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Badan Pengawas Obat dan Makanan RI

National Agency of Drug and Food Control


Republic of Indonesia
2009

Badan Pengawas Obat dan Makanan RI


National Agency of Drug and Food Control
Republic of Indonesia
2009

National Agency Drug and Food Control Republic of Indonesia


2009

HAK CIPTA DILINDUNGI UNDANG-UNDANG


Dilarang memperbanyak buku ini sebagian atau seluruhnya,
dalam bentuk dan dengan cara apapun juga, baik secara
mekanis maupun elektronis, termasuk fotocopy, rekaman, dan
lain-lain tanpa izin tertulis dari penerbit.

KATALOG DALAM TERBITAN


BADAN PENGAWAS OBAT DAN MAKANAN RI

Pedoman Cara Pembuatan Bahan Aktif Obat yang Baik


Jakarta : Badan POM RI, 2009
Hlm. 98 + 7 : 18 x 25 cm.

PENGANTAR

PREFACE

Seiring dengan perkembangan industri farmasi


di Indonesia dalam pembuatan obat,
khususnya dalam memproduksi bahan aktif
obat, Badan POM menerbitkan Pedoman Cara
Pembuatan Bahan Aktif Obat yang Baik
(CPBAOB).

In accordance with the development of


pharmaceutical industry in Indonesia on
manufacturing
of
medicinal
products
particulary in manufacturing of active
pharmaceutical ingredients, The National
Agency of Drug and Food Control issued the
GMP Guide for Active Pharmaceutical
Ingredients.

Pedoman ini merupakan panduan yang


digunakan dalam pembuatan Bahan Aktif
Obat (BAO) untuk menjamin bahwa Bahan
Aktif Obat senantiasa memenuhi persyaratan
mutu dan kemurnian yang ditetapkan agar
diperoleh
hasil
yang
konsisten,
dan
merupakan Aneks 8 dari Pedoman CPOB
yang berlaku dan suplemennya (jika ada).

This Guideline is intended to provide guidance


regarding Good Manufacturing Practice (GMP)
for the manufacturing of active pharmaceutical
ingredients (APIs) to ensure that APIs meet
the requirements for quality and purity to
produce consistent product,

Dalam penyusunan pedoman ini, acuan yang


digunakan antara lain PIC/S Annex 18 GMP
Guide for Active Pharmaceutical Ingredients
tahun 2009 dan ICH Q7A Good Manufacturing
Practice Guidance for Active Pharmaceutical
Ingredients tahun 2001.

In preparing this guideline, the References


used among others are the 2009 PIC/S Annex
18 GMP Guide for Active Pharmaceutical
Ingredients and the 2001 ICH Q7A Good
Manufacturing Practice Guidance for Active
Pharmaceutical Ingredients.

Pedoman ini berlaku untuk pembuatan BAO


yang digunakan sebagai produk obat untuk
manusia yang dibuat dengan cara sintesis
kimia, ekstraksi, kultur jaringan/fermentasi,
perolehan kembali, atau kombinasi apapun
dari proses tersebut.
Tahapan proses
pembuatan mencakup seluruh kegiatan yang
terdiri dari penerimaan bahan, produksi,
pengemasan, pengemasan ulang, pelabelan,
pelabelan
ulang,
pengawasan
mutu,
pelulusan, penyimpanan dan distribusi dari
BAO dan pengawasan terkait.

This Guide applies to the manufacture of APIs


for medicinal products for human use that are
manufactured
by
chemical
synthesis,
extraction, cell culture/ fermentation, recovery
from natural sources, or any combination of
these processes. The term manufacturing
includes all operations of receipt of materials,
production, packaging, repackaging, labeling,
relabelling, quality control, release, storage
and distribution of APIs and the related
controls.

Diharapkan penerapan Pedoman CPBAOB ini


akan meningkatkan mutu produk obat serta
memberikan perlindungan yang lebih baik
terhadap kesehatan masyarakat dan pada
akhirnya akan menjadi langkah progresif
terhadap perkembangan industri bahan aktif
obat di Indonesia sehingga mutu obat
mendapat pengakuan dan kepercayaan
internasional.

It is expected that the implementation of the


GMP Guide for Active Pharmaceutical
Ingredients will improve the quality of
pharmaceutical products and subsequently
provide better protection to the public health.
Additionally the GMP Guidelines for Active
Pharmaceutical Ingredients should be a
progressive step towards the development of
the
Indonesian
Active
Pharmaceutical
Ingredient Industries capability to produce
quality drug products that receive international
recognition and trust.

Edisi 2009

-i-

2009 Edition

Penghargaan dan ucapan terima kasih kami


sampaikan khususnya kepada Tim Penyusun
Buku Pedoman CPBAOB yang telah
memberikan sumbangan pikiran, waktu dan
tenaga mereka sehingga memungkinkan
penerbitan Pedoman CPBAOB. Ucapan
terima kasih juga kami sampaikan kepada
semua
pihak
yang
mendukung
dan
berpartisipasi baik secara langsung atau tidak
langsung dalam penyusunan dan penerbitan
buku Pedoman CPBAOB ini.

We would like to express our appreciation to


the National GMP Team who has given
valuable contribution on ideas, time and
energy, to enable the publication of this GMP
Guide for APIs. We also 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 developing
this GMP Guide.

Deputi Bidang Pengawasan


Produk Terapetik dan NAPZA,
Deputy for Therapeutic Products, Narcotics,
Psychotropics and Addictive Substances Control,

Dra. Lucky S. Slamet, M. Sc.

NIP: 19530612 198003 2 001

Edisi 2009

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2009 Edition

EDITOR TEAM

TIM PENYUSUN
Pengarah

Ketua

: 1. Kepala Badan POM


2. Deputi Bidang Pengawasan
Produk Terapetik dan
NAPZA

: Direktur Pengawasan Produksi


Produk Terapetik dan PKRT

Advisor

: 1. Head of National Agency


of Drug and Food Control
2. Deputy
of
Therapeutic
Products, Narcotics,
Psychotropics and
Addictive Substances
Control

Chairman : Director of Control of


Production of Therapeutic
Products and Household
Products
Anggota
Members

1. Anandayu Nurfachtiyani, S.Farm.


2. A. Retno Tyas Utami, Dra., M.Epid.
3. Bayu Wibisono, S.Si.
4. Dwi Ary Restuti, S.Farm.
5. Elis Sukmawati, Dra.
6. Mudi Yunita Bukit, Dra.
7. Rumondang Simanjuntak, Dra.
8. Shanti Marlina, S.Si.
9. Togi Hutadjulu, Dra., MHA
Tim Ahli
Expert Team
1. Adriansyah, Drs.
2. Amin Sjaugi, Drs.
3. Daniel Santoso, Dr.
4. Herny Prasetya, Dra.
5. H. Husni Azhar, Drs., MBA
6. Leiman Sutanto, Dr.
7. M. Sumarno, Drs.
8. Oenggoel Priboedhi, Drs.
9. Pawitra Kresno, Dra.
10. Retno Utami, Dra.
11. Rudy F.B. Mantik, Drs.
12. Sumaria Sudian, Dra.
13. Tanusoma Widjaja, Drs.
14. Uluan Sitorus, Dr.
15. V. Surjana, Drs.
16. Widiastuti Adiputra, Dra.

Edisi 2009

- iii -

2009 Edition

Daftar Isi

Table of Contents

DAFTAR ISI

TABLE OF CONTENTS

Halaman
PENGANTAR ......................................
i
TIM PENYUSUN .................................. iii
DAFTAR ISI ........................................ iv

PREFACE ...........................................
EDITOR TEAM ....................................
TABLE OF CONTENT ........................

Page
i
iii
iv

BAB 1 PENDAHULUAN .................


Tujuan .............................................
Ruang Lingkup ................................

1
1
2

CHAPTER 1 INTRODUCTION .....


Objective ........................................
Scope .............................................

1
1
2

BAB 2 MANAJEMEN MUTU ...........


..............................................
Prinsip .............................................
Tanggung Jawab Unit Mutu ............

5
5

Tanggung Jawab untuk Aktivitas


Produksi ..........................................
Audit Internal (Inspeksi Diri) ............
Pengkajian Mutu Produk .................

8
9
9

CHAPTER 2 QUALITY
MANAGEMENT .......
Principle ..........................................
Responsibilities of the Quality
Unit(s) .............................................
Responsibility for Production
Activities .........................................
Internal Audits (Self Inspection) ......
Product Quality Review ..................

BAB 3 PERSONALIA .....................


Kualifikasi Personil ..........................
Higiene Perorangan ........................
Konsultan ........................................

11
11
11
12

CHAPTER 3 PERSONNEL
Personnel Qualifications .................
Personal Hygiene ...........................
Consultants ....................................

11
11
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12

BAB 4 BANGUNAN DAN


FASILITAS ..........................
Desain dan Konstruksi ....................
Sarana Penunjang ..........................
Air ...................................................
Containment ...................................
Pencahayaan ..................................
Penanganan Limbah .......................
Sanitasi dan Perawatan ..................

13
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16
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17
17
17

CHAPTER 4 BUILDINGS AND


FACILITIES .............
Design and Construction ................
Utilities ............................................
Water ..............................................
Containment ...................................
Lighting ...........................................
Sewage and Refuse .......................
Sanitation and Maintenance ...........

13
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15
16
16
17
17
17

BAB 5 PERALATAN PROSES .......


Desain dan Konstruksi ....................
Perawatan dan Pembersihan
Peralatan ........................................
Kalibrasi .........................................
Sistem Komputerisasi .....................
BAB 6 DOKUMENTASI DAN
CATATAN ............................
Spesifikasi dan Sistem
Dokumentasi ...................................
Catatan Penggunaan dan
Pembersihan Peralatan ..................

Edisi 2009

CHAPTER 5 PROCESS
EQUIPMENT ............
Design and Construction ................
Equipment Maintenance and
Cleaning .........................................
Calibration ......................................
Computerized Systems ..................

19
19
20
22
22

CHAPTER 6 DOCUMENTATION
AND RECORDS ......
Documentation System and
Specifications .................................
Equipment Cleaning and Use
Record ............................................

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2009 Edition

Daftar Isi

Catatan Bahan Baku, Produk


Antara, Label dan Bahan
Pengemas Bahan Aktif Obat ..........
Prosedur Produksi Induk (Catatan
Produksi dan Pengawasan Induk) ..
........................................................
Catatan Bets Produksi (Catatan
Produksi dan Pengawasan Bets) ....
Catatan Pengawasan Mutu ............
Pengkajian Catatan Bets Produksi ..
BAB 7 PENGELOLAAN BAHAN ...
..............................................
Pengawasan Secara Umum ...........
Penerimaan dan Karantina .............
Pengambilan Sampel dan
Pengujian Bahan Produksi yang
Datang ............................................
Penyimpanan ..................................
Reevaluasi ......................................
BAB 8 PRODUKSI DAN
PENGAWASAN SELAMA
PROSES ..............................
Kegiatan Produksi ..........................
Batas Waktu ...................................
Pengambilan Sampel-SelamaProses dan Pengawasan-SelamaProses ............................................
Blending Bets Produk Antara atau
BAO ................................................
Pengawasan terhadap Kontaminasi

Table of Contents

Records of Raw Materials,


Intermediates, API Labelling and
Packaging Materials .......................
Master Production Procedures
(Master Production and Control
Records) .........................................
Batch Production Records (Batch
Production and Control Records) ..
Quality Control Records .................
Batch Production Record Review ...

27

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29
31
32

CHAPTER 7 MATERIALS
MANAGEMENT .......
General Controls ............................
Receipt and Quarantine .................
Sampling and Testing of Incoming
Production Materials .......................
........................................................
Storage ...........................................
Re-evaluation .................................

34
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35
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37

CHAPTER 8 PRODUCTION AND


IN-PROCESS
CONTROLS..............
Production Operations ....................
Time Limits .....................................
In-process Sampling and Controls .
........................................................
........................................................
Blending Batches of Intermediates
or APIs ...........................................
Contamination Control ....................

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CHAPTER 9 PACKAGING AND


IDENTIFICATION
LABELLING OF
APIs AND
INTERMEDIATES ....
General ..........................................
Packaging Materials .......................
Label Issuance and Control ............
........................................................
Packaging and Labelling
Operations ......................................

BAB 10 PENYIMPANAN DAN


DISTRIBUSI ........................
Prosedur Penyimpanan ..................
Prosedur Distribusi .........................

49
49
49

CHAPTER 10 STORAGE AND


DISTRIBUTION .......
Warehousing Procedures ...............
Distribution Procedures ..................

49
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49

BAB 11 PENGAWASAN MUTU ......


.............................................
Pengawasan Umum .......................

51
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CHAPTER 11 QUALITY
CONTROLS..............
General Controls ............................

51
51

BAB 9 PENGEMASAN DAN


IDENTIFIKASI LABEL BAO
DAN PRODUK ANTARA ....
..............................................
..............................................
Umum .............................................
Bahan Pengemas ...........................
Pengeluaran dan Pengendalian
Label ...............................................
Kegiatan Pengemasan dan
Pelabelan ........................................

Edisi 2009

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2009 Edition

Daftar Isi

Table of Contents

Testing of Intermediates and APIs .


Validation of Analytical Procedures
- see Section 12 .............................
Certificates of Analysis ...................
Stability Monitoring of APIs .............
Expiry and Retest Dating ................
........................................................
Reserve/Retention Samples ...........

53

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CHAPTER 12 VALIDATION ...........


Validation Policy .............................
Validation Documentation ...............
Qualification ....................................
Approaches to Process Validation ..
Process Validation Program ...........
Periodic Review of Validated
Systems ..........................................
Cleaning Validation ........................
Validation of Analytical Methods .....

66

CHAPTER 13 CHANGE CONTROL


..................................

Pengujian Produk Antara dan BAO .


Validasi Prosedur Analisis lihat
BAB 12 ...........................................
Sertifikat Analisis ............................
Pemantauan Stabilitas BAO ...........
Penanggalan Daluwarsa dan Uji
Ulang ..............................................
Sampel Pertinggal ..........................

53

BAB 12 VALIDASI ...........................


Kebijakan Validasi ...........................
Dokumentasi Validasi .....................
Kualifikasi ........................................
Pendekatan Validasi Proses ............
Program Validasi Proses .................
Pengkajian Berkala Sistem Validasi
.........................................................
Validasi Pembersihan ......................
Validasi Metode Analisis..................

58
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BAB 13 PENGENDALIAN
PERUBAHAN ......................
BAB 14 PENOLAKAN DAN
PENGGUNAAN KEMBALI
BAHAN ...............................
Penolakan........................................
Pengolahan Ulang ...........................
Pengerjaan Ulang ............................
Perolehan Kembali Bahan dan
Pelarut ............................................
Pengembalian..................................
BAB 15 PENANGANAN KELUHAN
DAN PENARIKAN
KEMBALI PRODUK ............
BAB 16 PABRIK (TERMASUK
LABORATORIUM)
PENERIMA KONTRAK .......
BAB 17 AGEN, PERANTARA,
PEDAGANG,
DISTRIBUTOR,
PERUSAHAAN
PENGEMASAN ULANG
DAN PERUSAHAAN
PELABELAN ULANG ........
Penerapan .......................................
Ketertelusuran BAO dan Produk
Antara yang Didistribusikan ............
Manajemen Mutu .............................
Pengemasan Ulang, Pelabelan

Edisi 2009

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CHAPTER 14 REJECTION AND


RE-USE OF
MATERIAL ..............
Rejection ........................................
Reprocessing .................................
Reworking ......................................
Recovery of Materials and Solvents
........................................................
Returns ...........................................

72

CHAPTER 15 COMPLAINTS AND


RECALLS ................
..................................

72

CHAPTER 16 CONTRACT
MANUFACTURERS
(INCLUDING
LABORATORIES) ...

74

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CHAPTER 17 AGENTS,
BROKERS,
TRADERS,
DISTRIBUTORS,
REPACKERS AND
RELABELLERS .......
Applicability ....................................
Traceability of Distributed APIs and
Intermediates ..................................
Quality Management ......................
Repackaging, Relabelling and

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2009 Edition

Daftar Isi

Ulang dan Penyimpanan BAO dan


Produk Antara .................................
Stabilitas .........................................
Transfer Informasi ...........................
Penanganan Keluhan dan
Penarikan Kembali ..........................
Penanganan Produk Kembalian .....
BAB 18 PEDOMAN SPESIFIK
UNTUK BAO YANG
DIBUAT DENGAN
KULTUR/ FERMENTASI
SEL .....................................
..............................................
Umum .............................................
Pemeliharaan Bank Sel dan
Penyimpanan Catatan ....................
Kultur Sel/ Fermentasi ....................
Pemanenan, Isolasi dan Pemurnian
........................................................
Langkah Penghilangan
Viral/Inaktivasi ................................

Table of Contents

Holding of APIs and Intermediates .


........................................................
Stability ...........................................
Transfer of Information ...................
Handling of Complaints and Recalls
........................................................
Handling of Returns ........................

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CHAPTER 18 SPECIFIC
GUIDANCE FOR
APIs
MANUFACTURED
BY CELL CULTURE/
FERMENTATION ....
General ..........................................
Cell Bank Maintenance and Record
Keeping ..........................................
Cell Culture/Fermentation ..............
Harvesting, Isolation and
Purification .....................................
Viral Removal/Inactivation Steps ....
........................................................

BAB 19 BAHAN AKTIF OBAT


YANG DIGUNAKAN
DALAM UJI KLINIS ............
Umum .............................................
Mutu ................................................
Peralatan dan Fasilitas ...................
Pengawasan Bahan Baku ..............
Produksi ..........................................
Validasi ...........................................
Perubahan ......................................
Pengawasan Laboratorium .............
Dokumentasi ...................................

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CHAPTER 19 APIs FOR USE IN


CLINICAL TRIALS ..
..................................
General ..........................................
Quality ............................................
Equipment and Facilities ................
Control of Raw Materials ................
Production ......................................
Validation .......................................
Changes .........................................
Laboratory Controls ........................
Documentation ...............................

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GLOSARIUM .......................................

91

GLOSSARY ........................................

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