tanzania, 21-25 august, 2006 dr. barbara sterzik, bfarm, bonn 1 guidelines and tools available trs...

Tanzania, 21-25 August, 2006

Dr. Barbara Sterzik, BfArM, Bonn 1

Guidelines and Guidelines and Tools availableTools available

TRS 937 and BTIF TRS 937 and BTIF (Bioequivalence Trial (Bioequivalence Trial

Information Form)Information Form)


2Dr. Barbara Sterzik, BfArM, Bonn

TRS 937TRS 937

Basic information including the Basic information including the latest scientific and technical latest scientific and technical advice in:advice in:

Technical Report Series (TRS) Technical Report Series (TRS) 937, 2006937, 2006



TRS 937TRS 937

Table of Content:Table of Content: General policyGeneral policy Quality control (specification and Quality control (specification and

tests, International reference tests, International reference materials, National laboratories)materials, National laboratories)

Quality assurance (GMP, Inspection, Quality assurance (GMP, Inspection, Distribution, Risk analysis, Stability)Distribution, Risk analysis, Stability)



TRS 937TRS 937

(Table of Content continue )(Table of Content continue )

PrequalificationPrequalification Regulatory guidance on Regulatory guidance on

InterchangeabilityInterchangeability Donation of medicinesDonation of medicines Regulatory guidance on post-approval Regulatory guidance on post-approval

changeschanges Nomenclature and computerized systemsNomenclature and computerized systems Summary and recommendationsSummary and recommendations



TRS 937TRS 937



TRS 937TRS 937

Annex 7Annex 7 (TRS 937, 2006, p. 347 ff): (TRS 937, 2006, p. 347 ff):

Multisource (generic) pharmaceutical Multisource (generic) pharmaceutical products:products:

Guidelines on registration Guidelines on registration requirements to establish requirements to establish

interchangeability.interchangeability.



TRS 937TRS 937

TRS 937 includes revisions/updates:TRS 937 includes revisions/updates:

Guidelines on registration requirements Guidelines on registration requirements to establish interchangeability (annex 7)to establish interchangeability (annex 7)

Guidance on selection of comparator Guidance on selection of comparator pharmaceutical drugs for equivalence pharmaceutical drugs for equivalence assessmentassessment

(revision of TRS 902, Annex 11)(revision of TRS 902, Annex 11)available on the web site available on the web site



TRS 937TRS 937

Proposal to waive in vivo Proposal to waive in vivo bioequivalence requirements for the bioequivalence requirements for the WHO Model List of Essential WHO Model List of Essential Medicines, immediate release, solid Medicines, immediate release, solid oral dosage forms (annex 8)oral dosage forms (annex 8)

available on the websiteavailable on the website Additional guidelines for Additional guidelines for

organizations performing in vivo organizations performing in vivo bioequivalence studies (annex 9)bioequivalence studies (annex 9)



TRS 937 – Annex 7TRS 937 – Annex 7

Multisource (generic) pharmaceutical Multisource (generic) pharmaceutical products:products:

GuidelinesGuidelines on registration requirements on registration requirements to establish interchangeability:to establish interchangeability:

Recommendations for sponsors on the Recommendations for sponsors on the requirements for approval a generic requirements for approval a generic productproduct

Generic products should be used only Generic products should be used only after approvalafter approval




Regulatory authorities should require the Regulatory authorities should require the documentation on:documentation on:

GMPGMPquality control specificationsquality control specificationspharmaceutical product pharmaceutical product

interchangeabilityinterchangeability applicable to orally administered drugs applicable to orally administered drugs

as well as to non-orally administered as well as to non-orally administered drugs (where systemic exposure measure drugs (where systemic exposure measure are suitable e.g. certain rectal, nasal are suitable e.g. certain rectal, nasal products)products)




No need for equivalence studies:No need for equivalence studies:e.g.e.g.parenterally administered product in parenterally administered product in aqueous solution (same API in same aqueous solution (same API in same molar concentration as comparator, molar concentration as comparator, similar excipients)similar excipients)ororsolution for oral use solution for oral use

equivalent gasesequivalent gases




Bioequivalence studies in humanBioequivalence studies in humanJustification (specific aim, problems, Justification (specific aim, problems,

risk)risk)Selection of investigatorsSelection of investigatorsStudy protocolStudy protocol

Study design Study design 2-period, single dose, cross-over study in 2-period, single dose, cross-over study in healthyhealthy

alternative designs in special circumstancesalternative designs in special circumstances




Subjects:Subjects:Number:Number:required sample size depends on required sample size depends on variability either known through variability either known through reasonable literature or by means of a reasonable literature or by means of a pilot studypilot study

considering: drop-outs and withdrawal considering: drop-outs and withdrawal Selection:Selection:healthy, mainly male, 18 – 55 y, healthy, mainly male, 18 – 55 y,




Subjects:Subjects:

Verifying health of volunteers ( e. g. Verifying health of volunteers ( e. g. ECG, clinical blood chemistry, blood ECG, clinical blood chemistry, blood pressure etc.)pressure etc.)

Phenotyping of volunteers (possible Phenotyping of volunteers (possible side effects with “poor metabolisers” side effects with “poor metabolisers” may cause drop-outs; variability may cause drop-outs; variability reduction/explanation)reduction/explanation)




Test product Test product (identical to the projected (identical to the projected commercial product; GMP; commercial product; GMP;

Comparator productComparator productnormally the innovator product normally the innovator product (quality, efficacy & safety well-(quality, efficacy & safety well-assessed)assessed)




No innovator available:No innovator available:

Nationally authorized innovatorsNationally authorized innovators WHO comparator product (see list WHO comparator product (see list

TRS 902)TRS 902) ICH et al. innovatorICH et al. innovator




Study conductStudy conduct

selection of doseselection of dose

sampling times (before dosing, at sampling times (before dosing, at least 1-2 points before Cmax, 2 points least 1-2 points before Cmax, 2 points around, 3-4 points during elimination)around, 3-4 points during elimination)

sample fluids sample fluids

pk parameterpk parameter

metabolitesmetabolites




Quantification of the API (and its Quantification of the API (and its metabolite/s)metabolite/s)(GLP; methods should meet the (GLP; methods should meet the requirements of specificity, sensitivity, requirements of specificity, sensitivity, accuracy, precision reproducibility)accuracy, precision reproducibility)

Statistical analysis (should be Statistical analysis (should be specified in the protocol before data specified in the protocol before data collection starts)collection starts)




Acceptance rangeAcceptance range (90% CI for AUC-ratio; Cmax-ratio of (90% CI for AUC-ratio; Cmax-ratio of relative bioavailability should lie relative bioavailability should lie within the acceptance range 0.80 – within the acceptance range 0.80 – 1.25)1.25)

Reporting of resultsReporting of results




In vitro TestingIn vitro Testing

For certain medicines and dosage For certain medicines and dosage forms , forms , in vitroin vitro documentation documentation of equivalenceof equivalencemay be appropriate (typically may be appropriate (typically solid oral dosage forms)solid oral dosage forms)



TRS 937 – Annex 7TRS 937 – Annex 7in vitro testingin vitro testing

Dissolution test as a surrogate Dissolution test as a surrogate equivalence testequivalence test

Criteria for dissolution tests are Criteria for dissolution tests are described and are not those described and are not those recommended in recommended in The The International PharmacopoeiaInternational Pharmacopoeia for for quality control.quality control.



TRS 937 – Annex 7TRS 937 – Annex 7in vitro testing in vitro testing

Criteria Criteria

Biopharmaceutics Classification Biopharmaceutics Classification System (BCS)System (BCS)is based on aqueous solubility and is based on aqueous solubility and intestinal permeability of the drug intestinal permeability of the drug substance.substance.

API is classified into four classesAPI is classified into four classes



TRS 937 – Annex 7TRS 937 – Annex 7in vitro testingin vitro testing

Class 1: high solubility, high Class 1: high solubility, high permeabilitypermeability

Class 2: low solubility, high Class 2: low solubility, high permeabilitypermeability

Class 3: high solubility, low Class 3: high solubility, low permeabilitypermeability

Class 4: low solubility, low permeabilityClass 4: low solubility, low permeability



BTIFBTIF

Bioequivalence Trial Information Bioequivalence Trial Information Form (BTIF)Form (BTIF)

filled out by the applicantfilled out by the applicant

Important for assessors:Important for assessors: Reference Reference to the study documentation (ref. to to the study documentation (ref. to pages, sections) should be given.pages, sections) should be given.



BTIFBTIF

Example of the structure of BTIF is Example of the structure of BTIF is presented.presented.

(see appendix)(see appendix)

tanzania, 21-25 august, 2006 dr. barbara sterzik, bfarm, bonn 1 guidelines and tools available trs...

Documents

bonn trs

barbara sterzik

interchangeability annex

tools available trs

bioequivalence requirements

registration requirements

bioequivalence studies

stability slide