Beruflich Dokumente
Kultur Dokumente
Presented By
Rutendo Kuwana
Training workshop: Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and
.assessment of data submitted to regulatory authorities, February 23-27, 2009, Kampala, Uganda
Presentation approach
Discuss aspects of the information that is required for the
API for WHO Prequalification
Use examples from literature as well as experience from
the WHO PQ Project
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Some definitions
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Enantiomers
cpds with same molecular formula as substance but differ in spatial
arrangement of atoms and are non-superimpossable mirror images
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Information from
literature and structures
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Guidelines
Guideline on Submission of Documentation for Prequalification of Multi-Source
(Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS,
Malaria and Tuberculosis [GuideGeneric]
Guidance on Variations to a prequalified Dossier [Variation Guide]
Guideline on Active Substance Master File Procedure [CPMP/QWP/227/02 Rev1]
Guideline on Active Pharmaceutical Ingredient Master File (APIMF) Procedure
[Draft]
Guideline on Summary of Requirements for Active Substances in the Quality Part of
the Dossier [CPMP/QWP/297/97 Rev 1 corr]
ICH Q3A [R] Impurities Testing Guideline: Impurities in New Drug Substances
[CPMP/ICH/2737/99]
ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug
Substances and New Drug Products: Chemical Substances [CPMP/ICH/367/96 corr]
ICH Q2A Validation of Analytical Procedures: Definitions and Terminology
[CPMP/ICH/381/95]
ICH Q2B Validation of Analytical Procedures: Methodology [CPMP/ICH/281/95]
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Literature support
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Properties of APIs
Scenarios:
API not described in BP, Ph., JP, Ph.Eur., or USP (non - compendial)
Considered new
(?) information on (adverse) drug reaction
Risk estimation high
Profound information necessary
API described in BP, Int.Ph., JP, Ph.Eur.,or USP (compendial)
Considered in use
Information on (adverse) drug reaction (monitored)
Risk estimation based on available data
Information necessary limited to data beyond the monograph
Essential control by the monograph
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Properties of API(s)
APIs not described in BP, PhInt, PhEur or USP
a) evidence of chemical structure
spectral data
Single crystal X-ray structure (sufficient) or
Spectrometric data (IR, 1H & 13C NMR, MS, etc.): QA certified
copies of the spectra and tabulated data with
assignments against structure/interpretation of data (narrative)
b) evidence of chemical structure
Isomerism
Stereochemistry
Discussion of potential isomeric forms
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Properties of API(s)
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Properties of API(s)
APIs described in BP, PhInt, PhEur or USP
Evidence of chemical structure
control of structure by suitable compendial identification tests
Properties relevant/critical for the performance of the API (not necessarily
covered by the monograph)
a) potential polymorphic forms
Influence on physicochemical and physical characteristics (solubility,
hardness, compressibility, density, melting point, etc.) Must be
controlled
b) particle size distribution
requirement for low solubility drugs (dissolution, bioequivalence)
c) additional characteristics
critical characteristics to be controlled to ensure consistent
performance of the API (e.g. hygroscopicity)
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Properties of API(s)
Categories of Antimalarials
APIs described in monographs of major international
pharmacopoeias ( 10 years)
Amodiaquine, Chloroquine, Dapsone, Quinine, Mefloquine,
Sulfadoxine/Pyrimethamine, Trimethoprim
APIs described in monographs of major international
pharmacopoeias (recently)
Arthemether, Artemisinin, Artemotil, Artenimol, Artesunate
APIs not described in monographs of major international
pharmacopoeias
Chlorproguanil, Lumefantrine, Naphthoquine, Piperaquine, Pyronaridine
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API
BP
EP
US
Int
JP
MI
Artemether
Artemisinin
Artemotil (arteether)
Artenimol
Artesunate
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APr
Cod
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API
BP
EP
Amodiaquine
US
Int
Lumefantrine
JP
MI
APr
Cod
Mefloquine
Pyrimethamine
Sulfadoxine
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Properties of Artemisinins
Artemisinin (C15H22O5)
7 centers of asymmetry
27 potential isomers
One isomer in biosynthesis
Chemical synthesis
Feasible but uneconomical
Chemical derivatization at
C-10 (carbonyl-moiety) converts
C-10 into an additional
stereoisomeric center:
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8
9
8a
12a
10
11
12
5a
5
1
4
2
Properties of Artemisinins
Manufacturer proposals
Melting range
a-Artemether
100C
b-Artemether
84 - 86C, 86 90C
+166-+173, +168-+173
20mg/ml C2H5OH
a-Artesunate
b-Artesunate
132-135C
+2.5-+3.5
a~b~Artenimol
+146 (15C)
(?mg/ml MeOH)
Diastereomers
may differ in their melting point/specific optical rotation
(in solution)
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Route(s) of synthesis
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- CEP holder,
- Site of manufacture of the API, site of manufacture of declared starting
material
- Grade (particle size or sterile) (if applicable)
- Ph. Eur. monograph according to which the Certification dossier has been
evaluated,
- Additional impurities and residual solvents not mentioned in the
monograph,
- Additional methods to those of the monograph as annexes,
- If sterile API, Method of sterilization + mention that process and validation
have been assessed
- Re-test period (if applicable)
- Packaging system and storage condition (if re-test period mentioned),
- Date of validity of the CEP
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API specifications
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Non-compendial APIs
Typical set of specifications
Appearance/description
Impurities
- Related organic substances (synthesis or degradation)
specified
unspecified and
total organic impurities
- Inorganic impurities, including catalysts
- Residual solvent(s)
Assay
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IMPURITIES
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Classes of Impurities
Organic
Inorganic
Residual solvents
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Organic Impurities
Starting materials
By products
Intermediates
Degradation products
Reagents, ligands and catalysts
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Inorganic Impurities
May be from manufacturing process and are normally
known and identified:
Solvents
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IMPURITIES
Identified impurity
Unidentified impurity
Specified impurity
Unspecified impurity
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Impurity Thresholds
Identification threshold Limit above which, impurities found are to be identified
either structurally or by a qualitative parameter e.g. RT in HPLC system
Qualification threshold Limit above which, impurities found are to be
toxicologically qualified
Reporting threshold Limit from which, impurities should be analytically reported
Maximum Daily
Dose
Reporting
Threshold
Identification
Threshold
Qualification
Threshold
2g/day
0.05%
lower)
lower)
0.05%
0.05%
2g/day
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0.03%
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IMPURITY EQUIVALENCE
To demonstrate that different sources of the API or routes of
synthesis are equivalent, checks on impurities are required to
show that
No new impurity is observed in the intermediate above 0.1%
No new impurity is observed in API above the qualification
threshold
Each existing impurity is within its stated limit
Total impurities are within the stated limit
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Cultivation reagents
Pesticide residues, fumigants, mycotoxins
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Site(s) of manufacture
The quality of APIs is dependent on
Manufacturing site
Equipment, personal, technology
Route of synthesis, operational conditions, IPCs
Impurity profile, stability (API & FPP)
The quality of an API may consequently impact the quality of a FPP
Change in manufacturing site
Alternate API-manufacturers
Change in route of synthesis
Alternate API-manufacturers
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Stability testing
Stress testing of API (forced degradation) helps
to identify the likely degradation products and pathways
to establish stability of the molecule
To verify specificity of stability assay method
e.g. Diode array detection for API peak purity !
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Stress factor
Conditions (e.g.)
Humidity
75% RH (solid)
Heat **
60C (solid)
Heat
water
Acid
0.1 M HCl
Conditions can be
changed to get required
degree of degradation
Base
0.1 M NaOH
Oxidative
3% H2O2
Photolytic
ICH Q1B
Metal ions
(optional)
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in support of and/or
to replace experimental data
Important Elements
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