1. Tanzania, 21-25 August, 2006 Dr. Barbara Sterzik, BfArM, Bonn 1 Guidelines and Tools available TRS 937 and BTIF (Bioequivalence Trial Information Form)

2. Tanzania, 21-25 August, 2006 2Dr. Barbara Sterzik, BfArM, Bonn TRS 937 Basic information including the latest scientific and technical advice in: Technical Report Series (TRS) 937, 2006

3. Tanzania, 21-25 August, 2006 3Dr. Barbara Sterzik, BfArM, Bonn TRS 937 Table of Content: General policy General policy Quality control (specification and tests, International reference materials, National laboratories) Quality control (specification and tests, International reference materials, National laboratories) Quality assurance (GMP, Inspection, Distribution, Risk analysis, Stability) Quality assurance (GMP, Inspection, Distribution, Risk analysis, Stability)

4. Tanzania, 21-25 August, 2006 4Dr. Barbara Sterzik, BfArM, Bonn TRS 937 (Table of Content continue ) Prequalification Prequalification Regulatory guidance on Interchangeability Regulatory guidance on Interchangeability Donation of medicines Donation of medicines Regulatory guidance on post-approval changes Regulatory guidance on post-approval changes Nomenclature and computerized systems Nomenclature and computerized systems Summary and recommendations Summary and recommendations

5. Tanzania, 21-25 August, 2006 5Dr. Barbara Sterzik, BfArM, Bonn TRS 937

6. Tanzania, 21-25 August, 2006 6Dr. Barbara Sterzik, BfArM, Bonn TRS 937 Annex 7 (TRS 937, 2006, p. 347 ff): Multisource (generic) pharmaceutical products: Guidelines on registration requirements to establish interchangeability.

7. Tanzania, 21-25 August, 2006 7Dr. Barbara Sterzik, BfArM, Bonn TRS 937 TRS 937 includes revisions/updates: Guidelines on registration requirements to establish interchangeability (annex 7) Guidelines on registration requirements to establish interchangeability (annex 7) Guidance on selection of comparator pharmaceutical drugs for equivalence assessment (revision of TRS 902, Annex 11) available on the web site Guidance on selection of comparator pharmaceutical drugs for equivalence assessment (revision of TRS 902, Annex 11) available on the web site

8. Tanzania, 21-25 August, 2006 8Dr. Barbara Sterzik, BfArM, Bonn TRS 937 Proposal to waive in vivo bioequivalence requirements for the WHO Model List of Essential Medicines, immediate release, solid oral dosage forms (annex 8) available on the website Proposal to waive in vivo bioequivalence requirements for the WHO Model List of Essential Medicines, immediate release, solid oral dosage forms (annex 8) available on the website Additional guidelines for organizations performing in vivo bioequivalence studies (annex 9) Additional guidelines for organizations performing in vivo bioequivalence studies (annex 9)

9. Tanzania, 21-25 August, 2006 9Dr. Barbara Sterzik, BfArM, Bonn TRS 937 – Annex 7 Multisource (generic) pharmaceutical products: Guidelines on registration requirements to establish interchangeability: Recommendations for sponsors on the requirements for approval a generic product Recommendations for sponsors on the requirements for approval a generic product Generic products should be used only after approval Generic products should be used only after approval

10. Tanzania, 21-25 August, 2006 10Dr. Barbara Sterzik, BfArM, Bonn TRS 937 – Annex 7 Regulatory authorities should require the documentation on: GMP quality control specifications pharmaceutical product interchangeability Regulatory authorities should require the documentation on: GMP quality control specifications pharmaceutical product interchangeability applicable to orally administered drugs as well as to non-orally administered drugs (where systemic exposure measure are suitable e.g. certain rectal, nasal products) applicable to orally administered drugs as well as to non-orally administered drugs (where systemic exposure measure are suitable e.g. certain rectal, nasal products)

11. Tanzania, 21-25 August, 2006 11Dr. Barbara Sterzik, BfArM, Bonn TRS 937 – Annex 7 No need for equivalence studies: e.g. parenterally administered product in aqueous solution (same API in same molar concentration as comparator, similar excipients) or solution for oral use No need for equivalence studies: e.g. parenterally administered product in aqueous solution (same API in same molar concentration as comparator, similar excipients) or solution for oral use equivalent gases

12. Tanzania, 21-25 August, 2006 12Dr. Barbara Sterzik, BfArM, Bonn TRS 937 – Annex 7 Bioequivalence studies in human Justification (specific aim, problems, risk) Selection of investigators Study protocol Bioequivalence studies in human Justification (specific aim, problems, risk) Selection of investigators Study protocol Study design 2-period, single dose, cross-over study in healthy Study design 2-period, single dose, cross-over study in healthy alternative designs in special circumstances

13. Tanzania, 21-25 August, 2006 13Dr. Barbara Sterzik, BfArM, Bonn TRS 937 – Annex 7 Subjects: Number: required sample size depends on variability either known through reasonable literature or by means of a pilot study Subjects: Number: required sample size depends on variability either known through reasonable literature or by means of a pilot study considering: drop-outs and withdrawal Selection: healthy, mainly male, 18 – 55 y, considering: drop-outs and withdrawal Selection: healthy, mainly male, 18 – 55 y,

14. Tanzania, 21-25 August, 2006 14Dr. Barbara Sterzik, BfArM, Bonn TRS 937 – Annex 7 Subjects: Verifying health of volunteers ( e. g. ECG, clinical blood chemistry, blood pressure etc.) Phenotyping of volunteers (possible side effects with “poor metabolisers” may cause drop-outs; variability reduction/explanation) Subjects: Verifying health of volunteers ( e. g. ECG, clinical blood chemistry, blood pressure etc.) Phenotyping of volunteers (possible side effects with “poor metabolisers” may cause drop-outs; variability reduction/explanation)

15. Tanzania, 21-25 August, 2006 15Dr. Barbara Sterzik, BfArM, Bonn TRS 937 – Annex 7 Test product (identical to the projected commercial product; GMP; Test product (identical to the projected commercial product; GMP; Comparator product normally the innovator product (quality, efficacy & safety well-assessed) Comparator product normally the innovator product (quality, efficacy & safety well-assessed)

16. Tanzania, 21-25 August, 2006 16Dr. Barbara Sterzik, BfArM, Bonn TRS 937 – Annex 7 No innovator available: Nationally authorized innovators Nationally authorized innovators WHO comparator product (see list TRS 902) WHO comparator product (see list TRS 902) ICH et al. innovator ICH et al. innovator

17. Tanzania, 21-25 August, 2006 17Dr. Barbara Sterzik, BfArM, Bonn TRS 937 – Annex 7 Study conduct Study conduct selection of dose sampling times (before dosing, at least 1-2 points before Cmax, 2 points around, 3-4 points during elimination) sample fluids pk parameter metabolites

18. Tanzania, 21-25 August, 2006 18Dr. Barbara Sterzik, BfArM, Bonn TRS 937 – Annex 7 Quantification of the API (and its metabolite/s) (GLP; methods should meet the requirements of specificity, sensitivity, accuracy, precision reproducibility) Quantification of the API (and its metabolite/s) (GLP; methods should meet the requirements of specificity, sensitivity, accuracy, precision reproducibility) Statistical analysis (should be specified in the protocol before data collection starts) Statistical analysis (should be specified in the protocol before data collection starts)

19. Tanzania, 21-25 August, 2006 19Dr. Barbara Sterzik, BfArM, Bonn TRS 937 – Annex 7 Acceptance range (90% CI for AUC-ratio; Cmax-ratio of relative bioavailability should lie within the acceptance range 0.80 – 1.25) Acceptance range (90% CI for AUC-ratio; Cmax-ratio of relative bioavailability should lie within the acceptance range 0.80 – 1.25) Reporting of results Reporting of results

20. Tanzania, 21-25 August, 2006 20Dr. Barbara Sterzik, BfArM, Bonn TRS 937 – Annex 7 In vitro Testing For certain medicines and dosage forms, in vitro documentation of equivalence may be appropriate (typically solid oral dosage forms)

21. Tanzania, 21-25 August, 2006 21Dr. Barbara Sterzik, BfArM, Bonn TRS 937 – Annex 7 in vitro testing Dissolution test as a surrogate equivalence test Criteria for dissolution tests are described and are not those recommended in The International Pharmacopoeia for quality control.

22. Tanzania, 21-25 August, 2006 22Dr. Barbara Sterzik, BfArM, Bonn TRS 937 – Annex 7 in vitro testing Criteria Criteria Biopharmaceutics Classification System (BCS) is based on aqueous solubility and intestinal permeability of the drug substance. API is classified into four classes

23. Tanzania, 21-25 August, 2006 23Dr. Barbara Sterzik, BfArM, Bonn TRS 937 – Annex 7 in vitro testing Class 1: high solubility, high permeability Class 2: low solubility, high permeability Class 3: high solubility, low permeability Class 4: low solubility, low permeability

24. Tanzania, 21-25 August, 2006 24Dr. Barbara Sterzik, BfArM, Bonn BTIF Bioequivalence Trial Information Form (BTIF) filled out by the applicant Important for assessors: Reference to the study documentation (ref. to pages, sections) should be given.

25. Tanzania, 21-25 August, 2006 25Dr. Barbara Sterzik, BfArM, Bonn BTIF Example of the structure of BTIF is presented. (see appendix)