Slide 1 May 2008 Training Workshop on Pharmaceutical Development with focus on Paediatric...
41
Slide 1 May 2008 Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Mumbai, India Date: May 2008 QUALITY BY DESIGN
-
Upload
martin-hood -
Category
Documents
-
view
213 -
download
0
Transcript of Slide 1 May 2008 Training Workshop on Pharmaceutical Development with focus on Paediatric...
Slide 1 May 2008
Training Workshop on Pharmaceutical Development
with focus on Paediatric Formulations
Mumbai, India
Date: May 2008
QUALITY BY DESIGN
Slide 2 May 2008
Dr Tom Sam
President
Industrial Pharmacy Section
International Pharmaceutical Federation (FIP)
QUALITY BY DESIGN
Slide 3 May 2008
QUALITY BY DESIGN
processes
products
Slide 4 May 2008
What is Quality?What is Quality?
Quality
Patient(or surrogate)
Target ProductQuality Profile
Requirements= need or expectations
“Good pharmaceutical quality represents an acceptably low risk of failing to achieve
the desired clinical attributes.”
Slide 5 May 2008
Which quality do we want for our medicines ? 6σ
Which quality do we want for our medicines ? 6σ
0,01
0,1
1
10
100
1000
10000
100000
1000000DPMO(defectspermillionopportunities)
2σ 3σ 4σ 5σ 6σ 7σ
Best-in-class
Airlines baggagecheck in
Restaurant bills
Lufthansa (6,6)
Quantas, SAS
Air India(5,8)EgyptAir (5,8)
Quelle: Motorola, Air SafetyOnlineSource: Motorola, Air Safety Online
Slide 6 May 2008
With which quality do we manufacture our medicines: 6σ, 5σ, 4σ, 3σ, 2σ ?
With which quality do we manufacture our medicines: 6σ, 5σ, 4σ, 3σ, 2σ ?
0,01
0,1
1
10
100
1000
10000
100000
1000000DPMO(defectspermillionopportunities)
2σ 3σ 4σ 5σ 6σ 7σ
Best-in-class
Airlines baggagecheck in
Restaurant bills
Lufthansa (6,6)
Quantas, SAS
Air India(5,8)EgyptAir (5,8)
Quelle: Motorola, Air SafetyOnlineSource: Motorola, Air Safety Online
Current Mfg
Quality provided
to patients
Slide 7 May 2008
How do we fill this quality gapin the pharmaceutical industry?How do we fill this quality gap
in the pharmaceutical industry?
SigmaSigma ppm Defectsppm Defects YieldYield
22
33
44
55
66
308,537308,537
66,80766,807
6,2106,210
233233
3.43.4
69.2%69.2%
93.3%93.3%
99.4%99.4%
99.98%99.98%
99.99966%99.99966%
Cost of QualityCost of Quality
25-35%25-35%
20-25%20-25%
12-18%12-18%
4-8%4-8%
1-3%1-3%
Current Mfg
Quality providedto patients
Data from: Dr. Doug Dean & Frances BruttinData from: Dr. Doug Dean & Frances BruttinPriceWaterhouseCoopersPriceWaterhouseCoopers
…………by testing !!!!by testing !!!!
Slide 8 May 2008
The quality mantraThe quality mantra
“Quality can not be tested into
products; it has to be built in
by design”
Slide 9 May 2008
How can we modernize our industry?How can we modernize our industry?
More knowledge of our products and processes, allowing better design and more control
Better management:- introduction of quality risk management- expansion of GMP to more extensive pharmaceutical quality system
Slide 10 May 2008
Dr Ajaz HussainDr Ajaz Hussain
‘‘Pharmaceutical GMPs Pharmaceutical GMPs
for the 21st Century’for the 21st Century’
Slide 11 May 2008
The knowledge pyramidThe knowledge pyramid
CORRELATIVE KNOWLEDGEWhat Is Correlated to What?
“CAUSAL" KNOWLEDGEWhat “Causes” What?
MECHANISTICKNOWLEDGE
How?
DESCRIPTIVE KNOWLEDGE: What?
Ne
ed
for
reg
ula
tory
ove
rsig
ht
Kn
owle
dge
based
decision
s
Desired State
Current State
FirstPrinciples Why?
Slide 12 May 2008
The New Quality Paradigm – The Evolving Regulatory Framework
The New Quality Paradigm – The Evolving Regulatory Framework
ICH Q8/Q8(R) - Pharmaceutical Development
PAT Guidance
ICH Q9 – Quality Risk Management
ICH Q10 – Pharmaceutical Quality Systems
ProductDesign
Process Design
Scale-up &Transfer
Commercial Manufacture
Product Life Cycle
Product
Slide 13 May 2008
Slide 14 May 2008
Definition: Quality by DesignDefinition: Quality by Design
Quality by Design 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.
EMEA/CHMP/ICH/518819/2007
Slide 15 May 2008
Quality by Design approach can be used for
Quality by Design approach can be used for
Active pharmaceutical ingredients
Materials incl excipients
Analytics
Simple dosage forms
Advanced drug delivery systems
Devices
Combination products (e.g. theranostics)
Slide 16 May 2008
Impact of QbDImpact of QbD
Companies re-organize their science
Universities change their curriculum
Health authorities change their assessment and inspection
Slide 17 May 2008
Step 1. Agree on the Target Product Profile
Step 2. Determine the Critical Quality Attributes (CQAs)
Step 3. Link the drug and excipient attributes and the
process parameters to the CQAs
Step 4. Define the Design Space
Step 5. Define the Control Strategy
Step 6. Prepare QbD registration file
Step 7. Product lifecycle management and
continual improvement
EM
EA
/CH
MP/
ICH
/518
819/
2007
QUALITY BY DESIGN
Slide 18 May 2008
What are the steps in aQuality by Design approach?
What are the steps in aQuality by Design approach?
1. TARGET PRODUCT PROFILE
2. CRITICAL QUALITY
ATTRIBUTES
6. PRODUCT LIFECYCLE
MNGMNT
3. LINK MAs AND PPs
TO CQAS
5. ESTABLISHCONTROL STRATEGY
4. ESTABLISHDESIGN SPACE
Slide 19 May 2008
Step 1. Agree on the Target Product Profile
Step 1. Agree on the Target Product Profile
Target Product Profile: - a prospective and dynamic summary of the quality characteristics of a drug product - that ideally will be achieved to ensure that the desired quality, and hence the safety and efficacy, of a drug product is realised.
The TPP forms the basis of design of the product.
Consider:
dosage form
route of administration
strength
release / delivery of the drug
pharmacokinetic characteristics (e.g., dissolution; aerodynamic performance)
drug product quality criteria (e.g., sterility, purity).
Slide 20 May 2008
TPP for paediatric dosage formTPP for paediatric dosage form
TPP adult TPP paediatric (may depend upon age group)
Slide 21 May 2008
What are the steps in aQuality by Design approach?
What are the steps in aQuality by Design approach?
1. TARGET PRODUCT PROFILE
2. CRITICAL QUALITY
ATTRIBUTES
6. PRODUCT LIFECYCLE
MNGMNT
3. LINK MAs AND PPs
TO CQAS
5. ESTABLISHCONTROL STRATEGY
4. ESTABLISHDESIGN SPACE
Slide 22 May 2008
CRITICAL QUALITY ATTRIBUTES - definition
CRITICAL QUALITY ATTRIBUTES - definition
A critical quality attribute (CQA) is 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.
EMEA/CHMP/ICH/518819/2007
Slide 23 May 2008
Step 2. Determine the Critical Quality Attributes (CQAs)
Step 2. Determine the Critical Quality Attributes (CQAs)
solid oral dosage forms:
typically those aspects affecting - product purity - product potency- product stability- drug release.
other delivery systems:
can additionally include more product specific aspects, such as- aerodynamic properties for inhaled products- sterility for parenterals, - adhesive force for transdermal patches.
Drug product CQAs are used to guide the product and process development.
Slide 24 May 2008
Product-centric Quality by DesignProduct-centric
Quality by Design
APIPurity
Chemical purity
Physical form
Raw Material quality
Formulation Process Related
Particle size
Mechanical Properties
Excipient Compatibility
DRUGPRODUCT
APIQuality Attributes
FormulationParameters
Excipient Quality
Attributes
Slide 25 May 2008
What are the steps in aQuality by Design approach?
What are the steps in aQuality by Design approach?
1. TARGET PRODUCT PROFILE
2. CRITICAL QUALITY
ATTRIBUTES
6. PRODUCT LIFECYCLE
MNGMNT
3. LINK MAs AND PPs
TO CQAS
5. ESTABLISHCONTROL STRATEGY
4. ESTABLISHDESIGN SPACE
Slide 26 May 2008
Step 3. Link the drug and excipient attributes and the process parameters to the CQAs
Step 3. Link the drug and excipient attributes and the process parameters to the CQAs
People
Equipment
Measurement
Process
Materials
Environment
INPUTS
(X)
y = ƒ(x)
OUTPUT
y
Inputs to the processcontrol variability
of the OutputQuality Attri
butes
Observation
Indiv
idual V
alu
e
4038363432302826242220
120
115
110
105
100
95
90
_X=102.37
UCL=116.68
LCL=88.05
I Chart
Observation
Indiv
idual V
alu
e
6058565452504846444240
115
110
105
100
95
90
85
80
_X=97.94
UCL=112.65
LCL=83.23
I Chart
Observation
Indiv
idual V
alu
e
8078767472706866646260
115
110
105
100
95
90
_X=99.63
UCL=111.55
LCL=87.71
I Chart
Observation
Indiv
idual V
alu
e
10098969492908886848280
110
105
100
95
90
85
_X=98.76
UCL=111.17
LCL=86.35
I Chart
Observation
Indiv
idual V
alu
e6058565452504846444240
115
110
105
100
95
90
85
80
_X=97.94
UCL=112.65
LCL=83.23
I Chart
Observation
Indiv
idual V
alu
e
8078767472706866646260
115
110
105
100
95
90
_X=99.63
UCL=111.55
LCL=87.71
I Chart
Process
Parameters
Observation
Indiv
idual V
alu
e
9181716151413121111
115
110
105
100
95
90
85
_X=99.95
UCL=114.17
LCL=85.72
I Chart
Source: Moheb Nasr, FDA
Slide 27 May 2008
Mapping the LinkageMapping the Linkage
Inputs: Outputs:
P1
P2
P3
M1
M2
CQA1
CQA2
CQA3
Relationships:CQA1 = function (M1)
CQA2 = function (P1, P3)CQA3 = function (M1, M2, P1)
P2 might not be needed in the establishment of design space
ProcessParameters
Material Attributes
CriticalQuality Attributes
So
urc
e: M
oh
eb N
asr,
FD
A
Slide 28 May 2008
Experimental Approach for Identifying Parameters
Experimental Approach for Identifying Parameters
1. Choose experimental design
(e.g., full factorial, d-optimal)
2. Conduct randomized experiments
ExperimentFactor AFactor BFactor C
1+--
2-+-
3+++
4 +-+
3. Analyze Data Determine significant factors
Design of Experiments (DOE) is an efficient method to determine relevant parameters and interactions
Slide 29 May 2008
ICH Q9 Quality Risk ManagementICH Q9 Quality Risk Management
4. Risk Review
1. Risk Assessment
2. Risk Control
Initiate Quality Risk Management Process
Output / Result of the QualityRisk Management Process
FormalRisk Management Process
The new language
Slide 30 May 2008
What are the steps in aQuality by Design approach?
What are the steps in aQuality by Design approach?
1. TARGET PRODUCT PROFILE
2. CRITICAL QUALITY
ATTRIBUTES
6. PRODUCT LIFECYCLE
MNGMNT
3. LINK MAs AND PPs
TO CQAS
5. ESTABLISHCONTROL STRATEGY
4. ESTABLISHDESIGN SPACE
Slide 31 May 2008
Step 4. Define the Design SpaceStep 4. Define the Design Space
The linkage between - the process inputs (input variables and process parameters) and - the critical quality attributes
can be described in the design space.
Slide 32 May 2008
Definition of Design SpaceDefinition of Design Space
The material attributes and process parameters that assure quality.
The multidimensional combination and interaction of input variables (e.g. material attributes) and process parameters that have beendemonstrated to provide assurance of quality.
Ro
ll p
res
su
re
Gap width
Screen Size
-100
0
100
200
300
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240 250 260
$Time (normalized)
Dataset - Run1-10a.M3Observed vs. Predicted $Time [Last comp.] (Aligned)
SIMCA-P+ 11.5 - 05/02/2007 23:17:07
Slide 33 May 2008
What are the steps in aQuality by Design approach?
What are the steps in aQuality by Design approach?
1. TARGET PRODUCT PROFILE
2. CRITICAL QUALITY
ATTRIBUTES
6. PRODUCT LIFECYCLE
MNGMNT
3. LINK MAs AND PPs
TO CQAS
5. ESTABLISHCONTROL STRATEGY
4. ESTABLISHDESIGN SPACE
Slide 34 May 2008
Design SpaceDesign Space
1a
EM
EA
/CH
MP
/IC
H/5
1881
9/20
07
Response surface plot of in-vitro release Response surface plot of in-vitro release
as a function of two critical parameters as a function of two critical parameters
of the mixing and lamination process.of the mixing and lamination process.
Contour plot of Contour plot of in-vitro releasein-vitro release
Contour plot of Contour plot of in-vitro releasein-vitro release
Slide 35 May 2008
Knowledge Space
Design Space
Control Space
Design Space
Slide 36 May 2008
Step 5. Define the Control StrategyStep 5. Define the Control Strategy
The control strategy should describe and justify how
in-process controls and
the controls of - input materials (drug substance and excipients), - container closure system, - intermediates and
the controls of end products
contribute to the final product quality
Slide 37 May 2008
5. CONTROL STRATEGY5. CONTROL STRATEGY
Elements of a control strategy can include, but are not limited to, the following:
• Control of input material attributes (e.g., drug substance, adhesive polymer, primary packaging materials) based on an understanding of their impact on processability or product quality
• Product specification(s)
• Controls for unit operations that have an impact on downstream processing or end-product quality (e.g., the impact of solvent on degradation)
• In-process or real-time release in lieu of end-product testing
• A monitoring program (e.g., full product testing at regular intervals) for verifying multivariate prediction models.
Slide 38 May 2008
What are the steps in aQuality by Design approach?
What are the steps in aQuality by Design approach?
1. TARGET PRODUCT PROFILE
2. CRITICAL QUALITY
ATTRIBUTES
6. PRODUCT LIFECYCLE
MNGMNT
3. LINK MAs AND PPs
TO CQAS
5. ESTABLISHCONTROL STRATEGY
4. ESTABLISHDESIGN SPACE
Slide 39 May 2008
Step 7. Product lifecycle management continual improvement
Step 7. Product lifecycle management continual improvement
Minimal ApproachQbD Approach
• Reactive (i.e., problem solving and corrective action)
• Preventive action
• Continual improvement facilitated
Slide 40 May 2008
Better processes will lead to products with less variability
Better processes will lead to products with less variability
Now (GMP) Now (GMP)
Drug Drug ProductProduct
Variable Variable InputInput
Fixed Fixed ProcessProcess
Variable Variable OutputOutput
Variable Variable InputInput
Adapted Adapted ProcessProcess
Consistent Consistent OutputOutput
PAT/QbDPAT/QbD
Slide 41 May 2008
The Revolution in Quality ThinkingThe Revolution in Quality Thinking
Quality by Testing and Inspection
Quality by Design
Enhanced• product knowledge• process understanding
quality assured by well designed product & process
