired, except for 1 hour before and after drug administration,  Provide subjects with standardized meals no less than 4 hours after drug administration  Ask subjects to abstain from alcohol for 24 hours before each study period and until after the last sample from each period has been collected. Drug Regulations : Online Resource for Latest Information 12/11/2013 18
  19. 19.  Fed studies test meal ◦ Use meals that provide the greatest effects on gastrointestinal (GI) physiology and systemic drug availability. ◦ Use a high-fatº & high calorie® test meal  º(approximately 50 per cent of total caloric content of the meal),  ®(approximately 800 to 1000 calories)  Test meal should derive approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively.  Provide the caloric breakdown of the test meal in the study report. Drug Regulations : Online Resource for Latest Information 12/11/2013 19
  20. 20.  Sample collection and sampling times: ◦ Sample blood, rather than urine or tissue. ◦ Measure the drug or metabolites in serum or plasma. ◦ Analyse whole blood when appropriate ◦ Draw blood samples at appropriate times to describe the absorption, distribution, and elimination phases of the drug ◦ Collect 12 to 18 samples, including a predose sample, per subject, per dose. ◦ Continue sampling for at least three or more terminal elimination half-lives of the drug Drug Regulations : Online Resource for Latest Information 12/11/2013 20
  21. 21.  Sample collection and sampling times: ◦ Finalize exact timing for sample collection based on the drug and the rate of input from the administered dosage form. ◦ Space sample collection to  Maximize concentration of drug in the blood (Cmax) and  Calculate terminal elimination rate constant (Kel) ◦ Obtain at least 3 to 4 samples during the terminal log-linear phase to obtain an accurate estimate of  from linear regression. z ◦ Record the actual clock time when samples are drawn ◦ Record the elapsed time related to drug administration. Drug Regulations : Online Resource for Latest Information 12/11/2013 21
  22. 22.  Subjects with predose plasma drug concentrations: ◦ Include the subject’s data without any adjustments in all pharmacokinetic measurements and calculations  If the predose concentration is  5 per cent of Cmax value in a subject with predose plasma concentration  If the predose value is greater than 5 per cent of Cmax, drop the subject from all BE study evaluations. Drug Regulations : Online Resource for Latest Information 12/11/2013 22
  23. 23.  Data deletion because of vomiting: ◦ Delete data from statistical analysis from subjects who experience emesis during the course of a BE study for immediate release products if vomiting occurs at or before 2 times median Tmax. ◦ Delete data from the analysis if a subject vomits during a period of time less than or equal to the dosing interval stated in the labelling of the product for modified release products. Drug Regulations : Online Resource for Latest Information 12/11/2013 23
  24. 24.  Pharmacokinetic information in submissions: ◦ Plasma concentrations and time points ◦ Subject, period, sequence, treatment ◦ Intersubject, intrasubject, and/or total variability, if available ◦ For single-dose BE studies:  AUC0-t, AUC0-inf, and C  max. In addition, report the following supportive information: Tmax, Kel and t1/2. ◦ For steady-state BE studies: AUC0-tau and CmaxSS. In addition, please report CminSS (concentration at the end of a dosing interval), CavSS (average concentration during a dosing interval), degree of fluctuation [(CmaxCmin)/CavSS], swing [(CmaxSS-CminSS)/CminSS], and Tmax. Drug Regulations : Online Resource for Latest Information 12/11/2013 24
  25. 25.  Statistical information in submissions: ◦ For AUC0-t, AUC0-inf, and Cmax:  Geometric means  Arithmetic means  Geometric mean ratios  90 per cent Confidence intervals (CI)  Do not round off CI values; therefore, to pass a CI limit of 80 to 125 per cent, the value would be at least 80.00 per cent and not more than 125.00 per cent.  Provide logarithmic transformation for measures used for BE demonstration. Drug Regulations : Online Resource for Latest Information 12/11/2013 25
  26. 26. ◦ Use  Two-period, two-sequence, two-treatment, singledose, crossover study design, or  A single-dose parallel study design, or  A replicate study design for BE studies. Drug Regulations : Online Resource for Latest Information 12/11/2013 26
  27. 27.  Perform a two-period, two-sequence, two-treatment, single-dose, crossover study using healthy subjects for systemically available drug release.  Give study subject each treatment (test, and RLD) in random order.  Crossover design may not be practical for drugs with long pharmacokinetic half-lives ◦ (i.e., longer than 24 hours). Drug Regulations : Online Resource for Latest Information 12/11/2013 27
  28. 28.  For drugs with long pharmacokinetic half- lives ◦ Use a single-dose, parallel design ◦ Administer each treatment to a separate group of subjects with similar demographics. ◦ Use general recommendations for study designs in designing crossover studies as well. Drug Regulations : Online Resource for Latest Information 12/11/2013 28
  29. 29.  A replicate crossover study may be an appropriate alternative to the parallel or nonreplicate crossover study described earler.  This can be conducted as either ◦ Partial (three-way) or ◦ Full (four-way) replication of treatment. ◦ Administer one or both treatments to the same subject on two separate occasions. Drug Regulations : Online Resource for Latest Information 12/11/2013 29
  30. 30.  The replicate design has the advantage of using fewer subjects  However each subject should receive more treatments than in the two-treatment, crossover design.  The replicate design is especially useful for highly variable drugs. Drug Regulations : Online Resource for Latest Information 12/11/2013 30
  31. 31.  Use the average BE method of analysis.  Use a scaled-average BE analysis for highly variable drugs.  Use this approach with a replicate study design.  Submit a complete protocol for review and comment before commencing the study to the FDA to use variations of these study designs or analysis methods (e.g., a sequential design or scaled-average BE), Drug Regulations : Online Resource for Latest Information 12/11/2013 31
  32. 32.  Use subjects of 18 years of age or older  Subjects should be representative of the general population considering the age, sex and race.  Include similar proportion of males and females if the drug will be used in both sexes.  Include as many subjects at or above the age of 60 if the drug is to be used predominantly in the elderly. Drug Regulations : Online Resource for Latest Information 12/11/2013 32
  33. 33.  Subjects in a study should be sufficient to provide adequate statistical power for BE demonstration,  FDA does not expect that there will sufficient power to draw conclusion for each sub group.  Statistical analysis is not recommended for each sub group.  Restrictions on admission into a study be based primarily on safety considerations. Drug Regulations : Online Resource for Latest Information 12/11/2013 33
  34. 34.  Safety considerations preclude the use of healthy volunteers.  Attempt to enrol patients that the drug is intended to treat and whose disease process and treatments are stable for the duration of the BE study.  An IND for certain BE studies may be required e.g. certain cytotoxic products. Drug Regulations : Online Resource for Latest Information 12/11/2013 34
  35. 35.  FDA recommends single-dose pharmacokinetic studies for both immediate and modified release drug products.  These studies are generally more sensitive than steady-state studies. Drug Regulations : Online Resource for Latest Information 12/11/2013 35
  36. 36.  Use steady state study to establish BE without disrupting a patient's on-going treatment ◦ when safety considerations suggest using patients who are already receiving the medication.  Carry out appropriate dosage administration and sampling to document the attainment of steady state. Drug Regulations : Online Resource for Latest Information 12/11/2013 36
  37. 37.  Ensure that bioanalytical methods for BE studies are accurate, precise selective, sensitive, and reproducible.  Refer a separate draft guidance for industry on Bio analytical method validation. Drug Regulations : Online Resource for Latest Information 12/11/2013 37
  38. 38.  Rate of absorption ( Peak Exposure) ◦ Assess the rate of absorption by measuring the peak drug concentration (Cmax) obtained directly from the data without interpolation  for both single-dose and steady-state studies,. ◦ Obtain information about rate of absorption from time-to-peak drug plasma concentration(Tmax) Drug Regulations : Online Resource for Latest Information 12/11/2013 38
  39. 39.  Partial Exposure ◦ Demonstrate BE by measurements of peak and total exposure  For orally administered immediate release drug products ◦ Use of partial AUC as an early exposure measure under certain circumstances. ◦ Relate the time to truncate the partial area to a clinically relevant pharmacodynamic (PD) measure. Drug Regulations : Online Resource for Latest Information 12/11/2013 39
  40. 40.  Extent of Absorption (Total Exposure) ◦ Use following indicators for single-dose studies  Area under the plasma/serum/blood concentration-time curve from time zero to time t (AUC0-t), where:  t is the last time point with a measurable concentration.  Area under the plasma/serum/blood concentration-time curve from time zero to time infinity (AUC0-inf), where:  AUC0-inf = AUC0-t + Ct/z  Ct is the last measurable drug concentration  z is the terminal or elimination rate constant calculated according to an appropriate method. Drug Regulations : Online Resource for Latest Information 12/11/2013 40
  41. 41.  Extent of Absorption (Total Exposure) ◦ For steady-state studies ◦ Use the area under the plasma, serum, or blood concentration-time curve over a dosing interval at steady-state (AUC0-tau)  where tau is the length of the dosing interval. Drug Regulations : Online Resource for Latest Information 12/11/2013 41
  42. 42.  Co-administration of food with oral drug products can influence BE.  Fed BE studies determine whether test and RLD products are bioequivalent when co- administered with meals.  Use a single-dose, two-period, two-treatment, two-sequence, crossover study for fed BE studies. Drug Regulations : Online Resource for Latest Information 12/11/2013 42
  43. 43.  Conduct a fed study when a fasting in vivo BE study is recommended for an orally administered, immediate release product  Exception when the dosage and administration section of the RLD labelling states that the product should be taken only on an empty stomach ◦ (e.g., the labelling states that the product should be administered 1 hour before or 2 hours after a meal). Drug Regulations : Online Resource for Latest Information 12/11/2013 43
  44. 44.  Conduct fasting and fed studies for orally administered, immediate release products labelled to be taken only with food. ◦ Exception when serious adverse events are anticipated with fasting administration. ◦ Conduct only a fed study. ◦ Fasting study is not recommended. Drug Regulations : Online Resource for Latest Information 12/11/2013 44
  45. 45.  Conduct a fed BE study in addition to a fasting BE study for all orally administered, modified-release drug products.  Conduct these studies on the highest strength of the drug product ◦ unless safety considerations preclude the use of that dose in study subjects. Drug Regulations : Online Resource for Latest Information 12/11/2013 45
  46. 46.  Conduct an additional BE study if the label of a modified release RLD product states that the product can be administered sprinkled in soft foods.  Sprinkle on one of the soft foods mentioned in the labelling of the RLD, normally applesauce for each treatment arm.  Follow the recommendations for fasting BE study aside from administration in the soft food. Drug Regulations : Online Resource for Latest Information 12/11/2013 46
  47. 47.  Administer specific beverage when labelling specifies that the product must be administered in a specific beverage.  Administer these products mixed with one of the beverages mentioned in the labelling.  Provide evidence that using additional beverages would not result in BE differences if additional beverages are listed. Drug Regulations : Online Resource for Latest Information 12/11/2013 47
  48. 48.  In Vitro Tests Predictive of Human In Vivo Bioavailability (In Vitro-In Vivo Correlation Studies) ◦ In vitro-in vivo correlation (IVIVC) is a scientific approach to describe the relationship between  An in vitro attribute of a dosage form (e.g., the rate or extent of drug release) and  A relevant in vivo response (e.g., plasma drug concentration or amount of drug absorbed). Drug Regulations : Online Resource for Latest Information 12/11/2013 48
  49. 49.  In Vitro Tests Predictive of Human In Vivo Bioavailability (In Vitro-In Vivo Correlation Studies) ◦ This model relationship facilitates the rational development and evaluation of extended-release dosage forms as a surrogate for bioavailability and/or BE testing and ◦ A tool for formulation screening and setting of the dissolution/drug release acceptance criteria. ◦ Additional information specifically on the development and validation of an IVIVC can be found in the guidance for industry on Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations. Drug Regulations : Online Resource for Latest Information 12/11/2013 49
  50. 50.  Pharmacodynamic ◦ Use a suitably validated pharmacodynamic method to demonstrate BE. ◦ Pharmacodynamic studies not recommended  For drug products that are intended to be absorbed into the systemic circulation  For which a pharmacokinetic approach can be used to establish BE. ◦ Use well-controlled BE studies with clinical endpoints in patients when it is not possible to use the previously described methods. Drug Regulations : Online Resource for Latest Information 12/11/2013 50
  51. 51.  In Vitro Studies ◦ BE can be evaluated using in vitro approaches (e.g., dissolution/drug release testing)  21 CFR 320.24(b). ◦ FDA does not recommend in vitro approaches for drug products that are intended to be systemically absorbed. ◦ Such approaches would be appropriate in other circumstances  (e.g., for drug products that bind bile acids in the gastrointestinal tract). Drug Regulations : Online Resource for Latest Information 12/11/2013 51
  52. 52.  For oral solutions, elixirs, syrups, tinctures, or other solubilized forms, an in vivo BE testing requirement may be waived for certain products on the ground that in vivo BE is self-evident.  In such instances, the applicant would be deemed to have complied with and fulfilled any requirement for in vivo BE data.  BE can be waived for ◦ An oral solution if the formulation has the same active ingredient in the same concentration and dosage form as the RLD, and ◦ Does not contain any excipient that significantly affects drug absorption or availability. Drug Regulations : Online Resource for Latest Information 12/11/2013 52
  53. 53.  Preapproval ◦ Conduct following studies for immediate release capsule and tablet products.  (1) a single-dose, fasting study comparing the highest strength of the test and RLD products and  (2) a single-dose, fed BE study comparing the highest strength of the test and RLD products. Drug Regulations : Online Resource for Latest Information 12/11/2013 53
  54. 54.  Preapproval ◦ Appropriate to conduct an in vivo study on a strength other than the highest with concurrence by the Division of Bioequivalence, OGD, if the following conditions are met:  Linear elimination kinetics has been documented over the therapeutic dose range  The higher strengths of the test and RLD products are proportionally similar to their corresponding lower strength.  Comparative dissolution testing on the higher strength of the test and RLD products has been submitted and found to be acceptable. Drug Regulations : Online Resource for Latest Information 12/11/2013 54
  55. 55.  Preapproval ◦ An in vivo BE requirement for one or more strength(s) can be waived based on  (i) acceptable BE study on the designated strength  (ii) acceptable in vitro dissolution testing of all the strengths  (iii) proportional similarity of the formulations across all strengths. Drug Regulations : Online Resource for Latest Information 12/11/2013 55
  56. 56.  Preapproval ◦ FDA guidance definition of proportionally similar  All active and inactive ingredients are in similar proportion between different strengths  e.g., a tablet of 50-mg strength has all the inactive ingredients—almost exactly half that of a tablet of 100mg strength, and almost twice that of a tablet of 25-mg strength. Drug Regulations : Online Resource for Latest Information 12/11/2013 56
  57. 57.  Preapproval ◦ FDA guidance definition of proportionally similar  For high-potency drug substances (where the amount of active drug substance in the dosage form is relatively low):  (1) the total weight of the dosage form remains nearly the same for all strengths (within + 10 % of the total weight of the strength on which a biostudy was performed),  (2) the same inactive ingredients are used for all strengths, and  (3) the change in any strength is obtained by altering the amount of the active ingredients and one or more of the inactive ingredients. Drug Regulations : Online Resource for Latest Information 12/11/2013 57
  58. 58.  Preapproval ◦ FDA guidance definition of proportionally similar  Active and inactive ingredients that are not in similar proportion between different considered proportionally strengths similar with can be adequate justification (such as dosage form proportionality studies that demonstrate equivalent in vivo bioavailability). Drug Regulations : Online Resource for Latest Information 12/11/2013 58
  59. 59.  Preapproval ◦ Under such circumstances  Accompany in vivo BE studies by in vitro dissolution profiles on all strengths of each product  Conduct the BE study comparing the test product and the RLD using the strength(s) specified in Approved Drug Products with Therapeutic Equivalence Evaluations. Drug Regulations : Online Resource for Latest Information 12/11/2013 59
  60. 60.  Preapproval ◦ For highly soluble, highly permeable, rapidly dissolving, and orally products, administered in demonstrate vitro BE data based immediate may on be the release drug acceptable to biopharmaceutics classification system. ◦ Consult product specific guidance for additional information on BE study design for a specific product. Drug Regulations : Online Resource for Latest Information 12/11/2013 60
  61. 61.  Post approval ◦ Refer to the guidance for industry Immediate Release Solid Oral Dosage Forms, Scale-Up and Post approval Chemistry, Manufacturing, and Controls; In Vitro Dissolution Bioequivalence Testing Documentation and for In vivo information regarding BE testing recommended for specified types of post approval changes. Drug Regulations : Online Resource for Latest Information 12/11/2013 61
  62. 62.  Post approval ◦ Make the in vitro comparison between the prechange and postchange products. ◦ When in vivo BE studies are recommended to support a postapproval change for an ANDA product, FDA recommends that applicants compare the postchange ANDA drug product to the RLD and not to the prechange ANDA product. Drug Regulations : Online Resource for Latest Information 12/11/2013 62
  63. 63.  Establish BE for a suspension in the same manner as for other solid oral dosage forms.  Perform In vivo studies and dissolution testing as described for immediate release products, or for modified release products. Drug Regulations : Online Resource for Latest Information 12/11/2013 63
  64. 64.  A delayed release drug product is a dosage form that releases a drug at a time later than immediately after administration ◦ (e.g., the drug product exhibits a lag time in quantifiable plasma concentrations).  Typically, the coatings (e.g., enteric coatings) have been designed to delay the release of medication until the dosage form has passed through the acidic medium of the stomach. Drug Regulations : Online Resource for Latest Information 12/11/2013 64
  65. 65.  In vivo tests for delayed release drug products are similar to those for extended release drug products.  FDA recommends that in vitro dissolution tests for these products document that ◦ They are stable under acidic conditions and ◦ That they release the drug only in a neutral medium (e.g., pH 6.8). Drug Regulations : Online Resource for Latest Information 12/11/2013 65
  66. 66.  An extended release drug product is a dosage form that allows a reduction in dosing frequency and reduces fluctuations in plasma concentrations when compared to an immediate release dosage form.  Extended release products can be formulated as capsules, tablets, granules, pellets, or suspensions.  If any part of a drug product includes an extended release component, the product should be treated as a modified release dosage form for the purposes of establishing BE, as specified in following slides. Drug Regulations : Online Resource for Latest Information 12/11/2013 66
  67. 67.  Conduct following studies for modified release products, ◦ (1) a single-dose, fasting study comparing the highest strength of the test with the RLD ◦ (2) a single-dose fed BE study comparing the highest strength of the test with the RLD product.  Multiple-dose studies are generally not recommended as singledose studies are considered more sensitive in addressing the primary question of BE. ◦ (e.g., release of the drug substance from the drug product into the systemic circulation), Drug Regulations : Online Resource for Latest Information 12/11/2013 67
  68. 68.  Additional products strengths may be of modified demonstrated release to be bioequivalent to the corresponding reference product strengths under 21 CFR 320.24(b)(6) if all of the following conditions have been met: Drug Regulations : Online Resource for Latest Information 12/11/2013 68
  69. 69.  The additional strength is proportionally similar in its active and inactive ingredients to the test product strength that underwent acceptable in vivo studies.  The additional strength has the same drug release mechanism as the strength of the test product that underwent an acceptable in vivo study. Drug Regulations : Online Resource for Latest Information 12/11/2013 69
  70. 70.  Dissolution testing of all strengths is acceptable.  FDA recommends that the drug products exhibit similar dissolution profiles between the strength on which BE testing was conducted and other strengths based on the f2 test in at least three dissolution media (e.g., pH 1.2, 4.5, and 6.8).  FDA recommends that applicants generate dissolution profiles on the test and RLD products of all strengths. Drug Regulations : Online Resource for Latest Information 12/11/2013 70
  71. 71.  Refer to FDA’s guidance for industry SUPAC: Modified Release Solid Oral Dosage Forms, Chemistry Manufacturing and Controls; In Vitro Dissolution Testing and In vivo Bioequivalence Documentation for information regarding BE testing recommended for specified types of postapproval changes for modified release dosage forms. Drug Regulations : Online Resource for Latest Information 12/11/2013 71
  72. 72.  Make an in vitro comparison between the approved (prechange) product and the test (postchange) product.  Use an f2 test to compare dissolution profiles.  An in vivo BE study may be needed if dissolution profiles are not shown to be similar.  When in vivo BE studies are recommended to support a postapproval change for an ANDA product, FDA recommends that applicants compare the postchange ANDA drug product to the RLD and not to the prechange ANDA product. Drug Regulations : Online Resource for Latest Information 12/11/2013 72
  73. 73.  Administer chewable tablets according to the directions on the label.  Chew the product if the label states that the tablet must be chewed before swallowing.  Swallow the product whole, with 240 mL of water, if the label gives the option of either chewing the product or swallowing it whole.  FDA recommends to conduct in vitro dissolution testing on intact, whole tablets of the chewable drug product. Drug Regulations : Online Resource for Latest Information 12/11/2013 73
  74. 74.  Always measure the parent drug in the dosage form in the biological fluids collected  Use alternates if accurate assay quantitation is not possible using state-of-the-art- technology. Drug Regulations : Online Resource for Latest Information 12/11/2013 74
  75. 75.  Measure only the parent drug, rather than metabolites, because the concentration-time profile of the parent drug is more sensitive to changes in formulation performance than a metabolite.  Concentration-time profile of metabolite is more reflective of metabolite formation, distribution, and elimination. Drug Regulations : Online Resource for Latest Information 12/11/2013 75
  76. 76.  Primary metabolite(s), formed directly from the parent compound, should be measured if they are both: ◦ (1) formed substantially through presystemic metabolism (firstpass, gut wall, or gut lumen metabolism) and ◦ (2) contribute significantly to the safety and efficacy of the product. ◦ Use this approach for all drug products, including pro-drugs. ◦ Analyse the parent drug using a confidence interval (CI) approach. Drug Regulations : Online Resource for Latest Information 12/11/2013 76
  77. 77.  Use the metabolite data to provide supportive evidence of a comparable therapeutic outcome.  Subject the metabolite data to the CI approach if the parent drug levels are too low to allow reliable analytical measurement in blood, plasma, or serum for an adequate length of time. Drug Regulations : Online Resource for Latest Information 12/11/2013 77
  78. 78.  Use an achiral assay to measure the racemate.  Measure individual enantiomers in BE studies when all of the following conditions have been met: ◦ (1) the enantiomers exhibit different pharmacodynamic characteristics, ◦ (2) the enantiomers exhibit different pharmacokinetic characteristics, ◦ (3) primary efficacy and safety activity reside with the minor enantiomer, and ◦ (4) nonlinear absorption is present (as expressed by a change in the enantiomer concentration ratio with change in the input rate of the drug) for at least one of the enantiomers.  Where all of these conditions are met apply BE analysis to the enantiomers separately. Drug Regulations : Online Resource for Latest Information 12/11/2013 78
  79. 79.  Certain drug products contain complex drug substances (e.g., active moieties or active ingredients that are mixtures of multiple synthetic and/or natural source components).  Some or all of the components of these complex drug substances cannot be fully characterized with regard to chemical structure and/or biological activity.  FDA does not encourage quantification of all active or potentially active components in pharmacokinetic studies. Drug Regulations : Online Resource for Latest Information 12/11/2013 79
  80. 80.  FDA recommends that applicants base BE studies on a small number of markers of rate and extent of absorption.  Select markers based on the characteristics of the drug product.  Criteria for marker selection ◦ Amount of the moiety in the dosage form, plasma, or blood levels of the moiety, and ◦ Biological activity of the moiety relative to other moieties in the complex mixture. Drug Regulations : Online Resource for Latest Information 12/11/2013 80
  81. 81.  For an oral immediate release product with a long elimination half-life drug (>24 hrs), ◦ Conduct a single-dose, crossover study, ◦ Use adequate washout period ◦ Use a BE study with a parallel design if the crossover study is problematic ◦ For either a crossover or parallel study, sample collection time should be adequate to ensure completion of gastrointestinal transit of the drug product and absorption of the drug substance.  (which usually occurs within approximately 2 to 3 days). Drug Regulations : Online Resource for Latest Information 12/11/2013 81
  82. 82. ◦ Use Cmax and a suitably truncated AUC to characterize peak and total drug exposure, respectively. ◦ Use an AUC truncated at 72 hours (AUC 0-72 hr) in place of AUC0-t or AUC0-inf for drugs that demonstrate low intrasubject variability in distribution and clearance. ◦ Do not use AUC truncation for drugs demonstrating high intrasubject variability. Drug Regulations : Online Resource for Latest Information 12/11/2013 82
  83. 83.  The first point of a concentration-time curve in a BE study is sometimes the highest point,  This raises questions of bias in the estimation of Cmax because of insufficient early sampling times.  Avoid this by a carefully conducted pilot study. Drug Regulations : Online Resource for Latest Information 12/11/2013 83
  84. 84.  Assess peak drug concentrations by ◦ Collecting samples between 5 and 15 minutes after dosing ◦ Followed by additional sample collections (e.g., two to five) in the first hour after dosing  Failure to include early (5-15 minute) sampling times leading to first time-point Cmax values may result in FDA not considering the data for affected subjects from the analysis. Drug Regulations : Online Resource for Latest Information 12/11/2013 84
  85. 85.  The consumption of alcoholic beverages can affect the release of a drug substance  The formulation can ◦ Lose its modified release characteristics ◦ Release drug rapidly ◦ Lead to altered systemic exposure.  This can have deleterious effects on the drug's safety and/or efficacy. Drug Regulations : Online Resource for Latest Information 12/11/2013 85
  86. 86.  Conduct in vitro studies to determine the potential for dose dumping in alcohol in vivo.  Conduct In vitro assessments of the drug release using media with various alcohol concentrations.  Conduct an in vivo BE study of the drug product when administered with alcohol.  Consult Individual Product Bioequivalence Recommendations and any available relevant product-specific guidance Drug Regulations : Online Resource for Latest Information 12/11/2013 86
  87. 87.  Endogenous compounds ◦ Drugs that are already present in the body ◦ The body produces them or they are present in the normal diet. ◦ These compounds are identical to the drug that is being administered, ◦ Difficult to determine the amount of drug released from the dosage form and absorbed by each subject ◦ Measure and approximate the baseline endogenous levels in blood (plasma) ◦ Subtract these levels from the total concentrations measured from each subject after the drug product has been administered. Drug Regulations : Online Resource for Latest Information 12/11/2013 87
  88. 88.  Recommended approaches for determining BE ◦ When the body produces the compound,  Measure multiple baseline concentrations in the time period before administration of the study drug  Subtract the baseline in an appropriate manner consistent with the pharmacokinetic properties of the drug. Drug Regulations : Online Resource for Latest Information 12/11/2013 88
  89. 89.  Recommended approaches for determining BE ◦ When there is dietary intake of the compound,  Strictly control the intake both before and during the study.  House subjects at a clinic before the study  Serve standardized meals containing an amount of the compound similar to that in the meals to be served on the pharmacokinetic sampling day Drug Regulations : Online Resource for Latest Information 12/11/2013 89
  90. 90.  Recommended approaches for determining BE ◦ For both of the approaches above,  Determine baseline concentrations for each dosing period that are period specific.  Set value to 0 before calculating the baseline-corrected AUC if a baseline correction results in a negative plasma concentration value.  Perform pharmacokinetic and statistical analysis on both uncorrected and corrected data  Determine BE based on the baseline-corrected data Drug Regulations : Online Resource for Latest Information 12/11/2013 90
  91. 91.  Determine BE using PK endpoints when a drug substance produces its effects by local action in the gastrointestinal tract.  Determine BE using clinical endpoints, pharmacodynamic endpoints and/or suitably designed and validated in vitro studies in addition to, or instead of, measuring drug plasma concentrations in other cases.  Consult the guidance for industry Bioequivalence Recommendations for Specific Products and any available relevant product-specific guidance Drug Regulations : Online Resource for Latest Information 12/11/2013 91
  92. 92.  Submit the method set forth in any related official United States Pharmacopeia (USP) drug product monograph.  If there is not an official monograph for the proposed product, use the FDA-recommended and the methods described in the USP general chapter on dissolution.  A dissolution methods database describing FDA- recommended and USP methods is available to the public at FDA Data base Drug Regulations : Online Resource for Latest Information 12/11/2013 92
  93. 93.  In case a new method is developed include following information in the submission: ◦ The pH solubility profile of the drug substance. ◦ Dissolution profiles generated at different agitation speeds  (e.g., 100 to 150 revolutions per minute (rpm)) for USP Apparatus I (basket), or  50 to 100 rpm for USP Apparatus II (paddle). Drug Regulations : Online Resource for Latest Information 12/11/2013 93
  94. 94.  In case a new method is developed include following information in the submission: ◦ Dissolution profiles generated on all strengths in at least three dissolution media  e.g., pH 1.2, 4.5, and 6.8 buffer  Water can be used as an additional medium.  If the drug being considered is poorly soluble, use appropriate concentrations of surfactants. Drug Regulations : Online Resource for Latest Information 12/11/2013 94
  95. 95.  Submit dissolution profiles with method set forth in the USP drug product monograph.  In case a USP drug product monograph is not available use either ◦ The FDA-recommended method (see the dissolution methods database) ◦ Develop a method that is specific for your product. Drug Regulations : Online Resource for Latest Information 12/11/2013 95
  96. 96.  Submit profiles using the methods described in the USP general chapter on dissolution or FDA methods in addition to those three described earlier (e.g., pH 1.2, 4.5 buffer, and 6.8 buffer).  Submit data using the FDA-recommended or USP method in addition to proposed method for comparison if a method different from the FDA- recommended or USP method. Drug Regulations : Online Resource for Latest Information 12/11/2013 96
  97. 97.  Select the agitation speed and medium that provide adequate discriminating ability, taking into account all the available in vitro and in vivo data.  Use dissolution data from three newly manufactured batches of test product to set dissolution specifications for modified release dosage forms. Drug Regulations : Online Resource for Latest Information 12/11/2013 97
  98. 98. This presentation was compiled by “ Drug Regulations” from freely available resources like the FDA on the World wide web.  “Drug Regulations” is a non profit organization which provides free online resource to the Pharmaceutical Professional.  Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals.  Drug Regulations : Online Resource for Latest Information 12/11/2013 98

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