PERMUKAAN PERALATAN
Bhn stabil
dgn SS
SS AISI
304
Cr 16-18 %
Ni 10-14 %
Mo 2-3 %
Produk
non steril
Produk
steril
SS AISI
316
Sistem pipa
air murni &
akua p.i.
Cr 18-20 %
Ni 8-12 %
BAHAN
Bhn yg reaktif
dgn non PTFE
Pelapis
GELAS
Bhn yg reak
tif dgn SS
PTFE
4.
5.
6.
LEDAKAN / KEBAKARAN
BHN MDH
TERBAKAR
Tutup
kedap api
& ledakan
Gas
Inert
UNSUR
PENDUKUNG
OKSIGEN
API / TITIK
PANAS
9.
10.
pada
jarak
yang
memadai
dari
5.
PEMIPAAN
PIPA + SAMBUNGAN
+ KATUP + ISOLATOR
PENANDAAN
PEMIPAAN
ARAH
ALIRAN
SUHU
WARNA
TEKANAN
PEMIPAAN
STIROFOM
INSULATOR
PIPA
KARET
BUSA
SINTETIS
WOL
GELAS
PENANDAAN PIPA
JENIS PIPA
WARNA DASAR
WARNA HURUP
Hitam
Udara bertekanan
Hitam
Hitam
Gas nitrogen
Hitam
Gas oksigen
Hitam
Gas karbondioksida
Hitam
LPG
Hitam
Hitam
Air murni
Hitam
Putih
PEMELIHARAAN
1. Peralatan harus dipelihara menurut interval yang sesuai
- Untuk mencegah malfungsi atau kontaminasi yang dapat mengubah
identitas, kualitas, atau kemurnian produknya.
4. Pemeliharaan peralatan
- Harus mempunyai dan mengikuti protap yang telah ditetapkan
KUALIFIKASI
&
VALIDASI
KALIBRASI
Serangkaian kegiatan dalam kondisi yang telah ditentukan, yang
menetapkan hubungan antara nilai yang ditunjuk oleh alat ukur
atau sistem pengukur, atau nilai yang ditampilkan oleh suatu
ukuran bahan dengan nilai sesuai dari suatu rujukan standar.
Batas yang dapat diterima hendaklah ditetapkan sebelumnya.
VALIDASI
Suatu tindakan pembuktian dengan cara yang sesuai bahwa tiap
bahan, proses, prosedur, kegiatan, sistem, perlengkapan atau
mekanisme yang digunakan dalam produksi dan pengawasan
mutu akan senantiasa mencapai hasil yang diinginkan
PRINSIP
PERENCANAAN VALIDASI
RIV
Data yg dicakup:
Kebijakan validasi
Struktur organisasi kegiatan validasi
DOKUMENTASI
Isi laporan:
Ringkasan hasil
Tanggapan thdp penyimpangan
Kesimpulan
Rekomendasi perbaikan
PQ Test Plan
Performance
Qualification
(ie. What)
Functional Design
(ie. How as schematic)
OQ Test Plan
Operational
(inc.FAT)
Qualification
Design
Development
Detail Design
(ie. How to make)
IQ Test Plan
(inc.PDI)
Installation
Qualification
Impact
Assessment
IMPLEMENTATION
ISPE Baseline Guide Vol.5
JENIS KUALIFIKASI
Kualifikasi Desain
( KD, Design Qualification = DQ )
Kualifikasi Instalasi
( KI, Installation Qualification = IQ )
Kualifikasi Operasional
Kualifikasi Kinerja
( KK, Performance Qualification = PQ )
KUALIFIKASI DESAIN
KUALIFIKASI INSTALASI
KUALIFIKASI OPERASIONAL
KUALIFIKASI KINERJA
Dokumentasi
Kalibrasi
Protap pengoperasian
Protap pembersihan
Perawatan preventif
PENGENDALIAN PERUBAHAN
( CHANGE CONTROL )
Tersedia protap mengenai
usulan perubahan thdp
bahan awal, komponen
produk, peralatan, lingkungan
kerja, metode produksi,
metode analisis, atau
perubahan yg mempengaruhi
mutu atau reprodusibilitas
proses
Prosedur pengendalian
perubahan:
Pastikan data pendukung
perubahan cukup
Mutu tdk dipengaruhi akibat
perubahan
Usulan perubahan yg
berpengaruh thdp mutu produk
atau reprodusibilitas proses:
Diajukan resmi
Didokumentasikan
Disetujui
VALIDASI ULANG
( REVALIDATION )
VALIDASI PEMBERSIHAN
( CLEANING VALIDATION )
Tujuan
Utk mengkonfirmasi
efektivitas prosedur
pembersihan
Penentuan batas
MA yg digunakan
Sudah divalidasi
Kepekaan tinggi utk
mendeteksi residu/
cemaran
VALIDASI PEMBERSIHAN
( CLEANING VALIDATION )
Hanya utk permukaan alat yg
bersentuhan langsung dgn
produk
Utk yg tdk bersentuhan
langsung dpt
dipertimbangkan
Harus ditetapkan
VALIDASI PEMBERSIHAN
( CLEANING VALIDATION )
CLEANING
VALIDATION
Jnos Pogny, pharmacist, PhD,
consultant to WHO
Pretoria, South Africa, 28 June 2005
E-mail: pogany@t-online.hu
2005.06.28.
35/35
WHO GMP
4.11
It is of critical importance that particular attention is paid to the
validation of ... cleaning procedures.
16.11
Contamination of ... a product by another material or product must be
avoided.
This risk of accidental cross contamination arises from ... products in
process, from residues on equipment.
Among the most hazardous contaminants are highly sensitizing
materials ... and highly active materials.
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WHO GMP
16.15
Before any processing operation is started, steps should be taken to
ensure that the work area and equipment are clean.
16.18
Time limits for storage of equipment after cleaning and before use
should be stated and based on data.
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Why do we validate
cleaning processes?
The cleaning process is an integral part of the pharmaceutical
manufacturing process.
Industry should view cleaning of equipment as the first
manufacturing step.
(It will have effect on the safety, efficacy and quality of the
batch to be manufactured.)
A cleaning process must be chosen based on products (e.g.,
ARVs, solid dosage forms), objectives, resources, and
limitations within each manufacturing company.
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GENERAL
CONSIDERATIONS
Potential Contaminants
Chemical contamination
Product residues
Decomposition residues
Cleaning or disinfecting agent residues
Microbiological contamination
Bacteria, moulds, pyrogens
Unintended materials
Airborne (particulate) matter
Lubricants, ancillary material (e.g. pieces of brushes)
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Manual Cleaning
Procedures
Equipment disassembly (if required)
Prewash and inspection (most visible material removed)
Wash (cleaning agent, temperature, multiple steps until visually
clean)
Initial rinses (rinse water, temperature)
Final rinse (minimum dissolved solids, microorganisms)
Reassembly (if required)
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Automated Cleaning
Procedures
Clean-in-place (CIP) systems (dishwasher-type equipment)
portable (tank and pump assemblies on wheels)
stationery, cabinet-type
Control system qualification (IQ, OQ and PQ: reproducibility,
water, temperature control)
Sampling (sampling port, pause capability)
Material supply (hard-plumbed supply lines, volume and
dispensing controls, potential impact of long storage periods)
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Standard Operating
Procedure(s) [SOP(s)]
Labeling
Cleaning equipment
maintenance and
calibration
2005.06.28.
Personnel training
43/35
Scrubbing agents
(compression of placebo
tablets to clean punches and
dies)
Cleaning agents
(acids, bases, surfactants,
etc., qualified type and brand
QC controlled)
Ancillary utilities
(steam and compressed air
qualified)
2005.06.28.
Cleaning tools
(standard sets of brushes,
rags, sponges)
Equipment
(thermometers, CIP systems
consisting of tanks, metering
pumps, heat exchangers,
etc. maintaned and kept in
calibrated status)
44/35
Frequency of Cleaning
Cleaning between batches of
2005.06.28.
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PRESENTATION IS LIMITED TO
SOLID PHARMACEUTICAL DOSAGE FORMS
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2005.06.28.
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2.
3.
4.
5.
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Analytical methods
The analytical methods used to detect residuals or
contaminants should be specific and be validated before the
cleaning validation study is carried out.
The specificity and sensitivity of the analytical methods should
be determined.
The analytical method and the percent recovery of
contaminants should be challenged in combination with the
sampling method(s).
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2005.06.28.
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An Illustrative Approach to
Cleaning Validation
ANTIRETROVIRAL
FPP(s)
Cleaning validation
(master) plan
Validation plan is based on risk analysis.
Cleaning of individual pieces of the manufacturing and packaging
equipment is validated with products selected as the worst
case.
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Risk Analysis
WATER SOLUBILITY
RISK FACTORS
T
O
X
I
C
I
T
Y
2005.06.28.
LOW
MODERATE
HIGH
HIGH
High
High
Moderate
MODERATE
High
Moderate
Moderate
LOW
Moderate
Moderate
Low
57/35
Category
High
Moderate
Low
58/35
CCategory
Category
ategory
High
solubil
ity
(<30
Moderate
ml/g)
solubility
(30 1000
ml/g)
Low
solubility
(> 1000
ml/g)
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TOXICITY
INDICATOR
SOLUBILITY IN WATER
Abacavir
Moderate
High
Efavirenz
Low
Low
Indinavir sulfate
Low
High
Lamivudine
Low
High
Nevirapine
Low
Low
Ritonavir
Low
Low
Saquinavir
Low
Low
Stavudine
Low
High
Zidovudine
Low
High
2005.06.28.
77 mg/mL at 25oC
100 mg/ml
90 g/ml at 25C
20 mg/mL at 25oC
60/35
Summary
This article describes the use of a one-pot processor for the cleaning
and cleaning validation of two drug compounds: water-soluble
theophylline and water-insoluble mebendazole.
Both substances were produced using wet granulation and microwave
drying, after which the processor was cleaned using its clean-in-place
(CIP) system.
Swab samples were taken from areas considered critical during
processing and analysed for remains of active ingredient.
It was concluded from the results that the processor's CIP system is
capable of removing both APIs to a level well within accepted
regulations.
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One-pot processor
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Acceptance criteria
10-ppm criterion
absolute mass criterion: NMT
1 g/cm2
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Study conclusions
This study has shown that the CIP system of this one-pot processor is
capable of removing both water-insoluble mebendazole and watersoluble theophylline from the system to a level significantly less than
acceptable maxima.
Although certain areas show a larger variation in results than others,
the reproducibility of the cleaning cycle can be considered good, as
the results for all areas were always consistent.
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