VALIDATION — APPLICATIONS

Validasi
 Validation
Proving that any materials, process, procedure, activity,
system, equipment or mechanism used in the production and
control consistently achieves the desired results.( ASEAN GMP
Guidelines ).

Establishing documented evidence which provides a high degree of

assurance that a specific process will consistently produce a
product meeting its predeterminated specifications and quality
assurance atributes

( US FDA, General Principles of validation, Rockville, Md., USA,

Center for Drug Evaluation and research(CDER)( May-1987)
 Validasi adalah:
1. Tindakan pembuktian (dokumentasi)
2. Dengan cara yang sesuai (metode)
3. Bahwa tiap bahan, prosedur, kegiatan, sistem,
perlengkapan, atau mekanisme yang
digunakan (objek/komponen)
4. Dalam produksi dan pengawasan (ruang
lingkup/scope)
5. Akan senantiasa mencapai hasil yang
diinginkan (sasaran/target)
 TABLE 1 Benefits of Validation
• Increased throughput
• • Reduction in rejections and reworks
• • Reduction in utility costs
• • Avoidance of capital expenditures
• • Fewer compliants about process-related failures
• • Reduced testing—in process and finished goods
• • More rapid/accurate investigations into process upsets
• • More rapid and reliable startup of new equipment
• • Easier scaleup from development work
• • Easier maintenance of the equipment
• • Improved employee awarerness of processes
• • More rapid automation
 Along with the introduction of the Validation life cycle, newer definitions of
validation have come into use that are more compatible with the new ways in which
validation is being performed (4).

• Validation is a defined program which, in combination with

routine production methods and quality control techniques,
provides documented assurance that a system is performing as
intended and/or that a product conforms to it predetermined
specifications.
• When practiced in a “life cycle” model it incorporates design,
development, evaluation, operational, and maintenance
considerations to provide both operational benefits and
regulatory compliance.
• —J. Agalloco (1991)
• VALIDASI PROSES

• A validated manufacturing process is one which has been proved

to do what it purports to do. The proof of validation is obtained
through the collection and evaluation of data, preferably
beginning from the process development phase and continuing
through into the production phase. Validation necessarily includes
process qualification (the qualification of materials, equipment,
systems, buildings, personnel), but it also includes the control of
the entire process for repeated runs. —FDA Definition (ca. 1978)
Three types of Validation are possible
• Prospective validation
Validation carried out before a process is really implemented
commercially. Usually a minimum of three consecutive
batches is requires to prove that the process leads to the
expectes result.

• Retrospective validation
Validation carried out in retrospect on an established, process.
Normally 20 to 30 batches are sufficient to prove the validity
of the process as carried out.

• Concurrent validation
Validation carried out an a process not validated prior to
commercialisation, or in which prospective validation was not
completely satisfactory, or in which changes are implemented
without interruption or which is not carried out very
frequently.
Product Design Storage
Components Quality Assurance Transportation
Vendors Distribution
Equipment Complaints

GMP

Quality Control

Quality control vs Quality Assurance

• QC : sample, test, measure, report (essentially laboratory
based function)
• QA : all aspects that collectively or individually influence
product quality (from design concept to consumer use)
Good Manufacturing Practices
Aim for the optimum of the 5 M’s
Materials
raw materials packaging materials printed materials
Methods
procedures processes analyses
Machines(Equipments)
equipment
Milieu(Buildings)
premises areas rooms
Men(Personel)
people
Dalam Formulasi dan Produksi ( Pharmaceutical Do-
sage Form and Production ) ada dua ( 2 ) tahap proses
yang memainkan peran sangat penting :
1.FORMULA OPTIMIZATION, i.e, the identification of
the best possible combination between the com –
position of dosage form and their mechanical and
biopharmaceutical characteristics

2.PROCESS VALIDATION, i.e, the assurance that spe-

cific production procedure always gives a product
meeting its predetermined specifications and qua –
lity attributes.
• Process design: Defining the commercial
manufacturing process based on knowledge
gained through development and scale-up
activities.
• Process qualification: Confirming that the
manufacturing process as designed is capable of
reproducible commercial manufacturing.
• Process validation: The collection and evaluation
of data, from the process design stage through
commercial production, which establishes
scientific evidence that a process is capable of
consistently delivering quality products.
Validation VS Verification,Testing,Calibration and Qualification
1.Testing : a technical operation that consists of determination of one or more
characteristics or perfomance of a given product, material, equipment,
organism, physical phenomena, process or service according to a specific
procedure

2.Calibration : the set of operation which establish under specific condition, the
relationship between values indicated by a measuring instrument or measuring
systemand the corresponding known values of the measured

3.Verification: Corfirmation by examination and provision of evidence that

specified requirements have been met

4.Qualification: action of proving that any equipment works correctly and leads
to expected result( EC Guide to Good Manufacturing Practice ).
• A validated manufacturing process is one which has
been proved to do what it purports to do. The proof of
validation is obtained through the collection and
evaluation of data, preferably beginning from the
process development phase and continuing through
into the production phase. Validation necessarily
includes process qualification (the qualification of
materials, equipment, systems, buildings, personnel),
but it also includes the control of the entire process for
repeated runs. —FDA Definition (ca. 1978
• Within the guideline the FDA provided the
following definition that clarified their
expectations (2):
• Process validation is a documented program
which provides a high degree of assurance that a
specific process will consistently produce a
product meeting its predetermined specifications
and quality attributes
• Methods validation.
• A series of systematic laboratory studies where the
performance characteristics of the analytical method
meet the requirements for intended analytical
• applications.
• The FDA states in their guidance document that
“Methods validation is the process of demonstrating
that analytical procedures are suitable for their
intended use.
• The methods validation process for analytical
procedures begins with the planned and systematic
• collection by the applicant of the validation data to
support analytical procedures.”
Concept on validation protocal for solid dosage form
Manufacturing Equipment Critical Parameter Testing Point
Mixing I Diosna P-50 Grann. Mixer Content uniformity
(Time, Speed/Setting,
Mixer Load)
Granulation Diosna P-50 Gran. Sol Appearence
- Temp Yield
- Quantity
Gran. Mixer
- Time
= Speed/setting
Drying Heraus, Hot air drier - Time RH
- Drying temp Bact. Count
Yield
Sieving Frewitt Mesh size RH, Part. Size Yield,
Bulk Dens, Tap.des
Mixing II Diosna P-50 - Time Appearance
- Speed/setting
- Mixer Load
Lubrication Diosna P-50 - Time Cont. Uniformity
- Speed/setting RH
- Mixer Load Yield
Compression Mnesty Betapress 16 - Compression speed Unif. Of Weigh, Hardness,
- Compression force Friab., Disint. Time, Etc
 PROGAM VALIDASI
• KOMPOSISI
Kode bahan Bahan awal Jumlah
awal
Prednison 1,60 kg
mikronized
Laktosa 39,60 kg
Amilum 19,20 kg
Talk 0,600 kg
Mg. Stearat 0,200 kg
Air dem. 6,600 kg
Mixer : Pmn, L, A
Waktu : 2, 5, 10, 15 min
Sampling : 3 tempat (kiri, tengah, kanan)
Tetapkan kadar  kesimpulan
 Program Validasi
• Hasil
Waktu Kiri Tengah Kanan
(min)
2 I I I
II rata-rata 93,2 % II rata-rata 104,4 % II rata-rata 102,0 %
III III III

5 I I I
II rata-rata 99,8 % II rata-rata 100,3 % II rata-rata 100,1 %
III III III

10 I I I
II rata-rata 99,9 % II rata-rata 100,1 % II rata-rata 100,2 %
III III III

15 I I I
II rata-rata 100,8 % II rata-rata 101,2 % II rata-rata 98,0 %
III III III

Homogenitas: 5-10 min T=7,5 min

• Figure 5.1 Diosna P-150 Granulator. The unit is shown on the right, and the inside of
the granulator bowl on the left showing the impeller blade and the chopper
FIGURE 6.3 Ribbon blender used for mixing powders and
preparing granulations. (Courtesy of Littleford Day.)
Carr’s Index(%) = (Tapped density – Poured density)/Tapped density x 100

Hausner Ratio = Tapped density (ρbmax)/Poured density(ρbmin)

Carr’s Index as an indication of powder flow

Carr’s Index( % ) Type of flow

5 – 15 Excellent
12 – 16 Good
18 – 21 Fair to passable*
23 – 35 Poor*
33 – 38 Very poor
40 Extremely poor
--------------------------------------------- -------------------------------------------
*May be improved by a glidant, e.g.
0.2 % Aerosil
 Angle of repose as an indication of powder flow properties

Angle of Repose ( degrees ) Type of flow

< 20 Excellent
20 - 30 Good
30 – 34 Passable*
> 40 Very poor

*May be improved by a glidant, e.g. 0.2%

Aerosil
 Hausner Rasio : ρ tapped/ρ bulk
Hausner Rasio Deskrpsi

1.0 – 1.11 Sangat bagus

1.12 – 1.18 Bagus
1.19 – 1.25 Agak bagus
1.26 – 1.34 Kurang bagus

1.35 – 1.45 Tidak bagus

Mesin Tablet

• FIGURE 8.1 A.
MiniTAblet Press for
development and small
scale production (Courtesy of
GlobePharma).
B.Highperformance
Double rotarytabletpress.
The Korsch Pharmapress R has a
maximum output of 1 million
tablets per hour, but for
continuous operation, it is
generally run to produce
600,000 to 800,000 tablets
per hour. (Courtesy of Korsch
Tableting)
Alat uji disolusi(pelepasan obat)
Perfamance Qualification(PQ).

*Dilakukan setelah pelaksanaan IQ dan OQ selesai dan disetujui

*Hal-hal yang termasuk dalam kegiatan PQ a.l.:
** Pengujian dengan menggunakan material yang sesungguhnya
atau simulasi produk berdasarkan kondisi proses yang
sebenarnya
** Jika memungkinkan dilakukan pembuktian thdp batas atas
atau batas bawah dari suatu operasi
** Kriteria Penerimaan
Rekualifikasi

1.Rekualifikasi dilakukan jika ada modifikasi atau pemindahan

fasilitas/peralatan

2.Modifikasi atau pemindahan fasilitas/peralatan harus melalui

peninjauan yang memadai dan memuaskan dan dokumen
Proposal Perubahan dibuat sesuai dengan protap prosedur
perubahan dan disyahkan oleh pejabat yang berwenang
 Equipment operational Qualification Report

• Equipment : _Manesty Unipress Tablet Press_______

• Location : _________
• Site : _Manufacturing Area___Identification
No._15848414093102___

A. EQUIPMENT DESCRIPTION
The tablet is used to form firm compact material of
designated shape and size by compression, directly from
powder blenf of ingredients, which will flow uniformly into
a die cavity and form into a tablet
B. OBJECTIVE
Demonstrate the capacity of the compression machine
operates at the required speeds and delivers product that
meets weight, hardness, thickness, friability, disintegration
and appearance specifications
C. TEST PROCEDURE
– Record the following readings in the worksheet
– Tablets per minute
– 20 reading of weight, hardness and thickness
– 4 reading of friability anf disintegration time
D. ACCEPTANCE CRITERIA
– Tablets per minute is not less than 1000
– RSD of weight, hardness and thickness is less than or equal to 4%
– Disintegration is NMT 30 minutes and friability is NMT 0.5%
E. TEST RESULTS
– The data was collected during manufacture of Tablet Capoten 12,5 mg
(batch ....). See the attached sheet
F. SAFETY OPERATION
– Remove the covers enclosing the ableting chamber. Start the medicine.
The medicine should not run.
G. CLEANING PROCEDURE
– To be developed
 Conclution & Statement of Quality
Weight, disintegration time, friability and thickness
parameters were within the acceptance criteria. Though 4 %
RSD criteria is not met for hardness, the machine
consistently produces tablets with the hardness well within
the acceptance range. Due to the shape of the tablets per
minute. The productionrate of the tablets is also well within
the accpetance criteria. Based on the results the Manesty
Unipress is qualified to operate within the specified range.

FINAL APPROVALS
• Plant Manufacturiing____ Date____
• PDD____Date___
• Quality Assurance____Date____
FIGURE 5.18 Computed gas chromatography mass spectrometry
used in bioanalytical studies. Consists of Hewlett
Packard Gas Chromatograph (Model 5890 A) and VG Mass
Spectrometer (Model UG 12–250). (Courtesy of Elan
Corporation, plc.)
FIGURE 5.19 Assay of product samples using high performance
liquid chromatography. (Courtesy of Paddock
Laboratories
 VALIDATION OF STERILIZATION PROCESSES
Different approaches and techniques are employed
for each of the major types of sterilization, viz.:
• Filtration (or other bulk sterilization) with
aseptic filling
• Heat — steam and dry
• Gaseous (e.g., ethylene oxide)
• Radiation
KEBIJAKAN PENERAPAN CPOB

MENJADI PRIORITAS BAGI YANG MEMPRODUKSI:

PRODUK DENGAN KEKRITISAN TINGGI:
•Narrow therapeutic window
•Toksisitas tinggi
•Sediaan steril
•Produk biologi
•Produk yang dibuat melalui proses yang kompleks
KEBIJAKAN PENERAPAN CPOB

• Bagi kelompok produk yang bukan termasuk

memiliki kekritisan tinggi haruslah tetap :
– menghindarkan pencemaran, campur-baur
– Menerapkan seluruh aspek CPOB yang essensial
 Validation of a Filtration/Bulk Sterilization
and Aseptic Filling Process

The two most common pharmaceutical applications

of aseptic processing methods are
*(a) the filling of liquid products following
sterilization by filtration, and
*(b) the filling of previously sterilized bulk
powder products
 VALIDASI SEDIAAN STERIL
Program Validasi Aseptik Sterilisasi Akhir
1. Personalia Tim Validasi Disusun Tim validasi Disusun Tim validasi
2. Fasilitas Ruangan Kelas A,B dan kelas C di Kelas C dan D
Pengolahan & Pengisian bawah LAF. HOOD Unit Pengendalian Udara
Validasi terhadap : Unit
Pengndalian Udara
-Tekanan Udara
-Suhu Udara
-Kelembapan Udara
-Jumlah Partikel
-Jumlah Mikroba
-Pertukaran udara per Jam
Integritas Filter HEPA
3. Fasilitas Penunjang Kualifikasi Fasilitas Penunjang Kualifikasi fasilita Penunjang
4. Peralatan Produksi
- Autoclave Dilakukan Uji Kualifikasi Dilakukan Uji Kualifikasi
- Oven Dilakukan Uji Kualifikasi Dilakukan Uji Kualifikasi
5. validasi proses Media Fill Tidak dilakukan
Pengisian
HOW to ASSURE the QUALITY of STERILE PRODUCTS

To PRODUCE STERILE PRODUCTS

Environmental control ( facility design )

Release
Materials Process Testing

Personnel ( training )
 Producing sterile drug products
Terminal sterilization
• Product containers are filled and
sealed under high-quality
environmental conditions
designed to minimize
contamination, but not to
guarantee sterility.
• Product in its final container is
subject to a sterilization process
such as heat or irradiation.
Aseptic processing
• Drug product, container, and
closure are subject to sterilization
separately, and then brought
together.
• Because there is no process to
sterilize the product in its final
container, it is critical that
containers be filled and sealed in
an extremely high –quality
environment.
Table 1 : Elements of Aseptic Manufacture
Task Relative ease of Personnel Effect on Sterility
Validation sensitivity Assurance

Component Sterilisation Easy Low Low

Product sterilisation Easy Low Low

Equipment Sterilisation Easy Low Low

Room Design N/A None Moderate

Particulate Monitoring Easy Very low Very low

Viable monitoring Moderate Very high Very high

Personil monitoring Moderate Very high Very high

Gowning of personil Difficult Very high Very high

Sanitization Difficult High Very high

Transfer of materials Difficult High High

Aseptic technique Difficult Very high Very high

Aseptic assembly Difficult Very high Very high
 Terminal Sterilization
Drug
Product

Sterile
Container Sterilization Drug
/ Closure Product !
Process

Excipiants

Sterilization Process must be compatible with all components !

 What is Aseptic Processing?

• The production of sterile drug products by

bringing together the product, container, and
closure that have been subjected to different
sterilization methods separately, and assembled
them in an extremely high quality environment
by skilled personnel using the right tools.
Aseptic Processing
Sterile
Drug Sterilization
Product Process
Drug
Product

Container Sterilization Sterile

Process Container

Sterile
Final
Sterilization
Sterile Aseptic Product
Closure
Process Closure Processing

Sterile
Excipient Sterilization
Process Excipient

Can use multiple sterilization processes each optimized for the individual component
Aseptic Processing: Essential Elements

Facility

Documentation Equipment

Aseptic
Finish Product Processing
Process
Testing

Control &
Personnel
Verification
Horizontal Laminar Air Flow ( LAF )
 QUALITY SYSTEM
Production System(Prosd&Pross) : Validasi

Fasility & Equipment System : Kualifikasi

Laboratory Controls System : Kualifikasi

Materials System : Validasi

Packaging & Labeling System :Validasi

The four pillars of a robust * aseptic process
–Personnel training & monitoring
–Environmental monitoring
–Facilities design & HVAC validation
–Process simulation (media fills)
The main steps in the validation of any such process may be summarized as
follows:

* As a prerequisite, all studies should be conducted in accordance with a detailed, pre-

established, protocol, or series of protocols, which in turn is subject to formal change
control procedures.
* Both the personnel conducting the studies, and those running the process(es) being
studied should be appropriately trained and qualified and (in all respects) be suitable and
competent to perform the tasks assigned to them.
*All data generated during the course of the studies should be formally reviewed and
certified, as evaluated against predetermined criteria.
*Suitable testing facilities, equipment, instruments, and methodology must be available.
*Suitable clean room facilities should be available, in terms both of the “local” and
“background” environments.
*Assurance that the clean room environment conforms to, and is maintained at, the
standard specified should be secured through initial commissioning (qualification) and
subsequently through the implementation of a program of retesting, in-process control
and monitoring.
*All processing equipment should be properly installed and maintained.
*When appropriate attention has been paid to the above, the aseptic process
• may be validated by means of process simulation (or “media fill”) studies.
*The process should be revalidated at defined intervals.
* Comprehensive documentation should be available to define, support, and record the
overall validation process.
• Protocols should give in detail:
1. The objectives and scope of the study, that is, there should be a clear definition
of purpose
2. A clear and precise definition of the process, equipment, system, or subsystem
that is to be the subject of the study, with details of performance characteristics
3. Installation and qualification requirements for new equipment
4. Any upgrading requirements for existing equipment, with justification for the
change(s) and a statement of qualification requirements
5. Detailed, step-wise statement of actions to be taken in performing the study (or
studies)
6. Assignment of responsibility for performing the study
7. Statements on all test methodology to be employed, with a precise statement of
the test equipment and materials to be used
8. Test equipment calibration requirements
9. References to any relevant standard operating procedures (SOPs)
10. Requirements for the content and format of the report on the study
11. Acceptance criteria against which the success (or otherwise) of the study is to
be evaluated
12. The personnel responsible for evaluating and certifying as acceptable each stage
in the study, and for the final evaluation and certification of the process as a whole,
all as measured against the predefined acceptance criteria
1.Personnel
2.Laboratory and Instruments
3.Clean Room Standards Monitoring
4.Equipment Qualification and Maintenance
5.Media Fill Studies (Solution Products)
6.Media Fill Acceptance Criteria
7.Media Fills Applied to Nonsolution Products
8.Revalidation
9.Data Review
10.Summary of Documentation Requirements
(Aseptic Process Validation)
Parameter Penentuan Klas :
1.Jumlah Partikel di udara lingkungan

2.Jumlah Mikroba di udara lingkungan dan Permukaa Obyek

3.Jumlah Pergantian Udara ( Air Change )

4.Kecepatan Aliran Udara ( Air Flow ),Pola aliran Udara

5.Filter ( Jenis dan Posisi )

6.Perbedaan Tekanan Antar Ruang

7.Temperatur ( t ) dan Kelembaban Relatif ( RH )

• Hubungan antara batas jumlah partikulat udara dan batas cemaran
mikroba pada tiap kelas kebersihan standards are tabulated below.

ISO 14644-1 Batas yang disarankan untuk cemaran mikroba

Class SELAMA KEGIATAN BERLANGSUNG
Sample Cawan papar Cawan Sarung
udara (f90mm) kontak tangan
cfu/m3 cfu/4 jam (f55mm) 5 jari
cfu/plate cfu/sarung
tangan
A 100 <1 <1 <1 <1
B 100 10 5 5 5
C 10 000 100 50 25 -
D 100 000 200 100 50 -
Tidak Tidak Tidak Tidak
> 100 000
ditentukan ditentukan ditentukan ditentukan

Ref. PICS GMP 2006 WHO TRS 902

 Ref. PICS GMP 2006 WHO TRS 902

AS PIC FDA At rest In operation

EA s Maximum permitted number of particles/m3 equal to or above
N
0,5 mm 5mm 0,5mm 5mm

I A 100 3 500 0 3 500 0

(UDAF)
I B 100 3 500 0 350 000 2000
(Turb.)
II C 10 000 350 000 2 000 3 500 000 20 000

III D 100 000 3 500 000 20 000 Not Not

defined defined
IV NC NC Not defined Not defined Not Not
defined defined

(LAF/UDAF) = laminar air flow or uni-directional air flow

(Turb.) = turbulent or non-uni-directional air flow
 Sterility Testing – Method Overview
• Limited number of samples: 4 to 20 containers per
medium for parenteral preparations
• Limited volume for analysis: Not less than 1mL for 1-
40mL containers; not less than 20mL for >40mL
containers
• 2 Media: Soybean-Casein Digest Medium and Fluid
Thioglycollate Medium
• 2 Temperatures: 22.5 + 2.5 °C and 32.5 + 2.5 °C
• 14 days of incubation
• Inspect for evidence of microbial growth (turbidity)
 Media Fills
• Validation of aseptic processing
• True parameter for assuring that a
manufacturing process is capable of
producing sterile pharmaceuticals using an
aseptic process.
• Media fill program provides evaluation of
multiple systems.
 Sterility Test Versus Media Fill
Sterility Test Media Fill

Guidance FDA Guidance for Industry FDA Guidance for Industry

Documents Code of Federal Regulations EU Guide to Good
Multiple Pharmacopeia Manufacturing Practice
Revision to Annex 1
Sample size/Lot Maximum 40 All
Media Soybean-Casein Digest Soybean-Casein Digest
Medium (TSB) Medium (TSB)
Fluid Thioglycollate Medium
(FTM)
Incubation TSB 14 days @ 20-25ºC TSB 7 days @ 20-25ºC
conditions FTM 14 days @ 30-35ºC TSB 7 days @ 30-35ºC
Growth Yes Yes
promotion
Test method Destructive: Non-destructive:
Sample contents transferred Integral container
Sensitivity False positives No false positives
Detects high level sterility Detects single vial failure
failure
Formulation Development
1x

Clinical Batches
1x,10x

Process Development
100x

Production Batches
100x
Dapus :
• 1.Carleton,F.J., and Agalloco,J.P.,1999, Validation Pharmaceutical
Processes ,Sterile Products, Secnd.ed,Revised and
aexpanded,Marcel Dekker Inc.,New York,669-702
• 2.Lieberman,H.A., Rieger,M.M and Banker,G.S,1998,
Pharmaceutical Dosage forms:Disperse Systems, Vol.3,Marcel
Dekker, Inc., New York, 479-512.
• 3. dll.