QUALITY BY DESIGN

Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations

Mumbai, India Date: May 2008

Slide 1 May 2008

QUALITY BY DESIGN
Dr Tom Sam President Industrial Pharmacy Section International Pharmaceutical Federation (FIP)

Slide 2 May 2008

QUALITY BY DESIGN

products

processes
Slide 3 May 2008

What is Quality?
Quality
Requirements = need or expectations Target Product Quality Profile

Patient
(or surrogate)

Good pharmaceutical quality represents an acceptably low risk of failing to achieve the desired clinical attributes.
Slide 4 May 2008

Which quality do we want for our medicines ? 6

DPMO
1000000

Restaurant bills Airlines baggagecheck in

(defectsper 100000 million opportunities) 10000

1000 100 10 1 0,1 0,01

Egypt Air (5,8) Air India(5,8) Lufthansa (6,6)

Best-in-class

Quantas, SAS

2
Slide 5 May 2008

7
Quelle: Motorola, Air SafetyOnline

Source: Motorola, Air Safety Online

With which quality do we manufacture our medicines: 6, 5, 4, 3, 2 ?

DPMO
1000000

Restaurant bills Airlines baggagecheck in

(defectsper 100000 million opportunities) 10000

1000 100 10 1 0,1 0,01

Egypt Air (5,8) Air India(5,8) Lufthansa (6,6)

Best-in-class

Quantas, SAS

2
Slide 6 May 2008

7
Quelle: Motorola, Air SafetyOnline

Source: Motorola, Air Safety Online

How do we fill this quality gap in the pharmaceutical industry?

Sigma ppm Defects
Current Mfg

Yield
69.2% 93.3% 99.4% 99.98% 99.99966%

Cost of Quality
25-35% 20-25% 12-18% 4-8% 1-3%

Quality provided to patients

2 3 4 5 6

308,537 66,807 6,210 233 3.4

by testing !!!!
Data from: Dr. Doug Dean & Frances Bruttin PriceWaterhouseCoopers

Slide 7 May 2008

The quality mantra

Quality can not be tested into products; it has to be built in

by design

Slide 8 May 2008

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 9 May 2008

Dr Ajaz Hussain

Pharmaceutical GMPs

for the 21st Century

Slide 10 May 2008

The knowledge pyramid

First Principles Why?

Knowledge based decisions

Need for regulatory oversight

MECHANISTIC KNOWLEDGE How?

Desired State

CAUSAL" KNOWLEDGE What Causes What?

CORRELATIVE KNOWLEDGE What Is Correlated to What?

Current State

DESCRIPTIVE KNOWLEDGE:
What?

Slide 11 May 2008

The New Quality Paradigm The Evolving Regulatory Framework

Product Life Cycle Product Design Process Design Scale-up & Transfer Commercial Manufacture

Product

ICH Q8/Q8(R) - Pharmaceutical Development

PAT Guidance
ICH Q9 Quality Risk Management ICH Q10 Pharmaceutical Quality Systems

Slide 12 May 2008

Slide 13 May 2008

Definition: 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.
Slide 14 May 2008

EMEA/CHMP/ICH/518819/2007

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 15 May 2008

Impact of QbD
Companies re-organize their science
Universities change their curriculum Health authorities change their assessment and inspection

Slide 16 May 2008

QUALITY BY DESIGN
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
Slide 17 May 2008

EMEA/CHMP/ICH/518819/2007

What are the steps in a Quality by Design approach?

2. CRITICAL QUALITY ATTRIBUTES 3. LINK MAs AND PPs TO CQAS

1. TARGET PRODUCT PROFILE

6. PRODUCT LIFECYCLE MNGMNT 5. ESTABLISH CONTROL STRATEGY

4. ESTABLISH DESIGN SPACE

Slide 18 May 2008

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.
Slide 19 May 2008

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).

TPP for paediatric dosage form

TPP adult TPP paediatric (may depend upon age group)

Slide 20 May 2008

What are the steps in a Quality by Design approach?

2. CRITICAL QUALITY ATTRIBUTES 3. LINK MAs AND PPs TO CQAS

1. TARGET PRODUCT PROFILE

4. ESTABLISH DESIGN SPACE

6. PRODUCT LIFECYCLE MNGMNT

5. ESTABLISH CONTROL STRATEGY

Slide 21 May 2008

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 22 May 2008

Step 2. Determine the Critical Quality Attributes (CQAs)

Drug product CQAs are used to guide the product and process development.
solid oral dosage forms: typically those aspects affecting - product purity - product potency - product stability - drug release.
Slide 23 May 2008

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.

Product-centric Quality by Design

Excipient Quality Attributes API Purity
DRUG PRODUCT

Chemical purity

Physical form
Raw Material quality

API Quality Attributes

Formulation Process Related Particle size Mechanical Properties Excipient Compatibility

Formulation Parameters

Slide 24 May 2008

What are the steps in a Quality by Design approach?

2. CRITICAL QUALITY ATTRIBUTES 3. LINK MAs AND PPs TO CQAS

1. TARGET PRODUCT PROFILE

4. ESTABLISH DESIGN SPACE

6. PRODUCT LIFECYCLE MNGMNT

5. ESTABLISH CONTROL STRATEGY

Slide 25 May 2008

Step 3. Link the drug and excipient attributes

and the process parameters to the CQAs

I Chart
115 UCL=111.55 110

Individual Value

105 _ X=99.63

100 95

90 LCL=87.71 60 62 64 66 68 70 72 Observation 74 76 78 80

People
I Chart
115 UCL=112.65 110 105 100 95 90 85 80 40 42 44 46 48 50 52 Observation 54 56 58 60 _ X=97.94

LCL=83.23

Individual Value

I N P U T S (X)

Equipment
I Chart
115 UCL=112.65 110 105 100 95 90 85 80 40 42 44 46 48 50 52 Observation 54 56 58 60 _ X=97.94

Inputs to the process control variability of the Output

Individual Value

LCL=83.23

y = (x)
115 110 105 100 95 90 85 1 11 21 31

Individual Value

I Chart
UCL=114.17

Measurement
120 115 110 105 100 95 90 LCL=88.05 20 22 24 26 28 30 32 Observation 34 36 38 40 UCL=116.68

Individual Value

_ X=102.37

Individual Value

I Chart

_ X=99.95

Process
I Chart
115 UCL=111.55 110 105 _ X=99.63 100 95

LCL=85.72 41 51 61 Observation 71 81 91

90 LCL=87.71 60 62 64 66 68 70 72 Observation 74 76 78 80

OUTPUT

Materials
I Chart
110 UCL=111.17 105

Individual Value

100

_ X=98.76

95

90 LCL=86.35 80 82 84 86 88 90 92 Observation 94 96 98 100

85

Environment

Source: Moheb Nasr, FDA

Slide 26 May 2008

Mapping the Linkage

Inputs:
M1 M2
Material Attributes

Outputs:
CQA1
Critical CQA2 Quality Attributes

CQA3 P1 P2 P3
Process Parameters Relationships: CQA1 = function (M1) CQA2 = function (P1, P3) CQA3 = function (M1, M2, P1)

P2 might not be needed in the establishment of design space

Slide 27 May 2008

Source: Moheb Nasr, FDA

Experimental Approach for Identifying Parameters

Design of Experiments (DOE) is an efficient method to determine relevant parameters and interactions
1. Choose experimental design
(e.g., full factorial, d-optimal)

2. Conduct randomized experiments

Experiment 1 2 3 4 Factor A + + + Factor B + + Factor C + +

3. Analyze Data
Determine significant factors

Slide 28 May 2008

ICH Q9 Quality Risk Management

Initiate Quality Risk Management Process

Formal Risk Management Process

1. Risk

Assessment

2.

Risk

Control

Output / Result of the Quality Risk Management Process

4.
Slide 29 May 2008

Risk Review

What are the steps in a Quality by Design approach?

2. CRITICAL QUALITY ATTRIBUTES 3. LINK MAs AND PPs TO CQAS

1. TARGET PRODUCT PROFILE

4. ESTABLISH DESIGN SPACE

6. PRODUCT LIFECYCLE MNGMNT

5. ESTABLISH CONTROL STRATEGY

Slide 30 May 2008

Step 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 31 May 2008

Definition 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 been demonstrated to provide assurance of quality.
Roll pressure

Gap width Screen Size

300

Dataset - Run1-10a.M3 Observed vs. Predicted $Time [Last comp.] (Aligned)

200

100

-100 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)
SIMCA-P+ 11.5 - 05/02/2007 23:17:07

Slide 32 May 2008

What are the steps in a Quality by Design approach?

2. CRITICAL QUALITY ATTRIBUTES 3. LINK MAs AND PPs TO CQAS

1. TARGET PRODUCT PROFILE

4. ESTABLISH DESIGN SPACE

6. PRODUCT LIFECYCLE MNGMNT

5. ESTABLISH CONTROL STRATEGY

Slide 33 May 2008

Design Space

1a
Response surface plot of in-vitro release as a function of two critical parameters
of the mixing and lamination process.
Slide 34 May 2008

Contour plot of in-vitro release

EMEA/CHMP/ICH/518819/2007

Design Space

Design Space

Knowledge Space

Control Space
Slide 35 May 2008

Step 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 36 May 2008

5. 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 37 May 2008

What are the steps in a Quality by Design approach?

2. CRITICAL QUALITY ATTRIBUTES 3. LINK MAs AND PPs TO CQAS

1. TARGET PRODUCT PROFILE

4. ESTABLISH DESIGN SPACE

6. PRODUCT LIFECYCLE MNGMNT

5. ESTABLISH CONTROL STRATEGY

Slide 38 May 2008

Step 7. Product lifecycle management continual improvement

Minimal Approach
Reactive

QbD Approach
Preventive

action

(i.e., problem solving and corrective action)

Continual improvement facilitated

Slide 39 May 2008

Better processes will lead to products with less variability

Now (GMP)
Variable Input Fixed Process Variable Output Drug Product Variable Input Adapted Process Consistent Output

PAT/QbD

Slide 40 May 2008

The Revolution in Quality Thinking

Quality by Testing and Inspection
Enhanced product knowledge process understanding

Quality by Design
quality assured by well designed product & process

Slide 41 May 2008