proses produksi
TRANSCRIPT
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Produksi; aturan, peralatan
Evaluasi
Skala produksi
Validasi dan spesifikasi produk
Kemasan
2007/8
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Mengacu pd GMP (Good Manufacturing Practice; FDA… (di indonesia : CPOB)
Memuat standar minimum produk berkualitas
Peraturan/regulasi domestik dan luar negeri; pabrik, suplier, distributor
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Outline, mencakup ; Organisasi dan personel Bangunan dan fasilitas Peralatan Kontrol komponen dan produk Produksi dan proses kontrol Kontrol pengemasan dan penandaan (labelling) Distributor Kontrol laboratorium Arsip dan laporan Pengembalian produk
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Pharmaceutical Quality by Design (QbD) ◦ QbD diartikan sebagai suatu rancangan dan
pengembangan formulasi dan proses produksi untuk menjamin kualitas dari produk Pemahaman dan kontrol formulasi serta proses
produksi merupakan variable yang dapat mempengaruhi kualitas dari suatu produk obat
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Generic Sponsor: Implementing
QbD in developmentand manufacturing
FDA OGD:Developed a Question-based Review System
that assesses sponsor’s QbD ANDAs
FDA’s Pharmaceutical cGMPfor the 21st Century
QbD Initiative
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QbR Questions Embodies QbD
Qualityby
Design
What attributes should the drug product possess?
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QbR Questions Embodies QbD
Qualityby
Design
How was the product designed to have these attributes?
Were alternative formulations or mechanisms investigated?
How were the excipients selected?
How was the final formulation optimized?
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QbR Questions Embodies QbD
Qualityby
Design
What are the unit operations in the drug product manufacturing process?
Why was the manufacturing process selected?
How are the unit operations related to the drug product quality?
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Unit OperationsMixing
CompressionCoating…
Drug Substance
Excipients
AssayUniformityImpurity
MetalRes Solvents
MoistureDiss
MeetSpec? Yes
No
10/30 out of
10,000,000
CFR 314.70(Code of Federal Regulations)
Change Guidance
?
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Unit OperationsMixing
CompressionCoating…
Drug Substance
Excipients
AssayUniformity
PurityDiss
“Always” Meet Spec
PAT
Clinical Relevance
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Penilaian thd efek perubahan produk; Identitas Kekuatan Kualitas Kemurnian Potensi Tiap perubahan mesti memuat informasi yg
ditentukan oleh FDA Rekomendasi; dokumen
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Peralatan; Memberikan desain dan ukuran yg sesuai
tujuan; peng-operasian, pembersihan dan perawatan
Tersusun dlm SOP (Standar Operating Procedures)
Skala produksi Jenis; particel size reduction or separation,
mixing, emulsificstion, deaeration, transfer, packaging)
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In proces control (IPC) Uji stabilitas; suhu, waktu (terkait
penyimpanan) Karakter fisik, kimia, biologi, kualitas
mikrobiologi Karakteristik sediaan
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Desain uji stabilitas Penetapan umur simpan; (informasi
penyimpanan yg tertera pd label produk) Pengujian; uji pd suhu kamar dan uji
dipercepat (ditetapkan oleh FDA) Berlaku utk semua produk Laporan hasil uji; informasi produk secara
umu, spesifikasi dan informasi metode uji, desain uji dan kondisi pengujian, data stabilitas dan informasi, analisa data, kesimpulan
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Laboratorium; research scala Skala pilot Skala produksi menentukan ;- Kalkulasi bahan- Pemilihan peralatan, metode- Evaluasi produk
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Standar kualitas produk Meliputi; pengujian, prosedur analitik, kriteria
penerimaan Konfirmasi thd kualitas bahan aktif, produk
obat, intermediate, bahan baku, pereaksi/reagensia, dan komponen lain termasuk sistem kontainer/kemasan
Kriteria penerimaan; batasan numerik, atau kriteria penjelasan hasil uji
Hasil konfirmasi disesuaikan dgn spesifikasi yg memuat hasil/kriteria yg diterima
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Pertimbangan umum Batasan penerimaan Rekomendasi prosedur analitik Regulasi Monitoring
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2007/8 19
Material
Tipe pengemasan
Pengisian
Persyaratan
Peralatan
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Pertimbangan ; Kemungkinan timbulnya “adverse effect”
thd produk Rute pemberian Performance of container Interaksi komponen kemasan-sediaan Kategori bahan pengemas; memenuhi
kriteria
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2007/8 21
Formulasi tepat ≈ tepat kemasan
◦ Wadah (Container)
◦ Penutup (Closure)
◦ Karton
◦ Kotak (Box)
◦ Penandaan (Labeling)
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2007/8 22
KRITERIA KEMASAN YANG BAIK
Dapat diisi tanpa kemungkinan hilangnya obat (tumpah/merembes)
Melindungi dari bahaya lingkungan (environmental hazards)
Sesuai dgn fungsi produk
Bebas dr interaksi antara produk-wadah
Biaya (Cost)
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2007/8 23
MATERIAL
◦ Logam
◦ Plastik, karet
◦ Kaca/gelas
◦ kombinasi
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2007/8 24
SENYAWA LOGAM
Kaleng◦ Metal resistant◦ Tin-coated tubes
Eye ointment tubes
Besi◦ Fabrication of drums, screw caps
Aluminum◦ Low atomic weight, very reactive.◦ Widely used e.g. neomycin or HC cream packed
in Al tubes.
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2007/8 25
PENUTUP
Menutup wadah dgn baik (mencegah hilangnya produk/menguap)
Tahan thd proses sterilisasi
Mencegah kontaminasi oleh mikrooganisme
Non-reaktif
Mudah dikeluarkan dan dipindahkan dari wadah
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2007/8 26
PENGISIAN Fasilitasi melalui pemanasan →
mengurangi viskositas. ◦ Careful to avoid: chemical degradation,
sedimentation of suspended solid if excessive reduction in viscosity by heating.
? Viscous product that contain surfactants, prone to aeration accelerate oxidation produce bubblesinterfere with pumping - right amount of
product not delivered to the container)
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2007/8 27
KEMASAN KRIM Wide-mouthed squat jars… in HTAA? Collapsible metal… problem? Flexible plastic tubes
◦ Reduce contamination, narrow orifice
LIMIT: ‘suck-back’- result in microbial contamination, oxidation,hydrolysis or dehydration
Aluminum tubes
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2007/8 28
KEMASAN SALEP Screw-capped amber glass Plastic pots (but…)
◦ Methyl salicylate incompatible with plastic containers
Collapsible metal tubes (but…)◦ Tend to shed metal particles near their screw-
threads
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2007/8 29
Dosage form Packaging
Solid Bottles, Blisters, SachetsJars
Liquids Bottles (glass & plastic)Drops, Nasal SpraysMetered dose pumps, Drinkable ampoules
Semi-solid Tubes (metal, plastic, laminate)
Cans/jars, Applicators
Sticks, Al-cold blister (suppositories)
Suppository blister strips
Sterile Vials (glass & plastic)Ampoules, Pre-filled syringesOphthalmic tubes (creams), Ophthalmic drops
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2007/8 30
Blister packaging, including "child resistant", "senior friendly".
Aluminum/aluminum (cold formed blisters) pouch filling (powders, liquids, creams, capsules,
tablets, softgels), "nitrogen flush" bottling (tablets, capsules, softgels) strip packaging (tablets, capsules, softgels) high volume commercial production stability testing clinical trials promotional samples
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2007/8 31
Cartoning
automated insertion of blisters and leaflets as well as bar code and pharma-code inspection (using electronic scanners to inspect leaflets and cartons)
Heat-sealed carton cards for blisters (samples for physicians and commercial production)
labeling for "double-blind study" or "open label study"patient kit assembly for clinical studies, (clinical study sites) according to specifications
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2007/8 32
PERSYARATAN KEMASAN DAN WADAH
akurat
kualitas terjamin
memenuhi persyaratan daerah setempat
bahasa yg tepat, instruksi penggunaan, peringatan dan penandaan harus jelas
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2007/8 33
plastic tubes
caps that snap off, twist off and pierce to open.
liquid, ointment.
1 to 5 ml sizes
can have reclosable or non-reclosable caps.
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2007/8 34
◦ 2 to 30 containers in connected blocks
◦ volumes from 0,12 ml to approximately 50 ml.
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2007/8 35
commercial and clinical trials packaging Slide pack
◦ To open, the patient must insert their index finger through an opening, pull the plastic trigger to the right to expose the foil, hold and press the blister to push medication through the foil and release the trigger - thus preventing access again.
E-Z tear
◦ To access, the patient must remove a single dose at the perforation - which will tear at bubble blister only. Note: the child resistant foil will not puncture.
Rx barrier pack
◦ Blisters are protected by a PVC cover (barrier) to prevent child from biting individual cavities
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2007/8 36
Capacities range from 15ml up to 1
gallon
with neck finishes of 28mm and larger
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2007/8 37
proof checking system
for packaging materials and documentation inspection.
utilizes CCD camera technology to capture images for quick comparison; clearly showing any changes.
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2007/8 38
positive pressure corridor with hepa terminal filter
positive pressure production rooms using hepa terminal filter and 18" above ground air return to create laminar air flow that ensures 99,997% air purity at 0.03 microns.
individual production rooms class 100 000.
individual production rooms where temperature and relative humidity are monitored.
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Including; Change in the package insert Package labelling Container label
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Manufacturer’s label- Nama obat;
nonpropietary name, propietary
- Identitas pabrik, pengemas, distributor
- Kuatitas; jumlah obat per unit, vol., dosis
- Logo “Rx only”, “caution”, etc
- Kondisi penyimpanan khusus
- No.lot/ no kontrol- Masa daluwarsa
Prescription label- Identitas apotek- Identitas resep- Identitas pasien- Nama obat dan
komponen lain- Aturan penggunaan
obat
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OTC labelling;- Nama produk- Nama industri, pengemas, distributor- Kuantitas komponen- Identitas substansi lain dlm produk- Pernyataan kategori farmakologi; dosis,
frekuensi, aturan pakai, dll- Peringatan dan perhatian penggunaan- Kondisi penyimpanan- No.lot dan masa kadaluwarsa