ROAD MAP PILOT PROJECT PENGEMBANGAN INDUSTRI OBAT

ROAD MAP
PILOT PROJECT PENGEMBANGAN
INDUSTRI OBAT KANKER BERBASIS
POTENSI SUMBER DAYA INDUSTRI LOKAL
Disampaikan oleh :Konsorsium INSINAS BNCT
Prof. Ir. Yohannes Sardjono, Ir. Slamet Santosa, M.Sc., Drs. Widarto
Prof. Edy Meiyanto, Apt., Dr. Bagaswoto P, Sp.KN.(Rad), Dr. Wigati, Sp. Rad.Onk
Drs. M. Wahyuli Syafari, Apt. Dr. Dede Anwar Musadad & Drs. Ahi, MT.
Para Peneliti dan Dosen Berkompetensi Fisika Medis, Farmasi, Kedokteran,
Biologi Radiasi, Kimia Radiasi, I&C, Mekanik.
Di JOGLOSEMARTOGO BALITAN
Prof. Koji Ono - Kyoto Univ.
Dikawal intensif:
Dir. POPB BPOM – Dra. Nurma Hidayati, M.Epid.
Dir. PKKR BAPETEN – Dr. Yus Rusdian A,
Institusi Pelaksana: Pusat Sains dan Teknologi Akselerator -BATAN
BATAN [PSTA, PTRR
PTKMR, PRFN, PDK ,PSJMN]
FK [UGM,UII,UNTAN],
F.FARMASI [UGM+UII] KEMENPERIN
PT. KIMIA
FISIKA FMIPA &FST &
FARMA Tbk
FT[UGM, UNY, UKSW,
(BUMN)
UIN, UNS, UNSOED,
BALITBANGKES RSUP SARDJITO
UNNES, UNUD] T.MESIN
(BLU)
BPOM, BAPETEN
FT UNY
RS PEND UNTAN &
RSUD SUDARSO
PMPROV KALBAR
IAEA Technical Meeting on
Research Reactor Users' Networks (RRUNs):
advances in neutron therapy, Johanes Berg
University, Minz Germany, July 1- 4, 2013
INTERNATIONAL CONFERENCE
THE APPLICATION OF NUCLEAR TECHNOLOGY
FOR NATIONAL SUSTAINABLE DEVELOPMENT : HEALTH,
AGRICULTURE, ENERGY, INDUSTRY & ENVIRONMENT
UKSW CENTRE OF JAVA INDONESIA, SEPT . 21-22, 2015
Calculation of estimate Potential Loss
(from existing RT Department patients)
12.106 pats
Reported new treatments in 2012 from 22 centers in Indonesia
(15% from estimated need)
250 million
Population
1 million
Cancer patients
4.3/ 1000
52.3%
Cancer prevalence
Need to be irradiated
500.000 pats
Need to be irradiated
US$ ???? ……….
Countable and uncountable
Jumlah kunjungan pasien dari
Indonesia rata-rata mencapai
1000 pasien per bulan dari 5
agen di Kalimantan Barat
Terutama penyakit kronis
seperti kanker
Road Map of
Prototype BNCT
2019 :
2018 :
2017 :
- Setup dan uji komponen
2016 :
- Pengadaan Prototype
Alat Kesehatan
(komponen Cyclotron
dan Compact Neutron
Generator)
2015 :
Set up project
management :
- Dokumen perijinan dan
sistem pengujian
- Dokumen DED
- Dokumen QA and QC
- Dokumen kontrak dan
kerja sama
- Pengadaan Prototype
Produksi Obat Baru
Boron Compound
Pharmaceutical Berbasis
Analog Curcumin
- Setup dan uji integrasi
komponen
- Komisioning Prototype
Alat Kesehatan
(Cyclotron dan Compact
Neutron Generator)
- Komisioning Prototype
Produksi Obat Baru
Boron Compound
Pharmaceutical Berbasis
Analog Curcumin
- Pengoperasian
Prototype Alat
Kesehatan (Cyclotron
dan Compact Neutron
Generator)
- Pengoperasian
Prototype Produksi
Obat Baru Boron
Compound
Pharmaceutical
Berbasis Analog
Curcumin
- Uji pre-Klinis dan
klinis
- Uji Coba Sistem
Prototype Alat
Kesehatan (Cyclotron
dan Compact Neutron
Generator) untuk
Terapi Kanker
- Uji Coba Sistem
Prototype Produksi
Obat Baru Boron
Compound
Pharmaceutical
Berbasis Analog
Curcumin untuk
Terapi Kanker
-Test kesesuaian
komponen (perbedaan
penerimaan dan
pengiriman)
- SDM (training dan studi
banding)
Badan Tenaga Nuklir Nasional
1/28/2015
6
Outline
Introduction
Road Map
Basic Principle & Conceptual
Design
Detail Engineering Design & Manufacture
[Prototype Boron Carrying Pharmaceutical
sebagai Obat baru]
Summary
Introduction
Analisis
Lingkungan Strategis
Badan Tenaga Nuklir Nasional
1/28/2015
9
Cancer Projection in The World until 2030
12,7 million
cases of
cancer
2008
14,09 million
cases of cancer
2012
22 million cases
of cancer
2030
(World Health Organization, 2012)
Cancer in Indonesia
7,44 %
8,06 %
9,66 %
Brain and Nervous system
Incidence: 4903 (1,6
%) (Oemiati et al, 2011)
Mortality : 3402 (1,7
%)
RADIOTHERAPY CENTER IN INDONESIA 2014
Government hospital
Private hospital
•Total :
•29 radiotherapy center (21 government, 8 private)
•43 radiotherapy equipment (25 Linac, 17 Cobalt, 1 GKS)
Waiting list
of RT
Services in
Indonesia
43.309.707
11.331.558
14.946.488
4.211.532
121.352.608
11.112.702
SEMARANG
12 months,
SURABAYA
03 months,
YOGYAKARTA
06 months,
JAKARTA
06 weeks
CAKUPAN RADIOTERAPI
RSCM: Rujukan Nasional
0.5%
0.7%
3%
3%
0.5%
3.2%
0.2%
11% 27% 1.8%
0.2%0.7%
0.5%
0.5%
36%
•
•
•
Jumlah pend. DKI (2012): 9.761.407 juta jiwa 1
Jumlah alat radiasi : 13  TT : Pop = 1 : 750rb
Data RSCM
– Jumlah pasien th 2012 : 2.101 org
– Jumlah pasien asal JKT hanya 766 (36,5%)
– Sisanya 63.5% rujukan luar Jakarta
EXISTING RADIOTHERAPY PATIENTS REFERAL SERVICES
13 RT equipment for 9.7 million population
But ………… 63.5 % of our patient come from outside of Jakarta
Introduction (Cancer cell)
Cancer Cell (Anonim, 2009)
Treatment
Surgery
Radiotherapy
Brachitherapy
Chemoterapy
BNCT
RRs and their applications world-wide (RRDB)
Application
Number of
RR involved
Involved /
Operational, %
Number of
countries
Education & Training
161
67
51
Neutron Activation Analysis
122
51
54
Radioisotope production
90
37
44
Neutron radiography
68
28
40
Material/fuel testing
60
25
25
Neutron scattering
48
21
32
Nuclear Data Measurements
42
18
20
Gem coloration
36
15
22
Si doping
35
15
22
Geochronology
26
11
21
Neutron Therapy (BNCT)
23
8
13
Other
95
40
29
Indonesia is no. 14 in the world
Contact:
19
D.Ridikas@iaea.org
INTRODUCTION
Boron Neutron Capture Therapy
Medical patient was injected by boron
compound before exposing
Neutron thermal will be captured by
Boron on cancer cell and selectively
irradiate cancer cells that have taken
up a sufficient amount of Boron and
simultaneously spare normal cells
The products of this reaction have
high linear energy transfer
characteristics (α particle = 150
keV/µm, Lithium-7 = 175 keV/µm )
Alpha Radiations will
destruct the cancer cell
without hurt another
healthy tissues
Road Map of R&D
Strategic Plan Hilirisasi
Produk Litbang BNCT
Badan Tenaga Nuklir Nasional
1/28/2015
22
Struktur Organisasi Konsorsium
BNCT
Badan Tenaga Nuklir Nasional
1/28/2015
23
SRUCTURE ORGANISATION 0F PILOT PROJECT
Basic Principle &
Conceptual Design
Conceptual Design of Collimator
Computer Code
(Bassler, 2013)
The collimator can be design with simulation. MCNP is the most computer
code that used to calculated particle transport. So, we can made collimator
design using MCNP5 simulation.
DESIGN NEUTRON SOURCE BNCT
I A E A - R e q u i re m e n t
Targeted Cells in deep area need neutron
thermal to be captured by boron. Hence, its
required epithermal neutron to accomodate
moderation Beam
effect Intensity
Beam Quality
If the beam intensity is less than required, exposing timing can be
extended. it makes the others beam quality component values increasing.
For that reason, beam quality is provided in ratio with epithermal
comparison
Kartini Nuclear Reactor as Neutron Source for
BNCT
Reactor
Core
15 cm
(Part 1)
117 cm
19 cm
(Part 2)
156 cm
PART OF COLLIMATOR
For Boron Neutron Capture Therapy
1. Collimator Wall
3. Thermal Filter
5. Aperture (Output)
2. Moderator
4. Gamma Shielding
1. To keep the neutron flux stay high
2. To reduce the fast neutron and Contribute epithermal neutron (Shifting Methode)
3. To Absorb thermal neutron (Filtering Methode)
4. To Attenuate Gamma Ray
5. To Control beam Convergenity
Summary of
Collimator
Components
Mechanical
Engineering
UNY
Partnership
Recommendation
material
Collimator Part
Best Availability
Collimator Wall
Pb, Bi, PbF2 , Ni
Ni (95 %)
Moderator
Al, Al2O3, dan AlF3
Al 1350 (99.5 %)
Gamma Shield
Pb, Bi
Pb
Filter
6Li
x
, 10B , 60Ni
-
Aperture
Pb, Bi, PbF2 , Ni
Ni (95 %)
Additional Safety Control
Boral
Boral
Some material is unavailable in indonesia, especially the pure version.
In this case, we use another material with impurity that can subtitute the pure versi
COMPONENTS
Optimation material and thickness
Material Impurity
FluksFluks
neutron
epitermal
Vs Collimator
wall
thicknesswall
of σa barn
Isotop
(NA) epitermal
Percentage
neutron
Vs
Collimator
58Ni (68.07%) , 60Ni (26.23%),
variation
material
thickness
of Ni 95%
Unsure
Ni – nat
4.5
3
Mn - 55
2.5
3.5
61Ni
Fe - nat
Si - nat
Cu - nat
C - nat
Ti – nat
2) 2x) 10
9 9
Φepi
(n/cm
x 10
Φ
epi(n/cm
4
32
2.5
1.5
2
1.51
1
0.5
0.5
00 46Ti
00
-0.5
-0.5
(1.14 %), 62Ni (3.64%),
64Ni (0.926%),
55Mn
(100%),
54Fe
(5.8%) , 56Fe (91.72%),
57Fe (2.2 %), 58Fe (0.28%),
28Si
12C
4.619
1.5
13.4118
1
2.585
Pb
(92.23%) , 29Si (4.67%),
30Si (3.1 %),
64Cu
95
Bi
0.5
0.1691
(69.15%), Cu (30.9%)
1
Ni
4.4678
(98.9%), 13C (1.1%)
0.5
0.0034
(8.0%), 47Ti (7.3%), 48Ti (73.8%),
0.5
1 1 1.5 50
3
0.5
1.5 2
22.5
2.5
49Ti (5.5%),
Ti (5.4%)
3.5 3
4 3.5 4.50.5 4 5
Collimator
thickness
Collimator
wallwall
thickness
(cm)(cm)
PbF2
5.5
4.5
65
17.294
6.5
Several unsure in this material have greater absorption cross section than
in 95 % of nickel, there is a shifting of peak point flux optimation
nickel. it makes shifting of peek point optimation happened.
MATERIALS
Optimation material & thickness
6
Al 1350 (99.5 %)
5
df/Φepi x 10-3
Thickne
ss
(cm)
4
Φepi
Ḋf / Φepi
Thickne
ss (cm)
2
Φepi
Ḋf / Φepi
11
5.32E+08
5.56E-11
1.16E+09
3.11E-11
12
8.46E+08
3.42E-11
1.5E+09
0
2.59E-11
13
1.15E+08
9E-11
7.72E+08
5
4.53E-11
10
14
2.77E+08
20
8.45E-12
25
15
5.57E+08
7.1E-13
2.47E-12
7.72E+08
Thickness16(cm) 2.49E+08
2.59E-11 Al AlF3 17Al2O3
2.43E+08
4.53E-11
18 2.99E+08
1.96E+09
1.47E-11
19
2.03E+08
4.53E-11
9
1.47E+09
1.11E-11
20
1.96E+08
9.83E-12
10
1.07E+09
1.99E-11
6
7
8
-2
1.96E+09
5
1.16E+09
6
1.5E+09
7
8
1.47E-11
15
3.11E-11
In this section, we
were not only
analyse the Fast
neutron dose rate
per epithermal flux,
but also ephitermal
30 neutron Flux it self
1.63E-11
1E-11
The Best material Candidate that can reduce fast neutron flux is Pure Aluminum
GAMMA SHIELD
Optimation material & thickness
Thickness (cm)
Φepi
Ḋγ / Φepi
Without Pb
Pb 0.5
5.57E+08
5.06E+08
1.51E-11
1.44E-12
Pb 1 cm
4.05E+08
1.16E-13
Pb 1.5 cm
4.02E+08
1.16E-13
BORAL
ADDITIONAL
Boron – Aluminum
Aperture Surrounding
Thickne
ss (cm)
thermal
epithermal
Fast
total
0.5
2.53E+05
8.21E+06
1.20E+07
2.05E+07
1
1.32E+05
5.88E+06
1.47E+07
2.07E+07
1.5
9.11E+04
9.84E+06
1.40E+07
2.40E+07
2
8.21E+04
8.64E+06
1.23E+07
2.11E+07
Aperture Hole
Ḋγ / Φepi
Thicknes
(cm)
Φepi
Ḋf / Φepi
0.5
5.12E+08
2.58E-13
1.20E-13
1
5.06E+08
2.49E-13
1.17E-13
1.5
5.03E+08
2.17E-13
1.16E-13
2
4.82E+08
2.26E-13
8.14E-13
FINAL RESULT
of Collimator Design & Optimation
Parameter
Value
IAEA Requirement
Φepi (n/cm2s)
Ḋf / Φepi (Gy-cm2 /n)
5.03 x 108
2.17 x 10-13
> 1,0 x 109
< 2,0 x 10-13
Ḋγ / Φepi (Gy-cm2 /n)
Φth / Φepi
J / Φepi
1.16 x10-13
0.120
0.835
< 2,0 x 10-13
< 0,05
> 0,7
ANOTHER FACILITIES
of BNCT therapy in the world
5
Neutron
Flux
comparison
4.5
4
3.5
3
2.5
2
Minimum
Requirement
Of Flux
1.5
1
0.5
0
Petten
(NL)
Espoo
(Fin)
Bariloch
e (Jpn)
Tokai
(Jpn)
Hsinchu
(Taiwan)
Yogyaka
rta (Ina)
Thermal Flux (1E+08 n/cm2s)
0.11
0.72
0.33
4.4
1.34
0.6036
Epithermal Flux (1E+09 n/cm2s)
0.34
1.2
0.65
1.7
1.07
0.503
Fast Flux (1E+08 n/cm2s)
0.26
0.34
0.44
0.95
0.77
2.81
ANOTHER FACILITIES
of BNCT therapy in the world
Beam Quality
comparison
30
25
20
15
10
Maximum
thermal/epi
ratio
Minimum
fastgamma
neutron
Maximum
dose
contamination
dose
contamination
5
0
Petten
(NL)
Espoo
(Fin)
Bariloche
(Jpn)
Tokai
(Jpn)
Hsinchu
(Taiwan)
Yogyaka
rta (Ina)
Gamma dose Contam. (1E-13Gy-cm2 /n)
4.74
0.9
0
3
1.95
1.16
Fast Neutron dose Contam. (1E-13Gy-cm2 /n)
10.3
3.3
9.7
3.3
4.2
2.17
Thermal/epi Ratio (%)
3.24
6.00
5.08
25.88
12.52
12.00
DED AND MANUFACTURE
OF COLLIMATOR BNCT
RESULT OF CNG COLLIMATOR
PbF2
Sulfur
40% Al +
60 % AlF3
Litiated
Polyetilene
Cadmium
Φepi
1.7 109
Dγ/Φepi
9.77 10 -14
Df/Φepi
Φth/Φepi
1.87 10 -13
6.04 10 -4
J/Φtot
1,69
Detail Engineering Design kolimator:
MCNP5 combined SHIELD-HIT12A
Kurkumin
BNCT
compound
Kurkumin tersubtitusi karboranil
42
A
SUMMARY
KESIMPULAN
• KEMENPERIN MENDUKUNG ROAD MAP
PILOT PROJECT PENGEMBANGAN INDUSTRI OBAT
KANKER BERBASIS POTENSI SUMBER DAYA INDUSTRI
LOKAL
• PERLUNYA DISUSUN REGULASI DAN KEBIJAKAN
PENGELOLAAN PENYAKIT KANKER SEBAGAI
PEMBUNUH UMAT NO.2. SETELAH JANTUNG
SECARA SIMULTAN DAN KOMPREHENSIF.
• PERLUNYA INTERVENSI KEMENTERIAN KESEHATAN
DALAM MEMASUKKAN INDUSTRI OBAT KANKER
DALAM BNCT KE DALAM BPJS
Badan Tenaga Nuklir Nasional
1/28/2015
45