QUALITY BY DESIGN (QBD) IN PHARMACEUTICAL INDUSTRY Ruchi Singh (F.Y M.Pharm ) Guided by : Dr.( Mrs.) Supriya Shidhaye

1

THE QUALITY MANTRA

“Quality can not be tested into

products; it has to be built in by

design”Joseph M Juran

2

CONTENTS :

3

1. QbD Basic concept

2. Steps in QbD

3. DoE as a tool for QbD

4. Example

5. Pros and cons

6. Conclusion

WHAT IS QUALITY?

Quality

Patient

Target ProductQuality Profile

Requirements= need or expectations

“Good pharmaceutical quality represents an acceptably low risk of failing to achieve

the desired quality attributes.”4

DEFINITION: QUALITY BY DESIGNQuality 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.

5

THE REVOLUTION IN QUALITY THINKING

Quality by Testing and Inspection

Quality by Design

Enhanced• product knowledge• process understanding

quality assured by well designed product & process6

INTRODUCED BY FDA IN 2002 ICH Q8 + ICH Q9 + ICHQ10Pharmaceutical Quality Risk Quality Development Management Management Quality by

Design

Quality by Design – GMP for the 21st Century

Merck & Co’s Januvia (2006) : first FDA approved product

7

=

QUALITY BY DESIGN APPROACH CAN BE USED FOR

API

Excipients

Analytics

Simple dosage forms

Advanced drug delivery system

Devices 8

STEPS IN A QUALITY BY DESIGN APPROACH?

1.QUALITY TARGET

PRODUCT PROFILE

2. CRITICAL QUALITY

ATTRIBUTES

6. PRODUCT LIFECYCLE

MNGMNT

3. LINK MAs AND PPs

TO CQAS

5. ESTABLISHCONTROL STRATEGY

4. ESTABLISHDESIGN SPACE

9

STEP1 : QUALITY TARGET PRODUCT PROFILE (QTPP) 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 realized.

The TPP forms the basis of design of the product.10

TARGET PRODUCT PROFILE (TPP) 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).

11

STEPS IN A QUALITY BY DESIGN APPROACH?

1.QUALITY TARGET PRODUCT PROFILE

2. CRITICAL QUALITY

ATTRIBUTES

6. PRODUCT LIFECYCLE

MNGMNT

3. LINK MAs AND PPs

TO CQAS

5. ESTABLISHCONTROL STRATEGY

4. ESTABLISHDESIGN SPACE

12

STEP 2. DETERMINE THE CRITICAL QUALITY ATTRIBUTES (CQAS)- 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. 13

STEP 2. DETERMINE THE CRITICAL QUALITY ATTRIBUTES (CQAS)

SOLID ORAL DOSAGE FORMS:

Particle size

Polymorphic form

Water content

Residual solvent

Organic and inorganic impurities

OTHER DELIVERY SYSTEMS:

Include more product specific aspects, such as

Sterility for Parenteral, Adhesive force for

transdermal patches.

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

14

STEPS IN A QUALITY BY DESIGN APPROACH?

1.QUALITY TARGET PRODUCT PROFILE

2. CRITICAL QUALITY ATTRIBUTES

6. PRODUCT LIFECYCLE

MNGMNT

3. LINK MAs AND PPs

TO CQAS

5. ESTABLISHCONTROL STRATEGY

4. ESTABLISHDESIGN SPACE

15

STEP 3. LINK THE DRUG AND EXCIPIENTS 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

Attribut

es

Observation

Individu

al Value

4038363432302826242220

120

115

110

105

100

95

90

_X=102.37

UCL=116.68

LCL=88.05

I Chart

Observation

Individu

al Value

6058565452504846444240

115

110

105

100

95

90

85

80

_X=97.94

UCL=112.65

LCL=83.23

I Chart

Observation

Individu

al Value

8078767472706866646260

115

110

105

100

95

90

_X=99.63

UCL=111.55

LCL=87.71

I Chart

Observation

Individu

al Value

10098969492908886848280

110

105

100

95

90

85

_X=98.76

UCL=111.17

LCL=86.35

I Chart

Observation

Individu

al Value

6058565452504846444240

115

110

105

100

95

90

85

80

_X=97.94

UCL=112.65

LCL=83.23

I Chart

Observation

Individu

al Value

8078767472706866646260

115

110

105

100

95

90

_X=99.63

UCL=111.55

LCL=87.71

I Chart

Process

Paramete

rs

Observation

Individu

al Value

9181716151413121111

115

110

105

100

95

90

85

_X=99.95

UCL=114.17

LCL=85.72

I Chart

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MAPPING THE LINKAGE

Input Output

P1

P2

P3

M1

M2

CQA1

CQA2CQA3

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

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ICH 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 ProcessThe

new

langua

ge

The primary objective is to find a harmful event in the process

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TOOLS FOR RISK MANAGEMENT Preliminary hazard analysis ( PHA)

Failure mode effect and criticality analysis ( FMECA)

Risk ranking

Risk filtering 19

What are the steps in aQuality by Design approach?

1.QUALITY TARGET PRODUCT PROFILE

2. CRITICAL QUALITY

ATTRIBUTES

6. PRODUCT LIFECYCLE

MNGMNT

3. LINK MAs AND PPs

TO CQAS

5. ESTABLISHCONTROL STRATEGY

4. ESTABLISHDESIGN SPACE

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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 beendemonstrated to provide assurance of quality.

21

STEPS IN A QUALITY BY DESIGN APPROACH?

1.QUALITY TARGET PRODUCT PROFILE

2. CRITICAL QUALITY

ATTRIBUTES

6. PRODUCT LIFECYCLE

MNGMNT

3. LINK MAs AND PPs

TO CQAS

5. ESTABLISHCONTROL STRATEGY

4. ESTABLISHDESIGN SPACE

22

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

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Knowledge Space

Design Space

Control Space

CONTROL SPACE

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STEP 5. CONTROL STRATEGYElements of a control strategy can include, but are not limited to, the following:

• Control of input material attributes based on an understanding of their impact on process ability or product quality

• Product specification(s)

• Controls for unit operations that have an impact on downstream processing or end-product quality

• In-process or real-time release in lieu of end-product testing 25

STEPS IN A QUALITY BY DESIGN APPROACH?

1.QUALITY TARGET PRODUCT PROFILE

2. CRITICAL QUALITY

ATTRIBUTES

6. PRODUCT LIFECYCLE MNGMNT

3. LINK MAs AND PPs

TO CQAS

5. ESTABLISHCONTROL STRATEGY

4. ESTABLISHDESIGN SPACE

26

STEP 6. PRODUCT LIFECYCLE MANAGEMENT CONTINUAL IMPROVEMENT

Minimal Approach

QbD Approach

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

• Preventive action

• Continual improvement facilitated

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BETTER PROCESSES UNDERSTANDING WILL LEAD TO PRODUCTS

WITH LESS VARIABILITY

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Current approach:-• Quality assured by testing and inspection• Data intensive submission• Specifications based on batch history• “Frozen process,” discouraging changes• Focus on reproducibility – often avoiding or ignoring variation

QbD Approach:-• Quality built into product & process by design, based on scientific understanding• Knowledge rich submission – showing product knowledge & process understanding• Specifications based on product performance requirements• Flexible process within design space, allowing continuous improvement• Focus on robustness – understanding and controlling variation

QbD replaces QbT( Quality by Testing)

Pre-formulat

ion studies

Literature

reviewformulatio

nQC and

Evaluation

Out Product

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Experimental Approach for Identifying Parameters

1. Choose Experimental Design (e.g., full factorial, fractional )

2. Conduct Randomized Experiments

3. Analyze Data Determine significant factors

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

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A DOE IS USEFUL TOIdentify important factorsEstablish process stabilityFind best operating conditions

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SQUARE GEO-GRAM

Graphical AnalysisGeo-Gram:The geo-gram is a geometrical representation of the data. The shape is determined by the number of factors ( i.e. 2 factors is a square, 3 factors is a cube), the number of levels and the distance between levels.

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5041

47

TempB

TimeA

+--

+This defines the inference space or the experimental boundaries of your experiment within your process.

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1a

Response surface plot Contour plot

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EXAMPLE: •3 factors at 2 level each

FACTOR LEVEL 1 LEVEL 2 Amount of super disintegrant

+ 1 -1

Amount of binder

+1-1

Amount of lubricant

+1-1

RESPONSE : 1. Disintegration time 2. Hardness

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23Factors

35

Level

EXAMPLE

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Pros and Cons• Scientific

understanding• Holistic approach• Less data to manage• Meaningful data• Fewer non conformances• Lean processes – more

cost efficient• Better control of

process• Continuous improvement• Managed based on risk• Patient first approach• Up to 30% savings*

• New concept – hard to get buy in

• Just starting to be recognised by authorities

• Culture change• Investment up front• Time to get to know

process and product• Difficult to apply

retrospectively

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CHALLENGES: Terminology Products not approved by QbD Training Programs Small Scale Industry Capital Risk

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SUMMARY:Quality by Design (QbD) presents to the industry , various pro’s like reduction in cost , a better model ,hassle free processes better interacted with FDA.

Along with that ,new technologies can be implemented once a thorough understanding of product is done.

For a manager ,It cuts down time to the industry , if used effectively.

Thus , it brings about a worthwhile change in every Pharmaceutical Operation and thus the popularity of this subject and shift in the paradigm is signified.

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ACKNOWLEDGEMENT Dr ( Mrs.) Supriya Shidhaye

Dr( Mrs. ) Rajashree Hirlekar

Mr. Vivek Nalawade

Ms Chaitali Surve

Mr. Priyank Parikh

Family and Friends 40

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• Juran, J.M. (1992) Juran on Quality by design – The New Steps for Planning Quality into Goods and Services,thefreepress

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• Jessy Shaji and Shital Lodha Response Surface Methodology for the Optimization of Celecoxib Self-microemulsifying Drug delivery System , Indian J Pharm Sci. 2008 Sep-Oct; 70(5): 585–590  10.4103/0250-474X.45395PMCID: PMC3038281

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•Jun Huan et al, Quality by design case study: An integrated multivariate approach to drug product and process development, International Journal of Pharmaceutics, 382 (2009) 23–32•Chi –Wan Chen, Christine Moore ,Role of Statistics in Pharmaceutical Development Using Quality-by-Design Approach – an FDA Perspective, September 27 -29, 2006.• Lindsay I Smith A tutorial on Principal Components Analysis February 26, 2002•Quality Risk Management (ICH Q9) EMA/INS/GMP/79766/2011.•Http://www.ceruleanllc.com/resources/published-articles-case-studies/#qbd• Spaceamit Mukharya et al, Quality risk management of top spray fluidized bed process for antihypertensive drug formulation with control strategy engendered by Box-behnken experimental design Int J Pharm Investig. 2013 Jan-Mar; 3(1): 15–28.•Http://www.ngpharma.com/article/PAT-and-qbd-in-pharmaceutical-development/•Http://www.drugregulations.org/2012/08/qbd-for-beginners-design-space.html?Q=qbd, qbd for beginners part 4 , uday shetty •Glodek, M et al., Pharm. Eng 2006, 26, 1-11.•Rath, T, Strong, D.O., Rath & Strong's Six Sigma Pocket Guide. Lexington, AON Consulting Worldwide, MA 2002.•International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for human use, topicq2 (R1): Validation of Analytical Procedures: Text and methodology, ICH, Geneva, Switzerland, 2005. 43

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