STABILITAS KEMAMPUAN SUATU PRODUK UNTUK BERTAHAN DALAM BATAS YANG DITETAPKAN SEPANJANG PERIODE PENYIMPANAN DAN PENGGUNAAN DIMANA SIFAT DAN KARAKTERISTIKNYA SAMA DENGAN YANG DIMILIKINYA PADA SAAT DIBUAT

The Reason for Performing Stability Studies “ The purpose of a stability study is to establish based on testing a minimum of three batches of the drug substance or product, a retest period or shelf life and label storage instruction, applicable to all future batches manufactured and packaged under similar circumstances”

Factors Influencing Stability The actual stability of a finished product will depend largely on : The formulation e.g. selection of excipients with their quantities, manufacturing process The packaging closure system e.g. selection of primary packaging material, possible interaction of the drug product with the packaging material.

Formal Stability Studies Long term Study Accelerated Study Intermediate Study Commitment Study Three Primary Batches Minimum requirement : 2 pilot batches 1 batch smaller as long as it is representative with Regard to the critical manuf. steps Three Production Batches

Main Objectives of Stability Testing Type of Study Use To select adequate (from the viewpoint of stability) formulations and container closure system Accelerated Development of the product (in the development phase) To determine shelf life and storage conditions Accelerated and real time (long term) Development of the product & of the registration dossier To substantiate the claimed shelf life Real time (long term) Registration dossier (in the post registration period) To verify no changes have been introduced in the formulation or manufacturing process that can adversely affect the stability of the product Quality assurance in general, including quality control

Different Scales of Manufacturing Process Laboratory Scale Batches Produced at the early research & development lab. Stage Very small size : 100 – 1000x less than production scale Pilot Batches In the process optimization stage Generally 10% of production scale or 100.000 unit whichever is greater (oral solid dosage forms) Provides the link between process dev. & industrial production of the product To challenge the method for routine production Production Scale Batches Produced in the routine production of product

PEMBAGIAN UJI STABILITAS UJI STABILITAS DIPERCEPAT (40C) (ACCELERATED STABILITY TESTING) Memperoleh Informasi apabila sediaan mengalami kondisi “STRESS” misalnya akibat suhu Transportasi yang Tinggi UJI STABILITAS ROOM TEMP. (30C) (REAL TEMP. STABILITY TESTING) Merupakan simulasi penyimpanan produk / obat yang sebenarnya atau pada kondisi normal DATA KEDUANYA DIPERLUKAN UNTUK REGISTRASI LOKAL MAUPUN INTERNATIONAL

Kondisi Iklim Dunia Zona Iklim Temperatur rata2 tahunan Kelembabam Udara Temperatur rata2 4 bulan terpanas Kelembaban Udara I :Iklim sedang (Belgia, perancis, Inggris, US) ≤ 15 °C Tanpa Batas ≤ 22 °C II : Iklim subtropik dan mediteranian (Cina; Jepang; Afrika; Spanyol) 15 – 22 °C 22 – 30 °C III : Iklim panas & Kering (Arab Saudi; Australia; Costa Rika) > 22 °C < 60 % > 30 °C < 65 % IV : Iklim panas & Basah (Hongkong ; India Srilangka; Brazil) ≤ 60 % > 65 %

CURRENT STABILITY REGULATION NO SPECIFICATION USP & WHO ICH DEP. KES. RI Factory 1 Room Temp.-Testing Temperature and humidity Zone I : 21 + 2 C 45 + 5 % RH Zone II : 25 + 2 C 60 + 5 % RH Zone III : 30 + 2 C 35 + 5 % RH Zone IV : 30 + 2 C 70 + 5 % RH 25 + 2 C 30 + 2 C 75 + 5 % RH (New one) Refer to Asean Stability Harmonization Guideline Testing frequency Every 3 months within the first year Every 6 months after the first year Annually Every 3 months within the first year 0, 1, 3, 6, 9, 12, 24, 36, 48, etc months 2 Accelerated Testing 40 + 2 C 0, 1, 2, 3, 6 months 0, 2, 4, 6 months 0, 1, 3, 6, 9 months Definisi Room Temp. pada reff. Resmi adalah 15 – 30 C (FI, USP &JP), maka untuk meng-cover range suhu tsb., disepakati uji 30 C. Kenapa kok 40 C, bukan 50 C atau 60 C ?

History of International Regulation of Stability Testing ASEAN All ASEAN countries are situated in CZ IV In the meeting in January & June 2004 it has been concluded that ICH & WHO guidelines were inadequately addressing the real climatic conditions in most of ASEAN countries ASEAN Guideline for Drug Product Stability Study (in preparation) : Long term condition : 30 ºC ± 2 / 75% RH ± 5% RH

Misalnya zona 4 dengan temp Misalnya zona 4 dengan temp. penyimpanan obat 30 C, menurut penelitian, setiap tahun terjadi sebanyak lk 20 hari suhu 35 C dan lk 50 hari suhu 32 C. Suhu transportasi bahkan lebih dari 32 - 35 C . Mempertimbangkan kondisi extrim / STRESS, US, Uni Eropa dan Jepang melakukan harmonisasi untuk pengujian dipercepat yaitu 40 C / 75% RH. Jadi untuk kepentingan internal, secara prinsip lebih dari 40 C tidak ada masalah. Tetapi untuk memenuhi permintaan external biasanya 40 C .

BAGAIMANA DI PABRIK LAIN? Secara prinsip, mereka memenuhi regulasi tsb. Dengan menggunakan “Climatic Chamber”, karena produk mereka relatif kecil.

Terima Kasih!!