Produksi; aturan, peralatan

Evaluasi Skala produksi Validasi dan spesifikasi produk Kemasan

2007/8

Mengacu pd GMP (Good Manufacturing Practice; FDA (di indonesia : CPOB) Memuat standar minimum produk berkualitas Peraturan/regulasi domestik dan luar negeri; pabrik, suplier, distributor

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

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

FDAs Pharmaceutical cGMP for the 21st Century QbD Initiative

Generic Sponsor: Implementing QbD in development and manufacturing

FDA OGD: Developed a Questionbased Review System that assesses sponsors QbD ANDAs

QbR Questions Embodies QbD

What attributes should the drug product possess?

Quality by Design

QbR Questions Embodies QbD

How was the product designed to have these attributes? Were alternative formulations or mechanisms investigated?

Quality by Design

How were the excipients selected?

How was the final formulation optimized?

QbR Questions Embodies QbD

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?

Quality by Design

Drug Substance

Unit Operations Mixing Compression Coating

Excipients

Impurity Metal Res Solvents Moisture Diss

10/30 out of Assay 10,000,00 Uniformity 0 Meet Spec? No Yes

CFR 314.70 (Code of Federal Regulations) Change Guidance

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Drug Substance

Clinical Relevance

Unit Operations Mixing Compression Coating

PAT

Always Meet Spec

Excipients

Assay Uniformity Purity Diss

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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

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)

In proces control (IPC) Uji stabilitas; suhu, waktu (terkait penyimpanan) Karakter fisik, kimia, biologi, kualitas mikrobiologi Karakteristik sediaan

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

Laboratorium; research scala Skala pilot Skala produksi menentukan ; - Kalkulasi bahan - Pemilihan peralatan, metode - Evaluasi produk

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

Pertimbangan umum Batasan penerimaan Rekomendasi prosedur analitik Regulasi Monitoring

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

Formulasi tepat tepat kemasan

Wadah (Container) Penutup (Closure) Karton Kotak (Box) Penandaan (Labeling)

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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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MATERIAL
Logam

Plastik, karet
Kaca/gelas kombinasi

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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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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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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 bubbles interfere with pumping - right amount of product not delivered to the container)
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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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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 screwthreads

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Dosage form

Packaging

Solid
Liquids

Bottles, Blisters, Sachets Jars

Bottles (glass & plastic) Drops, Nasal Sprays Metered dose pumps, Drinkable ampoules Tubes (metal, plastic, laminate) Cans/jars, Applicators Sticks, Al-cold blister (suppositories) Suppository blister strips Vials (glass & plastic) Ampoules, Pre-filled syringes Ophthalmic tubes (creams), Ophthalmic drops
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Semi-solid

Sterile

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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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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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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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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 2 to 30 containers in connected blocks volumes from 0,12 ml to approximately 50 ml.

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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 2007/8

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Capacities range from 15ml up to 1 gallon with neck finishes of 28mm and larger

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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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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

Manufacturers 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

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