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QUALITY BY DESIGN. Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Mumbai, India Date: May 2008. QUALITY BY DESIGN. Dr Tom Sam President Industrial Pharmacy Section International Pharmaceutical Federation (FIP). QUALITY BY DESIGN. products.

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Slide1 l.jpg

QUALITY BY DESIGN

Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations

Mumbai, India

Date: May 2008


Slide2 l.jpg

QUALITY BY DESIGN

Dr Tom Sam

President

Industrial Pharmacy Section

International Pharmaceutical Federation (FIP)


Quality by design l.jpg
QUALITY BY DESIGN

products

processes


What is quality l.jpg
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.”


Which quality do we want for our medicines 6 l.jpg
Which quality do we want for our medicines ? 6σ

Source: Motorola, Air Safety Online


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

Source: Motorola, Air Safety Online

Current Mfg

Quality provided

to patients


How do we fill this quality gap in the pharmaceutical industry l.jpg
How do we fill this quality gapin the pharmaceutical industry?

Sigma

ppm Defects

Yield

Cost of Quality

Sigma

ppm Defects

Yield

Cost of Quality

s

69.2%

25-35%

s

69.2%

25-35%

2

308,537

2

308,537

s

93.3%

20-25%

s

93.3%

20-25%

3

66,807

3

66,807

s

99.4%

12-18%

s

99.4%

12-18%

4

6,210

4

6,210

s

99.98%

4-8%

s

99.98%

4-8%

5

233

5

233

s

99.99966%

1-3%

s

99.99966%

1-3%

6

3.4

3.4

6

Current Mfg

Quality provided

to patients

……by testing !!!!

Data from: Dr. Doug Dean & Frances Bruttin

PriceWaterhouseCoopers


The quality mantra l.jpg
The quality mantra

“Quality can not be tested into products; it has to be built in by design”


How can we modernize our industry l.jpg
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


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Dr Ajaz Hussain

‘Pharmaceutical GMPs

for the 21st Century’


The knowledge pyramid l.jpg
The knowledge pyramid

Desired State

Knowledge based decisions

First

Principles

Why?

MECHANISTIC

KNOWLEDGE

How?

“CAUSAL" KNOWLEDGE

What “Causes” What?

Need for regulatory oversight

CORRELATIVE KNOWLEDGE

What Is Correlated to What?

Current State

DESCRIPTIVE KNOWLEDGE:

What?


The new quality paradigm the evolving regulatory framework l.jpg
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


Definition quality by design l.jpg
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.

EMEA/CHMP/ICH/518819/2007


Quality by design approach can be used for l.jpg
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)


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Impact of QbD

  • Companies re-organize their science

  • Universities change their curriculum

  • Health authorities change their assessment and inspection


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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

EMEA/CHMP/ICH/518819/2007


What are the steps in a quality by design approach l.jpg
What are the steps in aQuality 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


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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).


Tpp for paediatric dosage form l.jpg
TPP for paediatric dosage form

TPP adult

TPP paediatric (may depend upon age group)


What are the steps in a quality by design approach21 l.jpg
What are the steps in aQuality 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


Critical quality attributes definition l.jpg
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


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Step 2. Determine the Critical Quality Attributes (CQAs)

solid oral dosage forms:

typically those aspects affecting - product purity - product potency- product stability- drug release.

Drug product CQAs are used to guide the product and process development.

  • 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.


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Product-centric Quality by Design

Chemical purity

Physical form

Raw Material quality

Excipient

Quality

Attributes

API

Purity

API

Quality Attributes

Particle size

Mechanical

Properties

Excipient

Compatibility

Formulation

Process Related

Formulation

Parameters

DRUG

PRODUCT


What are the steps in a quality by design approach25 l.jpg
What are the steps in aQuality 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


Step 3 link the drug and excipient attributes and the process parameters to the cqas l.jpg
Step 3. Link the drug and excipient attributes and the process parameters to the CQAs

People

Process Parameters

Quality Attributes

Inputs to the process

control variability

of the Output

Equipment

I

N

P

U

T

S

(X)

y = ƒ(x)

Measurement

y

Process

OUTPUT

Materials

Source: Moheb Nasr, FDA

Environment


Mapping the linkage l.jpg
Mapping the Linkage

Outputs:

Inputs:

CQA1

M1

Critical

Quality Attributes

M2

CQA2

Material Attributes

CQA3

P1

P2

Relationships:

CQA1 = function (M1)

CQA2 = function (P1, P3)

CQA3 = function (M1, M2, P1)

P2 might not be needed in the establishment of design space

Source: Moheb Nasr, FDA

P3

ProcessParameters


Experimental approach for identifying parameters l.jpg
Experimental Approach for Identifying Parameters

Design of Experiments (DOE) is an efficient method to determine relevant parameters and interactions

2. Conduct randomized experiments

1. Choose experimental design

(e.g., full factorial, d-optimal)

3. Analyze Data

Determine significant factors


Ich q9 quality risk management l.jpg
ICH Q9 Quality Risk Management

Initiate Quality Risk

Management Process

1. Risk Assessment

2. Risk Control

Output / Result of the QualityRisk Management Process

4. Risk Review

FormalRisk Management Process

The new language


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What are the steps in aQuality 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


Step 4 define the design space l.jpg
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.


Definition of design space l.jpg
Definition of Design Space

Roll pressure

Gap width

Screen Size

  • The material attributes and process parameters that assure quality.

  • The multidimensionalcombination and interaction of input variables (e.g. material attributes) and process parameters that have beendemonstrated to provide assurance of quality.


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What are the steps in aQuality 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


Design space l.jpg
Design Space

1a

EMEA/CHMP/ICH/518819/2007

Response surface plot of in-vitro release

as a function of two critical parameters

of the mixing and lamination process.

Contour plot of in-vitro release


Design space35 l.jpg
Design Space

Design Space

ControlSpace

Knowledge Space


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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


5 control strategy l.jpg
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.


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What are the steps in aQuality 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


Step 7 product lifecycle management continual improvement l.jpg
Step 7. Product lifecycle management continual improvement


Better processes will lead to products with less variability l.jpg
Better processes will lead to products with less variability

Variable Input

Fixed Process

Variable Output

Now (GMP)

Drug Product

PAT/QbD

Variable Input

Adapted Process

Consistent Output


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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


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