Bio Equivalence Dossier Requirements
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Bioequivalence dossier requirements for the prequalification project WHO Training Workshop on Pharmaceutical Quality, Good Manufacturing Practice and Bioequivalence with a Focus on Artemisinines Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
1
Dossier requirements general
The product dossier should include information on: 1. Details of the product 2. Regulatory situation in other countries 3. Active pharmaceutical ingredient(s)- API
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
2
Dossier requirements general
(3. API continue) 3.1 Properties of the API(s) 3.2 Sites of manufacture 3.3 Route of synthesis 3.4 Specification API described in a pharmacopoeia API not described in a pharmacopoeia 3.5 Stability testing
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
3
Dossier requirements general
4. Finished product 4.1 Formulation 4.2 Sites of manufacture 4.3 Manufacturing procedure 4.4 Specifications for excipients 4.5 Specifications for finished product 4.6 Container/closure system(s) and other packaging
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
4
Dossier requirements general
(4. Finished product continue ) 4.7 Stability testing 4.8 Container labeling 4.9 Product information 4.10 Patient information and package inserts 4.11 Justification for any differences to the product in the country or countries issuing the submitted
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
5
Dossier requirements general
5. Interchangeability 5.1 Bioequivalence study 5.2 Summary of pharmacology, toxicology* and efficacy of the product (expert reports) * not required anymore for artemisinines but for
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
6
Basic guidelines In vivo Bioequivalence studies are clinical trials: in accordance with the guidelines on Good Clinical Practice Good Manufacturing Practice Good Laboratory Practice Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
7
Basic guidelines
Additional guidance
WHO TRS No. 937, 2006, Annex 9 Guidelines for organizations performing in vivo bioequivalence studies. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
8
Bioequivalence study report
The Bioequivalence study report should include information on: Ethics, Investigators and administrative structure Clinical phase of a study Bioanalytical method of study Pharmacokinetic and statistical analysis Study protocol
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
9
Bioequivalence study report 1. Ethical principles : current version of the Declaration of Helsinki Ethic Committee (EC) should be independent Information about the EC e.g. members constitution of meetings discussions, recommendations,
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
10
Bioequivalence study report
All clinical trial protocols, screening consent and informed consent forms (ICFs) should be reviewed, amended and approved by the EC before the start any trial-related activities. Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
11
Bioequivalence study report 2. Justification of the study design Specific aim, problems, risk, and benefit should be considered based on the knowledge of the pharmacokinetics, pharmacodynamics, therapeutics of the API. Information on the manufacturing procedure and used batch
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
12
Bioequivalence study report 3. Selection of Investigators Expertise, qualifications, competence Before starting: agreement between investigator(s) and sponsor on protocol monitoring auditing SOP responsibilities (study related) Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
13
Bioequivalence study report
Complete structure is presented:
Table of Contents (see example on Cd Rom 2) Bioequivalence Trial Information Form (BTIF)
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
14
Bioequivalence dossier requirements particulars General study design: A two-period, single-dose, cross-over study in healthy volunteers. Alternatives Using the API at a lower strength in case of toxicity (PK should be proportional, no solubility problems) Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
15
Bioequivalence dossier requirements particulars
single-dose, cross-over study in case of drugs with long elimination half-life (wash-out about 5 times terminal t1/2, not more than 3-4 weeks)
or parallel design (example: amodiaquine)
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
16
Bioequivalence dossier requirements particulars
Multiple dose, cross-over study in patients in case of an too toxic and/or too potent drug without interrupting the therapy.
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
17
Bioequivalence dossier requirements particulars Fixed-dose combination products: Comparison with c) an existing combination d) separate active APIs (drug)
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
18
Bioequivalence dossier requirements particulars ► Problem: no existing combination and no established therapeutic use of the individual APIs (Example: Artesunate/amodiaquine) ►Consequence: as there is no acceptable reference available, additionally clinical studies on efficacy and safety are necessary. Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
19
Bioequivalence dossier requirements SPC and PIL
EU – Guidelines -
A guideline on Summary of Product Characteristics - Notice to applicants; Rev0, December 1999)
-
Guideline on the readability of the label and package leaflet of medicinal products for human use – Notice to applicants; Vol. IIA Rev3, September 1999
WHO – Guideline - SPC: according to the EU guideline http://mednet3.who.int/prequal/
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
20
Bioequivalence dossier requirements SPC and PIL
The “generic” SPC + PIL = innovator SPC + PIL
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
21
Bioequivalence dossier requirements
Thank you for your attention
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
22
Dr. Barbara Sterzik, BfArM, Bonn
1
Dossier requirements general
The product dossier should include information on: 1. Details of the product 2. Regulatory situation in other countries 3. Active pharmaceutical ingredient(s)- API
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
2
Dossier requirements general
(3. API continue) 3.1 Properties of the API(s) 3.2 Sites of manufacture 3.3 Route of synthesis 3.4 Specification API described in a pharmacopoeia API not described in a pharmacopoeia 3.5 Stability testing
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
3
Dossier requirements general
4. Finished product 4.1 Formulation 4.2 Sites of manufacture 4.3 Manufacturing procedure 4.4 Specifications for excipients 4.5 Specifications for finished product 4.6 Container/closure system(s) and other packaging
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
4
Dossier requirements general
(4. Finished product continue ) 4.7 Stability testing 4.8 Container labeling 4.9 Product information 4.10 Patient information and package inserts 4.11 Justification for any differences to the product in the country or countries issuing the submitted
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
5
Dossier requirements general
5. Interchangeability 5.1 Bioequivalence study 5.2 Summary of pharmacology, toxicology* and efficacy of the product (expert reports) * not required anymore for artemisinines but for
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
6
Basic guidelines In vivo Bioequivalence studies are clinical trials: in accordance with the guidelines on Good Clinical Practice Good Manufacturing Practice Good Laboratory Practice Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
7
Basic guidelines
Additional guidance
WHO TRS No. 937, 2006, Annex 9 Guidelines for organizations performing in vivo bioequivalence studies. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
8
Bioequivalence study report
The Bioequivalence study report should include information on: Ethics, Investigators and administrative structure Clinical phase of a study Bioanalytical method of study Pharmacokinetic and statistical analysis Study protocol
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
9
Bioequivalence study report 1. Ethical principles : current version of the Declaration of Helsinki Ethic Committee (EC) should be independent Information about the EC e.g. members constitution of meetings discussions, recommendations,
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
10
Bioequivalence study report
All clinical trial protocols, screening consent and informed consent forms (ICFs) should be reviewed, amended and approved by the EC before the start any trial-related activities. Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
11
Bioequivalence study report 2. Justification of the study design Specific aim, problems, risk, and benefit should be considered based on the knowledge of the pharmacokinetics, pharmacodynamics, therapeutics of the API. Information on the manufacturing procedure and used batch
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
12
Bioequivalence study report 3. Selection of Investigators Expertise, qualifications, competence Before starting: agreement between investigator(s) and sponsor on protocol monitoring auditing SOP responsibilities (study related) Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
13
Bioequivalence study report
Complete structure is presented:
Table of Contents (see example on Cd Rom 2) Bioequivalence Trial Information Form (BTIF)
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
14
Bioequivalence dossier requirements particulars General study design: A two-period, single-dose, cross-over study in healthy volunteers. Alternatives Using the API at a lower strength in case of toxicity (PK should be proportional, no solubility problems) Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
15
Bioequivalence dossier requirements particulars
single-dose, cross-over study in case of drugs with long elimination half-life (wash-out about 5 times terminal t1/2, not more than 3-4 weeks)
or parallel design (example: amodiaquine)
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
16
Bioequivalence dossier requirements particulars
Multiple dose, cross-over study in patients in case of an too toxic and/or too potent drug without interrupting the therapy.
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
17
Bioequivalence dossier requirements particulars Fixed-dose combination products: Comparison with c) an existing combination d) separate active APIs (drug)
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
18
Bioequivalence dossier requirements particulars ► Problem: no existing combination and no established therapeutic use of the individual APIs (Example: Artesunate/amodiaquine) ►Consequence: as there is no acceptable reference available, additionally clinical studies on efficacy and safety are necessary. Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
19
Bioequivalence dossier requirements SPC and PIL
EU – Guidelines -
A guideline on Summary of Product Characteristics - Notice to applicants; Rev0, December 1999)
-
Guideline on the readability of the label and package leaflet of medicinal products for human use – Notice to applicants; Vol. IIA Rev3, September 1999
WHO – Guideline - SPC: according to the EU guideline http://mednet3.who.int/prequal/
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
20
Bioequivalence dossier requirements SPC and PIL
The “generic” SPC + PIL = innovator SPC + PIL
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
21
Bioequivalence dossier requirements
Thank you for your attention
Tanzania, 21-25 August 2006
Dr. Barbara Sterzik, BfArM, Bonn
22
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