proses produksi

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

5

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

6

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

QbR Questions Embodies QbD

Qualityby

Design

What attributes should the drug product possess?

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?

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?

10

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

?

11

Unit OperationsMixing

CompressionCoating…

Drug Substance

Excipients

AssayUniformity

PurityDiss

“Always” Meet Spec

PAT

Clinical Relevance

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

2007/8 19

Material

Tipe pengemasan

Pengisian

Persyaratan

Peralatan

Pertimbangan ; Kemungkinan timbulnya “adverse effect”

thd produk Rute pemberian Performance of container Interaksi komponen kemasan-sediaan Kategori bahan pengemas; memenuhi

kriteria

2007/8 21

Formulasi tepat ≈ tepat kemasan

◦ Wadah (Container)

◦ Penutup (Closure)

◦ Karton

◦ Kotak (Box)

◦ Penandaan (Labeling)

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)

2007/8 23

MATERIAL

◦ Logam

◦ Plastik, karet

◦ Kaca/gelas

◦ kombinasi

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.

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

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)

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

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

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

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

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

2007/8 32

PERSYARATAN KEMASAN DAN WADAH

akurat

kualitas terjamin

memenuhi persyaratan daerah setempat

bahasa yg tepat, instruksi penggunaan, peringatan dan penandaan harus jelas

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.

2007/8 34

◦ 2 to 30 containers in connected blocks

◦ volumes from 0,12 ml to approximately 50 ml.

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

2007/8 36

Capacities range from 15ml up to 1

gallon

with neck finishes of 28mm and larger

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.

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.

Including; Change in the package insert Package labelling Container label

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

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