PROCESS VALIDATION
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“Action of proving, in accordance with the principles of GMP, that any procedure, process, equipment, material, activity or system actually leads to the expected results”(EU GMP)
“ Establishing documented evidence that provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes”(FDA Guideline)
For pharmaceutical manufacturer, validation should be understood not as a DISCRETIONARY rule, but as a MANDATORY requirement with which there must be COMPLIANCEValidation is addressed regularly during regulatory inspection as well as during supplier audit.
(EU GMP)
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Poorly developed and insufficiently optimized processes are a serious deficiency frequently encountered in process validation on production scale
There is often insufficient data or material available to be used as a basis for determining Critical Processing Step and Critical Process Parameters
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To compensate for the steps that were commonly missed
during development stage commonly using of term :
“Challenges”, “Worst-case”, “Optimization” THESE ARE NOT ACTUALLY PART OF VALIDATION PROCESS
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Process Validation IS NOT
Process Development
Development
Optimisation
Scale-Up
Process
Validation
Determine Challenge
Critical Parameter
Establish “Proven
Acceptable Ranges”
Define Operations
Ranges for Critical
Parameters
Confirmation of Normal
Operating Ranges for
Critical Paramaters
Process Optimization
Proven Acceptable Ranges, adjusting a process to optimize some specified set of parameter without violating some constraint
Design optimization, process to find the best design parameter that satisfy the requirement, typically using design of experiment(DOE), statistic and optimization techniques to evaluate and determine the best design
Purpose of optimization to achieve the best design relative to a set of prioritized or parameters criteria including maximizing some parameters such as productivity, reliability, longevity, efficiency and utilization
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Focus to learn the process capability, and hence the
influencing factors and the process capability index of
each individual part of the process
Once the influencing factor are known, the process can
be optimized and statistical trust placed in the process
as part of permanent process validation therefore
requires permanent data recording and not simply
random data collation of three statistically insignificant
“consistency batches”
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Validation protocols have not been compiled or are not being followed
Information about the equipment used, critical process parameters, sampling plan/data, number of batches, acceptance criteria, data evaluation etc. are missing from validation documentation as well as the integrity of the data
Changes to validated processes are not being addressed
Regardless the enormous amount of time and effort required for validation activities, it is not easy, initially, validation should also be a tool for saving materials, making cost-savings and saving time.
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According to PIC- Principles of Qualification and
Validation; Various FDA Guidelines
There is no standard definition exists for the term of
Validation
Therefore, validation in development plan be understood
differently to validation during production
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Definition : Validation during development
Validation during pharmaceutical development includes all development
activities and their documentation, which guarantee and prove that the quality of
the future commercial product matches the quality of the composition of
development and clinical samples
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Validation task at
individual Development stages
- Up Scaling
- Product
Transfer
GLP
Standards
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Pre-
formulation
experiments
Process
developmentClinical
phase I
Manufacturing
of clinical test
samples
Clinical
phase III
Clinical
phase II Clinical phase
IV, commercial
goods
Cleaning validation
Production equipment
Further development and validation of
analytical method
Approval for clinical tests Marketing approvalTime axis :
Process validation
Laboratory
scale/pilot scale
Manufacturing
of clinical test
samples
Manufacturing
of clinical test
samples
Submission
of marketing
authorization
documentsProcess validation
Manufacturing
process
Development and
validation analytical
method
Cleaning verification
Laboratory scale/pilot
scale
Manufacturing/long-term
stability of registration
batches
No legal
require
ment
Fully GMP complaints, but
more favourable conditions
apply for process validation
Fully GMP complaints,
more stringent
requirement apply for
process validation
Fully GMP
complaints, fully-
validated process
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Validation at
Product Life cycle
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Laboratory batches
Commercial batches
Commercial batches
Pilot batches
Development
phase
Improvement
phase
Validation phase
Usage phase
Shut-down
Change phase
Life cycle Processes
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Released in Jan 2011.
This guidance incorporated
o QbD,
o Process Analytical Technology(PAT),
o Risk management and
o the Concept of life cycle approach to process validation.
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Stage 1 - Process Design
◦ Design and development
Quality Target Product Profile (QTPP)
Critical Quality Attribute (CQA)
Formulation and process development – Majority of process
a) Active Pharmaceutical Ingredient (API
b) Formulation development:
c) Process development
d) Design space:
◦ Establishing a Strategy for Process Control
Stage 2 – Process Qualification
◦ Design of the facility and qualification of the facilities, system, equipment and
utilities and
◦ Process Performance Qualification(PPQ).
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Stage 3 – Continued Process Verificationo To provide continual assurance that the process remains in a state of control during routine
commercial production.
o Quality system to monitor process data, to detect any undesirable process variability and the
necessary actions should be established.
o Data collected include process trend and quality material, inprocess material and finished product.
o The use of modern statistical software which enable literally instantaneous evaluation of data such
as control charting and process capability indicators is recommended.
o These data should be statistically trended and reviewed periodically by statistician to confirm the
validated state.
o It is recommended to use heightened sampling and testing of process parameters and quality
attributes in this stage until sufficient data generated for estimation of variability.
o This will form the basis for establishing level and frequency of routine sampling and monitoring.
o Process variability should be reviewed periodically. Annual review of manufacturing data
should be regarded as minimum requirement.
o The frequency and extent of review should be based on product/process risk considerations where
more frequent review is expected for critical process parameters and critical quality attributes.
o Periodic review can be adjusted accordingly when sufficient reliable product and process history
is demonstrated.
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Manufacturing processes may be developed using
1. Traditional approach
2. Continuous verification approach, based on QbD
approach
3. Hybrid approach, combined of both processes
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•mengendalikan aspek kritis kegiatan yang dilakukan
melalui kualifikasi dan validasi sepanjang siklus hidup
produk dan proses.
• Tiap perubahan yang direncanakan terhadap fasilitas,
peralatan, sarana penunjang, dan proses, yang dapat
memengaruhi mutu produk, hendaklah dikaji,
didokumentasikan secara formal dan dampak pada status
validasi atau strategi pengendaliannya.
• Sistem komputerisasi yang digunakan untuk pembuatan
obat hendaklah juga divalidasi sesuai dengan persyaratan
(Aneks 7) Sistem Komputerisasi
• Konsep dan pedoman yang relevan yang disajikan dalam
ICH Q8, Q9, Q10, dan Q11 hendaklah juga diperhitungkan
CPOB mempersyaratkan industri
farmasi
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Pendekatan manajemen risiko mutu hendaklah diterapkan sepanjangsiklus hidup obat.
Sebagai bagian dari sistem manajemen risiko mutu, keputusanmengenai cakupan dan luas kualifikasi-validasi fasilitas, peralatan, sarana penunjang, dan proses hendaklah didasarkan pada penilaianrisiko yang dijustifikasi dan didokumentasikan.
Validasi retrospektif tidak lagi dianggap sebagai pendekatanyang dapat diterima
Data pendukung kualifikasi dan/atau studi validasi yang diperolehdari sumber di luar program industri dapat digunakan, dengan syaratpendekatan ini telah dijustifikasi dan ada jaminan yang memadaibahwa pengendalian telah dilakukan saat mengambil alih data tersebut.
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1. Semua kegiatan kualifikasi dan validasi
hendaklah direncanakan dengan
mempertimbangkan siklus hidup fasilitas,
peralatan, sarana penunjang, proses dan
produk
2. Kegiatan kualifikasi dan validasi
hendaklah hanya dilakukan oleh
personel yang telah mendapat
pelatihan dan mengikuti prosedur
yang telah disetujui
3. Personel yang diberi tanggung jawab untuk
kualifikasi/validasi hendaklah melapor sebagaimana
ditetapkan dalam Sistem Mutu walaupun personel terkait
mungkin bukan bagian dari manajemen mutu atau
pemastian mutu. Namun, hendaklah tersedia fungsi
pengawasan terhadap mutu yang memadai di sepanjang
siklus hidup validasi
4. Elemen kunci program
kualifikasi dan validasi
hendaklah ditetapkan secara
jelas dan didokumentasikan
dalam Rencana Induk
Validasi (RIV) atau dokumen
lain yang setara
PENGORGANISASIAN DAN PERENCANAAN
KUALIFIKASI DAN VALIDASI
6.Untuk proyek berskala
besar dan kompleks,
perencanaan yang lebih
detil dan rencana validasi
yang terpisah dapat
membantu kejelasan7.Pendekatan manajemen risiko
mutu hendaklah digunakan untuk
kegiatan kualifikasi dan validasi.
Dalam hal peningkatan
pengetahuan dan pemahaman
setiap perubahan selama proyek
berlangsung atau selama produksi
komersial berjalan, penilaian risiko
hendaklah diulangi, jika diperlukan
dan hendaklah didokumentasikan
dengan baik
8. Pemeriksaan yang
memadai hendaklah
dilakukan terhadap
hasil kualifikasi dan
validasi untuk
memastikan integritas
semua data yang
diperoleh
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5. Dokumen RIV
atau yang setara
hendaklah
menetapkan sistem
kualifikasi/validasi
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1. Cara dokumentasi yang baik penting untuk mendukung
pengelolaan pengetahuan (knowledge management)
sepanjang siklus hidup produk
2. Semua dokumen yang dihasilkan selama kualifikasi dan
validasi disetujui dan disahkan
3. Saling keterkaitan antar dokumen dalam proyek validasi
yang kompleks ditetapkan dengan jelas
4. Protokol validasi disiapkan dengan menetapkan sistem,
atribut dan parameter kritis, serta kriteria keberterimaan
5. Jika sesuai, dokumen kualifikasi dapat digabungkan
bersama, misal Kualifikasi Instalasi (KI) dan Kualifikasi
Operasional (KO)
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6. Bila protokol validasi dan dokumentasi lain disediakan oleh pihak ketiga
yang menyediakan jasa validasi,
personel yang diberi wewenang di lokasi pabrik terkait hendaklah memastikan
kesesuaian dan kepatuhan terhadap prosedur internal sebelum disetujui.
Protokol dari pemasok dapat dilengkapi dengan dokumentasi/ protokol uji
tambahan sebelum digunakan
7. Setiap perubahan signifikan terhadap protokol yang disetujui selama
pelaksanaan validasi, misal kriteria keberterimaan, parameter operasional,
dan lain-lain, harus didokumentasikan sebagai penyimpangan dan
dijustifikasi secara ilmiah
8. Hasil yang tidak memenuhi kriteria keberterimaan
harus dicatat sebagai penyimpangan dan diselidiki secara menyeluruh sesuai
prosedur internal.
Setiap implikasinya terhadap validasi harus dituangkan dalam laporan
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9. Pengkajian dan pengambilan kesimpulan validasi
dilaporkan dan hasil yang diperoleh dibandingkan dengan kriteria
keberterimaan.
Tiap perubahan terhadap kriteria keberterimaan hendaklah dijustifikasi secara
ilmiah
10. Pelulusan formal untuk tahap berikutnya dalam kualifikasi dan validasi
proses
hendaklah disahkan oleh personel yang bertanggung jawab baik sebagai bagian
dari persetujuan laporan validasi maupun sebagai dokumen ringkasan terpisah.
Persetujuan bersyarat untuk melanjutkan ke tahap kualifikasi berikutnya dapat
diberikan jika kriteria keberterimaan tertentu atau penyimpangan belum
sepenuhnya ditangani namun tersedia penilaian yang terdokumentasi bahwa
tidak ada dampak signifikan pada kegiatan selanjutnya
• mencakup validasi awal dari proses baru, validasi bila terjadi perubahan proses, transfer lokasi pembuatan, dan verifikasiproses on-going
1. Ketentuan dan prinsipyang diuraikan dalam Butir-
butir ini berlaku untukpembuatan semua bentuk
sediaan obat..
• bahwa proses pengembangan produk yang andal diperlukan agar validasi proses berhasildilakukan dengan baik
2. Secara implisit tertuang
• Pedoman tentang Validasi Proses dimaksudkan untukmemberikan panduan mengenai informasi dan data yangdiperlukan dalam pengajuan izin ke regulator
• Namun, persyaratan CPOB untuk validasi proses berlanjut sepanjang siklus hidup produk
• Pendekatan ini hendaklah diterapkan untuk menautkanpengembangan produk dan proses
• memastikan proses pembuatan skala komersial secararutin dalam keadaan tervalidasi
3. Validasi proses dapatditerapkan bersamaan
dengan pedomantentang Validasi Proses
yang relevan
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• Traditional approach
• Continuous verification approach
• Hybrid approach
4. Proses pembuatan dapatdikembangkan dengan
menggunakan pendekatan
• harus dibuktikan keandalan proses dan memastikanmutu produk yang konsisten sebelum produkdiluluskan ke pasar.
5. terlepas dari pendekatan apapun yang digunakan,
• program validasi prospektif hendaklah diterapkanpada proses pembuatannya Validasi retrospektifmerupakan pendekatan yang tidak lagi dapatditerima
6. proses pembuatan yang menggunakan pendekatan
tradisional sebelum mendapatkanIzin Edar
• mencakup semua kekuatan produk yang akandipasarkan dan lokasi pembuatan.
7. Validasi proses produk baru
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8.Bracketing approach
• dapat dijustifikasi untuk produk baruberdasarkan pengetahuan proses yang ekstensif dari tahap pengembanganbersamaan dengan program verifikasi on-going yang sesuai
• Untuk validasi proses produk yang ditransfer dari satu lokasi ke lokasi lain atau pindah fasilitas dalam lokasi yang sama, pendekatan bracketing dapatmengurangi jumlah bets validasi
• Namun, harus tersedia pengetahuanproduk yang sudah diproduksi, termasukhasil dari validasi sebelumnya. Kekuatan, ukuran bets dan ukuran kemasan/jeniswadah yang berbeda juga dapatmenggunakan pendekatan bracketing jikatelah dijustifikasi
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9.Proses pembuatandan pengendalianproduk lama yang ditransfer ke lokasi
lain
• harus sesuaidengan Izin Edardan memenuhistandarpersyaratan IzinEdar yang berlakusesuai jenisproduk tersebut
• Variasi terhadapIzin Edar harusdidaftarkan sesuaiketentuan yang berlaku.
10.Validasi proses harus menetapkan
• semua atributmutu danparameter proses yang dianggappenting untukmemastikankeadaanterkendali danmutu produkyang memenuhipersyaratan dapatdipenuhi secarakonsisten olehproses tersebut.
11.Dasar penetapan
• parameter proses dan atribut mutuyang kritis atautidak kritis harusdidokumentasikandengan jelas, denganmempertimbangkan hasilpenilaian risiko
12.Penetapan betsyang diproduksi
• untuk validasiproses hendaklahberukuran samadengan bets yang dimaksudkanuntuk skalakomersial danpenggunaanukuran bets lain hendaklahdijustifikasi
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• Sudah dikualifikasi sebelum digunakan. 13. Peralatan, fasilitas, sarana penunjang, dan
sistem untuk validasi proses
• Sudah divalidasi sesuai tujuan penggunaannya14. Test methods
• pemahaman proses dari studi pengembangan atausumber lain harus dapat diakses oleh bagianterkait, kecuali jika ada justifikasi lain dan menjadipedoman untuk aktivitas validasi
15. Pendekatan apa pun yang digunakan untuk
semua produk,
• Harus melibatkan personel dari bagian produksi, pengembangan, atau penanggung jawab transfer darikedua pihak
• Semua bets dibuat oleh personel yang mendapat pelatihansesuai persyaratan CPOB dan terdokumentasi.
• Personel produksi harus terlibat dalam pembuatan bets validasi untuk memudahkan pemahaman produk
16. Pembuatan betsvalidasi,
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• dikualifikasi sebelum bets validasi mulai diproduksi. Jika tidak, hendaklah dibuat justifikasi berbasis prinsipmanajemen risiko mutu yang didokumentasikan
17. Pemasok bahan awaldan pengemasprimer/kritis
• Ketersediaan process knowledge yang mendasari justifikasi design space dan pengembangan model matematis (jika digunakan), sangat penting untuk memastikan strategi pengendalian proses
18. Specially/Important notice
• ditetapkan lebih dulu prosedur pelulusan bets validasi.
• Kondisi produksi harus sepenuhnya memenuhi persyaratanCPOB, kriteria keberterimaan validasi, dan kriteriaverifikasi proses kontinu (jika digunakan), serta sesuai dengan dokumen Izin Edar atau dokumen uji klinik yang disetujui
19. Pelulusan bets validasidan akan dipasarkan
Validasi proses obat uji klinik mengacu pada Aneks 6
Pembuatan Obat Uji Klinik
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• sejumlah bets produk diproduksi dalam kondisi rutinuntuk memastikan reprodusibillitas
1. Dalam pendekatansecara tradisional,
• didasarkan pada prinsip manajemen risiko mutu, memungkinkan
dibuat rentang variasi normal dan tren serta menghasilkan cukupdata untuk dievaluasi.
• Setiap industri farmasi harus menentukan dan memberi justifikasijumlah bets yang diperlukan untuk memberikan jaminan yang tinggi bahwa proses mampu menghasilkan produk yang bermutusecara konsisten.
• Tanpa mengurangi persyaratan pada butir 12.53, pada umumnya minimal produksi tiga bets berturut-turut dalamkondisi rutin dapat merupakan validasi proses
• Alternatif jumlah bets dapat dipertimbangkan dari justifikasi ametode pembuatan standar yang telah digunakan dan apakahproduk atau proses yang mirip telah digunakan sebelumnya di pabrik tersebut.
• Data validasi tiga bets awal mungkin dapat ditambahkan pada data yang diperoleh dari bets berikutnya sebagai bagian daripelaksanaan verifikasi on-going
2. Jumlah betsyang diproduksidan jumlahsampel yang diambil
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• the critical process parameter (CPP),
• critical quality attributes (CQA) dan
• kriteria keberterimaan terkait harusberdasarkan data pengembanganatau pemahaman proses/process knowledge yang terdokumentasi
• Protokol validasi proses hendaklahmencakup,
3. Protokol
validasi
proses harus
disiapkan
dengan
menjelaskan
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• selama proses pengembangan telah ditetapkan secara ilmiah, strategi pengendalian, yang memberikan tingkat kepastian mutuproduk yang tinggi, maka verifikasi proses secara kontinu dapatdilakukan sebagai alternatif untuk validasi proses tradisional
1. Untuk produkyang dikembangkanberdasarkanpendekatanquality by design (QbD
• a science based control strategy for the required attributes for incoming materials,
• critical quality attributes and
• critical process parameters to confirm product realization.
• should also include regular evaluation of the control strategy (RM-FG)
• Process Analytical Technology and multivariate statistical process control may be used as tools.
• each manufacturer must determine and justify the number of batches necessary to demonstrate a high level of assurance that the process is capable of consistently delivering quality product
2. Metode untukmemverifikasiproses harus
ditetapkan. Strategipengendalianproses harustersedia
Prinsip yang ditetapkan dalam ketentuan umum tetap berlaku
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Pendekatan hibrida daritradisional dan verifikasi
proses kontinu dapatdigunakan
• bilamana sudah diperolehpengetahuan danpemahaman yang tinggimengenai produk danproses yang diperolehdari pengalamanpembuatan dan data riwayat bets
Pendekatan ini jugadapat digunakan untuk
• kegiatan validasipascaperubahan atauselama verifikasi proses on-going meskipunproduk tersebut padaawalnya divalidasidengan menggunakanpendekatan tradisional
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• where there is a strong benefit-risk ratio for the patient, it may be acceptable not to complete a validation program before routine production starts and concurrent validation could be used.
• However, the decision to carry out concurrent validation must be justified and approved by NADFC, documented in the VMP for visibility and approved by Quality Assurance Head
1. In exceptional circumstances
• there should be sufficient data to support a conclusion that any given batch of product is uniform and meets the defined acceptance criteria.
2. Where a concurrent validation approach has
been adopted
• should be formally documented and available to the Quality Assurance Head prior to certification of the batch
3. The results and conclusion
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• therefore primary and secondary packaging equipment for finished and bulk products should be qualified
Variation in equipment processing parameters
especially during primary packaging may have a
significant impact on the integrity and correct
functioning of the pack, e.g. blister, strips, sachets and
sterile components
• should be carried out at the minimum and maximum operating ranges defined for the critical process parameters such as temperature, machine speed and sealing pressure or for any other factors
Qualification of the equipment used for
primary packing
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• all three approaches to process validation mentioned above, i.e. traditional, continuous and hybrid
Applicable to
• to ensure that a state of control is maintained throughout the product lifecycle with the relevant process trends evaluated
Manufacturers should monitor product quality
• At any point throughout the product lifecycle, it may be appropriate to modify the requirements taking into account the current level of process understanding and process performance
The extent and frequency of on-
going process verification should be reviewed
periodically
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• under an approved protocol or equivalent documents
• a corresponding report should be prepared to document the results obtained.
• Statistical tools should be used, where appropriate, to support any conclusions with regard to the variability and capability of a given process and ensure a state of control
On-going process
verification should be conducted
• throughout the product lifecycle to support the validated status of the product as documented in the Product Quality Review. Incremental changes over time should also be considered and the need for any additional actions, e.g. enhanced sampling, should be assessed
On-going process
verification should be used
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The control of change is an important part of knowledge management and should be handled within the Pharmaceutical Quality System
Written procedures should be in place to describe the actions to be taken if a planned change is proposed to a starting material, product component, process, equipment, premises, product range, method of production or testing, batch size, design space or any other change during the lifecycle that may affect product quality or reproducibility
Where design space is used, the impact on changes to the design space should be considered against the registered design space within the Marketing Authorisation and the need for any regulatory actions assessed
Quality risk management should be used to evaluate planned changes to determine the potential impact on product quality, Pharmaceutical Quality Systems, documentation, validation, regulatory status, calibration, maintenance and on any other system to avoid unintended consequences and to plan for any necessary process validation, verification or requalification efforts
Changes should be authorized and approved by the responsible persons or relevant functional personnel in accordance with the Pharmaceutical Quality System
Supporting data, e.g. copies of documents, should be reviewed to confirm that the impact of the change has been demonstrated prior to final approval
Following implementation, and where appropriate, an evaluation of the effectiveness of change should be carried out to confirm that the change has been successful
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1
2
3
4
5
6
7
Stage 1 Stage 2 Stage 3
Cont. Process Verification/
Qualification Stage/QbD approach
Traditional approach to validation
Ongoing Process Verification
Process Design Qualification
Process Qualification
Continued Process Verification
The commercial manufacturing process is defined based on knowledge
gained through development and scale-up activities
Confirming that the manufacturing process designed is capable of
reproducible commercial manufacturing
Assuring that the process remains in a state of control
EU-GMP/
PIC/CPOB
FDA
Identify sources of
VariabilityControl of Variability Monitoring Variability-remains “in control”
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Summary
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Current Approach – Quality By Testing
Finished
ProductManufacture
Excipients
and API
ExcipientPass / Fail
Specification
APIPass / Fail
Specification In Process TestingPass / Fail
Specification
QC TestingPass / Fail
Specification
• Acceptance criteria set on limited data eg 1 batch.
• Testing must be performed for batch to be released.
• Failing batch only investigated at end of process
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Current Focus of VALIDATION
• One off exercise, very little consideration on how the method will work in the
“real world”, operational conditions.
• Does it look good on paper – works for three batches so all ok?
• Robustness of documentation, not method
• No consideration of who will use method, what equipment, technology
advances.
Current Focus of TRANSFER
• One off exercise, usually seen as an exercise that gets in the way of the real
work.
• No transfer of method knowledge.
• Usually performed by most competent analyst – no consideration of day to day
use.
Current Practise for Method Validation and Transfer
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Process validation / transfer hasn’t worked and everyone is
surprised!!
• Root cause is usually found to be insufficient consideration of
the routine operating environment of the method during the
process validation exercise and the lack of a process to
capture and transfer method knowledge.
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Traditional approach
Research and Development
Pilot scale
Scaling up
Commercial batch and Process validation prospective, Concurrent and Retrospective
Annual Product Review/Product Quality Review
New Paradigm – QbD approach
Process validation Stages Trough Lifecycle Stage 1 : R&D, BA/BE, Trial,
Scaling up etc. Stage 2 : Process
validation/PPQ Stage 3 : CPV/PQR, Process
Robustness, SPC Process Analytical
technology/PAT Real-time Release Testing (RTRT) Operational Excellent - Lean Six
Sigma
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48
“You can’t test quality into drug products”
has been heard for decades – so what’s new?
Quality by Design
◦ It’s a culture - incorporates quality principles as well as
strong compliance function
◦ Incorporates risk assessment and management
◦ Refocuses attention and resources on what’s important to the
customer, i.e. the patients, health professionals, and
distribution chain
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What is Quality by Design?
Quality by Design (QbD) is:
A systematic approach to development thatbegins with predefined objectives andemphasizes product and processunderstanding and Process control, based onsound science and Quality Risk Management
ICH Q8(R2)
3
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Quality by Design (QbD) is
a concept first outlined by well-known quality expert Joseph M. Juran• He said quality can be planned and that most problems related to the way
that quality was planned (or not!) in the first place.• Quality cannot be tested into products – it has to be built by design.
who believed that quality could be planned, and that most quality crises and
problems relate to the way in which quality was planned in the first place.
◦ Based on FTR Philosophy
◦ Proactive & risk based approach for predictable & predefined quality
◦ Planning quality into the product and process
◦ A leading indicator for better controls & to handle quality crises and
problems early in the cycle
5010/10/2018
Quality
by
Design
(QbD)
Quality
By Design/
QbD
concept
Key characteristics of QbD
• A tool for focused & efficient drug development
• Is a dynamic and systematic process
• Relies on the concept that Quality can be built in as acontinuum
• Is applicable to Drug Product and Drug Substancedevelopment (chemicals / biologics)
• Is applicable to analytical methods
• Can be implemented partially or totally
• Can be used at any time in the life cycle of the Drug
• Is encouraged by Regulators (EMA & FDA)
10/10/2018 52
Goals of based on Guidance
• Design & develop wellunderstood procedures
Focus on what is critical to
patient safety & product quality
Quality by Design approach
Science
Risk
Design
Validation
Control
•
•
• V&V activities to ensure acapable process
Establish an appropriate control
strategy•
Slide 18 10/10/2018 53
What drives the process?Product
understanding is
required to design
the process.
Product Science
CriticalQuality
Attributes definethe process.
Process Risk
10/10/2018 54
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Figure 2
Iterative Approach
Quality Target Product Profile
Drug substance properties; prior knowledge
Proposed formulation and manufacturing process
Determination of
Cause – Effect relationships (Risk Identification with subsequent Risk Analysis)
Risk-based classification (Risk Evaluation)
Parameters to investigate (e.g. by DOE)(Risk Reduction 1: proposal 2: verified)
FORMULATION FORMULATION
DESIGN SPACEDESIGN SPACEPROCESS PROCESS
DESIGN SPACE DESIGN SPACE
BY UNIT OPERATIONBY UNIT OPERATION
CONTROL CONTROL
STRATEGYSTRATEGY
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Derived
Iterative ApproachTarget Product Profile
10/10/2018 56
Stage 1 Stage 2 Stage 3
Cont. Process Verification/
Qualification Stage/QbD approach
Traditional approach to validation
Ongoing Process Verification
Process Design Qualification
Process Qualification
Continued Process Verification
The commercial manufacturing process is defined based on knowledge
gained through development and scale-up activities
Confirming that the manufacturing process designed is capable of
reproducible commercial manufacturing
Assuring that the process remains in a state of control
EU-GMP/
PIC/CPOB
FDA
Identify sources of
VariabilityControl of Variability Monitoring Variability-remains “in control”
10/10/2018 57
Summary
Stage 1 Stage 2 Stage 3
Cont. Process Verification/
Qualification Stage/QbD approach
Traditional approach to validation
Ongoing Process Verification
Process Design Qualification
Process Qualification
Continued Process Verification
The commercial manufacturing process is defined based on knowledge
gained through development and scale-up activities
Confirming that the manufacturing process designed is capable of
reproducible commercial manufacturing
Assuring that the process remains in a state of controlFDA
Identify sources of
VariabilityControl of Variability Monitoring Variability-remains “in control”
10/10/2018 58
EU-GMP/
PIC/CPOB
Important Aspects of Stage 1• Clinical
• Characterisation
• Drug Release
• Pharmacokinetics
• Pharmacodynamic
• Pharmaceutical
process
• Therapeutic process
Analysis of the
Reference
Listed Drug
Product
• Drug Substance
• Excipients
• Drug Product
composition
• Manufacturing
process
Define the
Quality Target
Product Profile
TPP-QTPP
Create a
Control
Strategy-CS
Identify theCQAs
Define ProcessStepsCPPs-DS-RA
• Design of Experiments
• Risk Assessments
• Scale-up: Lab to Pilot
• Design Space
• Container Closure System
• Microbiological Attributes
Manufacturing
Process
Development
Drug Product
Formulation
Development
Pilot Bioequivalence
Study
Dissolution Method
Development
Components of Drug Product
5910/10/2018
CDS/UDT
BE study
BA/BE study
Process Validation Stages Trough LifecycleEU-GMP vs GMP-FDA
Roadmap for QbD
• Product Understanding and Process Knowledge
• Define Target Product Profile
• Define the Quality Target Product Profile
• Identify the Critical Quality Attributes
• Process Description
• Determine the Critical Process Parameters
• Determine the Design Space
• Perform a Risk (Assessment) Analysis
• Perform Experiments
• Identify a Control Strategy8
10/10/2018 60
Critical Quality Attributes (CQA)
“A physical, chemical, biological or microbiological
property or characteristic that should be within an
appropriate limit, range, or distribution to ensure the
desired product quality”.
Identify theCQAs
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Could be for Raw Materials, Excipients, Drug Substance, intermediate, container closure components.
Developed from extensive product development & understanding
May only have limited information at early Stage1, so first set of CQA’s may be based on prior knowledge & experience
Decisions on criticality should be identified using a scientificevidence and a risk-based approach.
Identify items that impact Safety, Quality, Identity, Potency,Purity (SQuIPP).
10/10/2018 62
Critical Quality Attribute
Drug Substance(chemical)
Appearance
Particle size
Morphic forms
Water content
Residual solvents
Organic impurities
Inorganic impurities
Heavy metals
Residue on ignition
Assay
Drug product(tablet)
Appearance
Identification
Hardness
Uniformity of dosage
Physical form
Dissolution
Impurities
Degradation products
Water contentAssay
Microbiological limits
10/10/2018 63
Risk in
1. Continuity of
Quality
attribute
2. Continuity of
Supply
3. Reasonable in
cost
1. Attributes not defined as critical could still be monitored during
the Development phase.
2. CQAs are subject to change as product and process
knowledge develops (Design of Experiment and Design
Space)
3. Continue using Quality Risk Management
4. CQAs are usually linked to test specifications
5. All CQAs should be fully understood and defined before
moving to stage 2
10/10/2018 64
Input Process Output
QTPP to Potential CQAs
Safety &Efficacy
Strength Quality Identity Potency Purity
Potential CQAs
10/10/2018 65
Drug release
Activity
DeliveryCrystallinity
Particle Size Distribution Morphology
Degradation
Impurity
The use of statistical experimental design such as Design of Experiment (DoE) is very useful to determine relationships, including multivariate interactions, between the variable inputs and the resulting outputs.
Risk analysis tools can be used to screen potential variables for DoE studies to minimize the total number of experiments conducted while maximizing knowledge gained.
The results of DOE studies can provide justification for establishing ranges of incoming component quality, equipment parameters, in-process material quality attributes, and also to establish Design Space (DS).
10/10/2018 66
“The multidimensional combination and interaction of
input variables (e.g., material attributes) and process
parameters that have been demonstrated to provide
assurance of quality.
Should be adopted by development teams as it results in
better process understanding and the knowledge
supports the control strategy
10/10/2018 67
Design Space
Previous
ExperienceLiterature
Technology
TransferFirst Principles
Material
AttributesScale-up
Process
Parameters
Risk
Assessment
Facility, Systems
& Equipment
Understanding
Experimental
DesignQTPP, CQAs,
CPPs and CS
10/10/2018 68
Knowledge
Space
Design
Space
Operational
Space
Design Space
1. Understanding of the relationship between Process Inputs and CQAs useful to understand the edge of failure for material attributes or Critical Process Parameters
2. Development of a Design Space is optional but can be described in a Regulatory Submission
3. Working within the design space is not considered as a change.
4. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process.
5. Design space is proposed by the applicant and is subject to regulatory assessment and approval.”
6. Could be applied to part of a process Risk Assessment
10/10/2018 69
Critical Process Parameters (CPPs)
“A process parameter whose
variability has an impact on a critical
quality attribute and therefore should
be monitored or controlled to ensure
the process produces the desired
quality”
(ICH Q8)
Critical Process Parameters (CPPs)
1. Subject Matter Experts (SMEs) from various departments
2. Provide documented rationale
3. A “Cause and Effect Diagram” to identify process input
parameters where variability may have largest impact to
product quality/process performance
4. As knowledge develops, other assessment tools are
useful
5. Quality Risk Management should be applied to all
Critical Stages/Proces Parameters of Stage 1 Process
Design
•
•
•
•
•
10/10/2018 71
Define Process
Steps & CPPs
Parameter Kritis - Validasi Parameter Kritis - QbD
Risk Quality Risk Management (QRM)
The QRM process must be systematicdefined policies and procedures
with
Must operate across the product lifecycle
Principles and methodologies should be clear scientific knowledge based analysis
Criteria and decisions from assessments shouldbe documented
10/10/2018 72
To select the optimal product design (e.g., parenteralconcentrates vs pre-mix) and process design (e.g., manufacturing technique, terminal sterilization vs. aseptic process).
To enhance knowledge of product performance over awiderange of material attributes (e.g., particle size distribution,moisture content, flow properties), processing options, and process parameters.
To assess the critical attributes of raw materials, solvents, Active Pharmaceutical Ingredient (API)-starting materials, API’s, excipients, or packaging materials.
10/10/2018 73
Ishikawa (fishbone) diagram is a very effective tool to
capture a brainstormed list of potential process inputs
impacting variation.
Mapping the manufacturing process using a process
flow diagram (PFD) is helpful to define the scope of
the risk assessment and to identify possible process
inputs
FMEA (failure modes and effects analysis) or use of a
prioritization matrix (cause and effect matrix)
10/10/2018 74
Control Strategy
“The controls can include parameters and attributes relatedto drug substance and drug product materials and
components, facility and equipment operating conditions, in-process controls, finished product specifications, and the
associated methods and frequency
(ICH Q10)
of monitoring and control”
Create a Control Strategy
10/10/2018 75
© ICH, November 2010
Control strategy derives from management of risk and should
lead to assurance of consistent quality of product in alignment
with the Quality Target Product Profile (QTPP)
Control strategy is:
◦ Not a new concept
◦ Not just specifications
◦ Based on product and process understanding and risk
management
◦ While design space is optional, control strategy is not.
© ICH, November 2010
Every process and product has an associated control strategy.
◦ There is one overall control strategy for a given product.
◦ There are control strategies for unit operations
◦ It could include some site specific aspects
For a given product, different approaches for the control strategy
are possible (e.g. in-process testing, RTRT, end product testing)
Specifications for API and drug product are still needed
for stability testing, regional regulatory testing
requirements, etc.
© ICH, November 2010
Control strategy and batch release should not be confused.
Control strategy is a key component, but not the only element
needed for the batch release decision.
Scale-up, technology transfer and manufacturing experience can
lead to refinements of the control strategy under the PQS
considering regulatory requirements
© ICH, November 2010
Process for defining the control strategy
◦ What are the quality criteria (QTPP)◦ Initial design of specific product & process◦ Assess prior knowledge to understand materials, process and product with
their impact Experience with different approaches to control
◦ Risk assessment for process steps and variables Assure all CPPs are identified during QRA
◦ Development to further determine what type of controls are appropriate for each variable
◦ Consider design space, if submitted◦ Specifications
Scale-up considerations
Quality system requirements of control strategy
◦ Implementation, maintenance and updating
© ICH, November 2010
Industry selects control approach based on multiple factors
◦ Factors may include analytical testing sensitivity, equipment
limitations, etc.
Regulators evaluate the control strategy and whether the risk has
been adequately controlled
Inspector reviews the implementation of the control strategy at
site, including adaptation at scale up, and the adequacy of the
site quality system to support it
Control Strategy
Built up based on previous knowledge and theoutcome of extensive product & process studies
Investigation of material attributes and process
•
•
parameters that were deemed high risk to the CQAsof the DP during initial risk assessment
Critical Material Attributes (CMAs) and Critical
Process Parameters (CPPs) were determined
Acceptable Operating Ranges were identified
•
•
• All variables that werein the control strategy
Can be further refined increases over time
deemed high risk are included
as process knowledge•
Create a Control
Strategy
8110/10/2018
Control Strategy
Details the excipient attributes to be controlled
In-process controls
•
•
• High-risk process parameter ranges identifieddevelopment
Proposed operating ranges for commercial
manufacture
Release specification also identified
Basis for Process Validation
during
•
•
•
• Note that post-approval changes relevantto the control strategy
Slide 91
Create a Control Strategy
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Knowledge
Space
Design
Space
Operational
Space
Product – Process Design Completion
Target of Stage 1
Final Stage of Complete Process Control Strategy
Important output of Stage 1
Will ensure that the process remains in control, created
based on process knowledge gained
Encompasses all elements of each unit operation of the
manufacturing process to be a systematically Critical
Process Parameter and proposed Design Space and
applied science and risk-based approaches-analysis and
techniques
All product attributes and process parameters should be in
a complete Process Control Strategy
•
•
•
•
•
8410/10/2018
Final CQA-CPP-DS-RS-CS
dalam
Parameter Kritis - QbD
10/10/2018 85
Stage 1 Stage 2 Stage 3
Qualification
StageTraditional
approach to
validation
Ongoing Process Verification
Process Design
Qualification
Process
Qualification
Continued Process VerificationAssuring that the process remains in a state of controlFDA
Identify sources of
VariabilityControl of Variability Monitoring Variability-remains “in control”
10/10/2018 86
EU-GMP/
PIC/CPOB
A process validation protocol should be prepared which defines the critical process parameters, critical quality attributes and the associated acceptance criteria which should be based on the development data or documented process knowledge
The number of batches manufactured should be based on quality risk management principles. Each manufacturer must determine and justify the number of batches necessary to demonstrate a high level of assurance that process is capable of consistently delivering quality product
It is generally capable acceptable that a minimum of three consecutive batches would constitute a validation of the process. An initial validation exercise with three batches may need to be supplemented with further data obtained from subsequent batches as part of an on-going process verification exercise
The information obtained thru the development study, should be made the good use of, by R&D and Production as well
10/10/2018 87
They number of batches should be determined thru quality risk
management. However, it is not easy to determine the required
number on science base, it is accepted to have 3 consecutive
batches
There were 3 process validation approaches in the previous
version, Prospective, Concurrent and Retrospective Validation
Among those three, only concurrent validation remains in the
new version but its meaning has been drastically changed
10/10/2018 88
New (2018)
Validation carried out in exceptional circumstances, justified on the basis of significant patient benefit, where the validation protocol is executed concurrently with commercialization of the validation batches
Old (2001)
Validation carried out during routine production of products intended for sale
These changes are reasonable, because validation should be always looking for the future.
In exceptional circumstance where there is a strong risk-benefit to the patient, it may be acceptable not to complete a validation program before routine production starts and concurrent validation could be used
10/10/2018 89
Define theQuality Target Product Profile
(QTPP)
Create aControlStrategy
Identify theCQAs
Define ProcessSteps & CPPs
Stage 1
Qualify Facility,Utilities,
Systems and Equipment
ImplementControlStrategy
ProcessValidation
(PPQ/PPV)
Stage 2
ContinuedStage 3 Process
Verification Science and Risk-based Approach at all
Stages of Lifecycle
10/10/2018 90
Process Validation Stages Trough LifecycleEU-GMP vs GMP-FDA
Stage 2 Process Qualification/Validation
Demonstrate that the process is capable ofreproducible commercial manufacture
•
It should be completed before productreleased commercially.
is•
Two parts to this Stage:•
Design & Qualification
of FSE
Process Performance Qualification
Product that meetspredetermined quality
attributes
9110/10/2018
URS Qualification
Facility/System/
Equipment
PPQ/PV
PPQ/PV
1. Kualifikasi F/M/S/MA mulai dari URS-DQ-IQ-OQ-PQ
2. Critical Process Parameter (CPP)/Parameter Kritis
3. Critical Quality Attributes (CQA)/Atribut Mutu RM/PM/FG termasuk Pengawasan dalam proses
4. Kajian Risiko dari setiap tahapan proses dan
5. kriteria keberterimaan terkait harus berdasarkan data pengembangan atau pemahaman proses/process knowledge yang terdokumentasi
6. Dilaksanakan sesuai dengan Protokol validasi proses yang telahdisusun
10/10/2018 92
UR
URS
Detail Design-1
FinalizedDesign -
DQ
FinalizedURS
DQ/IQ/OQ
Revise
Revise
Construction Unit
Design
Review
Engineering Unit
FAT, PDI, SAT
Final ProtocolIQ/OQ/PQ
10/10/2018 93
PQ/PPVCMC/CTD/
MPD
• Engineering Requirement• GMP Requirement
Qualification
Verification
URS QA Unit
Detail Design
OQ Protocol
IQ Protocol
DQ Protocol
OQ Report
IQ Report
DQ Report
Engineering Unit / User Unit
Check
Review
Approve
10/10/2018 94
Qualification
Validation can be defined as Qualification followed by Verification/Validation
Report
CMC/CTD/MPD
Protocol
PQ
OQ
IQ
DQ
Draft SOP
Reports
Raw Data
Training Education
Operator, Facilities & Equipment, Material, Method
Phase 2
Phase 1
Verification/Validation
Qualification
Master Production Document
10/10/2018 95
How many PPQ batches?
This depends on the risk and the following elements could beapplied to make the decision:
Based on expected coverage
Based on Target Process Confidence and Target Process
Capability
Rationale and experience-based justifications
10/10/2018 96
1
2
3
“should be based on sound science and the manufacturers overall levelof product and process understanding and demonstrable control”
Process design is evaluated to determine if the process
is capable manufacturing of reproducible commercial
manufacturing
10/10/2018 97
Stage 1 Stage 2 Stage 3
Qualification
StageTraditional
approach to
validation
Ongoing Process Verification
Process Design
Qualification
Process
Qualification
Continued Process Verification
FDA
Identify sources of
VariabilityControl of Variability Monitoring Variability-remains “in control”
10/10/2018 98
EU-GMP/
PIC/CPOB
MBMRMBPR
CMC/CTD/MPD
Batch Records
APR/PQRCPV/OPV
Investigation
Change ControlValidation
Product Master Formula
Knowledge Management
Risk Management
Triggers for CAPA Deviation Self Inspection Recall etc
Routine Production
Ongoing process verification
10/10/2018 99
Annual Product Review/APR
◦ Is yearly evaluation of the production and quality control data preparation
◦ The analysis of this data (e.g. from correlations, trends, deviations, unexpected
variability) results in valuable indications regarding the validation status of the
manufacturing process
◦ APR serves as “ongoing validation” and, on the other hand, the data obtained are
important prerequisites for ”Continuous Improvement” (CIP)
◦ CFR 211.180(e) basically specifies that the quality standard of every product must be
evaluated at least once a year on the current specifications and records to determine
whether modification to product specifications, manufacturing instructions or control
procedures are required
10/10/2018100
10/10/2018101
Product Quality Review/PQR
◦ Periodic review or rolling quality review of all licensed medicinal or drug
product including export only product
◦ the objective is to verifying the consistency of existing process, the
appropriateness of current specification for both starting materials and
finished goods
◦ to highlight any trends and to identify product and process improvement
There is no clear statement regarding the scope and
content of Annual Product Review then its is
important to set out company internal rule in
the form of as SOP
Although APR and PQR requirement are very similar, there are enough differences to justify the preparation of separate reports for the same product that is sold in each countries (US, EU, Domestic market etc)
It is possible to design a combined APR-PQR
Hybrid report that comply both, it will
need extra effort but to gain the information
but require less work to prepare separate report
10/10/2018102
APR is required for a
product manufactured
for the U.S.market
while PQR is for
product manufactured
by EU Country or
manufactured
elsewhere but intended
for the EU market.
Manufacturing and packaging instructions Batch manufacturing and packaging records In-process control records Analytical procedures Certificate of Analysis and Test protocol Testing procedure for RM/PM Sampling plans and reports Modification documents Marketing Authorizations submitted, approved or rejected Quality deviation report Complaints and recalls Stability data Returned or salvaged drug products
10/10/2018103
10/10/2018104
Requirement APR PQRTime covered by review
Summary of finding of review and recommendation
Product name, description, form and strength
List of batch numbers
Review of starting and packaging material -
In-process analytical result
Finished product analytical result
Rejected batches and reason for rejection
Stability result (during the course of a calendar year due to
changes in the RM/PM Spec, Supplier/manufacturer)
Reworked and reprocessed batches
Statistical treatment of data
Description of changes
Environmental control
Comparison the content of APR or PQR report
10/10/2018105
Requirement APR PQRYield
Deviations/variances/investigations/OOS/OOT
Complaints received and evaluation
Recalls and reason for recall
Returned and salvaged goods
Review of post marketing commitments -
Market authorizations submitted/approved/not approved -
Qualification status of equipment and utilities -
Validation process/cleaning/method -
Review of third party agreement -
Evaluation and Summary -
Conclusion
Approval name and signature
Comparison the content of APR or PQR report
Periodic Monitoring/Review
1. Risk-based analysis
• Frequency of the review may be based on a risk assessment
2. Review of regulations/GMP
3. Helps identify potential issues
4. Recommend planned improvements Six Sigma, Process
Robustness etc.
5. Documented CAPA with Conclusions
10/10/2018 106
Manufacturers should monitor product quality to
ensure that a state of control is maintained
throughout the product lifecycle
Ongoing process verification should be considered
where any individual change or successive
incremental changes during the product lifecycle
could have an impact on the validated status of the
process
This is the same concept as Continued Process Verification of FDA
10/10/2018 107
Continued Process Verification - FDA
10/10/2018 108
Maintenance the Validated State- Overall periodic review of the validated state
Change in the validated state of the process could impact productquality
Monitored via:
Change Control
Periodic Monitoring/Review
- data trending
- review analytical data from routine monitoring
- review process parameters
Demonstrates consistency of initial results
Statistical Process Control-SPC
Data from automation
10/10/2018109
Maurice Parlane,
ISPE Process Validation Team;
CBE Pty Ltd (Australia)
10/10/2018110
CPV/OPV in context
Maurice Parlane,
ISPE Process Validation Team;
CBE Pty Ltd (Australia)
Compliant validation does not require
lifecycle (QbD) approach; but must have:◦ Control strategy
◦ Evidence of robustness
PQS/QMS must be “ready” to manage CPV/OPV (VMP, infrastructure, work culture and tools)
Deficiencies/gaps in process understanding should dictate actions and approach
Prioritisation should be risk based
10/10/2018111
Before you start…
1. Corporate policies
2. SOPs
3. Validation approaches
4. Data analysis tools and systems
5. Staff trained in use of statistics
6. PLAN before do….
10/10/2018112
Volume of product in market
Number of patients served
Criticality or uniqueness incl. potential for shortage
Regulatory authority
ISPE Discussion Paper Legacy Products, 2016.
Quality history
Planned change or improvement
Manual/high risk control
Status of PV package for product
10/10/2018113
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CPV/OPVISPE Discussion Paper Legacy Products, 2016
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116
Terima kasih
10/10/2018