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SUPLEMEN I PEDOMAN CARA PEMBUATAN OBAT YANG BAIK 2006 FIRST SUPPLEMENT FOR GUIDELINES ON GOOD MANUFACTURING PRACTICES 2006

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Page 1: Buku Suplemen I

Badan Pengawas Obat dan Makanan RI

SUPLEMEN IPEDOMAN CARA PEMBUATAN OBAT YANG BAIK 2006

FIRST SUPPLEMENT FOR GUIDELINES ON GOOD MANUFACTURING PRACTICES 2006

Page 2: Buku Suplemen I

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

Republic of Indonesia2009

National Agency Drug and Food Control Republic of Indonesia2009

National Agency Drug and Food Control Republic of Indonesia2009

SUPLEMEN IPEDOMAN CARA PEMBUATAN OBAT YANG BAIK 2006FIRST SUPPLEMENT FOR GUIDELINES ON GOOD MANUFACTURING PRACTICES 2006

Page 3: Buku Suplemen I

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 TERBITANBADAN PENGAWAS OBAT DAN MAKANAN

Suplemen I Pedoman Cara Pembuatan Obat yang Baik 2006

Jakarta : Badan POM, 2009 Hlm. 115 + 6 : 17 x 24 cm.

Page 4: Buku Suplemen I

Dalam rangka pemutakhiran Pedoman Cara pembuatan Obat yang Baik (CPOB) tahun 2006, perlu diterbitkan Suplemen terhadap Pedoman Cara Pembuatan Obat yang Baik yang merupakan pemutakhiran, penambahan dari persyaratan sesuai Standar Internasional yang berlaku. Suplemen Pedoman CPOB ini adalah Suplemen yang pertama diterbitkan untuk melengkapi Pedoman CPOB 2006.

Suplemen Pedoman CPOB ini mengacu pada Standar Internasional antara lain WHO Technical Report Series (TRS) yakni TRS 937/2006, WHO guidelines, IAEA – RAS/02/09 Good Manufacturing Practices for Medicinal Products PIC/S 2006 dan Good Manufacturing Practices for Medicinal Products PIC/S 2009.

Suplemen 1 dari Pedoman CPOB ini berisi aspek yang belum tercantum dalam Pedoman CPOB tahun 2006 seperti Cara Pembuatan Radiofarmaka yang Baik, Penggunaan Radiasi Pengion dalam Pembuatan Obat, Sampel Pembanding dan Sampel Pertinggal, Cara Penyimpanan dan Pengiriman Obat yang Baik serta pemutakhiran Pedoman CPOB tahun 2006 sehingga sesuai PIC/S guidelines tahun 2009 yang terdiri dari Manajemen Mutu, Pembuatan Produk Cairan, Krim & Salep, Pengambilan Sampel Bahan Awal dan Bahan Pengemas dan Aneks 1. Pembuatan Produk Steril.

Khusus Bab 1. Manajemen Mutu dan Aneks 1 yang dibahas pada Suplemen Pedoman CPOB ini, menggantikan Bab 1 dan aneks 1 yang tercantum pada Pedoman CPOB tahun 2006, sedangkan penyesuaian yang lain merupakan tambahan terhadap Pedoman CPOB tahun 2006.

Pedoman Cara pembuatan radiofarmaka

Due to establish a current Good Manufacturing Practices (GMP) Guidelines 2006 edition, necessary to develop a GMP Supplement by updating with the current international requirement.This GMP Guidelines Supplement is the first published supplement in order to complete the GMP Guidelines 2006 edition.

References used for developing This GMP Guidelines Supplement are WHO Technical Report Series (TRS) TRS 937/2006, WHO guidelines, IAEA – RAS/02/09 Good Manufacturing Practices for Medicinal Products PIC/S 2006 and Good Manufacturing Practices for Medicinal Products PIC/S 2009.

This Supplement 1 of the GMP Guidelines consist of some aspects that haven’t covered in GMP Guidelines 2006 edition, such as Good Radiopharmaceutical Manufacturing Practices, The Use of Ionizing Radiation in The Manufacture of Medicinal Product, Reference and Retention Sample, Good Storage and Dispatch Practices, and updates of GMP Guidelines 2006 edition so it becomes in line with PIC/S Guidelines 2009 edition that includes Quality Management, Manufacturing of Liquid, Cream, and Ointment, Sampling of Starting and Packaging Material, Reference and Retained Sample, Annex 1. Manufacture of Sterile Pharmaceutical Products.Particular for Chapter 1. Quality Management and Annex 1 described in this supplement are the substitutes to Chapter 1 and Annex 1 in the GMP Guidelines 2006 edition, while other chapters are the addendum of GMP Guidelines 2006 edition.

Good radiopharmaceutical manufacturing

PENGANTAR PREFACE

Page 5: Buku Suplemen I

yang baik yang terdapat dalam suplemen ini menjadi pedoman bagi industri/rumah sakit yang memproduksi sediaan radiofarmaka.

Selanjutnya kami ucapkan terima kasih dan penghargaan kepada semua pihak, khususnya Tim Nasional CPOB Badan POM RI yang telah memberikan bantuan, dukungan dan partisipasi aktif baik secara langsung maupun tidak langsung dalam penyusunan Suplemen 1 dari Pedoman Cara Pembuatan Obat yang Baik ini.

practices in this supplement will guide the pharmaceutical industry/hospital which is concerned in radiopharmaceutical product manufacturing.

We also would like to express our gratitude and appreciation to all involved contributors particularly to the NADFC National GMP Team for the valuable contribution and active participation in developing this GMP Guidelines Supplement 1.

Deputi Bidang PengawasanProduk Terapetik dan NAPZA,

Deputy for Therapeutic Products, Narcotics,Psycotropics and Addictive Substances Control,

Dra. Lucky S. Slamet, M. Sc. NIP: 19530612 198003 2 001

Pengarah : 1. Kepala Badan POM

2. Deputi Bidang Pengawasan Produk Terapetik dan NAPZA

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

Aggota

TIM PENYUSUN TEAM

Page 6: Buku Suplemen I

Members

Tim Ahli

Expert

HalamanPENGANTAR ................................. i

DAFTAR ISI.................................... iv

SUPLEMEN BAB 1 – MANAJEMEN MUTU.............................................. 1

Prinsip ....................................... 1Pemastian Mutu ........................ 2

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

Pengakjian Mutu Produk........... 7Manajemen Risiko Mutu............. 9

PagePREFACE....................................... i

TABLE OF CONTENT……………... iv

SUPPLEMENT TO CHAPTER 1 – QUALITY MANAGEMENT…….….. 1

Principle………………………….. 1Quality Assurance………………. 2Good Manufacturing Practices For

Pharmaceutical Products (GMP) 4Quality Control…………………… 5Product Quality Review………… 7Quality Risk Management……… 9

DAFTAR ISI TABLE OF CONTENT

Page 7: Buku Suplemen I

SUPLEMEN BAB 6 – PEMBUATAN PRODUK CAIRAN, KRIM DAN SALEP ………………. 11

Prinsip…………………………… 11 Produksi………………………… 11

SUPLEMEN BAB 7 – PENGAMBILAN SAMPEL BAHAN AWAL DAN BAHAN …………….. 12 Prinsip………………………….. 12 Bahan Awal……………………. 12

ANEKS 1 – PEMBUATAN PRODUK STERIL………………… 14

Prinsip………………………….. 14Umum…………………………... 14Klasifikasi Ruang Bersih dan Peralatan Udara Bersih………. 16Pemantauan Ruang Bersih dan Sarana Udara Bersih…………. 17Teknologi Isolator…………….. 22

Teknologi Peniupan/Pengisian/ Penyegelan 23Produk yang Disterilisasi Akhir. 23Pembuatan secara Aseptik…... 24

Personil………………………… 25Bangunan dan Fasilitas……… 28Peralatan……………………… 31Sanitasi………………………... 32Air……………………………… 33Pengolahan…………………... 34Sterilisasi……………………… 38Filtrasi Obat yang tidak Dapat Disterilkan Dalam Wadah Akhirnya………………………. 45Indikator Biologis dan Kimiawi. 47Penyelesaian Produk Steril….. 48Pengawasan Mutu……………. 48

ANEKS 8 – PEMBUATAN RADIOFARMAKA........................ 50

Ruang Lingkup………………... 50Prinsip………………………….. 51Otoriita Pengawasan………….Personilia……………………… 52Bangunan dan Peralatan……. 55Produksi……………………….. 62Produksi Steril…………………Pelabelan……………………… 65Catatan Produksi dan Distribusi 69

SUPPLEMENT TO CHAPTER 6 – MANUFACTURE OF LIQUIDS, CREAMS AND OINTMENT……….. 11

Principle…………………………. 11Production………………………. 11

SUPPLEMENT TO CHAPTER 7 – SAMPLING OF STARTING AND PACKAGING MATERIALS........... 12

Principle…………………………. 12Starting Materials………………. 12

ANNEX 1 – MANUFACTURE OF STERILE PHARMACEUTICAL….. 14

Principle…………………………. 14General………………………….. 14Clean and air Device Classification……………………. 16Clean Room and Clean Air Device Monitoring……………………….. 17Isolator Technology…………….. 22Blow/Fill/Seal Technology……… 23

Terminally Sterilized Products… 23Aseptic Preparation…………….. 24

Personnel……………………….. 25Premises………………………… 28

Equipment………………………. 31Sanitation……………………….. 32Water……………………………. 33Processing……………………… 34Sterilization……………………… 38Filtration of Pharmaceutical Products Which Cannot be Sterilized in Their Final Container 45Biological and Chemical Indicators 47Finishing of Sterile Products 48Quality Control 48

ANNEX 8 – MANUFACTURE OF RADIOPHARMACEUTICALS…… 50

Scope………………………….… 50Prinsip…………………………... 51Regulatory Control……………..Personnel………………………. 52Premises and Equipment…….. 55Produksi………………….……... 62Sterile Production………………Labeling…………………….…... 65Production and Distribution 69

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Pengawasan Mutu…………… 70Distribusi dan Penarikan Kembali Produk…………….... 78Dokumentasi…………………. 79Proteksi dan Keselamatan terhadap Radiasi ....…………. 80Persyaratan Minimum untuk Pelulusan Produk .………….Persyaratan Minimum untuk Pelulusan Fasilitas...…………Radiofarmasi Rumah Sakit…. 80Glosarium..………… ..……...

ANEKS 10 – PENGGUNAAN RADIASI PENGION PADA PEMBUATAN OBAT................. 87

Pendahuluan.......................... 87Tanggung Jawab.................... 87Dosimetri................................ 88Validasi Proses....................... 89Commissioning Fasilitas......... 90Bangunan............................... 94Pemrosesan........................... 94Dokumentasi........................... 96Pemantauan Mikrobiologi....... 97

ANEKS 11 – SAMPEL PEMBANDING DAN SAMPEL PERTINGGAL............................. 98

Ruang Lingkup........................ 98Prinsip..................................... 98Durasi Penyimpanan................ 100Jumlah Sampel Pertinggal dan Sampel Pembanding............... 100Kondisi Penyimpanan.............. 101Kontrak Tertulis....................... 101Sampel Pembanding-Umum... 102

Sampel Pertinggal-Umum....... 102

Sampel Pembanding dan Pertinggal untuk Obat Impor... 103Sampel Pembanding dan Pertinggal Bila Industri Farmasi ditutup....................... 103

ANEKS 12 – CARA PENYIMPANAN DAN PENGIRIMAN OBAT

105

Records……………………..…..Quality Control……………..….. 70Distribution and Recalls….….... 78

Documentation……………..….. 79Radiation Protection and Safety 80

Minimum Requirement for Product Release…………..……………..Facility for Release-Minimum Requiremen…………..…………Hospital Radiopharmacy…..….. 80Glossary

ANNEX 9 USE OF IONISING RADIATION IN THE MANUFACTURE OF MEDICINAL PRODUCTS…..... 87

Introduction……………………... 87Responsibility…………………… 87Dosimetry……………………….. 88Validation of Process………….. 89Commissioning of the Plant…... 90Premises………………………… 94Processing………………………. 94Documentation…………………. 96Microbiological Monitoring…….. 97

ANNEX 11 – REFERENCE AND RETENTION SAMPLE……………. 98

Scope……………………………. 98Principle…………………………. 98Duration of Storage…………….. 100Size of Retention and Reference Samples……………. 100Storage Condition……………… 101Written Agreement…………….. 101Reference Sample-General Points…………………………… 102

Retained Sample-General Points………………………………. 102Reference and Retention Samples for Imported Products………… 103Reference and Retention Samples in Case of Closedown of A Manufacturer………………… 103

ANNEX 12 – GOOD STORAGE AND DISPATCH

105

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YANG BAIK.................................Prinsip...................................... 105Umum...................................... 105Personil................................... 106Organisasi dan Manajemen.... 106Manajenem Mutu.................... 107Bangunan dan Fasilitas Penyimpanan......................... 108Penerimaan............................ 108Kondisi Penyimpanan dan Transportasi........................... 109Kendaraan dan Perlengkapan 109Wadah Pengiriman dan Pelabelan............................... 110Pengiriman............................. 111Dokumentasi.......................... 112Keluhan.................................. 113Kegiatan-Kegiatan Kontrak.... 113Inspeksi Diri............................ 114

ANEKS 13 – PARAMETRIC RELEASE……………………….. 117Prinsip....................................... 117Parametric Release…………… 117Parametric Release untukProduk Sterile………………….. 117Glosarium………………………. 121

PRACTICES……………………....

Principle………………………… 105General………………….……… 105Personnel………………………. 106Organization and Management. 106Quality Management………….. 107Premises, Warehousing and Storage…………………….. 108Receipt…………………….……. 108Storage Condition and Transportation………….……… 109Vehicle and Equipment.…….… 109Shipment Containers and Container Labelling…….……… 110Dispatch………………….…….. 111Documentation………….…….. 112Complaint…………….….…….. 113Contract Activities……….…….. 113Self Inspection…………………. 114

ANNEX 13 – PARAMETRIC RELEASE……………………… 117Principle………………………… 117Parametric Release…………… 117Parametric Release for SterileProducts………………………. 117Glossary……………............... 121

SUPPLEMENT BAB 1

PRINSIP

Industri farmasi harus membuat obat sedemikian rupa agar sesuai den gan tujuan penggunaannya, memenuhi persyaratan yang tercantum dalam dokumen izin edar (registrasi) dan tidak menimbulkan risiko yang membahayakan penggunanya karena tidak aman, mutu rendah atau tidak efektif. Manajemen bertanggung jawab untuk pencapaian tujuan ini melalui suatu “Kebijakan Mutu”, yang memerlukan partisipasi dan

SUPPLEMENT CHAPTER 1

PRINCIPLE

The Pharmaceutical Industry must manufacture pharmaceutical products so as to ensure that they are fit for their intended use, comply with the requirements of the marketing authorization and do not place patients at risk due to inadequate safety, quality or efficacy. The attainment of this quality objective is the responsibility of senior/top management who determines the “Quality Policy”, requires the participation and commitment by staff in all

MANAJEMEN MUTU QUALITY MANAGEMENT

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komitmen dari semua jajaran di semua departemen di dalam perusahaan, para pemasok dan para distributor. Untuk mencapai tujuan mutu secara konsisten dan dapat diandalkan, diperlukan sistem Pemastian Mutu yang didesain secara menyeluruh dan diterapkan secara benar serta menginkorporasi Cara Pembuatan Obat yang Baik termasuk Pengawasan Mutu dan Manajemen Risiko Mutu.

Unsur dasar manajemen mutu adalah :

a) suatu infrastruktur atau sistem mutu yang tepat mencakup struktur organisasi, prosedur, proses dan sumber daya; dan

b) tindakan sistematis yang diperlukan untuk mendapatkan kepastian dengan tingkat kepercayaan yang tinggi, sehingga produk (atau jasa pelayanan) yang dihasilkan akan selalu memenuhi persyaratan yang telah ditetapkan. Keseluruhan tindakan tersebut disebut Pemastian Mutu.

Semua bagian sistem Pemastian Mutu hendaklah didukung dengan ketersediaan personil yang kompeten, bangunan dan sarana serta peralatan yang cukup dan memadai. Tambahan tanggung jawab legal hendaklah diberikan kepada kepala Manajemen Mutu (Pemastian Mutu).

1.1 Konsep dasar Pemastian Mutu, Cara Pembuatan Obat yang Baik (CPOB), Pengawasan Mutu dan Manajemen Risiko Mutu adalah aspek manajemen mutu yang saling terkait. Konsep tersebut diuraikan di sini untuk menekankan hubungan dan betapa penting konsep tersebut dalam produksi dan pengawasan produk.

PEMASTIAN MUTU

1.2 Pemastian Mutu adalah suatu konsep luas yang mencakup semua hal baik secara tersendiri maupun secara kolektif, yang akan memengaruhi mutu dari obat yang dihasilkan. Pemastian Mutu adalah totalitas semua pengaturan yang dibuat dengan tujuan untuk memastikan bahwa obat

departments and at all levels within the company, by the company's suppliers and by the distributors. To reliably achieve the quality objective there must be a comprehensively designed and correctly implemented system of Quality Assurance incorporating Good Manufacturing Practice and thus Quality Control and Quality Risk Management.

The basic elements of the quality management are: a) an appropriate infrastructure or

quality system encompassing the organizational structure, procedures, processes and resources;

b) systematic actions necessary to ensure adequate confidence that a product (or service) will satisfy given requirements for quality. The totality of these actions is termed Quality Assurance.

All parts of the Quality Assurance systems should be adequately resourced with competent personnel, and suitable and sufficient premises, equipment and facilities. There are additional legal responsibilities for the head of Quality Management (Quality Assurance).

1.1 The basic concepts of Quality Assurance, Good Manufacturing Practices, Quality Control and Quality Risk Management are inter-related aspects of quality management. They are described here in order to emphasize their relationships and their fundamental importance to the production and control of pharmaceutical products.

QUALITY ASSURANCE

1.2 Quality Assurance is a wide ranging concept which covers all matters which individually or collectively influence the quality of a product. It is the sum total of the organized arrangements made with the object of ensuring that pharmaceutical

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dihasilkan dengan mutu yang sesuai dengan tujuan pemakaiannya. Karena itu Pemastian Mutu mencakup CPOB ditambah dengan faktor lain di luar Pedoman ini, seperti desain dan pengembangan produk.

Sistem Pemastian Mutu yang benar dan tepat bagi industri farmasi hendaklah memastikan bahwa :

a) desain dan pengembangan obat dilakukan dengan cara yang memerhatikan persyaratan CPOB dan Cara Berlaboratorium Pengawasan Mutu yang Baik;

b) semua langkah produksi dan pengendalian diuraikan secara jelas dan CPOB diterapkan;

c) tanggung jawab manajerial diuraikan dengan jelas dalam uraian jabatan;

d) pengaturan disiapkan untuk pembuatan, pemasokan dan penggunaan bahan awal dan pengemas yang benar;

e) semua pengawasan terhadap produk antara dan pengawasan-selama-proses (in-process controls) lain serta validasi yang diperlukan dilakukan;

f) pengkajian terhadap semua dokumen yang terkait dengan proses, pengemasan dan pengujian bets, dilakukan sebelum memberikan pengesahan pelulusan untuk distribusi. Penilaian hendaklah meliputi semua faktor yang relevan termasuk kondisi pembuatan, hasil pengujian dan/atau pengawasan-selama-proses, pengka-jian dokumen produksi termasuk pengemasan, pengkajian penyimpang-an dari prosedur yang telah ditetapkan, pemenuhan persyaratan dari Spesifikasi Produk Jadi dan pemeriksaan produk dalam kemasan akhir;

g) obat tidak dijual atau dipasok sebelum kepala Manajemen Mutu (Pemastian Mutu) menyatakan bahwa tiap bets produksi dibuat dan dikendalikan sesuai dengan persyaratan yang tercantum dalam izin edar dan peraturan lain yang berkaitan dengan aspek produksi, pengawasan mutu dan pelulusan produk;

products are of the quality required for their intended use. Quality Assurance therefore incorporates Good Manufacturing Practices plus other factors outside the scope of this Guide such as product design and development.

The system of Quality Assurance appropriate for the manufacture of pharmaceutical products should ensure that:a) pharmaceutical products are designed

and developed in a way that takes account of the requirements of GMP and Good Practices for Quality Control Laboratory (GPCL);

b) production and control operations are clearly specified and GMP adopted;

c) managerial responsibilities are clearly specified in job description;

d) arrangements are made for the manufacture, supply and use of the correct starting and packaging materials;

e) all necessary controls on intermediate products, and any other in-process controls and validations are carried out;

f) all documentation relating to the batch processing, packaging and testing of each batch of finished product has been reviewed before authorizing release for distribution, assessment should embrace all relevant factors, including production conditions, results of in-process testing, a review of manufacturing (including, packaging) documentation an assessment of deviations from specified procedures, compliance with Finished Product Specification, and examination of the final finished pack;

g) pharmaceutical products are not sold or supplied before the head of Quality Management (Quality Assurance) has certified that each production batch has been produced and controlled in accordance with the requirements of the marketing authorization and any other regulations relevant to the production, control and release of pharmaceutical

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h) tersedia pengaturan yang memadai untuk memastikan bahwa, sedapat mungkin, produk disimpan, didistribu-sikan dan selanjutnya ditangani sedemikian rupa agar mutu tetap dijaga selama masa edar/simpan obat;

i) tersedia prosedur inspeksi diri dan/atau audit mutu yang secara berkala mengevaluasi efektivitas dan penerapan sistem Pemastian Mutu;

j) pemasok bahan awal dan pengemas dievaluasi dan disetujui untuk memenuhi spesifikasi mutu yang telah ditentukan oleh perusahaan;

k) penyimpangan dilaporkan, diselidiki dan dicatat;

l) tersedia sistem persetujuan terhadap perubahan yang berdampak pada mutu produk;

m) prosedur pengolahan ulang dievaluasi dan disetujui; dan

n) evaluasi mutu produk berkala dilakukan untuk verifikasi konsistensi proses dan memastikan perbaikan proses yang berkesinambungan.

CARA PEMBUATAN OBAT YANG BAIK (CPOB)

1.3 CPOB adalah bagian dari Pemastian Mutu yang memastikan bahwa obat dibuat dan dikendalikan secara konsisten untuk mencapai standar mutu yang sesuai dengan tujuan penggunaan dan dipersyaratkan dalam izin edar dan spesifikasi produk.

CPOB mencakup Produksi dan Pengawasan Mutu. Persyaratan dasar dari CPOB adalah:a) semua proses pembuatan obat

dijabarkan dengan jelas, dikaji secara sistematis berdasarkan pengalaman dan terbukti mampu secara konsisten menghasilkan obat yang memenuhi persyaratan mutu dan spesifikasi yang telah ditetapkan;

b) tahap proses yang kritis dalam pembuatan, pengawasan proses dan

products; h) satisfactory arrangements exist to

ensure, as far as possible, that the pharmaceutical products are stored, distributed and subsequently handled so that quality is maintained throughout their shelf life;

i) there is a procedure for self inspection and/or quality audit which regularly appraises the effectiveness and applicability of the quality assurance system;

j) suppliers of starting materials and packaging materials are evaluated and approved to meet the company's established quality specifications;

k) deviations are reported, investigated and recorded;

l) there are systems of approving changes that may have an impact on product quality;

m) reprocessing procedures for products are evaluated and approved; and

n) regular evaluations of the quality of pharmaceutical products are conducted with the objective of verifying the consistency of the process and ensuring its continuous improvement.

GOOD MANUFACTURING PRACTICES FOR PHARMACEUTICAL PRODUCTS (GMP)

1.3 GMP is that part of Quality Assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization and product specification.

GMP is concerned with both Production and Quality Control. The basic requirements of GMP are that:a) all manufacturing processes are clearly

defined, systematically reviewed in the light of experience and shown to be capable of consistently manufacturing pharmaceutical products of the required quality and complying with their specifications;

b) critical steps of manufacturing

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sarana penunjang serta perubahannya yang signifikan divalidasi;

c) tersedia semua sarana yang diperlukan dalam CPOB termasuk: personil yang

terkualifikasi dan terlatih; bangunan dan sarana

dengan luas yang memadai; peralatan dan sarana

penunjang yang sesuai; bahan, wadah dan

label yang benar;

prosedur dan instruksi yang disetujui; dan

tempat penyimpanan dan transpor-tasi yang memadai.

d) prosedur dan instruksi ditulis dalam bentuk instruksi dengan bahasa yang jelas, tidak bermakna ganda, dapat diterapkan secara spesifik pada sarana yang tersedia;

e) operator memperoleh pelatihan untuk menjalankan prosedur secara benar;

f) pencatatan dilakukan secara manual atau dengan alat pencatat selama pembuatan yang menunjukkan bahwa semua langkah yang dipersyaratkan dalam prosedur dan instruksi yang ditetapkan benar-benar dilaksanakan dan jumlah serta mutu produk yang dihasilkan sesuai dengan yang diharapkan. Tiap penyimpangan dicatat secara lengkap dan diinvestigasi;

g) catatan pembuatan termasuk distribusi yang memungkinkan penelusuran riwayat bets secara lengkap, disimpan secara komprehensif dan dalam bentuk yang mudah diakses;

h) penyimpanan dan distribusi obat yang dapat memperkecil risiko terhadap mutu obat;

i) tersedia sistem penarikan kembali bets obat manapun dari peredaran; dan

j) keluhan terhadap produk yang beredar dikaji, penyebab cacat mutu diinvestigasi serta dilakukan tindakan perbaikan yang tepat dan pencegahan pengulangan kembali keluhan.

PENGAWASAN MUTU

processes, control and supports and their significant changes are validated;

c) all necessary facilities for GMP are provided including : appropriately

qualified and trained personnel; adequate premises

and space;

suitable equipment and services;

correct materials, containers and labels;

approved procedures and instructions; and

suitable storage and transport;

d) instructions and procedures are written in an instructional form in clear and unambiguous language, specifically applicable to the facilities provided;

e) operators are trained to carry out procedures correctly;

f) records are made, manually and/or by recording instruments, during manufacture which demonstrate that all the steps required by the defined procedures and instructions were in fact taken and that the quantity and quality of the product was as expected. Any deviation is fully recorded and investigated;

g) records of manufacture including distribution which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form;

h) the storage and distribution (wholesaling) of the products minimizes any risk to their quality;

i) a system is available to recall any batch of product, from sale or supply; and

j) complaints about marketed products are examined, the causes of quality defects investigated and appropriate measures taken in respect of the defective products and to prevent re-occurrence.

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SUPLEMEN BAB 6

PRINSIP

Produk cairan, krim dan salep sangat rentan terhadap pencemaran mikroba dan pencemaran lain selama pembuatan. Dengan demikian tindakan khusus harus dilakukan untuk mencegah tiap pencemaran.

Catatan: Pembuatan produk cairan, krim dan salep harus dilakukan menurut CPOB atau dengan suplemen lain yang relevan. Suplemen ini hanya menekankan hal-hal spesifik dalam pembuatan produk ini.

PRODUKSI

1. Kualitas bahan yang diterima dalam tangki hendaklah diperiksa sebelum ditransfer ke dalam tangki penampung produk ruahan.

2. Bahan yang memungkinkan melepas serat atau cemaran lain, seperti kardus (cardboard) atau palet kayu, hendaklah tidak dimasukkan ke dalam area di mana produk atau wadah bersih terpapar ke lingkungan.

SUPPLEMENT TO CHAPTER 6

PRINCIPLE

Liquids, creams and ointments may be particularly susceptible to microbial and other contamination during manufacture. Therefore special measures must be taken to prevent any contamination.

Note: The manufacture of liquids, creams and ointments must be done in accordance with the GMP and with the other supplementary guidelines, where applicable. The present guidelines only stress points which are specific to this manufacture.

PRODUCTION

1. The quality of materials received in bulk tankers should be checked before they are transferred to bulk storage tanks.

2. Materials likely to shed fibres or other contaminants, like cardboard or wooden pallets, should not enter the areas where products or clean containers are exposed.

CAIRAN KRIM DAN SALEP LIQUIDS, CREAMS AND

OINTMENT

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Suplemen BAB 7 – Pengawasan Mutu Supplement of Chapter 7 – Quality Control

SUPLEMEN BAB 7

PRINSIP

Pengambilan sampel merupakan kegiatan penting di mana hanya sebagian kecil saja dari suatu bets yang diambil. kesimpulan yang absah secara keseluruhan tidak dapat didasarkan pada pengujian yang telah dilakukan terhadap sampel nonrepresentatif. Oleh karena itu cara pengambilan sampel yang benar adalah bagian yang esensial dari sistem Pemastian Mutu.

Catatan: Pengambilan sampel dijelaskan pada Bab 7 Pedoman CPOB, Butir 7.21 sampai dengan 7.22. Suplemen ini memberikan petunjuk tambahan pada pengambilan sampel bahan awal dan bahan pengemas.

BAHAN AWAL

1. Pengambilan sampel boleh dilakukan terhadap sebagian dari jumlah keseluruhan wadah bila telah tersedia prosedur tervalidasi yang menjamin bahwa tidak satu pun wadah bahan awal yang keliru diidentifikasi pada labelnya.

2. Validasi tersebut hendaklah mencakup minimal aspek – aspek berikut:a) sifat dan status pabrik pembuat dan

pemasok serta pemahaman mereka tentang ketentuan CPOB pada industri farmasi;

b) sistem Pemastian Mutu pabrik pembuat bahan awal;

c) kondisi pembuatan pada saat bahan awal tersebut diproduksi dan diperiksa;

d) sifat bahan awal dan produk jadi yang akan menggunakan bahan awal

SUPPLEMENT TO CHAPTER 7

PRINCIPLE

Sampling is an important operation in which only a small fraction of a batch is taken. Valid conclusions on the whole cannot be based on tests which have been carried out on non-representative samples. Correct sampling is thus an essential part of a system of Quality Assurance.

Note: Sampling is dealt with in Chapter 7 of the Guide to GMP, items 7.21. to 7.22. These supplementary guidelines give additional guidance on the sampling of starting and packaging materials.

STARTING MATERIALS

1. It is permissible to sample only a proportion of the containers where a validated procedure has been established to ensure that no single container of starting material will be incorrectly identified on its label.

2. This validation should take account of at least the following aspects:a) nature and status of the manufacturer

and of the supplier and their understanding of the GMP requirements of the pharmaceutical industry;

b) the Quality Assurance system of the manufacturer of the starting material;

c) the manufacturing conditions under which the starting material is produced and controlled;

d) the nature of the starting material and the medicinal products in which it will be

PENGAMBILAN SAMPEL BAHAN AWAL DAN BAHAN

PENGEMAS

SAMPLING OF STARTING AND PACKAGING

MATERIALS

Page 17: Buku Suplemen I

Suplemen BAB 7 – Pengawasan Mutu Supplement of Chapter 7 – Quality Control

tersebut.

Dengan pengaturan seperti pada kondisi di atas, dimungkinkan suatu prosedur tervalidasi yang mengecualikan keharusan pengujian identitas bagi tiap wadah bahan awal dapat diterima untuk:a) bahan awal yang berasal dari pabrik

yang hanya membuat satu bahan;b) bahan awal diterima langsung dari

pabrik pembuat atau dalam wadah tertutup asli dari pabrik pembuat yang telah dibuktikan kehandalannya dan telah diaudit secara berkala oleh Bagian Pemastian Mutu dari industri farmasi atau suatu badan terakreditasi.

Adalah tidak mungkin suatu prosedur dapat divalidasi secara memuaskan dalam hal:a) bahan awal yang dipasok oleh

perantara misal broker, di mana pabrik pembuat tidak dikenal atau tidak diaudit;

b) bahan awal digunakan untuk produk parenteral.

used.

Under such arrangements, it is possible that a validated procedure exempting identity testing of each incoming container of starting material could be accepted for:

a) starting materials coming from a single product manufacturer or plant;

b) starting materials coming directly from a manufacturer or in the manufacturer's sealed container where there is a history of reliability and regular audits by the manufacturer's Quality Assurance System or by an officially accredited body.

It is improbable that a procedure could be satisfactorily validated for:

a) starting materials supplied by intermediaries such as brokers where the source of manufacture is unknown or not audited;

b) starting materials for use in parenteral products.

Page 18: Buku Suplemen I

ANEKS 1

PRINSIP

Produk steril hendaklah dibuat dengan persyaratan khusus dengan tujuan memperkecil risiko pencemaran mikroba, partikulat dan pirogen, yang sangat tergantung dari ketrampilan, pelatihan dan sikap dari personil yang terlibat. Pemastian Mutu sangatlah penting dan pembuatan produk steril harus sepenuhnya mengikuti secara ketat metode pembuatan dan prosedur yang ditetapkan dengan seksama dan tervalidasi. Pelaksanaan proses akhir atau pengujian produk jadi tidak dapat dijadikan sebagai satu-satunya andalan untuk menjamin sterilitas atau aspek mutu lain.

UMUM

1 Pembuatan produk steril hendaklah dilakukan di area bersih, memasuki area ini hendaklah melalui ruang penyangga untuk personil dan/atau peralatan dan bahan. Area bersih hendaklah dijaga tingkat kebersihannya sesuai standar kebersihan yang ditetapkan dan dipasok dengan udara yang telah melewati filter dengan efisiensi yang sesuai.

2 Berbagai kegiatan persiapan komponen, pembuatan produk dan pengisian hendaklah dilakukan di ruang terpisah di dalam area bersih. Kegiatan pembuatan produk steril dapat digolongkan dalam dua kategori yaitu; pertama produk yang disterilkan dalam wadah akhir dan disebut juga sterilisasi akhir, kedua produk yang diproses secara aseptik pada sebagian atau semua tahap.

3 Area bersih untuk pembuatan produk steril digolongkan berdasarkan karakteristik lingkungan yang

ANNEX 1

PRINCIPLE

The manufacture of sterile products is subject to special requirements in order to minimize risks of microbiological contamination, and of particulate and pyrogen contamination, much depends on the skill, training and attitudes of the personnel involved. Quality Assurance is particularly important and this type of manufacture must strictly follow carefully established and validated methods of preparation and procedure. Sole reliance for sterility or other quality aspects must not be placed on any terminal process or finished product test.

GENERAL

1 The manufacture of sterile products should be carried out in clean areas, entry to which should be through airlocks for personnel and/or for equipment and materials. Clean areas should be maintained to an appropriate cleanliness standard and supplied with air which has passed through filters of an appropriate efficiency.

2 The various operations of component preparation, product preparation and filling should be carried out in separate areas within the clean area. Manufacturing operations are divided into two categories; firstly those where the product is terminally sterilized, and secondly those which are conducted aseptically at some or all stages.

3 Clean areas for the manufacture of sterile products are classified according to the required characteristics of the

1 For classification purposes in Grade A zones, a minimum sample volume of 1 m³ should be taken per sample location. For Grade A the airborne particle classification is ISO 4.8 dictated by the limit for particles ≥5.0 µm. For Grade B (at rest) the airborne particle classification is ISO 5 for both considered particle sizes. For Grade C (at rest & in operation) the airborne particle classification is ISO 7 and ISO 8 respectively. For Grade D (at rest) the airborne particle classification is ISO 8. For classification purposes EN/ISO 14644-1 methodology defines both the minimum number of sample locations and the sample size based on the class limit of the largest considered particle size and the method of evaluation of the data collected.

2 Portable particle counters with a short length of sample tubing should be used for classification purposes because of the relatively higher rate of precipitation of particles ≥5.0m in remote sampling systems with long lengths of tubing. Isokinetic sample heads should be used in unidirectional airflow systems.

3 “In operation” classification may be demonstrated during normal operations, simulated operations or during media fills as worst case simulation is required for this. EN ISO 14644-2 provides information on testing to demonstrate continued compliance with the assigned cleanliness classifications.

CLEAN ROOM AND CLEAN AIR DEVICE MONITORING

4 Clean rooms and clean air devices should be routinely monitored in operation and the monitoring locations based on a formal risk analysis study and the results obtained during the classification of rooms and/or clean air devices.

5 For Grade A zones, particle monitoring should be undertaken for the full duration of critical processing, including equipment assembly, except where justified by contaminants in the process that would damage the particle counter or present a

14 Where aseptic operations are performed monitoring should be frequent using methods such as settle plates, volumetric air and surface sampling (e.g. swabs and contact plates). Sampling methods used in operation should not interfere with zone protection. Results from monitoring should be considered when reviewing batch documentation for finished product release. Surfaces and personnel should be monitored after critical operations. Additional microbiological monitoring is also required outside production operations, e.g. after validation of systems, cleaning and sanitation.

Recommended limits for microbiological monitoring of clean areas during operation

Notes: (*) These are average values. (**) Individual settle plates may be exposed for less than 4 hours

15 Appropriate alert and action limits should be set for the results of particulate and microbiological monitoring. If these limits are exceeded operating procedures should prescribe corrective action.

ISOLATOR TECHNOLOGY

16 The utilization of isolator technology to minimize human interventions in processing areas may result in a significant decrease in the risk of microbiological contamination of aseptically manufactured products from the environment. There are many possible designs of isolators and transfer devices. The isolator and the background environment should be designed so that the required air quality for the respective zones can be realized. Isolators are constructed of various materials more or less prone to puncture and leakage. Transfer devices may vary from a single door to double door designs to fully sealed systems incorporating sterilization mechanisms.

17 The transfer of materials into and out of the unit is one of the greatest potential sources of contamination. In general the area inside the isolator is the local zone for high risk manipulations, although it is recognized that laminar air flow may not exist in the working zone of all such devices. The air classification required for the background environment depends on the design of the isolator and its application. It should be controlled and for aseptic processing be at least Grade D.

18 Isolators should be introduced only after appropriate validation. Validation should take into account all critical factors of isolator technology, for example the quality of the air inside and outside (background) the isolator, sanitation of the isolator, the transfer process and isolator integrity.

19 Monitoring should be carried out routinely and include frequent leak testing of the isolator and glove/sleeve system.

BLOW / FILL/ SEAL TECHNOLOGY

20 Blow/fill/seal units are purpose built

PEMBUATAN PRODUK STERIL

MANUFACTURE OF STERILE

PHARMACEUTICAL PRODUCTS

CARA PENYIMPANAN DAN PENGIRIMAN OBAT YANG

BAIK

GOOD STORAGE AND DISPATCH PRACTICES

PARAMETRIC RELEASEPARAMETRIC RELEASE

Page 19: Buku Suplemen I

1 For classification purposes in Grade A zones, a minimum sample volume of 1 m³ should be taken per sample location. For Grade A the airborne particle classification is ISO 4.8 dictated by the limit for particles ≥5.0 µm. For Grade B (at rest) the airborne particle classification is ISO 5 for both considered particle sizes. For Grade C (at rest & in operation) the airborne particle classification is ISO 7 and ISO 8 respectively. For Grade D (at rest) the airborne particle classification is ISO 8. For classification purposes EN/ISO 14644-1 methodology defines both the minimum number of sample locations and the sample size based on the class limit of the largest considered particle size and the method of evaluation of the data collected.

2 Portable particle counters with a short length of sample tubing should be used for classification purposes because of the relatively higher rate of precipitation of particles ≥5.0m in remote sampling systems with long lengths of tubing. Isokinetic sample heads should be used in unidirectional airflow systems.

3 “In operation” classification may be demonstrated during normal operations, simulated operations or during media fills as worst case simulation is required for this. EN ISO 14644-2 provides information on testing to demonstrate continued compliance with the assigned cleanliness classifications.

CLEAN ROOM AND CLEAN AIR DEVICE MONITORING

4 Clean rooms and clean air devices should be routinely monitored in operation and the monitoring locations based on a formal risk analysis study and the results obtained during the classification of rooms and/or clean air devices.

5 For Grade A zones, particle monitoring should be undertaken for the full duration of critical processing, including equipment assembly, except where justified by contaminants in the process that would damage the particle counter or present a

Notes: (*) These are average values. (**) Individual settle plates may be exposed for less than 4 hours

15 Appropriate alert and action limits should be set for the results of particulate and microbiological monitoring. If these limits are exceeded operating procedures should prescribe corrective action.

ISOLATOR TECHNOLOGY

16 The utilization of isolator technology to minimize human interventions in processing areas may result in a significant decrease in the risk of microbiological contamination of aseptically manufactured products from the environment. There are many possible designs of isolators and transfer devices. The isolator and the background environment should be designed so that the required air quality for the respective zones can be realized. Isolators are constructed of various materials more or less prone to puncture and leakage. Transfer devices may vary from a single door to double door designs to fully sealed systems incorporating sterilization mechanisms.

17 The transfer of materials into and out of the unit is one of the greatest potential sources of contamination. In general the area inside the isolator is the local zone for high risk manipulations, although it is recognized that laminar air flow may not exist in the working zone of all such devices. The air classification required for the background environment depends on the design of the isolator and its application. It should be controlled and for aseptic processing be at least Grade D.

18 Isolators should be introduced only after appropriate validation. Validation should take into account all critical factors of isolator technology, for example the quality of the air inside and outside (background) the isolator, sanitation of the isolator, the transfer process and isolator integrity.

19 Monitoring should be carried out routinely and include frequent leak testing of the isolator and glove/sleeve system.

BLOW / FILL/ SEAL TECHNOLOGY

20 Blow/fill/seal units are purpose built