Pharmaceutical
Research and Development
Considerations
Theo Dekker, D.Sc., consultant to WHO
Research Institute for Industrial Pharmacy
North-West University, Potchefstroom, South Africa
iiftgd@puk.ac.za
Feb 2005
Abbreviations
API
BCS
BP
CEP
EOI
FDC
FPP
ICH
Int.Ph.
R&D
TB
XRPD
USP
Feb 2005
The perspective
Pharmaceutical R & D provides the foundation of the
activities aimed at ensuring that the patient receives an
FPP (product) that consistently meets established
standards & specifications of
Safety
Efficacy
Quality
The FPP should be stable - and thus retain these standards
throughout the shelf-life,
if kept in the original packaging
when correctly distributed, stored & handled
Feb 2005
Pharmaceutical R&D
1.
2.
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4.
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Objective
To compile a comprehensive summary, with
conclusions, of all available information that may be
important for the development of the product
To have a standard (pro-forma) style for the report,
facilitating compilation/application
Assign experts in preparation of relevant parts
To use this report as base for development
pharmaceutics (though considered part thereof)
Example
4FDC anti-tuberculosis tablets
Feb 2005
3.
Category
Anti-tuberculosis agent
WHO model list of essential drugs (current)
Rifampicin 150 mg, Isoniazid 75 mg, Pyrazin-amide 400
mg & Ethambutol 2HCl 275 mg
Prequalification EOI requirement (current)
As for WHO model list as tablets
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5.
6.
7.
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Rifampicin
Isoniazid
Pyrazinamide
Ethambutol 2HCl
Total API weight
Typical tablet weight
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150 mg
75 mg
400 mg
275 mg
900 mg
~ 1.3 g
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oxidation
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hydrolysis
TG Dekker WHO, Malaysia
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Control on left
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4FDC-TB tablets
preventative/protective measures
Formulation - no sugar/lactose (isoniazid)
Separate granulation of rifampicin & isoniazid
Rifampicin as powder (not granulate)?
Prevent oxidation & hydrolysis
Low water content of tablet (USP 3.0%)
Protect product from moisture and oxygen
Non-permeable packaging
Do not remove from primary packaging
Avoid repackaging
Feb 2005
Light protection
Differential formulation, e.g. delayed release &
immediate release in one tablet ??
TG Dekker WHO, Malaysia
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Sample A
Sample D
Form II
Form II + amorph
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Rifampicin -XRPDs
Top:
Middle:
Bottom:
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A, B, E
(form II)
C, D
Form II + Amorph
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A, B, E
(form II)
C, D
(form II + amorph)
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3.
4.
Reference:
S. Q. Henwood, M. M. de Villiers, W. Liebenberg, A.P.
Ltter. Solubility and dissolution properties of generic
rifampicin raw materials. Drug Dev. & Ind. Pharm. 26,
403-408 (2000) (Research Institute for Industrial Pharm.)
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Solubility
Permeability
High
High
Low
High
High
Low
Low
Low
Class
Rifampicin
2 (tentative)
Isoniazid
1 (tentative)
Pyrazinamide
Ethambutol 2HCl
3 (tentative)
Data from:
M Lindenberg, S. Kopp, J. B. Dressman. Classification of
orally administered drugs on the World Health Organization
Model list of Essential Medicines according to the
biopharmaceutics classification system. Eur. J. Pharm.
Biopharm., 58, 265-278 (2004)
None of other TBs (mainly for injection, thus not classified) in
5th inv. for EOI in publication a number of ARVs are
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4.
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2.
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A
B,C
D
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Some conclusions
1.
2.
3.
4.
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