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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
Tanzania, 21-25 August
artemisinines but for
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

2006
Study protocol
Tanzania, 21-25 August
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
Tanzania, 21-25 August
used batch
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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