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Teknologi PATdalam
proses milling
Over-Driven Conical Screen Mill
Under-Driven Conical Screen Mill
Pendahuluan: proses milling yg umum dalam sediaan padat.
PAT
Dampak PAT: reduksi ukuran partikel.
• Kualitas
• Keterulangan proses
• Mengurangi cost produksi
• Mengurangi waktu
• Mempercepat pengiriman produk ke pasar
• Meningkatkan profit
PAT
PAT
Tujuan utama:
• Mengadopsi teknologi terkini• Meningkatkan kualitas tanpa harus khawatir akan validasi
resiko dan keterlambatan produk ke pasar.
Tujuan akhir:
• Kontrol kualitas melalui kontrol real-time dalam proses manufacturing, sehingga membantu analisa secara real-time analysis dan optimasi berkesinambungan.
PAT
Kunci sukses:
• Pada langkah awal, industri farmasi harus menentukan terlebih dahulu hal2 sebagai berikut:– Variable-variabel yg paling kritis – Kontrol apa saja yg diperlukan selama proses– Faktor-faktor yang dapat mempengaruhi degradasi
sample.
“… FDA has always emphasized PAT as a system for designing a manufacturing process”
PAT
PAT TOOLS:
• Sebagai instrumen multivarian untuk mendesesain, akuisisi data dan analisis.
• Analisa proses dan kontrol.
• Perbaikan berkesinambungan.
• Manajemen ilmu pengetahuan
• Data histori
PAT
KONTROL REAL TIME:
• Yang dimaksud kontrol real time dalam PAT: – Mengelola variabilitas yang terjadi dalam proses produksi
obat.
– Variabilitas dapat terjadi karena lebih dari satu sebab.
– Sebagian besar industri mempunyai batch record elektronik yg sudah berjalan bertahun-tahun:
• Penyusunan database
• Melihat pola dan trend untuk mengerti apa yang terjadi selama proses
PAT
“DATA IS NOT INFORMATION, UNTIL SOMEONE APPLIES INTELLIGENCE TO IT”
(Ref. 21 CFR part 11)
PAT
• Karakteristik kontrol kualitas konvensional:• Sampling di setiap tahap produksi melalui analisa destruktif.
– Siklus proses harus berhenti sampai hasil analisa selesai– Produk dan material harus disimpan di staging area WIP (work in
process) sampai parameter kualitas memenuhi syarat. – Bila hasil tidak memenuhi syarat, seluruh batch harus direject
atau dilakukan reproses.– Diperkirakan rata-rata 25% dari profit perusahaan dialokasikan
untuk menangani masalah oos (out of spec) produk.
PAT
• Karakteristik kontrol kualitas konvensional:
• Prosedur: harus berhenti di beberapa tahap produksi untuk memastikan hasil produksi memenuhi syarat.
Upstream Process
Blending & Milling
Granulation Drying MillingTabletPress
Downstream Process
QualityWIP
WIP staging points
Excerpt from American Pharmaceutical Review
QualityWIP
QualityWIP
QualityWIP
QualityWIP
QualityWIP
PAT
Karakteristik Kontrol real :
– Pemeriksaan secara in-line, at-line atau on-line (menggunakan sensor).
– Langsung melakukan pemeriksaan secara fisika dan kimia sehingga proses dapat berlangsung secara kontinu.
– Dapat dihubungkan dengan database sentral.– Memenuhi persyaratan audit trail (missal: 21 CFR Part 11)
Continuous Quality Control w/ either In-Line or At-Line
Upstream Process
Blending & Milling
Drying Milling Tablet Downstream Process
Granulation
Excerpt from American Pharmaceutical Review
PAT
• PAT dalam pengayakan.• Faktor-faktor yang berperan penting:
– Distribusi ukuran partikel dari material (PSD=particle size distribution).
• Variasi Distribusi ukuran partikel yang memenuhi syarat kualitas, kompaktibilitas dan/atau persyaratan untuk aplikasi selanjutnya
PAT
Raw Material
High-Shear Mixing
FBD
Dry Milling(Comil)
Contoh konfigurasi PAT: Proses Milling
Pre-conditioning(Comil)
Wet dispersion(Comil)
Downstream
NIRLaser Scatter
UV, etc.
NIRLaser Scatter
UV, etc.
PATContoh layout PAT: Proses produksi solid
DATA ACQUISITION POINT
PAT
• Pengaruh distribusi ukuran partikel terhadap produk akhir:
• Kekerasan tablet• Kekuatan ikatan antar granul• Kerapuhan
PAT
•Variasi pada true density mempengaruhi sifat alir, rendemen, friabilita, dsb.
•Perubahan densitas berpengaruh pada kekerasan
tablet, kekuatan ikatan antar granul dan kerapuhan.
Example API Lot A API Lot BTrue Density (g/ml) 1.58 1.54Dynamic Indentation (MPa) 195 83Tensile Strength (MPa) 1.8 0.5Bonding Index 0.9 0.6Brittle Fracture Index 0.6 0.1
Impurities % 2.7 0.4Mean Particle Size 20 µm 7 µm
Dampak: ukuran partikel (contoh)
PAT
VARIABLES : BATCH METHOD
COMIL
In-Feed(Product)
Process Q.A.Measurements
(IN HOURS)
EnvironmentVariables
(HSM,FBD, etc.)
ProductHolding
Feedback Control(Adjustments)
ProductReleased
Monitoring - slow, “too late” to affect current batches
Adjustments - labor intensive
Multiple batches rejected before correction
PAT
VARIABLES : CONTINUOUS METHOD
COMIL
In-Feed(Product)
In-Line Q.A.IN SECONDS:
(NIR,Laser Particle
Analysis)
ProductHolding
Instant Auto Adjust(RPM, Feed Rate)
ProductReleased
EnvironmentVariables
(HSM,FBD, etc.)
Monitoring – fast, immediate affect or near-term batches
Adjustments - quick and easy
Rapid - product release
PAT
BATCH Vs CONTINUOUS
CONTINUOUSBATCH
etc
Time
PSD Test – off line. Hours to release product or adjust process/rework/discard
PSD Test: in-line.Real time process adjustments
etc
Time
Q.A.
Mill
Bat
ch 1
Q.A.
Bat
ch 2
Bat
ch 3
Mill
Q.A. Q.A.
Bat
ch 1
Bat
ch 2
Bat
ch 3
MillQ.A.
Mill Mill
Q.A.
Mill
PAT
Monitoring terus menerus…….. Lebih hemat
– Menghilangkan rework thd seluruh batch
– Menghindari OOS satu batch penuh.
– Eliminate Rework of Entire Batches
– Waktu tunggu produksi berkurang krn waktu adjust lebih cepat.
– Dalam jangka panjang, menghilangkan waktu utk off-line
– Lebih cepat untuk mengendalikan pengaruh lingkungan luar.
PAT
Pengendalian: conical miiling
• Analisa langsung saat proses (IR, Particle Scatter – Laser De-fraction)
• Penyimpangan self adjustment
– RPM (Speed)
– Kecepatan input material
– Option: off mesin dan penggantian mesh/baling2 tetap menjadi bagian PAT.
• Variabel monitoring lainnya:
Temperatur (peningkatan gesekan)
Variasi amper (banyaknya massa granul)
PAT
Kontrol & indikator
COMIL
In-Feed(Product)
Impeller RPM
ElectricalCurrent
Temperature
PSD Milled Matl.via NIR or
Laser De-Fraction
Feed Rate(if control fed)
Finished(Product)
ToolingChange
INDIKATOR KONTROLStrain Gauge
Rotating Element
PAT
Contoh: distribusi ukuran partikel (in-line)
• NIR
• Kedalaman gelombang utk menembus sample
• Jendela untuk “melihat” sampel (non-invasive)
PAT
Jendela safir utk aplikasi NIR saat
proses milling.
3”
Co: Quadro Comil U20
PAT
Co: analisa distribusi ukuran partikel inline
• PARTICLE SIZE ANALYZERS (co. Malvern Insitech)
• Lubang sampling udara pada akhir mesin milling
• Material kembali ke hasil ayak (non-destruktif)
• Monitor & mengendalikan energi (co.ampere) – belum ada data ilmiah tapi lazim dilakukan.
PAT
Sinar laser menyinar sepanjang aliran granul
Sinar laser melalui 2 jendela gelas/safir :-Satu sisi sbg transmitter (sinar laser)-Satu sisi sbg receiver (photo detector)
Dipasang semprotan angin (air purge) untuk menjaga jendela tetap bersih dari debu granul.
Co: analisa distribusi ukuran partikel inline (lanjutan)
Malvern (www.malvern.com)
Masalah yg sering timbul:
Lensa mjd buram – debu partikel statik
PAT
Analisa Distribusi ukuran partikel in-line
• Teknologi lain
• Video Monitoring – cocok utk alat dgn tipe low-dust
• UV, sinar-X, suhu, tekanan, dsb.
Quadro Fine GrindModel: F-10
PAT
PSD ANALYSIS – FINE GRINDING (OFF-LINE)
Adapted from Malvern Case Study (www.malvern.com)
Control Feed
Fine Grind
Product Collector
Finished Product
Manual Periodic Samples
PAT
PSD ANALYSIS – FINE GRINDING (OFF-LINE)
Adapted from Malvern Case Study (www.malvern.com)
Manual Samplesapproximately every 75 seconds – results within “set point”
Manual Sample
PAT
PSD ANALYSIS – FINE GRINDING (IN-LINE)
Adapted from Malvern Case Study (www.malvern.com)
Control Feed
Fine Grind
Product Collector
ProductIn-line Laser Scattering
Technology(i.e. Insitec)
PAT: Milling Solutions
PSD ANALYSIS – FINE GRINDING (IN-LINE)
Adapted from Malvern Case Study (www.malvern.com)
Continuous Sampling vs. Material Loading and Amperage Draw
Continuous SamplingOriginal sample points
PAT: Milling Solutions
PSD ANALYSIS - FINE GRINDING (IN-LINE)
Adapted from Malvern Case Study (www.malvern.com)
Material Feed Rate (Transmission) affects Milled PSD
More Particles = Higher Amperage Draw (more work)More In-feed Particles = Coarser Milled Particles
Control Feed-rate (more evenly) = more consistent PSD
IN-LINE SENSOR PROVIDES INSTANTADJUSTMENT OF FEED-RATE
PAT: Milling Solutions
PSD ANALYSIS – FINE GRINDING: IN-LINE
Adapted from Malvern Case Study (www.malvern.com)
Control Feed
Fine Grind
Product Collector
Product
Signal to Adjust Feed Rate
PAT
PSD ANALYSIS – FINE GRINDING: IN-LINE
Adapted from Malvern Case Study (www.malvern.com)
Continuous Sampling
Original sample points
Amperage draw
Material Loading versus
PSD distribution
PAT: Milling Solutions
PSD ANALYSIS – QUADRO F10 FINE GRINDC/W IN-LINE INSITEC
PAT: Milling Solutions
In-Line Measuring/Sensing
NIR Sample
CASE STUDIES
PAT: Milling Solutions
Adapted from Brimrose Case Study (www.brimrose.com)
NIRS (Near Infrared Spectroscopy)
• Diffusively reflected light
• Absorption of any single wave-length is proportional to the reciprocal of the mean particle size
• Absorbance values increase with particle size
PAT
40 mesh aspirin
100 mesh aspirin
200 mesh aspirin
Major features of material are identical, but absorbance values increase with particle size
Adapted from Brimrose Case Study (www.brimrose.com)
Absorbance Values
PAT: Milling Solutions
Adapted from Brimrose Case Study (www.brimrose.com)
NIRS (Near Infrared Spectroscopy)
• NIRS may be used for the rapid determination of the particle size of solid materials.
• Each product within a company may require its own calibration
• NIR provides inexpensive and easily implemented means of making quantitative particle size determinations.
PAT: Milling Solutions
– Controlling and Monitoring Process Critical Control Points (PCCP) – real time adjustments
– Use in-line, at-line, on-line sensors; can be operated by production staff w/out analytical training – calibration is predetermined.
– Adopt Product/Process optimization strategies – implement available knowledge
SUMMARY:
PAT: Milling Solutions
SUMMARY …… cont’d.
– Must understand the process
• Determine Critical Parameters
• Determine Critical Quality Attributes (i.e. PSD)– Higher compression yield proportional to milled
formulations containing particles with tighter distribution
– Used to predict/adjust parameters
• Determine acceptable ranges– Design of Experiments (DOX). Process inputs &
variables adjusted systematically.
PAT: Milling Solutions
SUMMARY…….cont’d.
– Allow analytical experts to focus on few “out-of-spec” results, rather than analyzing all samples.
– “Modeled” data creates “index of wellness” - a slow shift can be detected and immediately corrected.
– Include analysis in conjunction with Blending, Granulating and Drying outputs
• Identify Critical Quality Attributes of each step to further optimize Milling process.
PAT: Milling Solutions
SUMMARY……… cont’d.
– Select technology/sensors robust for application including;
• Alarms, PSD measurements, material of construction, sensitivity, reproducibility, suitability for manufacturing environment, etc.
• Interfacing with Control and IT Systems, statistical software, reporting, Part 11 compliance, data storage and retrieval.
• Feedback and Feed-forward controls (automatic mill parameter adjustments)
TERIMA KASiH