QUALITY

BY DESIG

N (QBD)

IN A

PI

DR ANTH

ONY CRASTO

1

THE QUALITY MANTRA

“Quality can not be tested into products; it

has to be built in by design”

Joseph M Juran

WHAT IS QUALITY BY DESIGN?

“You can’t test quality into drug products” has been heard for decades – so what’s new?

It’s a culture - incorporates quality principles as well as strong compliance function

Incorporates risk assessment and managementRefocuses attention and resources on what’s important to the customer, i.e. the patients, health professionals, payors and distribution chain

QUALITY BY DESIGN

Continuous improvement is a hallmark of quality by design

G. Taguchi on Robust Design: design changes during manufacture can result in the last product produced being different from the first product

In pharmaceutical manufacturing, we don’t want this – patients and physicians must count on each batch of drug working just like the batches that came before

QUALITY BY DESIGN

In generic pharmaceutical manufacturing, there are additional constraints

Fixed bioequivalence targets Regulatory requirements to duplicate formulation of innovator drug Lack of access to innovator development data

LEAD POINTS 1. QbD Basic concept

2. Steps in QbD

3. DoE as a tool for QbD

4. Example Torcetrapib

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.”

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.

THE REVOLUTION IN QUALITY THINKING

Quality by Testing and Inspection

Quality by Design

Enhanced• product knowledge• process understanding

quality assured by well designed product & process

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

=

QUALITY BY DESIGN (QBD)

Myth : An expensive development tool !

Fact : A tool that makes product development and commercial scale manufacturing simple !

Actually saves money !

How ?

OUTLINE

FDA initiatives for quality The desired state Quality by design (QbD) and design space (ICH

Q8)

Application of statistical tools in QbD Design of experiments Model building & evaluation Statistical process control

FDA’S INITIATIVE ON QUALITY BY DESIGN

In a Quality-by-Design system: The product is designed to meet patient requirements

The process is designed to consistently meet product critical quality attributes

The impact of formulation components and process parameters on product quality is understood

Critical sources of process variability are identified and controlled

The process is continually monitored and updated to assure consistent quality over time

Qualityby

Design

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

DESIGN SPACE (ICH Q8)

Definition: The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality

Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post-approval change process.

Design space is proposed by the applicant and is subject to regulatory assessment and approval

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 Process

The new

language

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

CURRENT VS. QBD APPROACH TO PHARMACEUTICAL

DEVELOPMENTCurrent Approach QbD Approach

Quality assured by testing and inspection

Quality built into product & process by design, based on scientific understanding

Data intensive submission – disjointed information without “big picture”

Knowledge rich submission – showing product knowledge & process understanding

Specifications based on batch history

Specifications based on product performance requirements

“Frozen process,” discouraging changes

Flexible process within design space, allowing continuous improvement

Focus on reproducibility – often avoiding or ignoring variation

Focus on robustness – understanding and controlling variation

MAPPING THE LINKAGE

Input Output

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

PHARMACEUTICAL DEVELOPMENT & PRODUCT

LIFECYCLE

Candidate Selection

Product Design & Development

Process Design & Development

Manufacturing Development

ProductApproval

Continuous Improvement

Design of Experiments

(DOE)

Model BuildingAnd Evaluation

Process Design & Development:Initial ScopingProcess CharacterizationProcess OptimizationProcess Robustness

Statistical Tool

Product Design & Development:Initial ScopingProduct CharacterizationProduct Optimization

Manufacturing Development and Continuous Improvement:

Develop Control SystemsScale-up PredictionTracking and trending

StatisticalProcess Control

Pharmaceutical Development & Product

Lifecycle

BACKGROUND OF FDA’S “PHARMACEUTICAL QUALITY FOR THE 21ST CENTURY INITIATIVE

In 2002, FDA identified a series of ongoing problems and issues in pharmaceutical manufacturing that traditional approaches had not solved

FDA undertook an internal and external assessment of the causes

As a result, the agency started a major change initiative that is continuing

Stimulating more use of PAT was an early component of initiative

STATE OF REGULATION CIRCA 2002

Pharmaceutical manufacturing HIGHLY regulated (e.g., compared to foods, fine chemicals)

Cost of cGMP compliance very high

Despite this: process efficiency and effectiveness low (high wastage and rework); and level of technology not comparable to other industries

FUNCTIONAL CONSEQUENCES

Inability to predict effects of scale-up

Lack of agility – usually takes years to bring up a new production site

Operations fragmented around globe

Inability to understand reasons for manufacturing failures

RESULT: FOR REGULATORS

Extensive oversight of manufacturing resource-intensive (in era of cost reductions and increased mandates)

Expensive and time-consuming litigation and legal actions in cGMP area

Need to deal with recalls and shortages of medically necessary drugs

RESULT: FOR INDUSTRY

Culture: antithesis of “continuous improvement”

Less focus on quality, more on compliance

Regulatory burden high and costly, but not viewed as contributing to better science

Consequences of noncompliance: potentially catastrophic

Lack of innovation: “test but don’t tell”

OUTCOMES

• High cost of production for products due to– Low efficiencies in manufacturing – Waste– Long manufacturing cycle times based on testing requirements during

production• Drug shortages due to inability to manufacture• Lack of improvements based on new technologies• Slowed development/access for investigational drugs• Need for intensive regulatory oversight

• More than 40 years ago, Congress required that all drugs must be produced in accordance with Current Good Manufacturing Practice (cGMP).

• Requirement was intended to address significant concerns about substandard drug manufacturing practices by applying quality assurance and quality control principles to drug manufacturing.

• Last comprehensive revisions to the regulations implementing cGMP requirements occurred over 25 years ago.

• The initiative was started in August 2002 as the Pharmaceutical cGMPs for the 21st Century - A Risk-Based Approach initiative to enhance and modernize the regulation of pharmaceutical manufacturing and product quality — to bring a 21st century focus to this critical FDA responsibility. 

FDA NEEDED TO MODERNIZE PHARMACEUTICAL MANUFACTURING REGULATION

THE DESIRED STATE: A MUTUAL GOAL OF INDUSTRY, SOCIETY AND THE REGULATORSA maximally efficient, agile, flexible pharmaceutical

manufacturing sector that reliably produces high quality drug products without extensive regulatory oversight

Qbd on cleaning

GUIDANCE FOR INDUSTRY: QUALITY SYSTEMS APPROACH TO PHARMACEUTICAL CGMP REGULATIONS

Help manufacturers bridge between 1978 regulations and modern quality systems and risk management approaches

Extends beyond CGMP expectations; however, does not create requirements on manufacturers. Implementation of this model should ensure compliance and encourage use of science, risk management and other principles of the 21st Century Initiative.

Describes a comprehensive quality system model and how CGMP regulations link to QS elements

“When fully developed and effectively managed, a quality system will lead to consistent, predictable processes that ensure that

pharmaceuticals are safe, effective, and available for the consumer.”

QUALITY SYSTEMS : IMPLEMENTATION AND INTERNATIONAL DEVELOPMENT AS THE PQS

• Manufacturers with a robust quality system and appropriate process knowledge can implement many types of improvements and take responsibility for quality

–Eliminate most of the burden of CMC post approval regulatory submissions

–Allow for more focused and fewer FDA inspections–Adoption by industry is starting to take hold – fewer

deviations, cost savings in manufacturing• ICH adopted this concept as Q 10

Pharmaceutical Quality System (PQS) to fulfill the ICH Quality Vision

–Covers the product lifecycle from pharmaceutical development, tech transfer, commercial manufacturing, to discontinuation

–Focuses on the commercial manufacturing process, predicted by development and utilizes knowledge for process improvement and future development

INTERNATIONAL HARMONIZATION

In addition to Q10, Quality Systems:

Q8 Pharmaceutical Development

Q9 Quality Risk Management

HEPARIN WAS A WAKEUP CALL

• Up to 30% contamination of finished product

• Present worldwide in various APIs: many countries affected

• Undetected by acceptance and release testing

• Persisted in drug supply until serious adverse events triggered investigation

• Brought home the need for vigilance throughout supply chain and in all global settings

SIGNIFICANT CHALLENGES FOR BOTH MANUFACTURERS AND FDA• Explosion of globalized manufacturing

• Increased complexity of supply chains

• Greater potential for exploitation (e.g., counterfeits, terrorism)

• Global regulatory system still fragmented

• (US) Erosion of inspectional coverage over last several decades

• (US) Lack of modern IT (e.g., registration and listing systems, inspection tracking, imports)

IMPROVEMENTS STARTED IN 21ST CENTURY INITIATIVE ARE CRITICALGlobal harmonization of manufacturing standards

Continuous improvement in manufacturing science

Application of quality risk management

Quality by design

ROLE OF THIS PAT WORKSHOP

Gathering of academics, pharmaceutical industry, FDA, PAT equipment manufacturers

Goal: update on use of the technology, present case studies, understand barriers to more widespread adoption

Understanding of how PAT fits into the future of quality by design

QUALITY BY DESIGN APPROACH CAN BE USED FOR

STEPS IN A QUALITY BY DESIGN APPROACH?

1.QUALITY TARGET

PRODUCT PROFILE

1.QUALITY TARGET

PRODUCT PROFILE

2. CRITICAL QUALITY

ATTRIBUTES

2. CRITICAL QUALITY

ATTRIBUTES

6. PRODUCT LIFECYCLE

MNGMNT

6. PRODUCT LIFECYCLE

MNGMNT

3. LINK MAs AND PPs

TO CQAS

3. LINK MAs AND PPs

TO CQAS

5. ESTABLISHCONTROL STRATEGY

5. ESTABLISHCONTROL STRATEGY

4. ESTABLISHDESIGN SPACE

4. ESTABLISHDESIGN SPACE

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.

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.

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.

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 Output

Quality 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

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

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

4 DESIGN SPACE ………..LATER

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

STEP 5. DEFINE THE CONTROL STRATEGYThe 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

TOOLS FOR RISK MANAGEMENT

Preliminary hazard analysis ( PHA)

Failure mode effect and criticality analysis ( FMECA)

Risk ranking

Risk filtering

BETTER PROCESSES UNDERSTANDING WILL LEAD TO PRODUCTS WITH LESS VARIABILITY

What are the steps in aQuality by Design approach?

1.QUALITY TARGET

PRODUCT PROFILE

1.QUALITY TARGET

PRODUCT PROFILE

2. CRITICAL QUALITY

ATTRIBUTES

2. CRITICAL QUALITY

ATTRIBUTES

6. PRODUCT LIFECYCLE

MNGMNT

6. PRODUCT LIFECYCLE

MNGMNT

3. LINK MAs AND PPs

TO CQAS

3. LINK MAs AND PPs

TO CQAS

5. ESTABLISHCONTROL STRATEGY

5. ESTABLISHCONTROL STRATEGY

4. ESTABLISHDESIGN SPACE

4. ESTABLISHDESIGN SPACE

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.

STEPS IN A QUALITY BY DESIGN APPROACH?

1.QUALITY TARGET

PRODUCT PROFILE

1.QUALITY TARGET

PRODUCT PROFILE

2. CRITICAL QUALITY

ATTRIBUTES

2. CRITICAL QUALITY

ATTRIBUTES

6. PRODUCT LIFECYCLE

MNGMNT

6. PRODUCT LIFECYCLE

MNGMNT

3. LINK MAs AND PPs

TO CQAS

3. LINK MAs AND PPs

TO CQAS

5. ESTABLISHCONTROL STRATEGY

5. ESTABLISHCONTROL STRATEGY

4. ESTABLISHDESIGN SPACE

4. ESTABLISHDESIGN SPACE

Knowledge Space

Design Space

Control Space

CONTROL SPACE

DESIGN OF EXPERIMENTS (DOE)

Structured, organized method for determining the relationship between factors affecting a process and the response of that process

Application of DOEs: Scope out initial formulation or process design Optimize product or process Determine design space, including multivariate

relationships

DOE METHODOLOGY

(1) Choose experimental design (e.g., full factorial, d-optimal)

(2) Conduct randomized experiments

(4) Create multidimensional surface model (for optimization or control)

(3) Analyze data

Experiment

Factor A Factor B Factor C

1 + - -2 - + -3 + + +4 + - +

A

BC

www.minitab.com

A DOE IS USEFUL TO

Identify important factors

Establish process stability

Find best operating conditions

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.

35

5041

47

TempB

TimeA

+--

+

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

1a

Response surface plotResponse surface plot Contour plot Contour plot Contour plot Contour plot

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 variationQbD replaces QbT( Quality by Testing)

Pre-formulation studies

Literature review

formulationQC and Evaluati

on

Out Product

QbD

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

MODEL BUILDING & EVALUATION - EXAMPLES

Models for process development Kinetic models – rates of reaction or degradation Transport models – movement and mixing of mass or

heat

Models for manufacturing development Computational fluid dynamics Scale-up correlations

Models for process monitoring or control Chemometric models Control models

All models require verification through statistical analysis

Chemometrics is the science of relating measurements made on a chemical system or process to the state of the system via application of mathematical or statistical methods (ICS definition)

Aspects of chemometric analysis: Empirical method Relates multivariate data to single or multiple responses Utilizes multiple linear regressions

Applicable to any multivariate data: Spectroscopic data Manufacturing data

Model Building & Evaluation - Chemometrics

QUALITY BY DESIGN & STATISTICS

Statistical analysis has multiple roles in the Quality by Design approach

Statistically designed experiments (DOEs)Model building & evaluationStatistical process controlSampling plans

A SHARED VISION OF QUALITY

GPhA supports the FDA CGMP initiativeGeneric drug manufacturing companies:Exist to make affordable drug therapies available to allCompanies, staff, volumes and revenues are smallerIt is completely appropriate that regulatory

requirements apply to all companies small and large, as long as regulatory guidance provides flexibility in recognition of more limited resources at smaller firms

SUGGESTED ACTIONS

Give credit for good performanceContinue to reduce unnecessary

supplementsContinue to develop the Pharmaceutical

InspectorateReward process innovationEliminate unnecessary testing

requirementsAddress oversight of overseas API mfrs

Solid-State Polymorphism

Different crystalline forms of the same drug substance (ICH Q6A)

•Crystalline forms•Solvates (Hydrates)•Amorphous forms

Pharmaceutical Solid Polymorphism

Drug Product Bioavailability/Bioequivalence

Solubility/Dissolution

Processability /Manufacturability

Mechanical Properties/Hygroscopicity

Stability

Chemical Reactivity

02468

10

0 2 4 6 8 10 12

Time

Co

nc

02468

10

0 2 4 6 8 10 12

Time

Co

nc

Dissolution/Solubility Limited Oral Absorption

(e.g. chloramphenicol palmitate)

0

2

4

6

8

0 2 4 6 8 10 12

Time

Co

nc

0

2

4

6

8

0 2 4 6 8 10 12

Time

Co

nc

Gastric Emptying or Permeation Limited Oral Absorption

(e.g. ranitidine HCl)

Form I

Form II Intestinal Membrane

Solubility: Form II > Form I

Polymorphism and the Effect on Bioavailability

Intestinal Membrane

Polymorphism and the Effect on Stability

Crystalline: Degradation: 0.5% Amorphous: Degradation: 4.5%

Formulation I

Crystalline: Degradation 0.6%Amorphous Degradation 0.7%

Formulation II Optimize the formulation mitigate degradation pathways(e.g., adjust pH microenvironment to limit degradation, anti-oxidant to limit oxidative degradation)

X Crystalline/Amorphous

Polymorphism and the Effect on Manufacturability

E. Joiris , Pharm. Res. 15 (1998) 1122-1130

Paracetamol Form I Paracetamol Form I I

Direct Compression

Paracetamol Form I I Paracetamol Form I

Wet Granulation

Formulation Variables

Selection and Control of Polymorphic Forms?

Biopharmaceutical Properties

Manufacturing Process Variables

Intrinsic Properties of Different Forms

N O 2

N

H

S

C

N

C H 3

“

N O 2

N

H

S

C

N

C H 3

“ ”

Regulatory Considerations:Can One Consider Polymorphs to be the Same Active?

Materials ScienceJ. Am. Chem. Soc. 122 (2000) 585-591

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2

4

6

8

0 2 4 6 8 10 12

Time

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nc

0

2

4

6

8

0 2 4 6 8 10 12

Time

Co

nc

Form I Form II

Drug Product Safety/Effectiveness

QBD PARADIGM: POLYMORPHS

From ICH Q8: “The physicochemical and biological properties of the drug

substance that can influence the performance of the drug product and its

manufacturability, or were specifically designed into the drug substance

(e.g. solid state properties), should be identified and discussed. “

Expectation that sponsors justify in pharmaceutical development the selection and control of the polymorphic form (as applicable) to achieve drug product performance characteristics, stability and ensure manufacturability

FDA REGULATORY SCHEME21 CFR 320.1(c), Food and Drugs, Definitions: Pharmaceutical equivalent means drug

products in identical dosage forms that contain identical amounts of the identical active

drug ingredient, i.e., the same salt or ester of the same therapeutic moiety…; do not

necessarily contain the same inactive ingredients; and meet the identical compendial or

other applicable standard of identity, strength, quality, and purity, including potency.

Phosphate Sulfate

Same Active Moiety

Different Active Ingredients

FDA Regulatory Scheme: Pharmaceutical Alternatives No Possibility for Therapeutic Equivalence for Different Salts

Co-CrystalsA

AA

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C-A+

C- C-C-

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C- C-C-

C- C-C-C-

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A+A+

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Salts Co-crystals

Polymorphs

Crystalline Molecular Complexes: Co- Crystal / Salt Continuum

Crystalline Molecular Complexes: Analogous to Polymorph Solvate

(Except other Component in CrystalLattice is a Solid (not Liquid))

Where Do Co-Crystals Fit in Our Regulatory Scheme?

A

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C- C-C-

C- C-C-C-

A+

A+

A+A+

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A+A+

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Salts

Co-crystals??

Polymorphs

Same APISame Active Moiety Different API

Where Do Co-Crystals Fit?

Is a New RegulatoryClass of Solids Needed?

CASE STUDY –API TORCETRAPIBThe concept and application of quality by design

(QbD) principles has been and will undoubtedly continue to

be an evolving topic in the pharmaceutical industry.

However, there are few and limited examples that demonstrate

the actual practice of incorporating QbD assessments,

especially for active pharmaceutical ingredients (API)

manufacturing processes described in regulatory submissions.

We recognize there are some inherent and fundamental

differences in developing QbD approaches for drug

substance (or API) vs drug product manufacturing processes.

In particular, the development of relevant process understanding

for API manufacturing is somewhat challenging

relative to criteria outlined in ICH Q8 (http://www.ich.org/

cache/compo/276–254–1.html) guidelines, which are primarily

oriented toward application of QbD for drug product

manufacturing. ……………………………………………J Pharm Innov (2007) 2:71–86

In an effort to establish a consensus and develop consistency, industry and regulators have frequently described quality by design (QbD) by dividing it into three fundamental, interrelated concepts: control strategy, design space, and criticality.1 Figure 1 describes a QbD approach for developing design space, establishing control strategy, and delineating criticality for an active pharmaceutical ingredient (API) that essentially serves as a map for how these conceptual elements were used to establish design space for the torcetrapib API manufacturing process. A preliminary assessment of the QbD strategy for the manufacture of the API typically begins early in development when chemists and engineers evaluate synthetic route selection as well as intermediate quality attributes (QAs) impacting API specifications. As a default, established API specification limits serve as a primary control standard for QAs and surrogate control in the absence of a process control strategy and relevant intermediate specifications.

Torcetrapib (CP-529,414, Pfizer) was a drug being developed to treat hypercholesterolemia (elevated cholesterol levels) and preventcardiovascular disease.

The API specification, by default, serves as a predictor of critical QAs (CQAs) because the combination of their measurements may directly correlate to potential impact to the safety and efficacy of the drug product and thus to the

patient. API CQAs may include physical characteristics beyond such things as the impurity specification of the API, e.g., particle size, polymorphic form, and salt selection are Mrelevant for drug product manufacture.3 The analytical

control strategy for an API manufacturing process that evolves during development is routinely focused with the attention on the formation and purge of impurities and their cascade effects on the multiple process steps, including the

potential impact to the API’s CQAs. To establish design space, a formal, prospective risk assessment is executed in accordance with ICH Q9 (B in Fig. 1). A process risk assessment is performed as a precedent to formally develop a design space for the commercial manufacturing process so that potential critical process parameters (CPPs) can be identified. In general, a process risk assessment considers prior knowledge, mechanistic understanding of the chemistry,

and relevant chemical manufacturing experiences.

Starting and Raw Materials

Before parameters and ranges can be evaluated in any multivariate designed experiment, the appropriate quality of SMs (or key intermediates) and raw materials must be established. For the torcetrapib manufacturing process,

some of the specifications of compound 4 were deemed CQAs because of their direct impact on controlling the relative genotoxic impurities in steps 5 and 6. In addition, ECF (raw material) is a commodity chemical used in step 5 that is incorporated into the structure of the API. Fate and purge development work, batch history, and appropriate communications with vendors are a few methods to establish appropriate specifications for SMs and raw

materials. Appropriate specifications were established for each of these materials before any of the multivariate designs were initiated for torcetrapib, and by default, some of these specifications were deemed CQAs. The validity of

a multivariate experimental design used to establish a design space depends on understanding the functional relationship between these CQAs/specifications and the API CQAs.

CONCLUSION ON CASE STUDY

We have provided a case study of a QbD effort, including a risk assessment, for the torcetrapib drug substance process. Fundamentally, different from the drug product, API processes have multiple steps. Understanding the functional

relationship between FAs, QAs, and process parameters as they progress through the manufacturing process is the most universally challenging aspect of QbD for API

development. Analytical specifications and control strategy aspects of the QbD plan remain the foundation for change throughout the evolution of the manufacturing process (from phase I to launch).

The role of the chemist and engineer during the course of development is to effectively eliminate as many of the CQAs and CPPs as possible from the commercial manufacturing process through continuous improvement efforts.

Designed experiments generate the data required to establish a design space for commercial manufacturing processes, while providing the process understanding that facilitates sound business decisions. First principles ofchemistry can expand this “toolbox” to include kinetic models, computer predictive programs, and more diverse concepts of prior knowledge.

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.

SUMMARY

The public expects their drugs to be of reliable high quality

Tradition of empirical development of formulation and manufacturing process makes reliability a challenge

Globalization introduces more risks of quality problems

FDA introduced “Pharmaceutical Quality for 21st Century” to address these challenges

SUMMARY

Improved manufacturing science (QbD), when paired with a robust quality system, is the key to reliable drug quality

Technologies such as PAT are crucial to implementing the knowledge gained from QbD in a meaningful and efficient way

FDA encourages adoption of these technologies, and is modifying its own processes in order to facilitate this change

CONCLUSION

Quality by Design and the FDA CGMP Initiative make excellent business and scientific sense

The generic pharmaceutical industry welcomes the opportunity to work with FDA

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THANKYOUDR ANTHONY CRASTOamcrasto@gmail.comhttp://newdrugapprovals.org/