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PROCESS VALIDATION - FARMASI INDUSTRI

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Page 1: PROCESS VALIDATION - FARMASI INDUSTRI

PROCESS VALIDATION

10/10/2018 1

Page 2: PROCESS VALIDATION - FARMASI INDUSTRI

10/10/2018 2

Page 3: PROCESS VALIDATION - FARMASI INDUSTRI

“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

10/10/2018 4

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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10/10/2018 5

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

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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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10/10/2018 10

Validation task at

individual Development stages

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- 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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10/10/2018 12

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

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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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10/10/2018 23

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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10/10/2018 25

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

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• 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

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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 41

Summary

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10/10/2018 42

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10/10/2018 43

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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

4410/10/2018

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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

10/10/2018 47

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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

10/10/2018

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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

10/10/2018 49

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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

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Quality

by

Design

(QbD)

Quality

By Design/

QbD

concept

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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

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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

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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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10/10/2018 55

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

Fo

rmu

lati

on

un

de

rsta

nd

ing

Fo

rmu

lati

on

un

de

rsta

nd

ing

Pro

ce

ss

un

de

rsta

nd

ing

Pro

ce

ss

un

de

rsta

nd

ing

Re

Re-- e

va

lua

tio

n a

nd

co

nfi

rma

tio

ne

va

lua

tio

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nd

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Derived

Iterative ApproachTarget Product Profile

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10/10/2018 56

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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

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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

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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

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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

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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).

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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

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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

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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

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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).

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“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

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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

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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

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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)

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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

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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

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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.

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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)

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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

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© 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.

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© 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.

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© 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

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© 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

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© 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

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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

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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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10/10/2018 83

Knowledge

Space

Design

Space

Operational

Space

Product – Process Design Completion

Target of Stage 1

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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

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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

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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

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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

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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

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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

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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

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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

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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

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URS QA Unit

Detail Design

OQ Protocol

IQ Protocol

DQ Protocol

OQ Report

IQ Report

DQ Report

Engineering Unit / User Unit

Check

Review

Approve

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Qualification

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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

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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

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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

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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

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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

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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

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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.

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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

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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

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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

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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

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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

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Continued Process Verification - FDA

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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

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Maurice Parlane,

ISPE Process Validation Team;

CBE Pty Ltd (Australia)

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CPV/OPV in context

Maurice Parlane,

ISPE Process Validation Team;

CBE Pty Ltd (Australia)

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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

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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….

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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

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CPV/OPVISPE Discussion Paper Legacy Products, 2016

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Terima kasih

10/10/2018