MSc. Jorge Mendonça
Líder e coordenador projeto FACT
BRASIL
Far-Manguinhos / FIOCRUZ
17de Abril de 2008
Um Projeto Global
Rede FACT
Modelo colaborativo da
DNDi ilustrado pelo
Projeto FACT
Uni Bordeaux, France:
desenvolvimento
farmacêutico de AS/AQ
CNRFP,
Burkina Faso:
ensaio clínico de AS/AQ
Uni Sains, Malaysia:
devt of metodologia
analítica, PK humanos &
animal
Far Manguinhos, Brazil:
desenvolvimento
farmacêutico de AS/MQ,
toxicologia
AS/AQ: artesunato/am odiaquina
AS/MQ: artesunato/mefloquina
PK/PD: farm acocinética/farm acodinâmica
DNDi, MSF, TDR,
Far-Manguinhos,
EC’s INCODEV:
financiam ento
DNDi/TDR:
coordenação
científica e gestão de
projeto
Uni Oxford, UK: PK/PD,
estudos in vitro and
moleculares
Uni Mahidol,
Thailand:
ensaio clínico de
AS/MQ
-- - - - - Inform ação compartilhada
----------- Inform ação/dados/m étodos com partilhados
Um produto Global
ASMQ
O comprimido azul dos trópicos
• América do Sul;
• Ásia;
• Possivelmente África.
FARMANGUINHOS
MISSÃO:Contribuir para a promoção da saúde pública,
por meio da produção de medicamentos, do
desenvolvimento tecnológico e difusão de
conhecimentos.
VISÃO: Ser um centro de referência da pesquisa, do
desenvolvimento e da produção farmacêutica
brasileira.
FOCO: Priorizar o acesso da população brasileira aos
programas governamentais de saúde.
ÁREAS ENVOLVIDAS NO PROJETO FACT
AAR
AAR
NVQ
NVQ
LTF
GQ
GQ
LDVA
COMERCIAL
COMERCIAL
PCP
PCP
CQ
CQ
PRODUÇÃO
PRODUÇÃO
Controle
Controle da
da
Qualidade
Qualidade
Ministério
Ministérioda
daSaúde
Saúde
PMA
PMA
ENGENHARIA
ENGENHARIA
Estrutural Organizacional FACT - Farmanguinhos
Tecnologia Farmacêutica
LTF
Alessandra Viçosa
Qualidade
LDVA /NVQ
Érico Daemon
Coordenador local – Jorge Mendonça
Consultores do projeto (CATALENT,
Dra Isabela Ribeiro e
Dra. Luciana Barros)
Jorge Mendonça
Far-Manguinhos / FIOCRUZ
17de Abril de 2008
ASMQ
The development of a co-formulation
FROM THE BLUEPRINT TO THE BLUE PILL
BLUEPRINT
?
BLUE PILL
9
THE BLUEPRINT OF THE BLUE PILL
BLUEPRINT
•
Quality components (AS, MQ, Excipients)
•
Smallest possible size (Minimum excipients)
•
Good aspect (Coating)
•
Paediatric strengths
•
Simple (1 or 2 tables for 3 days)
•
Stable (Process and Tropical conditions)
•
Adequate biopharmaceutical properties.
10
APIs Characteristics ?
MEFLOQUINE HYDROCHLORIDE
ARTESUNATE
X
Stability: Not Critical issue
Stability: Critical issue
11
Mefloquine Hydrochloride
Manufacturer: Abbott GmBH & Co. KG - Germany/ Sifavitor – Italy (New supplier)
E-DMF available, Comply with EP
Exists in known different polymorphs (A,B,C,D and E)
Other Preformulation tests:
Bulk and Tapped density
Hausner ratio: Fair
Carr index: Fair
Repose angle: Poor
Water content: Máx 3 %
Particle size distribution
Thermal analysis
X – ray
Problem: Poor Flow !
12
Artesunate
Manufacturer: Knoll AG - Switzerland
E-DMF available, FDA inspected Manufacturing Site, Comply with IP.
Artesunate does not show polymorphism.
Particle size profile (Knoll)
Batches 2.05
4.05
d50 = 77µ
77µm
d50 = 132µ
132µm
Different Particle size profile !!!
13
Formulation design
Smallest excipient quantities
Smallest tablet size
Stable formulation: APIs x Excipients compatibility
Simple composition
Artesunate - API
Mefloquine Hydrochloride - API
APIs - About 70 % of the formulation
Microcrystalline cellulose - Diluent
Sodium croscarmellose - Disintegrant
Magnesium stearate – Lubricant
Opadry white - Coating
Blue Lake FDC 2 - Coating
Excipients - About 30 % of the formulation
Coating function: Taste masking , light protection and good aspect
14
High dosage X Low dosage
Same formulation and different average mass
Average mass/4 =
Low Dosage
Artesunate + Mefloquine (25 +55) mg
Fast disintegration time
High Dosage
Artesunate + Mefloquine (100 +220)
mg
No problems to child
administration in the
spoon !!
15
And about the quality of excipients?
Microcrystalline cellulose – Comply with EP
Sodium croscarmellose - Comply with EP
Magnesium stearate – Comply with EP - Animal origin
Very important to good processability in production area.
Opadry white
Blue Lake FDC 2
Pharmaceutical grade
The nice aspect of the BLUE tablets required
this kind of materials.
16
Process Choice/ Optimizing Stability
Mefloquine Dry Granulation
Mixing
To improve MQ flow
Addition of Artesunate – Dry process
Tabletting
Coating
Packaging
Aluminium foil
High Humidity Protection
Clinical Trial packaging
17
Dosing Schedule
18
Packaging (Simplicity and Patient Compliance)
6 to 11 months
1 – 5 years
6 – 11 years
12 years or older
19
DR profiles of tablets
MQ release
AS release
20
Stability / Liability of the product : stress testing
•Stability-indicating assay and related substances
method
•Degradation peaks from artesunate
• <1 % degradation to light and humidity
•~3% of unknown impurities in oxidative
conditions
•Strong degradation with heat
•Excipients not found to increase degradation
Table 11.
Qualitative comparision of chromatograms in solid state stress conditions
Sample/Condition Control Sample
Heat (Chamber)
Humidity
Light
(non degraded)
Artesunate
-5
0
45
0
5
10
15
15
25
30
35
40
5
Name
RetentionTime
Area
25
30
35
40
45
-5
0
Minutes
5
10
15
20
5
10
10
15
Name
RetentionTime
Area
25
30
35
40
45
5
10
15
25
30
35
40
-5
0
45
Minutes
5
15
5
10
25
30
35
40
15
20
-5
0
45
5
35
40
-5
0
45
35
40
45
5
10
15
10
15
UNK 1
20
25
30
35
40
45
mAU
5
0
25
30
35
40
45
1:211nm
,8nm
FACT
comprimidospulvluz1
Name
RetentionTime
Area
-5
0
20
UNK 2
DHA 1
M
inutes
25
30
35
40
5
10
15
20
45
Minutes
15
10
Name
RetentionTime
Area
5
DetectorA(211nm)
FACT
Excipienteluz1
Name
RetentionTime
Area
5
40
25
Minutes
20
25
30
35
40
-5
0
45
-5
0
5
10
15
20
30
35
40
45
-5
0
5
10
15
10
5
0
20
25
Minutes
30
35
40
5
10
15
20
25
30
35
40
45
Minutes
45
30
35
40
45
-5
0
15
DetectorA(211nm)
FACT
5comprimidosumid1
Name
RetentionTime
Area
10
m AU
Name
RetentionTime
Area
25
Minutes
15
1:211nm,8nm
FACT
5comprimidosaquec1
12.42 23533
5
0
20
15
9.22 22695
10
15
10
mAU
Name
Retention Time
Area
10
5
Minutes
15
DetectorA(211nm)
FACT
compPApulvcontrole1
5
0
-5
0
45
5
0
-5
0
1:211nm
,8nm
FACT
5com
primidosluz1
Name
RetentionTime
Area
5
10.83 27331
35
8.50 9078
30
mefloquina 18.65 225093583
0
-5
0
30
Mefloquina 17.81 155464440
25
m AU
5
30
DetectorA(211nm)
FACT
Excipienteumid1
Artesunato 4.58 1088733
20
12. 13 55948
15
mefloquina 18.57 196539129
mAU
10
10
Mefloquina 16.80 147357702
10
artes unato 4.86 993530
Drug Product
(5 tablets) a
Name
RetentionTime
Area
5
0
5
Minutes
15
25
0
0
-5
0
25
mAU
mAU
10
15
mAU
Name
RetentionTime
Area
5
20
Minutes
DetectorA(211nm)
FACT
Excipienteaquec2
8.80 19669
mAU
10
15
DetectorA(211nm)
FACT
Excipienteumid1
Art esunat o 4. 37 683638
15
Name
RetentionTime
Area
5
10
Minutes
Placebo
15
Minutes
15
12.48 38138
Name
RetentionTime
Area
9.22 17399
5
0
20
10
DetectorA(211nm
)
FACT
M
PMQluz1
0
mefloquina 18.71 227951463
10
mAU
12.10 91852
10
5
45
DetectorA(211nm)
FACT
comprimidospulvumid1
Artesunato 4.58 1092846
0
20
Name
RetentionTime
Area
8.79 69158
mAU
5
40
Minutes
15
Mefloquina 16.83 144992502
0
-5
0
10
35
10
0
20
30
15
5
-5
0
1:211nm,8nm
FACT
comprimidospulvaquec1
Artesunato 4.37 663291
5
mefloquina 18.57 196539129
mAU
10
15
DetectorA(211nm)
FACT
compPApulvcontrole1
Name
Retention Time
Area
artes unato 4.86 993530
15
25
Minutes
DetectorA(211nm)
FACT
MPMQumid1
Minutes
Drug Product
(pulverized)
artesunato 4.28 1213890
m AU
-5
0
45
15
0
20
20
Artesunato 4.17 683606
-5
0
mAU
5
10
DetectorA(211nm)
FACT
MPMQaquec1
mAU
10
Mefloquina 18.32 220675326
mAU
10
5
Minutes
15
mefloquina 17.77 231923498
40
11.00 22602
35
8.59 6157
30
MQ
Mefloquina 17. 86 158308532
25
0
DetectorA(211nm
)
FACT
rMPAScontroleluz2
Name
RetentionTime
Area
Artes unat o 4.17 607707
20
DetectorA(211nm)
FACT
MPMQcontrole1
Name
Retention Time
Area
5
-5
0
13.37 32306
15
10
18.52 233393882
10
Minutes
15
15
DetectorA(211nm)
FACT
MPAScontroleumid1
Name
RetentionTime
Area
5
0
mAU
5
0
12.24 18956
-5
0
Mefloquine
5
mefloquina 16.88 207082379
0
10
mAU
5
15
DetectorA(211nm)
FACT
uMPASaquec1
Name
RetentionTime
Area
4.51 1074375
mAU
10
artesunato 4.65 1222921
15
DetectorA(211nm)
FACT
MPAScontrole1
Name
RetentionTime
Area
4.80 1070536
mAU
10
(Artesunato)
15
10
15
HPLC-3D detector
20
25
30
35
40
45
Minutes
5
10
15
20
25
30
35
40
45
Minutes
a
= non pulverized, intacts
21
Stability Studies – 36 Months
22
The Product: 1st Fixed-Dose ACT with 3-Year
Shelf Life
23
Manufacturing History and Status
Batches
BatchesSize
Size
Batches
2x
BatchesSize
Size Batches
BatchesSize
Size
BatchesSize
Size Batches
2x100
100Kg
Kg
2x
16
Kg
2x
2x
44xx16
2x 16 Kg
2x12
12Kg
Kg
2x16
16Kg
Kg
16Kg
Kg
2006
2004
Stability Studies
Acre/Pará
Clinical Trials
Drugs used in:
- Thailand Studies
- Acre/Pará Clinical Trials
2007
Jan/ 2008
Acre Clinical Trials
New MQ Supplier Batches
Validation
Validation
Batches
Batches
ri
p
A
08
0
l2
!
Market Batches
24
THE BLUE PILL
Quality components (AS, MQ, Excipients)
Smallest possible size (Minimum excipients)
Good aspect (Coating)
Paediatric strengths
Simple (1 or 2 tables for 3 days)
Stable (Process and Tropical conditions)
Adequate biopharmaceutical properties.
25
Jorge Mendonça
Far-Manguinhos / FIOCRUZ
17de Abril de 2008
Conceitos do projeto
• Facilidade de Uso (1 ou 2 cps por dia);
• Uso pediátrico;
• Menor tamanho possível e bom aspecto;
•Estável tanto em processo quanto em
condições tropicais;
• Mais barato que os medicamentos
isolados.
PROCESSOS E PESSOAS
TIME FACT
TIME ANALÍTICO
Estudo clínico na Tailândia
Estudo clínico no Acre
Produção
Produção
Agradecimentos:
• Farmanguinhos FIOCRUZ
• DNDi
• Dr. Jean-René Kiechel
• Dra. Isabela Ribeiro
• Eloan Pinheiro
• Eduardo Costa
• Dra. Núbia Boechat
OBRIGADO PELA ATENÇÃO
[email protected] (Coordenador)
[email protected] (Tecnologia Farmacêutica)
[email protected] (Qualidade)
[email protected] (consultora)