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MSc. Jorge Mendonça
Líder e coordenador projeto FACTBRASIL
Far-Manguinhos / FIOCRUZ17de Abril de 2008
Rede FACTDNDi/TDR:
coordenaçãocientífica e gestão de
projeto
Uni Bordeaux, France:desenvolvimento
farmacêutico de AS/AQ
Uni Sains, Malaysia:devt of metodologia
analítica, PK humanos & animal
Uni Oxford, UK: PK/PD, estudos in vitro and
moleculares
Uni Mahidol, Thailand:
ensaio clínico deAS/MQ
Far Manguinhos, Brazil:desenvolvimento
farmacêutico de AS/MQ, toxicologia
CNRFP, Burkina Faso:
ensaio clínico de AS/AQ
Modelo colaborativo da DNDi ilustrado pelo Projeto FACT
AS/AQ: artesunato/amodiaquinaAS/MQ: artesunato/mefloquinaPK/PD: farmacocinética/farmacodinâmica
-- - - - - Informação compartilhada----------- Informação/dados/métodos compartilhados
DNDi, MSF, TDR, Far-Manguinhos, EC’s INCODEV: financiamento
Um Projeto Global
• América do Sul;• Ásia;• Possivelmente África.
Um produto Global
ASMQO comprimido azul dos trópicos
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.
FARMANGUINHOS
ÁÁREAS ENVOLVIDAS NO PROJETO FACTREAS ENVOLVIDAS NO PROJETO FACT
PMAPMA
ENGENHARIA ENGENHARIA
PCPPCP
CQCQ
AARAAR
COMERCIALCOMERCIAL
Ministério da SaúdeMinistério da Saúde
PRODUÇÃOPRODUÇÃO Controle da Qualidade
Controle da Qualidade
NVQNVQ GQGQ
LTF LDVA
Qualidade LDVA /NVQÉrico Daemon
Tecnologia Farmacêutica LTFAlessandra Viçosa
Consultores do projeto (CATALENT, Dra Isabela Ribeiro eDra. Luciana Barros)
Coordenador local – Jorge Mendonça
Estrutural Organizacional FACT - Farmanguinhos
Jorge Mendonça
Far-Manguinhos / FIOCRUZ17de Abril de 2008
ASMQ ASMQ
The development of a coThe development of a co--formulationformulation
FROM THE FROM THE BLUEBLUEPRINT TO THE PRINT TO THE BLUE BLUE PILL PILL
BLUEBLUEPRINTPRINT BLUE BLUE PILLPILL??
9
BLUEBLUEPRINTPRINT
THE THE BLUEBLUEPRINT OF THE PRINT OF THE BLUE BLUE PILL PILL
•• Quality components (AS, MQ, Excipients)Quality components (AS, MQ, Excipients) �� ���� ��
•• Smallest possible size (Minimum excipients)Smallest possible size (Minimum excipients) �� ���� ��
•• Good aspect (Coating)Good aspect (Coating) �� ���� ��
•• Paediatric strengthsPaediatric strengths
•• Simple (1 or 2 tables for 3 days)Simple (1 or 2 tables for 3 days) �� ���� ��
•• Stable (Process and Tropical conditions)Stable (Process and Tropical conditions) �� ���� ��
•• Adequate biopharmaceutical properties.Adequate biopharmaceutical properties.
10
APIs Characteristics ?APIs Characteristics ?
MEFLOQUINE HYDROCHLORIDEMEFLOQUINE HYDROCHLORIDE ARTESUNATEARTESUNATE
XX
Stability: Not Critical issueStability: Not Critical issue Stability: Critical issueStability: Critical issue
11
Mefloquine HydrochlorideMefloquine Hydrochloride
Manufacturer: Abbott GmBH & Co. KG Manufacturer: Abbott GmBH & Co. KG -- Germany/ Sifavitor Germany/ Sifavitor –– Italy (Italy (New supplierNew supplier)) ��
EE--DMF available, Comply with EPDMF available, Comply with EP
Exists in known different polymorphs (A,B,C,D and E)Exists in known different polymorphs (A,B,C,D and E) ��
Other Preformulation tests:Other Preformulation tests:
Bulk and Tapped densityBulk and Tapped densityHausner ratio: FairHausner ratio: Fair �� ���� ��Carr index: FairCarr index: Fair �� ���� ��Repose angle: Repose angle: PoorPoor ��Water content: MWater content: Mááx 3 %x 3 %Particle size distributionParticle size distributionThermal analysisThermal analysisX X –– rayray
Problem: Poor Flow !Problem: Poor Flow !
12
ArtesunateArtesunate
Manufacturer: Knoll AG Manufacturer: Knoll AG -- SwitzerlandSwitzerland
EE--DMF available, FDA inspected Manufacturing Site, Comply with IP.DMF available, FDA inspected Manufacturing Site, Comply with IP.
Artesunate does not show polymorphism.Artesunate does not show polymorphism.
Particle size profile (Knoll)Particle size profile (Knoll) ��
Batches 2.05 4.05Batches 2.05 4.05
Different Particle size profile !!!Different Particle size profile !!!dd
5050= 77= 77µµmm dd
5050= 132= 132µµmm
13
Formulation designFormulation design
Simple compositionSimple composition
Artesunate Artesunate -- APIAPI
Mefloquine Hydrochloride Mefloquine Hydrochloride -- APIAPI
Microcrystalline cellulose Microcrystalline cellulose -- DiluentDiluent
Sodium croscarmellose Sodium croscarmellose -- DisintegrantDisintegrant
Magnesium stearate Magnesium stearate –– LubricantLubricant
Opadry white Opadry white -- CoatingCoating
Blue Lake FDC 2 Blue Lake FDC 2 -- CoatingCoating
APIs APIs -- About 70 % of the formulationAbout 70 % of the formulation
Excipients Excipients -- About 30 % of the formulationAbout 30 % of the formulation
Simple compositionSimple composition
Artesunate Artesunate -- APIAPI
Mefloquine Hydrochloride Mefloquine Hydrochloride -- APIAPI
Microcrystalline cellulose Microcrystalline cellulose -- DiluentDiluent
Sodium croscarmellose Sodium croscarmellose -- DisintegrantDisintegrant
Magnesium stearate Magnesium stearate –– LubricantLubricant
Opadry white Opadry white -- CoatingCoating
Blue Lake FDC 2 Blue Lake FDC 2 -- CoatingCoating
Simple compositionSimple composition
Artesunate Artesunate -- APIAPI
Mefloquine Hydrochloride Mefloquine Hydrochloride -- APIAPI
Microcrystalline cellulose Microcrystalline cellulose -- DiluentDiluent
Sodium croscarmellose Sodium croscarmellose -- DisintegrantDisintegrant
Magnesium stearate Magnesium stearate –– LubricantLubricant
Opadry white Opadry white -- CoatingCoating
Blue Lake FDC 2 Blue Lake FDC 2 -- CoatingCoating
Coating function: Taste masking , light protection and good aspect
Stable formulation: APIs x Stable formulation: APIs x ExcipientsExcipients compatibilitycompatibility
Smallest excipient quantitiesSmallest excipient quantities Smallest tablet sizeSmallest tablet size
14
High dosage X Low dosageHigh dosage X Low dosage
High DosageArtesunate + Mefloquine (100 +220)
mg
Low DosageArtesunate + Mefloquine (25 +55) mg
Average mass/4 = Average mass/4 =
Same formulation and different average massSame formulation and different average mass
No problems to child administration in the
spoon !!
Fast disintegration time
15
And about the quality of excipients?And about the quality of excipients?
Microcrystalline cellulose Microcrystalline cellulose –– Comply with EP Comply with EP
Sodium croscarmellose Sodium croscarmellose -- Comply with EPComply with EP
Magnesium stearate Magnesium stearate –– Comply with EP Comply with EP -- Animal originAnimal origin
�� Very important to good processability in production area.Very important to good processability in production area.
Opadry whiteOpadry white
Blue Lake FDC 2Blue Lake FDC 2Pharmaceutical gradePharmaceutical grade
The nice aspect of the The nice aspect of the BLUE BLUE tablets required tablets required
this kind of materials.this kind of materials.
16
Process Choice/ Optimizing StabilityProcess Choice/ Optimizing Stability
Tabletting
Mixing
Mefloquine Dry Granulation
Coating
Packaging
To improve MQ flowTo improve MQ flow
Addition of Artesunate Addition of Artesunate –– DryDry processprocess
Aluminium foilAluminium foil
High Humidity ProtectionHigh Humidity Protection Clinical Trial packagingClinical Trial packaging
17
Dosing ScheduleDosing Schedule
18
Packaging (Simplicity and Patient Compliance)Packaging (Simplicity and Patient Compliance) �� ���� ��
6 to 11 months 6 – 11 years1 – 5 years 12 years or older
19
DR profiles of tabletsDR profiles of tablets
MQ releaseMQ release
AS releaseAS release
20
Stability / Liability of the product : stress testingStability / Liability of the product : stress testing
MQ
UNK 2
DHA 1
UNK 1
Table 11. Qualitative comparision of chromatograms in solid state stress conditions Sample/Condition Control Sample
(non degraded) Heat (Chamber) Humidity Light
Artesunate
Minutes
0 5 10 15 20 25 30 35 40 45
mA
U
-5
0
5
10
15
4
.80
1
070
53
6
Detector A (211nm)FACTMPAScontrole1
NameRetention TimeArea
Minutes
0 5 10 15 20 25 30 35 40 45
mA
U
-5
0
5
10
15
arte
suna
to
4.65
12
2292
1
Detector A (211nm)FACTuMPASaquec1
NameRetention TimeArea
Minutes
0 5 10 15 20 25 30 35 40 45
mA
U
-5
0
5
10
15
4
.51
107
43
75
Detector A (211nm)FACTMPAScontroleumid1
NameRetention TimeArea
Minutes
0 5 10 15 20 25 30 35 40 45
mA
U
-5
0
5
10
15
arte
sun
ato
4.
28
12
138
90
Detector A (211nm)FACTrMPAScontroleluz2
NameRetention TimeArea
Mefloquine
Minutes
0 5 10 15 20 25 30 35 40 45
mA
U
-5
0
5
10
15
Mef
loqu
ina
18.
32
22
0675
326
Detector A (211nm)FACTMPMQcontrole1
NameRetention TimeArea
Minutes
0 5 10 15 20 25 30 35 40 45
mA
U
-5
0
5
10
15
(Art
es
una
to)
1
2.2
4 1
895
6
me
flo
quin
a
16
.88
20
70
823
79
Detector A (211nm)FACTMPMQaquec1
NameRetention TimeArea
Minutes
0 5 10 15 20 25 30 35 40 45
mA
U
-5
0
5
10
15
1
3.3
7
32
30
6
1
8.5
2
23
339
38
82
Detector A (211nm)FACTMPMQumid1
NameRetention TimeArea
Minutes
0 5 10 15 20 25 30 35 40 45
mA
U
-5
0
5
10
15
me
flo
quin
a
17.
77
2
31
92
349
8
Detector A (211nm)FACTMPMQluz1
NameRetention TimeArea
Drug Product (pulverized)
Minutes
0 5 10 15 20 25 30 35 40 45
mA
U
-5
0
5
10
15
arte
sun
ato
4.
86
993
530
mef
loq
uina
18
.57
19
6539
129
Detector A (211nm)FACTcompPApulvcontrole1
NameRetention TimeArea
Minutes
0 5 10 15 20 25 30 35 40 45
mA
U
-5
0
5
10
15
Art
es
una
to
4.3
7
663
29
1
8
.79
6
915
8
1
2.1
0 9
18
52
Me
floq
uin
a 1
6.8
3 1
44
992
502
1: 211 nm, 8 nmFACTcomprimidospulvaquec1
NameRetention TimeArea
Minutes
0 5 10 15 20 25 30 35 40 45
mA
U
-5
0
5
10
15
Art
esu
nato
4
.58
10
928
46
9
.22
17
399
1
2.4
8
381
38
mef
loqu
ina
1
8.7
1 2
279
514
63
Detector A (211nm)FACTcomprimidospulvumid1
NameRetention TimeArea
Minutes
0 5 10 15 20 25 30 35 40 45
mA
U
-5
0
5
10
15
Art
esun
ato
4.1
7 6
077
07
8
.59
615
7
1
1.0
0
226
02
Me
floqu
ina
17.
86
158
3085
32
1: 211 nm, 8 nmFACTcomprimidospulvluz1
NameRetention TimeArea
Placebo
Minutes
0 5 10 15 20 25 30 35 40 45
mA
U
-5
0
5
10
15Detector A (211nm)FACTExcipienteumid1
NameRetention TimeArea
Minutes
0 5 10 15 20 25 30 35 40 45
mA
U
-5
0
5
10
15Detector A (211nm)FACTExcipienteaquec2
NameRetention TimeArea
Minutes
0 5 10 15 20 25 30 35 40 45
mA
U
-5
0
5
10
15Detector A (211nm)FACTExcipienteumid1
NameRetention TimeArea
Minutes
0 5 10 15 20 25 30 35 40 45
mA
U
-5
0
5
10
15Detector A (211nm)FACTExcipienteluz1
NameRetention TimeArea
Drug Product (5 tablets) a
Minutes
0 5 10 15 20 25 30 35 40 45
mA
U
-5
0
5
10
15
arte
sun
ato
4.
86
993
530
mef
loq
uina
18
.57
19
6539
129
Detector A (211nm)FACTcompPApulvcontrole1
NameRetention TimeArea
Minutes
0 5 10 15 20 25 30 35 40 45
mA
U
-5
0
5
10
15
Art
esu
nato
4.
37
6836
38
8
.80
19
669
1
2.13
55
948
Mef
loqu
ina
16
.80
1
4735
770
2
1: 211 nm, 8 nmFACT5comprimidosaquec1
NameRetention TimeArea
Minutes
0 5 10 15 20 25 30 35 40 45
mA
U
-5
0
5
10
15
Art
esu
nat
o 4
.58
10
887
33
9
.22
22
695
1
2.4
2 2
353
3
me
floqu
ina
18
.65
22
5093
583
Detector A (211nm)FACT5comprimidosumid1
NameRetention TimeArea
Minutes
0 5 10 15 20 25 30 35 40 45
mAU
-5
0
5
10
15
Art
es
una
to
4.1
7 6
836
06
8
.50
90
78
1
0.8
3
273
31
Me
floq
uin
a 1
7.8
1
155
464
440
1: 211 nm, 8 nmFACT5comprimidosluz1
NameRetention TimeArea
a= non pulverized, intacts
•~3% of unknown impurities in oxidative conditions •Strong degradation with heat•Excipients not found to increase degradation
•Stability-indicating assay and related substances method•Degradation peaks from artesunate• <1 % degradation to light and humidity
HPLC-3D detector
21
Stability Studies Stability Studies –– 36 Months36 Months
22
The Product: 1st Fixed-Dose ACT with 3-Year Shelf Life
23
Manufacturing History and StatusManufacturing History and Status
Batches Size 2x 100 Kg4 x 16 Kg
Batches Size Batches Size 2x 100 Kg2x 100 Kg4 x 16 Kg4 x 16 Kg
Stability StudiesStability Studies
Drugs used in:Drugs used in:-- Thailand StudiesThailand Studies-- Acre/ParAcre/Paráá Clinical TrialsClinical Trials
20042004
Acre/ParAcre/ParááClinical TrialsClinical Trials
Batches Size 2x 16 Kg
Batches Size Batches Size 2x 16 Kg2x 16 Kg
Batches Size 2x 16 Kg
Batches Size Batches Size 2x 16 Kg2x 16 Kg
April 2
008 !
20062006
Batches Size 2x 12 Kg
Batches Size Batches Size 2x 12 Kg2x 12 Kg
20072007 Jan/ 2008Jan/ 2008
ValidationBatches
ValidationValidationBatchesBatches
Acre Clinical TrialsAcre Clinical TrialsNew MQ Supplier BatchesNew MQ Supplier Batches
Market BatchesMarket Batches
24
THE THE BLUE BLUE PILL PILL
�� Quality components (AS, MQ, Excipients)Quality components (AS, MQ, Excipients) �� ���� ��
�� Smallest possible size (Minimum excipients)Smallest possible size (Minimum excipients) �� ���� ��
�� Good aspect (Coating)Good aspect (Coating) �� ���� ��
�� Paediatric strengthsPaediatric strengths
�� Simple (1 or 2 tables for 3 days)Simple (1 or 2 tables for 3 days) �� ���� ��
�� Stable (Process and Tropical conditions)Stable (Process and Tropical conditions) �� ���� ��
�� Adequate biopharmaceutical properties.Adequate biopharmaceutical properties.
25
Jorge Mendonça
Far-Manguinhos / FIOCRUZ17de Abril de 2008
• Facilidade de Uso (1 ou 2 cps por dia);• Uso pediátrico;• Menor tamanho possível e bom aspecto;•Estável tanto em processo quanto emcondições tropicais;• Mais barato que os medicamentos isolados.
Conceitos do projeto
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
jsouza@far.fiocruz.br (Coordenador)a_vicosa@far.fiocruz.br (Tecnologia Farmacêutica)edamon@far.fiocruz.br (Qualidade)lucianapbg@yahoo.com (consultora)
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