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QUALITY BY DESIGN
and
PROCESS VALIDATION
11/26/2018 1
11/26/2018 2
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
311/26/2018
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
11/26/2018 4
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.
11/26/2018 5
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
611/26/2018
11/26/2018 7
PART I: PHARMACEUTICAL DEVELOPMENT
1. INTRODUCTION
1.1 Objective of the Guideline
1.2 Scope
2. PHARMACEUTICAL DEVELOPMENT
2.1 Components of the Drug Product
2.1.1 Drug Substance
2.1.2 Excipients
2.2 Drug Product
2.2.1 Formulation Development
2.2.2 Overages
2.2.3 Physicochemical and Biological Properties
2.3 Manufacturing Process Development
2.4 Container Closure System
2.5 Microbiological Attributes
2.6 Compatibility
3. GLOSSARY
11/26/2018 8
PART II: ANNEX TO PHARMACEUTICAL DEVELOPMENT
1. INTRODUCTION
2. ELEMENTS OF PHARMACEUTICAL DEVELOPMENT
2.1 Quality Target Product Profile
2.2 Critical Quality Attributes
2.3 Risk Assessment: Linking Material Attributes and Process Parameters to Drug Product
CQAs
2.4 Design Space
2.4.1 Selection of Variables
2.4.2 Describing a Design Space in a Submission
2.4.3 Unit Operation Design Space(s)
2.4.4 Relationship of Design Space to Scale and Equipment
2.4.5 Design Space Versus Proven Acceptable Ranges
2.4.6 Design Space and Edge of Failure
2.5 Control Strategy
2.6 Product Lifecycle Management and Continual Improvement
11/26/2018 9
3. SUBMISSION OF PHARMACEUTICAL DEVELOPMENT AND RELATED INFORMATION IN COMMON TECHNICAL DOCUMENTS (CTD)
FORMAT
3.1 Quality Risk Management and Product and Process Development
3.2 Design Space3.3 Control Strategy 3.4 Drug Substance Related Information
4. GLOSSARY
Appendix 1. Differing Approaches to Pharmaceutical Development
Appendix 2. Illustrative Examples
11/26/2018 10
▪ 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.
11/26/2018 11
❑ 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).
11/26/2018 12
❑ 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.
11/26/2018 13
14
“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
11/26/2018
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
11/26/2018 15
Quality
by
Design
(QbD)
Quality
By Design/
QbD
concept
What drives the process ?
Product
understanding is
required to design
the process.
Product Science
CriticalQuality
Attributes definethe process.
Process Risk
11/26/2018 17
Development Stages based on QbD
Define the
Quality Target
Product Profile
(QTPP)
Create a
Control
Strategy
Identify theCQAs
Define ProcessSteps & CPPsStage 1
Qualify Facility,
Utilities,
Systems and
Equipment
Implement the
Control
Strategy
Process
Validation
(PPQ)
Stage 2
Continued
Stage 3
Slide 13
Continued ProcessVerification Science and Risk-based Approach at
all Stages of Lifecycle
11/26/2018QbD - TPI 18
Identify sources of Variability – Product understanding
Control of Variability – Process understanding
Monitoring Variability-remains “in control”
R&D
Manufacturing
Process
Robustness
Stage 1 - Process Flow
Identify sources of Variability – Product understanding
Define theQuality Target Product Profile
TPP-QTPP-PPK
Create aControlStrategy -CS
Identify theCQAs
Define ProcessStepsCPPs –DS-RA
Stage 1
Qualify Facility,Utilities,
Systems and Equipment
Implement theControlStrategy
ProcessValidation
(PPQ)
Stage 2
ContinuedStage 3 Process
Verification Science and Risk-based Approach at all
Stages of Lifecycle
11/26/2018QbD - TPI 19
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
11/26/2018QbD - TPI 20
CDS/UDT
BE study
Product
design
BA/BE study
Tablet
Quality Target Product Profile
A prospective summary ofthe quality characteristics ofa drug product that ideallywill be achieved
the desired • Quality, • Safety and • Efficacy
of the drug product
Example
• Oral administration
• Immediate Release or
Modified Release tablet
• Stable at room temperature
at least 2 years
• Single tablet dosed three
times daily
• Adult – child - infants
• Safety ➔ Toxicity, side effect,
• Efficacy
• effect therapy
• bioavailability
• bioequivalence11/26/2018QbD - TPI 21
ICH Q8(R2)
Definition
document containing detailed description of Establish pre-defined TPP
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
2211/26/2018
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).
11/26/2018 23
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
11/26/2018 24
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
11/26/2018 25
Input Process Output
QTPP to Potential CQAs
Safety &Efficacy
Strength Quality Identity Potency Purity
Potential CQAs
11/26/2018 26
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).
11/26/2018 27
▪ “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
11/26/2018 28
Design Space
Previous
ExperienceLiterature
Technology
TransferFirst Principles
Material
AttributesScale-up
Process
Parameters
Risk
Assessment
Facility, Systems
& Equipment
Understanding
Experimental
DesignQTPP, CQAs,
CPPs and CS
11/26/2018 29
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
11/26/2018 30
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
•
•
•
•
•
11/26/2018 32
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
11/26/2018 33
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
3411/26/2018
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
11/26/2018 35
11/26/2018 36
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
•
•
•
•
•
3711/26/2018
Final CQA-CPP-DS-RS-CS
dalam
Parameter Kritis - QbD
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”
11/26/2018 38
Summary
11/26/2018 39
Manufacturing processes may be developed using
1. Traditional approach
2. Continuous verification approach, based on QbD
approach
3. Hybrid approach, combined of both processes
11/26/2018 40
“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)
11/26/2018 41
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
11/26/2018 42
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
11/26/2018 43
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
11/26/2018 44
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”
11/26/2018 45
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.
11/26/2018 46
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
11/26/2018 47
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
11/26/2018 48
Validation task at
individual Development stages
- Up Scaling
- Product
Transfer
GLP
Standards
11/26/2018 49
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
11/26/2018 50
Validation at
Product Life cycle
11/26/2018 51
Laboratory batches
Commercial batches
Commercial batches
Pilot batches
Development
phase
Improvement
phase
Validation phase
Usage phase
Shut-down
Change phase
Life cycle Processes
•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
11/26/2018 52
• 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
11/26/2018 53
• 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
11/26/2018 54
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
11/26/2018 55
• 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
11/26/2018 56
• 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
11/26/2018 57
• selama proses pengembangan telah ditetapkan secarailmiah, strategi pengendalian, yang memberikan tingkatkepastian mutu produk yang tinggi, maka verifikasi proses secara kontinu dapat dilakukan sebagai alternatif untukvalidasi 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
11/26/2018 58
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
11/26/2018 59
• 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
11/26/2018 60
• 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
11/26/2018 61
11/26/2018 62
11/26/2018 63
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
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”
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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
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CDS/UDT
BE study
BA/BE study
Process Validation Stages Trough LifecycleEU-GMP vs GMP-FDA
Product
information
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Define
Product
Intended
Use and
pre-
definition
of Quality
targets (wrt
clinical
relevance,
efficacy and
safety)
Identify
Critical
Quality
Attributes
(CQAs)
having an
impact on
product
Quality
Summarise
Prior
Scientific
Knowledge
(drug
substance,
excipients;
similar
formulations
and
processes).
Initial Risk
Assessment
Make key
decisions to
develop
iteratively New
Scientific
Knowledge
e.g. DoE, PAT,
linking
material
attributes and
process
parameters
that impact on
CQAs
Summarise
Scientific
Understand-
ing of
Product and
Process.
Justify and
describe
Multi-
dimension
Space that
assures
Quality
Define
Control
Strategy
based on
Design Space
leading to
Control of
Quality
using
Quality
Risk Mgmt.
(Process
Robutness)
CSDSPr.P
Dev
PKCQAsQTPP
Application of Quality by Design through a Product’s lifecycle
CI
Identify
appropriate Improvement
Operate
Change
Manageme
nt System
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
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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”
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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
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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
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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
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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
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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
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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
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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
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1. RIV
2. Protokol
3. Sampling
4. Penetapan Parameter kritis
5. Evaluasi
6. Laporan
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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
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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
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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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”
11/26/2018 84
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
11/26/2018 85
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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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
▪ 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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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
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
11/26/2018 91
▪ 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
11/26/2018 93
▪ 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)
11/26/2018 95
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
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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
The big challenges to Pharmaceutical Industry is to provide safe medicinal drug
products in high quality and for affordable price that are compliant with the
appropriate legal requirements and state-of-the-art procedures
The achievable prices for drug products decrease and, in order to maintain R&D
investment, the companies are motivated to reduce their cost without impact to
product quality
There are methods available and already in place.
◦ Most of them are used with economical objectives to save effort in achieving targets.
◦ All of them contribute to quality demands and have been invented to reach quality
goals
◦ They don’t have to be implemented but they are often very helpful to reduce effort and
cost, and to demonstrate the value of quality
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One among the famous method is Six Sigma – Process Robustness
➢ A set of practices to systematically improve processes by eliminating defects.
➢ A holistic and flexible method that combines known tools with the aim to improve all types of processes◦ Mathematically SS refers to a maximum of 3,4 defects per millions
opportunities.
◦ Within the scope of SS it is assumed that a process shifts about plus and minus 1.5 standard deviations
The concept of Six Sigma lies much more in the approach to a problem rather than in the tools used to solve it
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Six sigma approach can be thought of at 3 main levels◦ Optimizing individual metric◦ Using the proven methodology to reduce defect and improve these metric◦ Ensuring alignment between the individual metrics and the overall strategic
goal
The equation : Y = f(x) + E◦ Y = output of interest, such metric of Time, Quality or Cost
◦ X = represent the input factors which have been an impact on the output Y
◦ F() = represent the mathematical function which defines the relationship between X and Y
◦ E = the unknown portion since the equation might not be able to explain hundred percent of the total variability
The GOAL ◦ To clearly define the Y to improve and the target level to achieve◦ Identify all the critical X in the equation and understand the relationship
between X themselves and on Y◦ To reduce E to a very small portion
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By doing this, it becomes possible to accurately
control the output of the process
Need Six Sigma Tools and Methodology Expert▪ Basic understanding of statistical procedures and techniques
▪ Basic understanding of the organization’s overall business process
▪ Experience in managing projects of varying size and complexity
▪ Leading cross-functional teams
▪ Experience in teaching, coaching and/or internal consulting roles
▪ Key responsibilities include :
- Identification and confirmation of potential projects and saving
- Running Process Robustness analysis
- Planning, leading and completing projects :
o Setting project metric and goals
o Selecting team members (including green belts)
o Using DMAIC methodology
o Selecting appropriate tools, following correct methodology, and confirming results
o Communicating progress, issues and success to team and management
o Ensuring team remains within timeline and cost targets
o Teaching tools, concepts and techniques to project members
o Sharing praise and celebrating success
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• Project
selection
• Team
selection
• Create
project
charter
• Set metric
and goal
• Process
analysis
• Voice of
customer
CSSCQAs
Define
Six Sigma Approach - DMAIC Phases
CI
Measure Analyze Improve Control
• Define
Project and
boundaries
• Collect data
on current
state
• Assess
suitability of
measurement
system
• Determine
current
performance
level
• Identify
potential
cause
• Reduce
potential
causes down
to vital few
• Create
process
model based
on vital
factors
• Determine
new
optimum for
process
validate
results
• Confirm
process is
stable and
capable
• Implement
monitoring
procedures
• Update
quality
systems
• Standardize
ACTIVITIES
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• Project
Charter sheet
• Process Flow
diagram
• Process yield
• Voice of
customer
• Kano
analysis
• Historical
data plot
• Pareto
diagram
CSSCQAs
Define
Six Sigma Approach - DMAIC Phases
CI
Measure Analyze Improve Control
• Process
mapping
• Data collection
plan
• Process
capability
• Measurement
system
analysis
• Gage R&R
• FMEA
• Cause and
Effect diagram
• XY diagram
• Detailed
process map
• Graphical
data analysis
tools
• Hypothesis
testing
• Variance,
regression
and
correlation
analysis
• Simulations
• Design of
Experiment
(historical,
screening,
full or partial
factorial etc.
• Response
surface
design
• Improvement
impact and
benefit
• Process
capability
• SPC chart
• Control plan
• FMEA
• Replication
opportunities
• Project
report
TOOLS
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Terima kasih
11/26/2018
