Badan Pengawas Obat dan Makanan National Agency of Drug and Food Control

Republik Indonesia

Republic of Indonesia 2006

GUIDELINES ON GOOD MANUFACTURING

PEDOMAN

CARA PEMBUATAN OBAT YANG BAIK

Edisi 2006 - i - 2006 - Edition

PENGANTAR

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. 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. 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”. 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,

PREFACE

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. Due to the rapid development of science andtechnology 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. 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. 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.

Edisi 2006 - ii - 2006 Edition

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

The GMP Guidelines will be updated periodically and revised as necessary. Implementation of this GMP Guidelines isexpected 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. 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 inIndonesia. 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 NoNo.HK.00.06.0511, dated 24 Januari 2006. 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

Edisi 2006 - iii - 2006 Edition

TIM REVISI BUKU PEDOMAN CPOB EDISI 2006

Pengarah : 1. Kepala Badan POM 2. DeputiBidang Pengawasan Produk Terapetik dan NAPZA Ketua : Direktur Pengawasan Produksi Produk Terapetik dan PKRT.

GMP REVISION TEAM FOR THE 2006 EDITION

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

Anggota Members 1. Amin Sjaugi, Drs. 2. Berni Somalinggi, Dra. 3. Daniel Santoso, Dr. 4. Elis Sukmawati, Dra. 5. Herny Prasetya, Dra. 6. Kustantinah, Dra. 7. Lina Astuti, Dra, M.Med.Sc. 8. Mahendra, Drs. 9. M. Sumarno, Drs. 10. Mudi Yunita Bukit, Dra. 11. Oenggoel Pribudhi, Drs. 12. Pawitra Kresno, Dra. 13. Ratna Sosialin, Dra. 14. Retno Utami, Dra. 15. Rudy F. B. Mantik, Drs. 16. Rumondang Simanjuntak, Dra. 17. Sumaria Sudian, Dra. 18. Tanusoma Widjaja, Drs. 19. Togi Hutadjulu, Dra., MHA 20. Uluan Sitorus. Dr. 21. V. Surjana, Drs. 23. Dra. Yuli Hastini

Edisi 2006 - iv - 2006 Edition

D A F T A R I S I Halaman PENGANTAR ................................... i DAFTAR ISI ...................................... iv PENDAHULUAN............................... 1 Prinsip ............................................ 1 Umum............................................. 1

BAB 1 - MANAJEMEN MUTU Prinsip............................................. 3

Pemastian Mutu.............................. 4 Cara Pembuatan Obat yang Baik (CPOB) ................................... 5

Pengawasan Mutu.......................... 7 Pengkajian Mutu Produk................. 9

BAB 2 - PERSONALIA .................... 11 Prinsip............................................. 11 Umum............................................. 11 Personil Kunci................................. 11 Organisasi, Kualifikasi dan Tanggung Jawab............................ 12 Pelatihan......................................... 15

BAB 3 - BANGUNAN DAN FASILITAS.......................... 17 Prinsip............................................. 17 Umum............................................. 17 Area Penimbangan......................... 19 Area Produksi ................................. 19 Area Penyimpanan ......................... 22 Area Pengawasan Mutu ................. 24 Sarana Pendukung......................... 25

BAB 4 - PERALATAN ........................ 26 Prinsip ........................................... 26

Desain dan Konstruksi.................... 26 Pemasangan dan Penempatan ...... 28 Perawatan ..................................... 28

BAB 5 - SANITASI DAN HIGIENE . 30 Prinsip............................................. 30 Higiene Perorangan........................ 30 Sanitasi Bangunan dan Fasilitas .... 32 Pembersihan dan Sanitasi Peralatan. 34

TABLE OF CONTENT Page

P R E F A C E ........................................ i TABLE OF CONTENT ........................... iv INTRODUCTION ................................... 1 Principle.............................................. 1 General............................................... 1 CHAPTER 1 - QUALITY MANAGEMENT

Principle ............................................ 3 Quality Assurance ............................ 4 Good Manufacturing Practices for Pharmaceutical Products (GMP) ...... 5 Quality Control .................................. 7 Product Quality Review .................... 9

CHAPTER 2 - PERSONNEL ................. 11 Principle ............................................ 11 General ............................................. 11 Key Personnel .................................. 11 Organization, Qualification and Responsibilities ................................. 12 Training ............................................. 15

CHAPTER 3 - PREMISES .................... 17

Principle ............................................ 17 General ............................................. 17 Weighing Areas ................................. 19 Production Areas .............................. 19 Storage Areas ................................... 22 Quality Control Areas ........................ 24 Ancillary Areas .................................. 25

CHAPTER 4 - EQUIPMENT................... 26

Principle ............................................ 26 Design and Construction ................... 26 Installation and Location .................... 28 Maintenance ...................................... 28

CHAPTER 5 - SANITATION AND HYGIENE ...................... 30

Principle ............................................ 30 Personnel Hygiene ............................ 30 Premises Sanitation........................... 32 Equipment Cleaning and Sanitation .. 34

Daftar Isi Table of Content

Edisi 2006 - v - 2006 - Edition

Validasi Prosedur Pembersihan dan Sanitasi ................................... 35

BAB 6 - P R O D U K S I .................. 36 Prinsip............................................. 36 Umum............................................. 36 Bahan Awal ................................... 38 Validasi Proses............................... 41 Pencegahan Pencemaran

Silang ............................................. 42 Sistem Penomoran Bets/lot ............ 43 Penimbangan dan Penyerahan ...... 44 Pengembalian................................. 45 Pengolahan .................................... 46 Bahan dan Produk Kering............... 47 Pencampuran dan Granulasi .. 48 Pencetakan Tablet................... 49 Penyalutan .............................. 49 Pengisian Kapsul Keras .......... 50 Penandaan Tablet Salut dan Kapsul .............................. 50 Cairan, Krim dan Salep (non steril) ..................................... 50 Bahan Pengemas ........................... 52 Kegiatan Pengemasan ................... 53 Pra-kodifikasi Bahan Pengemas ............................... 53 Kesiapan Jalur......................... 54 Praktik Pengemasan ............... 54

Penyelesaian Kegiatan Pengemasan............................. 57

Pengawasan-Selama-Proses........... 58Bahan dan Produk yang Ditolak, Dipulihkan dan Dikembalikan ......... 59 Karantina dan Penyerahan Produk Jadi ....................................... 61 Catatan Pengendalian Pengiriman Obat .................................................. 63 Penyimpanan Bahan Awal, Bahan Pengemas, Produk Antara, Produk

Ruahan dan Produk Jadi ................... 63 Penyimpanan Bahan Awal dan Bahan Pengemas................ 65 Penyimpanan Produk Antara, Produk Ruahan dan Poduk Jadi.. 66 Pengiriman dan Pengangkutan ......... 66

BAB 7 - PENGAWASAN MUTU ..... 68 Prinsip ............................................. 68 Umum.............................................. 68 Cara Berlaboratorium Pengawasan

Mutu Yang Baik............................... 70

Validation of Cleaning and Sanitation Procedures ........................................ 35

CHAPTER 6 - PRODUCTION ............... 36

Principle ............................................ 36 General ............................................. 36 Starting Materials............................... 38 Process Validation............................. 41 Prevention of Cross-Contamination in Production ........................................ 42 Batch and Lot Numbering System ..... 43 Weighing and Dispensing .................. 44 Returns .............................................. 45 Processing ........................................ 46 Dry Material and Products ................. 47

Mixing and Granulating ................ 48 Compression................................. 49 Coating ......................................... 49 Hard Capsule Filling...................... 50 Coated Tablet and Capsule Printing.......................................... 50

Liquids, Creams, and Ointments (non-sterile) ....................................... 50 Packaging Materials .......................... 52 Packaging Operations ...................... 53

Pre-coding of Components ........... 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

CHAPTER 7- QUALITY CONTROL ..... 68 Principle ............................................ 68 General ............................................. 68 Good Quality Control Laboratory Practices ........................................... 70

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Edisi 2006 - vi - 2006 - Edition

Pengawasan Bahan Awal, Produk Antara,Produk Ruahan dan Produk Jadi ................................... ..... 75 Dokumentasi................................. ..... 76 Pengambilan Sampel.................... ..... 76 Bahan Awal ................................ 77 Bahan Pengemas ....................... 78 Kegiatan Pengambilan Sampel .. 78

Persyaratan Pengujian ............... 80 Pengendalian Lingkungan ....... .. 81 Pengawasan-Selama-Proses ..... 82 Pengujian Ulang Bahan yang Diluluskan................................ 82 Pengolahan Ulang ................... 82 Evaluasi Pengawasan Mutu terhadap Prosedur Produksi ... 83 Studi Stabilitas............................ 83

BAB 8 - INSPEKSI DIRI DAN

AUDIT MUTU ....................... 85 Prinsip............................................. 85 Aspek Untuk inspeksi Diri ............... 85 Tim Inspeksi Diri ............................. 86 Cakupan dan Frekuensi Inspeksi Diri .................................................. 86 Laporan Inspeksi Diri ...................... 86 Tindak Lanjut .................................. 87 Audit Mutu ..................................... 87 Audit dan Persetujuan Pemasok .... 87

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

BAB 10 - DOKUMENTASI ................ 96 Prinsip............................................. 96 Umum ............................................. 96 Dokumen yang Diperlukan ............. 98 Spesifikasi.................................. 98 Spesifikasi Bahan Awal.............. 98 Spesifikasi Bahan Pengemas .... 99 Spesifikasi Produk Antara dan Produk Ruahan.......................... 99

Control of Starting Materials, Intermediate, Bulk and Finished Products ............................................ 75 Documentation ................................. 76 Sampling ........................................... 76

Starting Materials .......................... 77 Packaging Materials...................... 78 Sampling Operations .................... 78 Test Requirements ...................... 80 Environment Control ..................... 81 In-process Control......................... 82 Retesting of Approved Materials ... 82 Reprocessing................................ 82 Quality Control Evaluation on Production Procedures ................. 83 Stability Study ............................... 83

CHAPTER 8 - SELF INSPECTION AND QUALITY AUDITS ........ 85

Principle ............................................ 85 Item for Self Inspection ...................... 85 Team of Self Inspection ..................... 86 Coverage and Frequency of Self Inspection .......................................... 86 Self Inspection Report ....................... 86 Follow - up Action .............................. 87 Quality Audit ...................................... 87 Suppliers’ Audit and Approval............ 87

CHAPTER 9 - HANDLING OF PRODUCT COMPLAINT, PRODUCT RECALL AND RETURNED PRODUCTS ................. 89

Principle............................................. 89 Complaints......................................... 89 Recalls............................................... 91 Returned Products............................. 94 Documentation .................................. 95

CHAPTER 10 - DOCUMENTATION ..... 96

Principle ............................................ 96 General ............................................. 96 Documents Required ........................ 98

Specifications .............................. 98 Specifications for Starting Materials ....................................... 98 Specifications for Packaging Materials ...................................... 99 Specifications for Intermediate and Bulk Product........................... 99

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Edisi 2006 - vii - 2006 - Edition

Spesifikasi Produk Jadi .............. 100 Dokumen Produksi..................... 100 Dokumen Produksi Induk........... 101 Prosedur Pengolahan Induk ...... 101 Prosedur Pengemasan Induk .... 102 Catatan Pengolahan Bets .......... 103 Catatan Pengemasan Bets ........ 104 Prosedur dan Catatan................ 106 Penerimaan ........................ 106 Pengambilan Sampel.......... 106 Pengujian............................ 107 Lain-lain .............................. 107

BAB 11 - PEMBUATAN DAN ANALISIS BERDASARKAN KONTRAK .......................... 109 Prinsip............................................. 109 Umum ............................................ 109 Pemberi Kontrak............................. 110 Penerima Kontrak......................... 110 Kontrak .......................................... 111

BAB 12 KUALIFIKASI DAN VALIDASI ...................... ... 113 Prinsip........................................... 113 Perencanaan Validasi................... 113 Dokumentasi................................. 114 Kualifikasi ..................................... 114 Kualifikasi Desain (KD) ............ 114 Kualifikasi Instalasi (KI) ............ 115 Kualifikasi Operasional (KO) ..... 115 Kualifikasi Kinerja (KK) .............. 116 Kualifikasi Fasilitas, Peralatan dan Sistem Terpasang yang telah operasional........................ 116 Validasi Proses ................................. 116 Umum ........................................ 116 Validasi Prospektif (Prospective Validation) .................................. 117 Validasi Konkuren (Concurrent Validation).................................. 118 Validasi Retrospektif (Retrospective Validation) .......... 119 Validasi Pembersihan ..................... 120 Pengendalian Perubahan ............... 121 Validasi Ulang................................. 121 Validasi Metode Analisis................. 122

Jenis Metode Analisis yang Divalidasi .............................. 122

Specifications for Finished Products ....................................... 100 Production Documents.................. 100 Master Production Document ....... 101 Master Processing Procedure....... 101 Master Packaging Procedure........ 102 Batch Processing Record ............. 103 Batch Packaging Record .............. 104 Procedures and Records .............. 106

Receipt ................................ 106 Sampling.............................. 106 Testing................................. 107 Others.................................. 107

CHAPTER 11 – CONTRACT MANUFACTURE AND ANALYSIS ………… 109

Principle .......................................... 109 General ........................................... 109 The Contract Giver ......................... 110 The Contract Acceptor .................... 110 The Contract ................................... 111

CHAPTER 12 – QUALIFICATION AND VALIDATION ............ 113

Principle .......................................... 113 Planning For Validation.................... 113 Documentation ............................... 114 Qualification ..................................... 114 Design Qualification ............... 114

Installation Qualification ......... 115 Operational Qualification........ 115 Performance Qualification...... 116 Qualification of Established (in-use) Facilities, Systems and Equipment ....................... 116

Process Validation........................... 116 General..................................... 116 Prospective Validation .............. 117 Concurrent Validation ............... 118 Retrospective Validation........... 119

Cleaning Validation.......................... 120 Change Control ............................... 121 Revalidation..................................... 121 Validation of Analytical Procedures .. 122

Types of Analytical Procedure to be Validated…………………. 122

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Edisi 2006 - viii - 2006 - Edition

ANEKS

ANEKS 1 - PEMBUATAN PRODUK

STERIL.............................. 125 Prinsip ............................... 125 Umum ............................... 125 Teknologi Isolator.................... .... 130 Teknologi Peniupan / Pengisian/ Penyegelan.............................. .... 131 Produk yang Disterilisasi Akhir .... 131 Pembuatan Secara Aseptis .......... 132 Personil .................................... 133 Bangunan dan Fasilitas ................ 136 Peralatan .................................... 139 Sanitasi .................................... 140 Air ................................................. 141 Pengolahan................................... 142 Sterilisasi ............................... 145 Sterilisasi Akhir ...................... 147 Sterilisasi Cara Panas ........... 147 Sterilisasi Cara Panas Basah 148 Sterilisasi Cara Panas kering. 149 Sterilisasi Dengan Cara Radiasi................................... 149 Sterilisasi Dengan Gas dan Fumigan................................. 151 Filtrasi Obat yang Tidak Dapat Disterilkan Dalam Wadah Akhirnya......................... 152 Indikator Biologis dan Kimiawi ... 154 Penyelesaian Produk Steril ........ 155 Pengawasan Mutu ..................... 155

ANEKS 2 - PRODUKSI PRODUK BIOLOGI........................... 157 Ruang Lingkup........................... 157 Prinsip ....................................... 157 Personil ...................................... 158 Bangunan, Fasilitas dan Peralatan ................................... 159 Sarana Pemeliharaan dan Penanganan Hewan .................. 162 Dokumentasi .............................. 163 Produksi..................................... 163 Bahan Awal.............................. 163 Lot Benih dan Sistem Bank Sel 163 Prinsip Kerja ............................ 165 Pengawasan Mutu ..................... 166

AN N E X E S

ANNEX 1 - MANUFACTURE OF STERILE

PHARMACEUTICAL PRODUCTS ..................... 125

Principle .......................................... 125 General ........................................... 125 Isolator Technology ........................ 130 Blow/Fill/Seal Technology ............... 131 Terminally Sterilized Products ........ 131 Aseptic Preparation ........................ 132 Personnel ....................................... 133 Premises ......................................... 136 Equipment ...................................... 139 Sanitation ........................................ 140 Water ............................................... 141 Processing ...................................... 142 Sterilization ..................................... 145

Terminal Sterilization ................ 147 Sterilization by Heat ................. 147 Sterilization by Moist Heat ....... 148 Sterilization by Dry Heat .......... 149 Sterilization by Radiation ......... 149 Sterilization by Gases and Fumigants ................................ 151

Filtration of Pharmaceutical Products which cannot be Sterilized in their Final Container ........................................ 152 Biological and Chemical Indicators.. 154 Finishing of Sterile Products ........... 155 Quality Control ................................ 155

ANNEX 2 - MANUFACTURE OF

BIOLOGICAL PRODUCTS .. 157 Scope ............................................. 157 Principle .......................................... 157 Personnel ....................................... 158 Premises and Equipment ................ 159 Animal Quarters and Care .............. 162 Documentation ............................... 163 Production ...................................... 163

Starting Materials ......................... 163 Seed Lot and Cell Bank System .. 163 Operating Principles ..................... 165

Quality Control ................................ 166

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Edisi 2006 - ix - 2006 - Edition

ANEKS 3 - PEMBUATAN GAS

MEDISINAL ...................... 167 Prinsip........................................ 167 Personil ...................................... 167 Bangunan, Fasilitas dan Peralatan ................................... 168 Bangunan dan fasilitas.......... 168 Peralatan............................... 168 Dokumentasi .............................. 170 Produksi..................................... 171 Produksi Produk Ruahan ...... 171 Pengisian dan Pelabelan ...... 172 Pengawasan Mutu ..................... 176 Penyimpanan dan Pelulusan ..... 177

ANEKS 4 - PEMBUATAN INHALASI DOSIS TERUKUR BER- TEKANAN (AEROSOL)... 179 Prinsip…………………………………… 179 Bangunan, Fasilitas dan Peralatan....................................... 179 Produksi dan Pengawasan Mutu… 180

ANEKS 5 - PEMBUATAN PRODUK DARAH ........................... 182 Prinsip ........................................ 182 Manajemen Mutu ....................... 183 Personil dan Pelatihan ............... 183 Pengambilan Darah dan Plasma... 184 Uji Screening untuk Screening Penanda Inspeksi ……………….. 186 Ketertelusuran dan Tindakan Pasca Pengambilan ................... 186 Bangunan dan Fasilitas.............. 188 Area Penerimaan dan Penyimpanan barang ............ 188 Area Pembuatan ................... 188 Peralatan.................................... 189 Sanitasi dan Higiene .................. 191 Higiene Perorangan .............. 191 Sanitasi Bangunan dan Fasilitas................................. 191 Pembersihan dan Sanitasi Peralatan............................... 192 Validasi Prosedur Pembersihan dan Sanitasi .......................... 193 Produksi ..................................... 193 Penyediaan Komponen......... 193 Pengolahan ........................... 193 Pelabelan .............................. 193 Pelulusan Produk .................. 194

ANNEX 3 - MANUFACTURE OF

MEDICINAL GASES ……… 167 Principle ………………………………. 167 Personnel ………………………………167 Premises and Equipment …………… 168

Premises ……………………… 168 Equipment…………………………168

Documentation ………………………. 170 Production ……………………………. 171

Bulk Production…………………. 171 Filling and Labeling..................... 172

Quality Control ................................ 176 Storage and Release ...................... 177

ANNEX 4 - MANUFACTURE OF PRESSURIZED METERED DOSE INHALER (AEROSOL) …… 179

Principle .......................................... 179 Premises and Equipment ................ 179 Production and Quality Control ....... 180

ANNEX 5 - MANUFACTURE OF BLOOD PRODUCTS .................... 182

Principle .......................................... 182 Quality Management........................ 183 Personnel and Training.................... 183 Blood and Plasma Collection........... 184 Screening Tests for Infectious Screening Markers............................................ 186 Traceability and Post Collection Measures......................................... 186 Premises.......................................... 188

Goods Receipt and Storage Areas ........................................ 188 Manufacturing Areas…............. 188

Equipment ....................................... 189 Sanitation and Hygiene.................... 191

Personnel Hygiene...................... 191 Premises Sanitation .................... 191 Equipment Cleaning and Sanitation.................................... 192 Validation of Cleaning and Sanitation Procedures................. 193

Production ....................................... 193 Component Preparation .............. 193

Processing ................................ 193 Labelling .................................... 193 Release of Products................... 194