Fithrul, farmasiindustri.

com

QUALITY BY DESIGN
and
PROCESS VALIDATION
Fithrul, farmasiindustri.com
 Current Approach – Quality By Testing
Fithrul, farmasiindustri.com

Excipient
Pass / Fail
Specification

Excipients Finished
Manufacture
and API Product

API
Pass / Fail
QC Testing
Specification In Process Testing
Pass / Fail
Pass / Fail
Specification
Specification

• Acceptance criteria set on limited data eg 1 batch.

• Testing must be performed for batch to be released.
• Failing batch only investigated at end of process
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Current Practise for Method
Validation and Transfer

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.
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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.
 Fithrul, farmasiindustri.com

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
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 Fithrul, farmasiindustri.com

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
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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
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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 Space
3.3 Control Strategy
3.4 Drug Substance Related Information
4. GLOSSARY
Appendix 1. Differing Approaches to Pharmaceutical
Development
Appendix 2. Illustrative Examples
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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.
 Fithrul, farmasiindustri.com

❑ 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 Verification

o 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.
 Fithrul, farmasiindustri.com

“You can’t test quality into drug products”

has been heard for decades – so what’s new?

Quality by Design
◦ It’s a culture - incorporates quality principles as well as
strong compliance function
◦ Incorporates risk assessment and management
◦ Refocuses attention and resources on what’s important to the
customer, i.e. the patients, health professionals, and
distribution chain
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What is Quality by Design?

Quality by Design (QbD) is:

A systematic approach to development that
begins with predefined objectives and
emphasizes product and process
understanding and Process control, based on
sound science and Quality Risk Management

ICH Q8(R2)

3
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Quality
By Design/
QbD
concept
Quality
by
Design
(QbD)
What drives the process ?
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Product
understanding is
Product required to design Science
the process.

Process Critical Risk

Quality
Attributes define
the process.
Development Stages based on QbD
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Define the
Quality Target Identify the Define Process Create a
Stage 1 Product Profile
(QTPP)
CQAs Steps & CPPs Control
Strategy
R&D
Identify sources of Variability – Product understanding

Implement the Qualify Facility, Process

Stage 2 Control Utilities,
Systems and
Validation
Manufacturing Strategy (PPQ)
Equipment

Control of Variability – Process understanding

Continued

Continued
Stage 3 Process
Verification Science and Risk-based Approach at
Process
Robustness all Stages of Lifecycle
Monitoring Variability-remains “in control”
Slide 13
Stage 1 - Process Flow Fithrul, farmasiindustri.com

Identify sources of Variability – Product understanding

Define the
Quality Target Define Process Create a
Stage 1 Product Profile
Identify the
CQAs Steps Control
TPP-QTPP- CPPs –DS-RA Strategy -CS
PPK

Qualify Facility,
Implement the Process
Stage 2 Control
Utilities,
Validation
Systems and
Strategy (PPQ)
Equipment

Continued
Stage 3 Process
Verification Science and Risk-based Approach at all
Stages of Lifecycle
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Important Aspects of Stage 1
• Clinical Product Tablet
• Characterisation design
• Drug Release Analysis of the • Drug Substance
• Excipients Components
• Pharmacokinetics Reference
• Drug Product of Drug
• Pharmacodynamic Listed Drug Product
• Pharmaceutical Product
composition
• Manufacturing
process
• Therapeutic process process

Define the
Create a
Quality Target Identify the Define Process
CQAs Steps Control
Product Profile
CPPs-DS-RA Strategy-CS
TPP-QTPP

Dissolution Pilot Drug Product Manufacturing

Method Bioequivalence Formulation Process
Development Study Development Development

BA/BE study • Container Closure System

• Design of Experiments • Microbiological Attributes
BE study
• Risk Assessments
CDS/UDT • Scale-up: Lab to Pilot
• Design Space
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Quality Target Product Profile ICH Q8(R2)

document containing detailed description of Establish pre-defined TPP

Definition Example

A prospective summary of
• Oral administration
the quality characteristics of • Immediate Release or
a drug product that ideally Modified Release tablet
will be achieved
the desired
• Stable at room temperature
• Quality, at least 2 years
• Safety and • Single tablet dosed three
• Efficacy
of the drug product
times daily
• Adult – child - infants
• Safety ➔ Toxicity, side effect,
• Efficacy
• effect therapy
• bioavailability
• bioequivalence
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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 the
CQAs
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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 scientific
evidence and a risk-based approach.
 Identify items that impact Safety, Quality, Identity, Potency,
Purity (SQuIPP).
 Critical Quality Attribute
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Drug Substance Drug product

(chemical) (tablet)
Appearance Appearance
Particle size Identification
Morphic forms Hardness Risk in
1. Continuity of
Water content Uniformity of dosage Quality
Residual solvents Physical form attribute
Organic impurities 2. Continuity of
Dissolution Supply
Inorganic impurities
Impurities 3. Reasonable in
Heavy metals cost
Degradation products
Residue on ignition
Water content
Assay Assay
Microbiological limits
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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

Input Process Output

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QTPP to Potential CQAs

Safety &
Efficacy

Strength Quality Identity Potency Purity

Drug release Particle Size Distribution Morphology

Activity Potential CQAs Degradation
Delivery Impurity
Crystallinity
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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
Design Space Fithrul, farmasiindustri.com

Knowledge
Previous Literature
Experience Space
Technology
First Principles Transfer
Design
Space
Material Scale-up
Attributes

Operational Risk
Process Space Assessment
Parameters

Facility, Systems
Experimental
& Equipment
Design
QTPP, CQAs, Understanding

CPPs and CS
 Fithrul, farmasiindustri.com
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)

(ICH Q8)

“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”
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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
Define Process
Steps & CPPs
Parameter Kritis - Validasi Parameter Kritis - QbD
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Risk ➔ Quality Risk Management (QRM)

The QRM process must be systematic with

defined policies and procedures

Must operate across the product lifecycle

Principles and methodologies should be clear ➔

scientific knowledge based analysis

Criteria and decisions from assessments should

be documented
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Control Strategy
Create a
• Built up based on previous knowledge and the Control
Strategy
outcome of extensive product & process studies
• Investigation of material attributes and process
parameters that were deemed high risk to the CQAs
of 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 were deemed high risk are included
in the control strategy
• Can be further refined as process knowledge
increases over time
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Control Strategy
Create a
Control
• Details the excipient attributes to be controlled Strategy

• In-process controls
• High-risk process parameter ranges identified during
development
• Proposed operating ranges for commercial
manufacture
• Release specification also identified
• Basis for Process Validation
• Note that post-approval changes relevant
to the control strategy

Slide 91
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Product – Process Design Completion

Target of Stage 1

Knowledge
Space

Design
Space
Operational
Space
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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

Final CQA-CPP-DS-RS-CS
dalam
Parameter Kritis - QbD
 Summary Fithrul, farmasiindustri.com

Cont. Process Verification/

Qualification Stage/QbD approach
Traditional approach to validation
EU-GMP/ Ongoing Process Verification
PIC/CPOB

Stage 1 Stage 2 Stage 3

Identify sources of Control of Variability Monitoring Variability-remains “in control”
Variability
Continued Process Verification
FDA Assuring that the process remains in a state of control

Process Qualification
Confirming that the manufacturing process designed is capable of
reproducible commercial manufacturing
Process Design Qualification
The commercial manufacturing process is defined based on knowledge
gained through development and scale-up activities
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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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“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 COMPLIANCE
Validation 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

To compensate for the steps that were commonly missed

during development stage ➔ commonly using of term :
“Challenges”, “Worst-case”, “Optimization”
THESE ARE NOT ACTUALLY PART OF VALIDATION PROCESS
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Process Validation IS NOT

Process Development

Development Determine Challenge

Critical Parameter
Optimisation
Establish “Proven
Acceptable Ranges”
Scale-Up Define Operations
Ranges for Critical
Parameters

Process Confirmation of Normal

Operating Ranges for
Validation 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

Definition : Validation during development

Validation during pharmaceutical development includes all development
activities and their documentation, which guarantee and prove that the quality of
the future commercial product matches the quality of the composition of
development and clinical samples
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Validation task at
individual Development stages
Time axis : Approval for clinical tests Fithrul, Marketing approval
farmasiindustri.com

Pre- Process Clinical Clinical Clinical

formulation development phase I phase II phase III Clinical phase
experiments IV, commercial
Manufacturing
of clinical test Manufacturing Manufacturing goods
samples of clinical test of clinical test Submission
samples of marketing
samples
authorization
Process validation Process validation documents
Laboratory Manufacturing
scale/pilot scale process
- Up Scaling Manufacturing/long-term
- Product stability of registration
Cleaning verification Transfer batches
Laboratory scale/pilot Cleaning validation
scale Production equipment
Development and
validation analytical Further development and validation of
method analytical method

No legal Fully GMP complaints,

Fully GMP complaints, but Fully GMP
GLP more stringent
require Standards
more favourable conditions
requirement apply for
complaints, fully-
ment apply for process validation validated process
process validation
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Validation at
Product Life cycle
Life cycle Processes
Fithrul, farmasiindustri.com

Development
Laboratory batches
phase

Pilot batches Improvement

phase

Commercial batches Validation phase Change phase

Commercial batches Usage phase

Shut-down
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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
CPOB memengaruhi mutu produk, hendaklah dikaji,
mempersyarat didokumentasikan secara formal dan dampak pada status
kan industri validasi atau strategi pengendaliannya.
farmasi
• 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
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1. Ketentuan dan prinsip • mencakup validasi awal dari proses baru,

yang diuraikan dalam Butir- validasi bila terjadi perubahan proses,
butir ini berlaku untuk
pembuatan semua bentuk transfer lokasi pembuatan, dan verifikasi
sediaan obat.. proses on-going

• bahwa proses pengembangan produk yang

2. Secara implisit tertuang andal diperlukan agar validasi proses berhasil
dilakukan dengan baik
• Pedoman tentang Validasi Proses dimaksudkan untuk
memberikan panduan mengenai informasi dan data yang
3. Validasi proses dapat diperlukan dalam pengajuan izin ke regulator
diterapkan bersamaan • Namun, persyaratan CPOB untuk validasi proses
dengan pedoman berlanjut sepanjang siklus hidup produk
tentang Validasi Proses • Pendekatan ini hendaklah diterapkan untuk menautkan
pengembangan produk dan proses
yang relevan • memastikan proses pembuatan skala komersial secara
rutin dalam keadaan tervalidasi
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4. Proses pembuatan dapat • Traditional approach

dikembangkan dengan • Continuous verification approach
menggunakan pendekatan • Hybrid approach

• harus dibuktikan keandalan proses dan memastikan

5. terlepas dari pendekatan apa
pun yang digunakan, mutu produk yang konsisten sebelum produk
diluluskan ke pasar.

6. proses pembuatan yang • program validasi prospektif hendaklah diterapkan

menggunakan pendekatan pada proses pembuatannya Validasi retrospektif
tradisional sebelum mendapatkan merupakan pendekatan yang tidak lagi dapat
Izin Edar diterima

7. Validasi proses produk baru

• mencakup semua kekuatan produk yang akan
dipasarkan dan lokasi pembuatan.
 Fithrul, farmasiindustri.com

• dapat dijustifikasi untuk produk baru

berdasarkan pengetahuan proses yang
ekstensif dari tahap pengembangan
bersamaan dengan program verifikasi on-
going yang sesuai
• Untuk validasi proses produk yang
ditransfer dari satu lokasi ke lokasi lain
8.Bracketing atau pindah fasilitas dalam lokasi yang
sama, pendekatan bracketing dapat
approach mengurangi jumlah bets validasi
• Namun, harus tersedia pengetahuan
produk yang sudah diproduksi, termasuk
hasil dari validasi sebelumnya. Kekuatan,
ukuran bets dan ukuran kemasan/jenis
wadah yang berbeda juga dapat
menggunakan pendekatan bracketing jika
telah dijustifikasi
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1. Dalam pendekatan • sejumlah bets produk diproduksi dalam kondisi rutin

secara tradisional, untuk memastikan reprodusibillitas

• didasarkan pada prinsip manajemen risiko mutu, memungkinkan

dibuat rentang variasi normal dan tren serta menghasilkan cukup
data untuk dievaluasi.
• Setiap industri farmasi harus menentukan dan memberi justifikasi
2. Jumlah bets jumlah bets yang diperlukan untuk memberikan jaminan yang
tinggi bahwa proses mampu menghasilkan produk yang bermutu
yang diproduksi secara konsisten.
• Tanpa mengurangi persyaratan pada butir 12.53, pada
dan jumlah umumnya minimal produksi tiga bets berturut-turut dalam
kondisi rutin dapat merupakan validasi proses
sampel yang • Alternatif jumlah bets dapat dipertimbangkan dari justifikasi
diambil ametode pembuatan standar yang telah digunakan dan apakah
produk 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 dari
pelaksanaan verifikasi on-going
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• the critical process parameter

(CPP),
3. Protokol
validasi • critical quality attributes (CQA) dan
proses harus • kriteria keberterimaan terkait harus
disiapkan berdasarkan data pengembangan
atau pemahaman proses/process
dengan knowledge yang terdokumentasi
menjelaskan
• Protokol validasi proses hendaklah
mencakup,
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1. Untuk produk
yang • selama proses pengembangan telah ditetapkan secara
dikembangkan ilmiah, strategi pengendalian, yang memberikan tingkat
berdasarkan kepastian mutu produk yang tinggi, maka verifikasi proses
pendekatan secara kontinu dapat dilakukan sebagai alternatif untuk
quality by validasi proses tradisional
design (QbD
• a science based control strategy for the required attributes for incoming
2. Metode untuk materials,
memverifikasi • critical quality attributes and
proses harus • critical process parameters to confirm product realization.
ditetapkan. • should also include regular evaluation of the control strategy (RM-FG)
Strategi • Process Analytical Technology and multivariate statistical process control
pengendalian may be used as tools.
proses harus • each manufacturer must determine and justify the number of batches
tersedia necessary to demonstrate a high level of assurance that the process is capable
of consistently delivering quality product

Prinsip yang ditetapkan dalam ketentuan umum tetap berlaku

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Pendekatan hibrida dari

tradisional dan verifikasi Pendekatan ini juga
proses kontinu dapat dapat digunakan untuk
digunakan
• bilamana sudah diperoleh • kegiatan validasi
pengetahuan dan pascaperubahan atau
pemahaman yang tinggi selama verifikasi proses
mengenai produk dan on-going meskipun
proses yang diperoleh produk tersebut pada
dari pengalaman awalnya divalidasi
pembuatan dan data dengan menggunakan
riwayat bets pendekatan tradisional
 Fithrul, farmasiindustri.com

• 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
1. In exceptional and concurrent validation could be used.
circumstances • 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

2. Where a concurrent • there should be sufficient data to support a conclusion

validation approach has that any given batch of product is uniform and meets
been adopted the defined acceptance criteria.

3. The results and • should be formally documented and available to the

Quality Assurance Head prior to certification of the
conclusion batch
 Fithrul, farmasiindustri.com

• under an approved protocol or equivalent documents

On-going
process • a corresponding report should be prepared to document the
results obtained.
verification
should be • Statistical tools should be used, where appropriate, to support any
conducted conclusions with regard to the variability and capability of a given
process and ensure a state of control

On-going • throughout the product lifecycle to support the validated status of

process the product as documented in the Product Quality Review.
Incremental changes over time should also be considered and the
verification need for any additional actions, e.g. enhanced sampling, should
should be used be assessed
Fithrul, farmasiindustri.com
Fithrul, farmasiindustri.com
 Summary Fithrul, farmasiindustri.com

Cont. Process Verification/

Qualification Stage/QbD approach
Traditional approach to validation
EU-GMP/ Ongoing Process Verification
PIC/CPOB

Stage 1 Stage 2 Stage 3

Identify sources of Control of Variability Monitoring Variability-remains “in control”
Variability
Continued Process Verification
FDA Assuring that the process remains in a state of control

Process Qualification
Confirming that the manufacturing process designed is capable of
reproducible commercial manufacturing
Process Design Qualification
The commercial manufacturing process is defined based on knowledge
gained through development and scale-up activities
 Fithrul, farmasiindustri.com

Cont. Process Verification/

Qualification Stage/QbD approach
Traditional approach to validation
EU-GMP/ Ongoing Process Verification
PIC/CPOB

Stage 1 Stage 2 Stage 3

Identify sources of Control of Variability Monitoring Variability-remains “in control”
Variability
Continued Process Verification
FDA Assuring that the process remains in a state of control

Process Qualification
Confirming that the manufacturing process designed is capable of
reproducible commercial manufacturing
Process Design Qualification
The commercial manufacturing process is defined based on knowledge
gained through development and scale-up activities
 Process Validation Stages Trough Lifecycle
Fithrul, farmasiindustri.com

EU-GMP vs GMP-FDA
Product
information
Important Aspects of Stage 1
• Clinical
• Characterisation
• Drug Release Analysis of the • Drug Substance
• Excipients Components
• Pharmacokinetics Reference
• Drug Product of Drug
• Pharmacodynamic Listed Drug Product
• Pharmaceutical Product
composition
• Manufacturing
process
• Therapeutic process process

Define the
Create a
Quality Target Identify the Define Process
CQAs Steps Control
Product Profile
CPPs-DS-RA Strategy-CS
TPP-QTPP

Dissolution Pilot Drug Product Manufacturing

Method Bioequivalence Formulation Process
Development Study Development Development

BA/BE study • Container Closure System

• Design of Experiments • Microbiological Attributes
BE study
• Risk Assessments
CDS/UDT • Scale-up: Lab to Pilot
• Design Space
 Fithrul, farmasiindustri.com
Application of Quality by Design through a Product’s lifecycle

QTPP CQAs PK Pr.P DS CS CI

Dev
Define Identify Summarise Make key Summarise Define
Product Critical Prior decisions to Scientific Control Identify
Intended Quality Scientific develop Understand- Strategy appropriate
Improvement
Use and Attributes Knowledge iteratively New ing of based on
Scientific Product and Operate
pre- (CQAs) (drug Design Space
Knowledge Process. Change
definition having an substance, leading to
Manageme
of Quality impact on excipients; e.g. DoE, PAT, Justify and Control of
similar linking describe nt System
targets (wrt product Quality
clinical Quality formulations material Multi- using
relevance, and attributes and dimension Quality
efficacy and processes). process Space that Risk Mgmt.
safety) Initial Risk parameters assures (Process
Assessment that impact on Quality Robutness)
CQAs
 Fithrul, farmasiindustri.com

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 Strategy
8
Fithrul, farmasiindustri.com
 Fithrul, farmasiindustri.com

Qualification
Traditional
Stage
approach to
validation
EU-GMP/ Ongoing Process Verification
PIC/CPOB

Stage 1 Stage 2 Stage 3

Identify sources of Control of Variability Monitoring Variability-remains “in control”
Variability
Continued Process Verification
FDA Assuring that the process remains in a state of control

Process
Qualification

Process Design
Qualification
 Fithrul, farmasiindustri.com

➢ 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
 Fithrul, farmasiindustri.com

▪ 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
 Fithrul, farmasiindustri.com

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
 Fithrul, farmasiindustri.com
Process Validation Stages Trough Lifecycle
EU-GMP vs GMP-FDA

Define the
Quality Target Create a
Stage 1 Product Profile
Identify the
CQAs
Define Process
Steps & CPPs
Control
(QTPP) Strategy

Implement Qualify Facility,

Process
Stage 2 Control Utilities,
Systems and
Validation
Strategy (PPQ/PPV)
Equipment

Continued
Stage 3 Process
Verification Science and Risk-based Approach at all
Stages of Lifecycle
 Fithrul, farmasiindustri.com
Stage 2 Process Qualification/Validation

• Demonstrate that the process is capable of

reproducible commercial manufacture
• It should be completed before product is
released commercially.
• Two parts to this Stage:

Design & Process Product that meets

Qualification Performance
of FSE Qualification
predetermined quality
attributes

URS → Qualification PPQ/PV

Facility/System/
Equipment
 Fithrul, farmasiindustri.com

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 telah
disusun
 Fithrul, farmasiindustri.com

Verification

Engineering
UR CMC/CTD/
Unit
MPD
PQ/PPV
Qualification
Construction Unit
Revise Finalized FAT, PDI,
URS URS SAT

Design • Engineering Requirement

Review • GMP Requirement
Finalized
Detail DQ/IQ/OQ
Design -
Design-1 DQ Final Protocol
Revise
IQ/OQ/PQ
 Fithrul, farmasiindustri.com

Engineering Unit / User Unit

URS QA Review Qualification

Check
Unit
Approve

OQ
Protocol
OQ Report

IQ
Protocol
IQ Report

Detail DQ
Design Protocol
DQ Report
 Fithrul, farmasiindustri.com

Validation can be defined as Qualification followed by Verification/Validation

CMC/CTD/ Master Production

MPD Document

Report Verification/
Phase 2 Validation
Protocol

PQ Draft
SOP

Training OQ
Phase 1 Reports Qualification
Education
IQ
DQ Raw Data

Operator, Facilities & Equipment, Material, Method

 Fithrul, farmasiindustri.com

1. RIV
2. Protokol
3. Sampling
4. Penetapan Parameter kritis
5. Evaluasi
6. Laporan
How many PPQ batches?
Fithrul, farmasiindustri.com

“should be based on sound science and the manufacturers overall level

of product and process understanding and demonstrable control”

This depends on the risk and the following elements could be

applied to make the decision:

1 Rationale and experience-based justifications

Based on Target Process Confidence and Target Process

2 Capability

3 Based on expected coverage

Process design is evaluated to determine if the process

is capable manufacturing of reproducible commercial
manufacturing
 Fithrul, farmasiindustri.com

Traditional approach New Paradigm – QbD approach

 Process validation Stages Trough
 Research and Development
Lifecycle
 Pilot scale
 Stage 1 : R&D, BA/BE, Trial,
 Scaling up Scaling up etc.
 Commercial batch and  Stage 2 : Process

Process validation validation/PPQ

 Stage 3 : CPV/PQR, Process
prospective, Concurrent Robustness, SPC
and Retrospective  Process Analytical
 Annual Product technology/PAT
Review/Product Quality  Real-time Release Testing (RTRT)
Review  Operational Excellent - Lean Six
Sigma
Fithrul, farmasiindustri.com
 Fithrul, farmasiindustri.com

Qualification
Traditional
Stage
approach to
validation
EU-GMP/ Ongoing Process Verification
PIC/CPOB

Stage 1 Stage 2 Stage 3

Identify sources of Control of Variability Monitoring Variability-remains “in control”
Variability
Continued Process Verification
FDA
Process
Qualification

Process Design
Qualification
 Fithrul, farmasiindustri.com

Ongoing process verification

APR/PQR
MBMR Batch
MBPR Records CPV/OPV
Routine Production Triggers for CAPA
▪ Deviation
▪ Self Inspection
▪ Recall etc
Product Master
Formula
➢ Knowledge
Management Investigation
➢ Risk Management

CMC/CTD/
MPD Validation Change Control
 Fithrul, farmasiindustri.com

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
 Fithrul, farmasiindustri.com

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

 Fithrul, farmasiindustri.com

▪ 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
Comparison the content of APR or PQR report
Fithrul, farmasiindustri.com

Requirement APR PQR

Time 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  
 Fithrul, farmasiindustri.com
Comparison the content of APR or PQR report
Requirement APR PQR
Yield  
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  
 Fithrul, farmasiindustri.com

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
 Fithrul, farmasiindustri.com

▪ 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

 Fithrul, farmasiindustri.com

Continued Process Verification - FDA

▪ Maintenance the Validated State
- Overall periodic review of the validated state
▪ Change in the validated state of the process could impact product
quality
▪ 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
Fithrul, farmasiindustri.com

Maurice Parlane,
ISPE Process Validation Team;
CBE Pty Ltd (Australia)
 Fithrul, farmasiindustri.com

CPV/OPV in context

Maurice Parlane,
ISPE Process Validation Team;
CBE Pty Ltd (Australia)
 Fithrul, farmasiindustri.com

 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
 Fithrul, farmasiindustri.com

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….
 Fithrul, farmasiindustri.com

▪ 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
 Fithrul, farmasiindustri.com
CPV/OPV
ISPE Discussion Paper Legacy Products, 2016
 Fithrul, farmasiindustri.com

 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

One among the famous method is Six Sigma – Process Robustness

 Fithrul, farmasiindustri.com

➢ 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
 Fithrul, farmasiindustri.com

 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
By doing this, it becomes possible to accurately
control the output of the process
 Fithrul, farmasiindustri.com

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
 Six Sigma Approach - DMAIC Phases
Fithrul, farmasiindustri.com

Define Measure Analyze Improve Control

CQAs S CS CI
ACTIVITIES
• Project • Define • Identify • Create • Confirm
selection Project and potential process process is
• Team boundaries cause model based stable and
selection • Collect data • Reduce on vital capable
• Create on current potential factors • Implement
project state causes down • Determine monitoring
charter • Assess to vital few new procedures
• Set metric suitability of optimum for • Update
and goal measurement process quality
• Process system validate systems
analysis • Determine results • Standardize
• Voice of current
customer performance
level
 Six Sigma Approach - DMAIC Phases
Fithrul, farmasiindustri.com

Define Measure Analyze Improve Control

CQAs S CS CI
TOOLS
• Project • Process • Detailed • Simulations • Process
Charter sheet mapping process map • Design of capability
• Process Flow • Data collection • Graphical Experiment • SPC chart
diagram plan data analysis (historical, • Control plan
• Process yield • Process tools screening, • FMEA
• Voice of capability • Hypothesis full or partial • Replication
customer • Measurement testing factorial etc. opportunities
• Kano system • Variance, • Response • Project
analysis analysis regression surface report
• Historical • Gage R&R and design
data plot • FMEA correlation • Improvement
• Pareto • Cause and analysis impact and
diagram Effect diagram benefit
• XY diagram
Fithrul, farmasiindustri.com
 Fithrul, farmasiindustri.com

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