WHO Training Workshop on Pharmaceutical
Quality, GMP and Bioequivalence with a focus on
artemisinines
Pharmaceutical quality by
design and development
János Pogány, pharmacist, Ph.D.
consultant to WHO
Guilin, China, 10 January 2006
E-mail: pogany@t-online.hu
2006.01.09.
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Abbreviations
API
Active Pharmaceutical Ingredient
BP
British Pharmacopoeia
FDC Fixed-Dose Combination
FPP
Finished Pharmaceutical Product
ICH
International Conference on Harmonization
PhEur European Pharmacopoeia
PhInt International Pharmacopoeia
USP
United States Pharmacopeia
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Subjects for discussion
1.
DESIGN (product-specific research)



2.
DEVELOPMENT (manufacturing process)



3.
Desk research
API (specifications, stress stability testing, etc.)
FPP (pre-formulation, stability studies, etc.)
Laboratory
Pilot plant
Production plant
Main points again
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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
3.2.2 Information from literature
(Desk research)
EOI – Oral Preparations




Artesunate* + Amodiaquine
Artemether* + Lumefantrine*
Artesunate* + Mefloquine
Artesunate* + SP (sulphadoxine / pyrimethamine)
* No comparator at the beginning * High-risk API
+ ... FDC or co-blistered (co-packaged) FPPs
All oral FPPs include paediatric formulations.
(EOI is included in the Notes Page of this and the subsequent slides)
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EOI – Other dosage forms
 Artemether Injection and rectal FPPs
 Artemotil (arteether) Injection
 Artesunate Injection and rectal FPPs
Only FPPs listed in the EOI are discussed.
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Artemisinin
 Active antimalarial constituent of the traditional Chinese
medicinal herb 青蒿素 Artemisia annua L., Compositae
 Artemisinin has seven (7) centers of assymetry but
Artemisia annua makes only one configuration
(Identification)
 Practically insoluble in water
 The bond energy of the O-O bond is ~30 kcal/mol
 When the peroxide comes into contact with high iron
concentrations, the molecule becomes unstable and
"explodes" into free radicals.
 The API, the capsules and the tablets are official in the
Ph. Int. Not included in the current EOI.
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Artemether

Practically insoluble in water

Artemether injection is an
oily soulution
 The API, the capsules, the
tablets and the injection are
official in the Ph. Int.
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Artenimol
 Practically insoluble in
water. Slightly soluble in
ethanols and
dichloromethane.
 Both the API and the
tablets are official in the
Ph. Int.
 Not included in the
current EOI
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Artesunate
 Very slightly soluble in
water
 The ester linkage is in
alpha configuration.
 Both the API and the
tablets are official in the
Ph. Int.
 Two functional groups are
liable to decomposition
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Metabolism of Artemether and Artesunate
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Amodiaquine
Amodiaquine Hydrochloride USP, C20H22ClN3O.2HCl.2H2O. Merck
Index: pH of 1% aqeous solution is from 4.0 to 4.8.
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Mefloquine hydrochloride
 Has an optically active
carbon
 Very slightly soluble in water
 Has no reactive functional
groups under general
environmental conditions
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Lumefantrin
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Pharmaceutical information
 Artemisinin derivatives may have α- or β-configuration and
each of them can exist in two conformations. The literature
does not reveal any impact of the geometric isomerism on
efficacy, safety or quality of artemisinins.
 The internal peroxide bound is the most reactive part of the
molecule. When the peroxide comes into contact with high
iron concentrations, the molecule becomes unstable and
"explodes" into free radicals.
 The ester bound of artesunate is liable to hydrolysis.
 The non-artemisinin APIs in the EoI are chemically stable.
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Biopharmaceutical information
 The internal peroxide bound is fundamental for antimalarial
activity.
 Artemisinin has a




poor solubility in both water and oil,
short pharmacological half life,
high first-pass metabolism, and
poor oral bioavailability.
 Its lactol ethers –artemether and arteether– are soluble in oils.
 The lactol hemiester –artesunate– is slightly soluble in water
and soluble at a basic pH.
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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
3.2 Pharmaceutical development
3.2.1 Company research and development
The Pharmaceutical Development section should contain information on
the development studies conducted to establish that the dosage form, the
formulation, manufacturing process, container closure system,
microbiological attributes and usage instructions are appropriate for the
purpose specified in the application. The studies described here are
distinguished from routine control tests conducted according to
specifications.
The summary should highlight the evolution of the formulation design
from initial concept up to the final design and it should also take into
consideration the choice of drug product components (e.g., the properties
of the drug substance, excipients, container closure system, the
manufacturing process, and, if appropriate, knowledge gained from the
development of similar drug product(s).
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Qualification Stage
Key elements
Design & C Installation
Facilities and
Engineering phase
Validation Stage
Operation
Prospective
Concurrent
Manufacturing Start-Up
Equipment
(Validation Protocols)
(Batch Records and Validation documentation)
Product and Process
Design (formulation)
Scale-Up
Production
(Validation of
(Critical attributes
(process optimization
(final batch size,
analytical
and Stability Testing)
and pilot batches)
reproducible
methods)
quality)
Quality Development
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Product-specific physical API properties
Introduction of
the API starting
material(s) into
process
Production
Isolation and
of intermediate(s)
purification
Physical
processing
and
packaging
Product-specific physical properties depend on crystallization
and subsequent physical processing.
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Potentially critical attributes of API
Key physicochemical characteristics:
1.
2.
3.
4.
5.
6.
7.
Solubility over the physiological pH range (e.g., BCS, dissolution testing,
cleaning validation)
Octanol-water partition (BCS)
Particle size (pharmaceutical and bioequivalence, processability)
Polymorphic or solid state form (if relevant)
Bulk density, untapped and tapped (processability)
Flowability (processability)
Color, olor, taste, consistency (choice of dosage form)
should be discussed and supported by experimental data.
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Solubility of artesunate
pH
Dissolved material (mg/ml)
1
1,9
5
1,5
6
3,5
7
10,2
8
12,2
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Degradation of artesunate in aqueous solution
Conditions
Time (h)
Degradation (%)
Water
2
0
0.1N HCl
2
74
0.1N NaOH
2
100
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Relationship between permeability coefficient
and octanol-water partition
1 Prednisolone
...
3 Dexamethazone
...
9 Dexamethazone-acetate
...
11 Progesterone
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Particle size
When the solubility of an API is less than 0.1
mg/ml and does not change with pH in the
physiological range, then the optimisation of the
particle size during preformulation may be critical
to efficacy or pharmaceutical equivalence. Other
researchers believe that particle size may be
critical at a solubility of 1 mg/ml or less.
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Potentially critical attributes of API
Cross reference to stress testing (forced degradation):
1.
2.
3.
4.
5.
6.
Sensitivity to temperature (wet granulation, sterilization)
Sensitivity to moisture (wet granulation, hygroscopicity)
Sensitivity to light (packing materials)
Sensitivity to oxidation (inert gas atmosphere in ampoules)
Sensitivity to pH (FDC with HCL salts of weak bases)
Sensitivity to metal ions (internal peroxide bond)
Expected degradants, manufacturing conditions, etc.
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Rate of water absorption as a function of RH
0,45
Lg RH, %
0,40
35%
0,35
55%
75%
0,30
100%
0,25
28
25
22
19
16
13
10
7
4
1
0,20
Lg time, t (3 min. units)
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Overages in the formulation
Information should be provided on the
1. amount of overage,
2. reason for the overage (e.g., to compensate for
expected and documented manufacturing
losses), and
3. justification for the amount of overage (API but
not EXCIPIENT).
The overage should be included in the amount of
drug substance listed in the batch formula.
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Compatibility of APIs in FDCs
 Artemether + Lumefantrine
 Artesunate + Amodiaquine.2HCl
 Artesunate + Mefloquine.HCl
 Artesunate + Sulphadoxine/Pyrimethamine (SP)
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Compatibility of the API with excipients
and diluents
 Magnesium stearate is incompatible with salts of
weak bases and strong acids (e.g.
Amodiaquine.2HCl) because the formed MgCl2 is
highly hygroscopic and, as a result, its lubricant
properties also change.
 The compatibility of the drug product with
reconstitution diluents should be addressed, e.g.
in Artesunate injection.
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Selection of excipients - Talc
Time (week)
Talc A
Salicylic acid, %
Talc B
Salicylic acid, %
0
0.10
0.10
4
0.32
5.85
8
0.41
13.00
12
0.80
28.50
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Selection of tablet mass
Composition
A
B
C
API (mg)
500
500
500
Excipients (mg)
200
125
56
700
625
556
Granules, LOD (%)
0,9
0,8
0,8
Median diameter (μm)
194
186
189
Tablets, hardness (kp)
12.8
13.3
12.4
0.7
0.5
0.5
Tablet mass (mg):
Friability (%)
Disintegration time
6’30’’7’40’’ 10’50’’
Dissolution (%, 15’)
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96.6
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95.6
96.7
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Selection of binder and solvent
Povidone, water (W), ethanol (E)
W-E
W
E
Granules
LOD(%)
0.8
0.9
0.8
Median diameter (μm)
186
179
184
Average weight (mg)
626
624
628
Hardness (kp)
13.3
11.2
12.9
Friability (%)
0.5
0.5
0.4
Tablets
Disintegration time
Dissolution (%, 15’)
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7’4’’ 2’10’’ 6’35’’
95.6
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96.3
75.7
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Special requirements
In case of tablets designed with a score line,
information should be given whether or not
reproducible dividing of the tablets has been shown.
e.g. „the scoreline is only to facilitate breaking for
ease of swallowing and not to divide into equal
doses”, „the tablet can be divided into equal halves”.
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Dissolution testing*

Dissolution testing is used for the selection of the formulation and
comparison of the dissolution profiles with that of the innovator
product and clinical batches. This should be a basic strategy in
pharmaceutical development to maximize the chances of
bioequivalence.
 Limits should be set for each API in fixed-dose FPPs.
 The dissolution method should be incorporated into the stability
and quality control programs.
 Multipoint dissolution profiles of both the test and the reference
FPPs should be compared.
*Supplement 1 to the Generic Guideline.
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Dissolution testing


2.
3.
4.
Three media - 900 ml or less - all at 37°C

Buffer pH 1.2, SGF without enzymes or 0.1M HCl

Buffer pH 4.5

Buffer pH 6.8 or SIF without enzymes
Water may be used additionally (not instead of)
Paddle at 50 or basket at 100 rpm
Twelve units of each product in all 3 media
Dissolution samples collected at short intervals, e.g.

10, 15, 20, 30, 45 and 60 minutes

Analyse samples for all APIs, when applicable
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% dissolved
Hypothetical dissolution profile
of a 2-FDC FPP
120
100
80
60
40
20
0
Series1
Series2
Series3
Series4
0
15
30
45
60
minutes
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Artemether injection
Possible design and development issues:
 Selection of oil.
 Heat stability of the oil and the oily solution of
artemether (standard conditions for dry heat
sterilization: NLT 160oC, two hours)
 Alternatively, sterile filtration under aseptic
conditions.
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Artesunate injection
 In the treatment of severe malaria, intravenous artesunate is
more rapidly acting than intravenous quinine in terms of
parasite clearance, is safer, and is simpler to administer, but
whether it can reduce mortality is uncertain.
 „Every 60mg vial contained anhydrous artesunic acid, which
we dissolved in 1mL 5% sodium bicarbonate and then mixed
with 5mL of 5% dextrose before injecting as a bolus into an
indwelling intravenous cannula”.
www.thelancet.com
2006.01.09.
Vol366 August 27, 2005
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4-FDC antituberculosis FPP
Originator FPP in ICH region
 None
FPP in current Essential Drug List
 Rifampicin
150 mg
 Isoniazid
75 mg
 Pyrazinamide
400 mg
 Ethambutol
275 mg
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4FDC-TB tablets exposed to
40°C/75%RH for one week
Two different products. “Bleeding” may start after more
exposure to stress testing without packing material. (NorthWest University, South Africa)
Control on left
Control on left
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Critical quality variables
1. The formulation is hygroscopic, sensitive to light and
unstable.
2. Moisture content of FPP and intermediates.
3. Ethambutol.2HCl provides acidic conditions to
accelerate decomposition between rifampicin and
isoniazid.
4. Packing materials are critical for stability.
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Special attention in assessment
 Compatibility of APIs with each other and with
excipients.
 Stress stability of the final formulation.
 Equilibrium moisture content of granules and
uncoated tablets.
 Control of temperature and RH during the
manufacturing process.
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Special attention in assessment
 Specifications and sampling of the primary packing
materials.
 Heavy-duty compression machine.
 Validation batches and annual product review reports.
 Stability testing of the FPP to include visual
inspection, assay, impurities and degradants (in
particular isonicotinyl hydrazone), water, hardness,
and other attributes.
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Container closure system
 The choice and rationale for selection of the container
closure system for the commercial product [described in
3.10 Container/closure system(s) and other packaging]
should be discussed.
 The data should include details on:




tightness of closure.
protection of the contents against external factors.
container/contents interaction (e.g. sorption, leaching).
influence of the manufacturing process on the container (e.g.
sterilisation conditions).
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Microbiological attributes
 The microbiological attributes of the FPP should be
discussed in this section. The discussion should include,
for example:

The rationale for performing or not performing microbial
limits testing for non-sterile FPPs (e.g., Decision Tree #8 in
ICH Q6A Specifications).

Antimicrobial preservative effectiveness should be
demonstrated during development.
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Pivotal batches
A tabulated summary of the compositions of the clinical,
bioequivalence, stability and validation FPP batches
together with documentation (batch number, batch size,
manufacturing date and certificate of analysis at batch
release) and a presentation of dissolution profiles must be
provided.
Results from comparative in vitro studies (e.g.,
dissolution) or comparative in vivo studies (e.g.,
bioequivalence) should be discussed when appropriate.
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Manufacturing Process Development
The progress from pre-formulation (size:1x) →
formulation (10x) → pilot manufacture (100x but not less
than 100,000 capsules or tablets) → production scale
(approved batch size) manufacture should be shown in the
dossier submitted for prequalification to be logical,
reasoned and continuous.
A pilot batch is manufactured by a procedure fully
representative of and simulating that to be applied to
a full production scale batch.
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Manufacturing Process Development


Significant differences between the manufacturing
processes used to produce batches for pivotal clinical trials
(safety, efficacy, bioavailability, bioequivalence) or primary
stability studies and the process described in 3.5
Manufacturing process should be discussed.
The information should include, for example,




the identity (e.g., batch number) and use of the batches produced
(e.g., bioequivalence study batch number),
the manufacturing site,
the batch size, and
significant equipment differences (e.g., different design,
operating principle, size).
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Manufacturing Process Development
 The selection, the control, and any improvement
of the manufacturing process described in 3.5
Manufacturing process should be explained.
 Appropriateness of the equipment used for the
intended product(s) should be discussed.
 Process development studies should provide the
basis for process improvement, process
validation, continuous process verification (where
applicable), and any process control requirements.
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Manufacturing Process Development
 An assessment of the ability of the process to reliably
produce a product of the intended quality e.g., the
performance of the manufacturing process under



different operating conditions,
at different scales, or
with different equipment can be provided.
 Unsatisfactory processes must be modified and improved
until a validation exercise proves them to be satisfactory.
 An understanding of process robustness can be useful in
risk assessment and risk reduction.
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Compression
Tabletting machine
BB3
Granules, (Mg-stearate %)
BB3
β-Press
0.25
0. 50
0.50
LOD (%)
1.5
1.5
1.5
Median diameter (μm)
341
341
341
Tablets
Average weight (mg)
605
607
599
Hardness (kp)
10.9
9.7
7.3
Friability (%)
0.3
0.5
0.8
6’48
’’
14’19
’’
8’14
’’
99.5
76.7
92.0
Disintegration time
Dissolution (%, 15’)
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Film-coating conditions
Spraying conditions
Film-coater
Nozzle (mm)
Spraying pressure (psi)
Inlet temperature (oC)
Outlet temperature (oC)
Spray rate (g/min)
Drum speed (rpm)
2006.01.09.
Pilot batch 1
Manesty
0.8
40/25
81
45
36
8
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Pilot batch 2
Manesty
0.8
40/25
71
44
26
10
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Film-coating results
Pilot batch 1
Quality parameter
Core
Pilot batch 2
Coated
Core
Coated
Weight increase (%)
2.12
2.04
Appearance
good
good
Mean thickness (mm)
4.25
4.28
4.34
4.37
Hardness (kp)
9.2
14.7
8.7
10.8
Friability (%)
0.3
0
0.44
0
Disintegration time
3’40’’5’32’’1’44
’’
2’46’’
Dissolution (15’, %)
-
98
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93
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-
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Main points again
 Development pharmaceutics is an essential part of
applications for prequalification.
 Desk research gives valuable design and development
information.
 The specifications of an API are finalized during
pharmaceutical development studies.
 FPP design, characterization and selection should follow a
scientific methodology.
 Manufacturing process design and optimization identifies
the critical attributes whose control leads to the batch-tobatch consistency of quality.
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Literature
1.
Monographs from the Merck Index®, 13th edition
(2001).
2.
Xuan-De Luo and Chia-Chiang Shen: The Chemistry,
Pharmacology and Clinical Applications of Qinghaosu
(Artemisinin) and its Derivatives (Med. Research Reviews,
Vol. 7, No.1, 29-52 (1987).
3.
The International Pharmacopoeia, 3rd ed., Volume 5,
185-233, WHO, Geneva (2003).
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THANK YOU
谢谢!
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