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PEDOMAN CARA PEMBUATAN OBAT YANG BAIK GUIDELINES ON GOOD MANUFACTURING Badan Pengawas Obat dan Makanan National Agency of Drug and Food Control Republik Indonesia Republic of Indonesia 2006 PENGANTAR PREFACE Pedoman Cara Pembuatan Obat yang Baik The Indonesian Good Manufacturing Practice (CPOB) pert...

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PEDOMAN CARA PEMBUATAN OBAT YANG BAIK GUIDELINES ON GOOD MANUFACTURING

Badan Pengawas Obat dan Makanan National Agency of Drug and Food Control Republik Indonesia Republic of Indonesia 2006

PENGANTAR

PREFACE

Pedoman Cara Pembuatan Obat yang Baik (CPOB) pertama kali diterbitkan pada tahun 1988, kemudian disusul dengan penerbitan. Petunjuk Operasional Penerapan CPOB pada tahun 1989 untuk memberikan penjelasan dalam penjabaran sehingga Pedoman ini dapat diterapkan secara efektif di industri farmasi.

The Indonesian Good Manufacturing Practice (GMP) guidelines for pharmaceuticals was first developed in 1988 and enforced since 1989. To make the guidelines effectively applicable and implementable, an Operational Manual for GMP Implementation was then developed in 1989.

Sejalan dengan perkembangan ilmu pengetahuan dan teknologi di bidang farmasi, Pedoman CPOB edisi pertama sekaligus Petunjuk Operasional Penerapan CPOB telah direvisi pada tahun 2001 yang terdiri dari 10 bab dan 3 addendum. Selanjutnya untuk mengantisipasi era globalisasi dan harmonisasi dalam bidang farmasi terutama pemenuhan terhadap persyaratan dan standar produk farmasi global terkini, Pedoman CPOB hendaklah diperbaiki secara berkesinambungan mengikuti perkembangan ilmu pengetahuan dan teknologi serta pergeseran paradigma dalam melakukan pengawasan terhadap mutu produk. Oleh karena itu, Pedoman CPOB Edisi 2001 direvisi kembali menjadi Pedoman CPOB yang dinamis Edisi Tahun 2006.

Due to the rapid development of science and technology in the pharmaceutical field, the first edition of GMP Guidelines was revised in 2001 which consisted of 10 chapters and 3 addenda. To anticipate globalisation era and harmonisation within the pharmaceutical sector particularly in compliance with the current requirements and standards of global pharmaceutical products, the GMP Guidelines should continuously be updated in line with the development of science and technology. Thus, the GMP Guidelines 2001 Edition is again revised to the current GMP Guidelines 2006 Edition.

Dibandingkan dengan edisi sebelumnya, Pedoman CPOB Edisi 2006 mengandung perbaikan sesuai persyaratan CPOB dinamis, antara lain “Kualifikasi dan Validasi“, “Pembuatan dan Analisis Obat Berdasarkan Kontrak”, “Pembuatan Produk Steril” dan penambahan beberapa bab serta aneks yaitu “Manajemen Mutu”, “Pembuatan Produk Darah”, “Sistem Komputerisasi”, dan “Pembuatan Produk Investigasi untuk Uji Klinis”.

The previous guidelines is improved by updating with the current GMP requirements, among others for Qualification and Validation, Contract Manufacture and Analysis, Manufacturing of Sterile Pharmaceutical Products and addition of new chapters and annexes for Quality Management System, Manufacture of Blood Products, Manufacture of Investigational Products for Clinical Trial and Computerised System.

Dalam Pedoman CPOB Edisi Tahun 2006, acuan yang digunakan antara lain WHO Technical Report Series yakni TRS 902/2002, TRS 908/2003, TRS 929/2005, dan TRS 937/2006, Good Manufacturing Practices for Medicinal Products PIC/S 2006,

References used for revision of this GMP Guidelines are WHO–TRS 902/2002, WHO – TRS 908/2003, WHO–TRS 929/2005, WHO– TRS 937/2006, Guide to GMP for Medicinal Products PIC/S 2006 and other International GMP Codes.

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dan “international codes of GMP” lain. Pedoman CPOB akan dikaji ulang secara periodis dan direvisi, bila perlu.

The GMP Guidelines will be updated periodically and revised as necessary.

Diharapkan penerapan Pedoman CPOB ini akan meningkatkan mutu produk farmasi/obat secara terus menerus serta memberikan perlindungan yang lebih baik terhadap kesehatan masyarakat. Akhirnya akan menjadi langkah progresif terhadap perkembangan industri farmasi di Indonesia sehingga mutu obat mendapat pengakuan dan kepercayaan internasional.

Implementation of this GMP Guidelines is expected to continually improve the quality of pharmaceutical products and subsequently provide better protection to the public health. Additionally the GMP Guidelines should be a progressive step towards the development of the Indonesian pharmaceutical industries’ capability to produce quality drug products that receive international recognition and trust.

Penghargaan dan ucapan terima kasih kami sampaikan khususnya kepada Tim Revisi Buku Pedoman dan Petunjuk Operasional CPOB Edisi Tahun 2006 yang telah memberikan sumbangan pikiran, waktu dan tenaga mereka sehingga memungkinkan penerbitan Pedoman CPOB ini yang diharapkan dapat mempercepat penyebaran upaya penerapan CPOB bagi industri farmasi di Indonesia.Tim Revisi Buku Pedoman dan Petunjuk Operasional CPOB Edisi Tahun 2006 tersebut ditunjuk dalam Surat Keputusan Kepala Badan Pengawas Obat dan Makanan No.HK.00.06.0511, Tanggal 24 Januari 2006.

We would like to express our appreciation and gratitude to the National GMP Team for Revision of GMP Guidelines and Operation Manual for Implementation of GMP Edition 2006 who have given valuable contribution on ideas, their time and energy, to enable the publication of this GMP Guidelines which is expected to accelerate the implementation of current GMP requirements in the pharmaceutical industries in Indonesia. The GMP Team for Revision of GMP Guidelines and Operation Manual for Implementation of GMP 2006 Edition was appointed by the Head of National Agency of Drug and Food Control under Decree No No.HK.00.06.0511, dated 24 Januari 2006.

Kami juga mengucapkan banyak terima kasih kepada semua pihak yang mendukung dan berpartisipasi baik secara langsung atau tidak langsung dalam penyusunan dan penerbitan buku Pedoman CPOB ini.

We would like to express our gratitude and respect to all other contributors, staf of National Agency of Drug and Food Control and other participants who are directly or indirectly involved in revising this GMP Guidelines

Deputi Bidang Pengawasan Produk Terapetik dan NAPZA, Deputy for Therapeutic Products, Narcotics, Psycotropics and Addictive Substances Control,

Dra. Lucky S. Slamet, M. Sc. NIP 140099151

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TIM REVISI BUKU PEDOMAN CPOB EDISI 2006 Pengarah

GMP REVISION TEAM FOR THE 2006 EDITION

: 1. Kepala Badan POM

Advisor

: 1. Head of National Agency of Drug and Food Control 2. Deputy of Therapeutic Products, Narcotics, Psychotropics and Addictive Substances Control

Chairman

: Director for Control of Production of Therapeutic Products and Household Products

2. DeputiBidang Pengawasan Produk Terapetik dan NAPZA Ketua

: Direktur Pengawasan Produksi Produk Terapetik dan PKRT.

Anggota Members 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 23.

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Amin Sjaugi, Drs. Berni Somalinggi, Dra. Daniel Santoso, Dr. Elis Sukmawati, Dra. Herny Prasetya, Dra. Kustantinah, Dra. Lina Astuti, Dra, M.Med.Sc. Mahendra, Drs. M. Sumarno, Drs. Mudi Yunita Bukit, Dra. Oenggoel Pribudhi, Drs. Pawitra Kresno, Dra. Ratna Sosialin, Dra. Retno Utami, Dra. Rudy F. B. Mantik, Drs. Rumondang Simanjuntak, Dra. Sumaria Sudian, Dra. Tanusoma Widjaja, Drs. Togi Hutadjulu, Dra., MHA Uluan Sitorus. Dr. V. Surjana, Drs. Dra. Yuli Hastini

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2006 Edition

DAFTAR

TABLE OF CONTENT

ISI

Page

Halaman PENGANTAR ...................................

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P R E F A C E ........................................

i

DAFTAR ISI ......................................

iv

TABLE OF CONTENT ...........................

iv

PENDAHULUAN............................... Prinsip ............................................ Umum.............................................

1 1 1

INTRODUCTION ................................... Principle.............................................. General...............................................

1 1 1

BAB 1 - MANAJEMEN MUTU Prinsip............................................. Pemastian Mutu.............................. Cara Pembuatan Obat yang Baik (CPOB) ................................... Pengawasan Mutu .......................... Pengkajian Mutu Produk................. BAB 2 - PERSONALIA .................... Prinsip............................................. Umum ............................................. Personil Kunci................................. Organisasi, Kualifikasi dan Tanggung Jawab............................ Pelatihan.........................................

CHAPTER 1 - QUALITY MANAGEMENT Principle ............................................ Quality Assurance ............................ Good Manufacturing Practices for Pharmaceutical Products (GMP) ...... Quality Control .................................. Product Quality Review ....................

3 4 5 7 9 11 11 11 11 12 15

3 4 5 7 9

CHAPTER 2 - PERSONNEL ................. Principle ............................................ General ............................................. Key Personnel .................................. Organization, Qualification and Responsibilities ................................. Training .............................................

11 11 11 11 12 15

BAB 3 - BANGUNAN DAN FASILITAS.......................... Prinsip............................................. Umum ............................................. Area Penimbangan ......................... Area Produksi ................................. Area Penyimpanan ......................... Area Pengawasan Mutu ................. Sarana Pendukung .........................

CHAPTER 3 - PREMISES ....................

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17 17 17 19 19 22 24 25

Principle ............................................ General ............................................. Weighing Areas ................................. Production Areas .............................. Storage Areas ................................... Quality Control Areas ........................ Ancillary Areas ..................................

17 17 19 19 22 24 25

BAB 4 - PERALATAN ........................ Prinsip ........................................... Desain dan Konstruksi.................... Pemasangan dan Penempatan ...... Perawatan .....................................

26 26 26 28 28

CHAPTER 4 - EQUIPMENT................... Principle ............................................ Design and Construction ................... Installation and Location .................... Maintenance ......................................

26 26 26 28 28

BAB 5 - SANITASI DAN HIGIENE

30

CHAPTER 5 - SANITATION AND HYGIENE ...................... Principle ............................................ Personnel Hygiene ............................ Premises Sanitation........................... Equipment Cleaning and Sanitation ..

30 30 30 32 34

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Prinsip............................................. Higiene Perorangan........................ Sanitasi Bangunan dan Fasilitas .... Pembersihan dan Sanitasi Peralatan.

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Daftar Isi

Validasi Prosedur Pembersihan dan Sanitasi ................................... BAB 6 - P R O D U K S I .................. Prinsip............................................. Umum ............................................. Bahan Awal ................................... Validasi Proses ............................... Pencegahan Pencemaran Silang ............................................. Sistem Penomoran Bets/lot ............ Penimbangan dan Penyerahan ...... Pengembalian................................. Pengolahan .................................... Bahan dan Produk Kering............... Pencampuran dan Granulasi .. Pencetakan Tablet................... Penyalutan .............................. Pengisian Kapsul Keras .......... Penandaan Tablet Salut dan Kapsul .............................. Cairan, Krim dan Salep (non steril) ..................................... Bahan Pengemas ........................... Kegiatan Pengemasan ................... Pra-kodifikasi Bahan Pengemas ............................... Kesiapan Jalur......................... Praktik Pengemasan ............... Penyelesaian Kegiatan Pengemasan............................. Pengawasan-Selama-Proses........... Bahan dan Produk yang Ditolak, Dipulihkan dan Dikembalikan ......... Karantina dan Penyerahan Produk Jadi ....................................... Catatan Pengendalian Pengiriman Obat .................................................. Penyimpanan Bahan Awal, Bahan Pengemas, Produk Antara, Produk Ruahan dan Produk Jadi ................... Penyimpanan Bahan Awal dan Bahan Pengemas................ Penyimpanan Produk Antara, Produk Ruahan dan Poduk Jadi.. Pengiriman dan Pengangkutan ......... BAB 7 - PENGAWASAN MUTU ..... Prinsip ............................................. Umum.............................................. Cara Berlaboratorium Pengawasan Mutu Yang Baik ...............................

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Table of Content

Validation of Cleaning and Sanitation Procedures ........................................

35 36 36 36 38 41

CHAPTER 6 - PRODUCTION ............... Principle ............................................ General ............................................. Starting Materials............................... Process Validation ............................. Prevention of Cross-Contamination in Production ........................................ Batch and Lot Numbering System ..... Weighing and Dispensing .................. Returns .............................................. Processing ........................................ Dry Material and Products ................. Mixing and Granulating ................ Compression................................. Coating ......................................... Hard Capsule Filling...................... Coated Tablet and Capsule Printing.......................................... Liquids, Creams, and Ointments (non-sterile) ....................................... Packaging Materials .......................... Packaging Operations ...................... Pre-coding of Components ...........

42 43 44 45 46 47 48 49 49 50 50 50 52 53 53 54 54

35 36 36 36 38 41 42 43 44 45 46 47 48 49 49 50 50 50 52 53 53

Line Clearance.............................. 54 Packaging Practices ..................... 54 Completion of the Packaging Operations .................................... 57 In-process Control ............................. 58 Rejected, Recovered and Returned Materials ............................................ 59 Finished Product Quarantine and Delivery to Finished Stock ................. 61 Control Record for Shipment of Pharmaceutical Products .................. 63 Storage of Starting Materials, Packaging Materials, Intermediates, Bulk Products and Finished Product......................... 63 Storage of Starting Materials and Packaging Materials..................... 65 Storage of Intermediate, Bulk and Finished Products ................. 66 Dispatch and Transport ..................... 66

57 58 59 61 63 63 65 66 66

CHAPTER 7- QUALITY CONTROL ..... Principle ............................................ General ............................................. Good Quality Control Laboratory Practices ...........................................

68 68 68 70

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Daftar Isi

Pengawasan Bahan Awal, Produk Antara,Produk Ruahan dan Produk Jadi ................................... ..... Dokumentasi................................. ..... Pengambilan Sampel.................... ..... Bahan Awal ................................ Bahan Pengemas ....................... Kegiatan Pengambilan Sampel .. Persyaratan Pengujian ............... Pengendalian Lingkungan ....... .. Pengawasan-Selama-Proses ..... Pengujian Ulang Bahan yang Diluluskan ................................ Pengolahan Ulang ................... Evaluasi Pengawasan Mutu terhadap Prosedur Produksi ... Studi Stabilitas............................ BAB 8 - INSPEKSI DIRI DAN AUDIT MUTU ....................... Prinsip............................................. Aspek Untuk inspeksi Diri ............... Tim Inspeksi Diri ............................. Cakupan dan Frekuensi Inspeksi Diri .................................................. Laporan Inspeksi Diri ...................... Tindak Lanjut .................................. Audit Mutu ..................................... Audit dan Persetujuan Pemasok ....

Table of Content

Control of Starting Materials, Intermediate, Bulk and Finished Products ............................................ Documentation ................................. Sampling ........................................... Starting Materials .......................... Packaging Materials...................... Sampling Operations .................... Test Requirements ...................... Environment Control ..................... In-process Control......................... Retesting of Approved Materials ...

75 76 76 77 78 78 80 81 82 82 82

Reprocessing ................................ Quality Control Evaluation on Production Procedures ................. Stability Study ...............................

83 83

CHAPTER 8 - SELF INSPECTION AND QUALITY AUDITS ........ Principle ............................................ Item for Self Inspection ...................... Team of Self Inspection ..................... Coverage and Frequency of Self Inspection .......................................... Self Inspection Report ....................... Follow - up Action .............................. Quality Audit ...................................... Suppliers’ Audit and Approval............

85 85 85 86 86 86 87 87 87

75 76 76 77 78 78 80 81 82 82 82 83 83 85 85 85 86 86 86 87 87 87

BAB 9 - PENANGANAN KELUHAN TERHADAP PRODUK, PENARIKAN KEMBALI PRODUK DAN PRODUK KEMBALIAN ......... 89 Prinsip............................................. 89 Keluhan .......................................... 89 Penarikan Kembali Produk ............. 91 Produk Kembalian .......................... 94 Dokumentasi ................................... 95

CHAPTER 9 - HANDLING OF PRODUCT COMPLAINT, PRODUCT RECALL AND RETURNED PRODUCTS ................. 89 Principle............................................. 89 Complaints......................................... 89 Recalls............................................... 91 Returned Products............................. 94 Documentation .................................. 95

BAB 10 - DOKUMENTASI ................ Prinsip............................................. Umum ............................................. Dokumen yang Diperlukan ............. Spesifikasi.................................. Spesifikasi Bahan Awal..............

96 96 96 98 98 98

Spesifikasi Bahan Pengemas ....

99

CHAPTER 10 - DOCUMENTATION ..... Principle ............................................ General ............................................. Documents Required ........................ Specifications .............................. Specifications for Starting Materials ....................................... Specifications for Packaging Materials ...................................... Specifications for I...