CPOB

Pertemuan 6
Kualifikasi dan Validasi
Prinsip
• Semua perangkat keras dan lunak yang digunakan
dalam proses pembuatan obat hendaklah dikualifik
asi dan / atau divalidasi.
• Apabila suatu peralatan dilengkapi dengan sistem k
omputerisasi, maka kualifikasi dapat dilakukan seca
ra bersamaan dan kualifikasi perangkat lunak hend
aklah memerhatikan persyaratan yang tercantum p
ada Aneks 7. Sistem Komputerisasi.
• Kegiatan validasi meliputi kualifikasi (personil, peral
atan, sistem dan instrumen), kalibrasi alat ukur dan
validasi (prosedur dan proses).
• Terminologi ’validasi’ sering juga digunakan untuk
menggantikan terminologi kualifikasi kinerja, tetapi
untuk memperoleh pengertian yang jelas terhadap
konsep validasi, kualifikasi kinerja dibedakan dari ke
giatan validasi proses.
• Misal, kualifikasi kinerja mesin cetak tablet dilakuka
n untuk membuktikan kinerja mesin cetak tablet an
tara lain kekerasan dan keseragaman bobot tablet,
sedangkan validasi proses dilakukan dengan meng
amati semua parameter mutu tablet.
• Data kekerasan dan keseragaman bobot tablet dala
m rangka kualifikasi kinerja mesin cetak tablet dapa
t diperoleh dari data validasi proses.
Komponen / proses yang memerlukan
kualifikasi dan/atau validasi
• personil;
• konstruksi dan desain bangunan dan fasilitas;
• peralatan produksi;
• instrumen laboratorium;
• metode analisis;
• sarana penunjang kritis mencakup antara lain sistem pengolah
an air, sistem tata udara dan sistem udara bertekanan;
• perubahan pemasok dan atau spesifikasi bahan awal dan baha
n pengemas;
• transfer proses produksi dan metode analisis*;
• perubahan ukuran bets;
• prosedur pengolahan dan prosedur pengemasan;
• prosedur pembersihan; dan
• sistem komputerisasi.
Perencanaan Validasi
• Hendaklah dibuat dokumen RIV yang menyajikan in
formasi mengenai program kerja validasi perusahaa
n. Dokumen ini hendaklah juga memberi rincian jad
wal kerja validasi yang harus dilaksanakan dengan
memerhatikan urutan pelaksanaan misal sebelum melaks
anakan validasi proses:
a. personil;
b. alat;
c. metode analisis;
d. sarana penunjang kritis; dan
e. bangunan;
harus sudah terkualifikasi termasuk alat-alat ukur terka
it.
Dapat dilihat pada contoh format rencana induk validasi
• Pemantauan pencapaian RIV yang sudah ditetapka
n hendaklah dilakukan secara berkala.
• Dokumen mengacu pada
- monitoring, cakupan validasi, dan kualifikasi
- jadwal program kualifikasi dan validasi
- jadwal program validasi proses
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• Selain yang tercantum dalam buku Pedoman CPO
B, RIV dapat dilengkapi juga dengan data:
1. Personalia
• Jumlah personil untuk kegiatan kualifikasi dan valid
asi
• Kualifikasi dan pelatihan personil
2 . Prosedur pelaksanaan kualifikasi dan validasi
• Proses spesifik; dan
• Kriteria keberterimaan atau pelulusan (secara umu
m)
3. Tim Validasi dan Manajemen
4 . Daftar Protap yang akan digunakan
5 . Program dan Jadwal Kualifikasi dan Validasi,
• RIV dapat dibuat tersendiri untuk suatu proyek bes
ar dan / atau kompleks, misal Bangunan dan Fasilit
as baru, Sistem Tata Udara, Sistem Pengolahan Air
dan Sistem Komputerisasi, Fasilitas Betalaktam, Fasi
litas Steril, Validasi Metode Analisis, Validasi Pembe
rsihan atau digabungkan ke dalam satu Dokumen
RIV.

• Dokumentasi secara umum terbagi dua: protokol (protap)

dan laporan
Kualifikasi
• Design Qualification
• Installation Qualification
• Operasional Qualification
• Performance Qualification
DQ
• Design Qualification is used at the stage where a design
that has been developed from the cGMP and other Health
and Safety Guidelines, is reviewed and documented by
competent persons to ensure that the designed equipment,
if built, will satisfy all the detailed specified requirements.

• The Design Qualification is the only document that is

going to confirm that the design will work. It must be
carried out by qualified people who can challenge the
design performance. If you have no such persons on your
staff you must contract them in, or contract the DQ out.
DQ
The scope of the DQ must include but is not limited to:

• Verification that the design will achieve the URS requirements.

• Verification that the design is cGMP, and where software is used ,
conforms to the life cycle model requested in the VP and detailed in
GAMP 4.
• Verification that the design complies with the VMP.
• Verification that the utility services required are available and
validated.
• Verification that all the required support documentation is specified.
• Verification that the system will be calibratable.
• Verification that the system will be maintainable.
• Verification of operation staff training requirements.
• Verification that the system will operate in a manner safe to both
product and staff.
• Verification that the system conforms to all applicable national
standards and guidelines.
IQ
• FDA definition of installation qualification is: Establi
shing confidence that process equipment and ancill
ary systems are compliant with appropriate codes a
nd approved design intentions, and that manufact
urer recommendations are suitably considered. In p
ractice, the installation qualification is the executed
test protocol documenting that a system has the ne
cessary prerequisite conditions to function as expec
ted.
 IQ

• Installation Qualification Protocol verifies the pro

per installation and configuration of a system.
• This can include ensuring that necessary files hav
e been loaded, equipment has been installed, th
e necessary procedures have been approved, or t
he appropriate personnel have been trained.
• The requirements to properly install the system
were defined in the Design Specification.
• Installation Qualification must be performed bef
ore completing the Operational Qualification or
Performance Qualification.
 OQ

• Operational Qualification Protocol is a collection of test

cases used to verify the proper functioning of a system.
• The operational qualification test requirements are
defined in the Functional Requirements Specification.
• Operational Qualification is usually performed before
the system is released for use.
• FDA definition of operational qualification is:
Establishing confidence that process equipment
and sub-systems are capable of consistently
operating within stated limits and tolerances. In
practice, the operational qualification is the
executed test protocol documenting that a
system meets the defined functional
requirements, or that the system does what it’s
supposed to do.
 PQ

• Performance Qualifications are a collection of

test cases used to verify that a system performs
as expected under simulated real-world
conditions.
• The performance qualification tests
requirements defined in the User Requirements
Specification (or possibly the Functional
Requirements Specification).
• Sometimes the performance qualification is
performed by power users as the system is being
released.
• FDA definition of performance qualification is:
Establishing confidence through appropriate
testing that the finished product or process
produced by a specified process meets all
release requirements for functionality and safety
and that procedures are effective and
reproducible. In practice, the performance
qualification is the executed test protocol
documenting that a system meets the defined
requirements to function in the production
environment.
Poin penting dalam CPOB mengenai Kualifikasi

• Sebelum dilakukan Kualifikasi Desain hendaklah leb

ih dahulu dibuat spesifikasi dari fasilitas, sistem ata
u alat yang akan digunakan
• Penyusunan Data Kualifikasi Instalasi (KI) hendakla
h mempertimbangkan hasil Factory Acceptance Tes
t (FAT) dan Site Acceptance Test (SAT); FAT dan SA
T dapat dijadikan sebagai dokumen penunjang Lap
oran KI
• Kalibrasi alat ukur hendaklah dilaksanakan pada ta
hap KI
Validasi
• Pembersihan
• Proses
• Metode Analisis
• Ulang
Pembersihan
• Validasi prosedur pembersihan dilakukan untuk seti
ap peralatan / mesin yang kontak langsung dengan
produk (zat aktif).
• Kajian risiko dilakukan untuk mengkaji apakah suat
u prosedur pembersihan, setelah dipakai untuk me
mbuat semua produk yang menggunakan alat yan
g sama perlu divalidasi.

• Pembersihan Alat Baru atau Alat sesudah perawata

n atau perbaikan. Pertimbangan khusus diberikan d
alam melakukan pencucian awal peralatan baru da
n pencucian setelah pembongkaran mesin untuk di
perbaiki untuk memastikan sisa-sisa debu maupun
pelumas.
Metode Analisis Pembersihan
Metode analisis yang digunakan untuk menganali
sis sampel validasi pembersihan harus divalidasi.
• Metode analisis harus memiliki kemampuan unt
uk menganalisis kadar cemaran sampel yang sa
ma dengan batas yang ditetapkan di kriteria ke
berterimaan.
• Limit kuantitasi (LOQ) dari metode analisis adal
ah sama atau lebih kecil darivbatas kriteria kebe
rterimaan.
• Waktu tunggu sampel (sample aging time / ket
angguhan) adalah waktuvtunggu yang diperbol
ehkan untuk sampel ditunda pengujiannya.
• Batas perolehan kembali (recovery) pada validas
i metode analisis pemeriksaan residu hendaklah
minimal 80%.
Metodologi yang sensitif dan spesifik untuk penetapan kad
ar cemaran antara lain:
• KCKT.
• TOC (Total Organic Carbon) untuk validasi pembersihan
peralatan termasuk secara CIP (Clean in Place).
Pertimbangan metode TOC:
• Memiliki tingkat validasi yang tinggi.
• Hanya satu metoda yang diperlukan untuk seluruh valid
asi prosedur pembersihan alat.
• Metode sederhana dan lebih mudah divalidasi dibandin
gkan metode KCKT.
• Namun dalam penetapan air bilasan dengan teknik TO
C, tidak memungkinkan untuk membedakan karbon yan
g berasal dari cemaran bahan aktif obat, eksipien ataup
un bahan deterjen.
Validasi prosedur pembersihan dan kriteria keberterimaan residu
produk dapat dilakukan terhadap tiap produk atau kelompok
produk berdasarkan pertimbangan sifat dan dosis terapetik pr
oduk. Pengelompokan dapat dilakukan dengan menggunakan
metode matriks dan pengkajian risiko sebagai berikut:
a) Tiap batas residu dari suatu produk ditetapkan sesuai sifat prod
uk berkaitan yang spesifik;
b) Dari kelompok produk sejenis dapat dipilih satu produk yang m
ewakili kelompok tersebut; dan
c) Kelompok produk yang disusun menurut nilai risiko, misal
• kelompok produk dengan kelarutan tinggi;
• kelompok produk berkekuatan (potensi atau dosis) pada tingk
at yang relatif sama;
• kelompok produk dengan toksisitas tinggi; dan
• kelompok produk yang tingkat residunya sulit terdeteksi.
• Batas residu ditetapkan dengan memerhatikan kondisi terburu
k dari prosedur pembersihan dan analisis risiko.
Validasi Metode Analisis
Validasi Proses
• Prospective
• Concurrent
• Retrospective
Prospective
• Prospective validation is carried out during the development stage by
means of a risk analysis of the production process, which is broken
down into individual steps: these are then evaluated on the basis of past
experience to determine whether they might lead to critical situations.

• Where possible critical situations are identified, the risk is evaluated,

the potential causes are investigated and assessed for probability and
extent, the trial plans are drawn up, and the priorities set. The trials are
then performed and evaluated, and an overall assessment is made. If, at
the end, the results are acceptable, the process is satisfactory.
Unsatisfactory processes must be modified and improved until a
validation exercise proves them to be satisfactory. This form of
validation is essential in order to limit the risk of errors occurring on the
production scale, e.g. in the preparation of injectable products.
Concurrent
• Concurrent validation is carried out during normal
production. This method is effective only if the
development stage has resulted in a proper understanding
of the fundamentals of the process. The first three
production-scale batches must be monitored as
comprehensively as possible.1The nature and
specifications of subsequent in-process and final tests are
based on the evaluation of the results of such monitoring.
• Concurrent validation together with a trend analysis
including stability should be carried out to an appropriate
extent throughout the life of the product.
Retrospective
• Retrospective validation involves the examination of past experience of production on the
assumption that composition, procedures, and equipment remain unchanged; such
experience and the results of in-process and final control tests are then evaluated. Recorded
difficulties and failures in production are analysed to determine the limits of process
parameters. A trend analysis may be conducted to determine the extent to which the process
parameters are within the permissible range.

• Retrospective validation is obviously not a quality assurance measure in itself, and should
never be applied to new processes or products. It may be considered in special
circumstances only, e.g. when validation requirements are first introduced in a company.
Retrospective validation may then be useful in establishing the priorities for the validation
programme. If the results of a retrospective validation are positive, this indicates that the
process is not in need of immediate attention and may be validated in accordance with the
normal schedule. For tablets which have been compressed under individual pressure-
sensitive cells, and with qualified equipment, retrospective validation is the most
comprehensive test of the overall manufacturing process of this dosage form. On the other
hand, it should not be applied in the manufacture of sterile products.
Revalidation
• Revalidation is needed to ensure that changes in the
process and/or in the process environment, whether
intentional or unintentional, do not adversely affect
process characteristics and product quality.

• Revalidation may be divided into two broad categories:

• Revalidation after any change having a bearing on product

quality.
• Periodic revalidation carried out at scheduled intervals.
• Revalidation after changes. Revalidation must be performed on
introduction of any changes affecting a manufacturing and/or standard
procedure having a bearing on the established product performance
characteristics. Such changes may include those in starting material,
packaging material, manufacturing processes, equipment, in-process
controls, manufacturing areas, or support systems (water, steam, etc.).
Every such change requested should be reviewed by a qualified
validation group, which will decide whether it is significant enough to
justify revalidation and, if so, its extent.

• Revalidation after changes may be based on the performance of the

same tests and activities as those used during the original validation,
including tests on subprocesses and on the equipment concerned. Some
typical changes which require revalidation include the following:
• • Changes in the starting material(s). Changes in the physical properties, such as density, viscosity, particle
size distribution, and crystal type and modification, of the active ingredients or excipients may affect the
mechanical properties of the material; as a consequence, they may adversely affect the process or the
product.

• • Changes in the packaging material, e.g. replacing plastics by glass, may require changes in the packaging
procedure and therefore affect product stability.

• • Changes in the process, e.g. changes in mixing time, drying temperature and cooling regime, may affect
subsequent process steps and product quality.

• • Changes in equipment, including measuring instruments, may affect both the process and the product;
repair and maintenance work, such as the replacement of major equipment components, may affect the
process.

• • Changes in the production area and support system, e.g. the rearrangement of manufacturing areas and/or
support systems, may result in changes in the process. The repair and maintenance of support systems, such
as ventilation, may change the environmental conditions and, as a consequence, revalidation/requalification
may be necessary, mainly in the manufacture of sterile products.

• • Unexpected changes and deviations may be observed during self-inspection or audit, or during the
continuous trend analysis of process data.
• Periodic revalidation. It is well known that process changes may occur gradually even if experienced operators work correctly
according to established methods. Similarly, equipment wear may also cause gradual changes. Consequently, revalidation at
scheduled times is advisable even if no changes have been deliberately made.

• The decision to introduce periodic revalidation should be based essentially on a review of historical data, i.e. data generated
during in-process and finished product testing after the latest validation, aimed at verifying that the process is under control.
During the review of such historical data, any trend in the data collected should be evaluated.

• In some processes, such as sterilization, additional process testing is required to complement the historical data. The degree of
testing required will be apparent from the original validation.

• Additionally, the following points should be checked at the time of a scheduled revalidation:

• • Have any changes in master formula and methods, batch size, etc., occurred? If so, has their impact on the product been
assessed?

• • Have calibrations been made in accordance with the established programme and time schedule?

• • Has preventive maintenance been performed in accordance with the programme and time schedule?

• • Have the standard operating procedures (SOPs) been properly updated?

• • Have the SOPs been implemented?

• • Have the cleaning and hygiene programmes been carried out?

• • Have any changes been made in the analytical control methods?

 Thank You

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