Pratical Pat for Milling Equipment - Version 2

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