Dr KyQUALITY by DESIGN:From Theory to Practice

8/11/2019 Dr KyQUALITY by DESIGN:From Theory to Practice

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Keep On Rising

QUALITY by DESIGN:

From Theory to Practice

Soula Kyriacos, PhDResearch & Development Manager

PHARMALINE

HEALTH INSIGHT, June 2011


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What is Quality by Design (QbD)?

A systematic approach to development that begins withpredefined objectives and emphasizes product andprocess understanding and process control, based on

sound science and quality risk management (ICH Q8(R))

QbD means designing and developing formulations andmanufacturing processes to ensure predefined product quality.

Understanding and controlling formulation and manufacturing processvariables affecting the quality of a drug product.

Dependence of consistent quality product on risk assessment, basedon process understanding.

Best solution but also major challenge to the Pharmaceuticalindustry whose processes are fixed in time, despite inherent processand material variability.


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Moheb Nasr


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Moheb Nasr

QbD GOAL: develop a process that can accommodate the range of

acceptable variability for maintaining product quality . MANUFACTURING FLEXIBILITY


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QbD is Product and Process

Product Knowledge mechanistic understanding of howvariability impacts product

Material variability -PSD, surface area, moisture content, etc. Process variability -granulation, tableting conditions, etc.

Product Specification to provide continued assurance of clinical performance

Product Performance

ensuring product quality as dissolution links/relates productattributes to clinical performance

Moheb Nasr


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Benefit for pharmaceutical industry

Improved efficiency and flexibility whilstmaintaining high quality standards.

Rapid introduction of state-of-the art science and technology

Encouraged continuous manufacturing process improvements

Real-time quality controlreduced end-product release

testing Fewer lost batches

Fewer manufacturing deviations, saving costly investigative

hours Reduced out-of-specification results, reducing rework

From a Reactive to a Proactive Decision System forPharmaceutical Quality


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Components of a QbD Program

Statistical Analysis/ Modeling

e.g. Statistically designed experiments (DOEs)

Efficient method for determining impact of multiple parameters andtheir interactions.

Design Space

The multidimensional combination and interaction of inputvariables (e.g., material attributes) and process parametersthat have been demonstrated to provide assurance of quality.

Translation what combination(s) of input settings will meet thespecifications for the output(s)?

Working within the design space is not considered as a

change. REGULATORY FLEXIBIBLITY


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Process Analytical Technology (FDA PAT Guidance,2004)

A system for designing, analyzing, and controllingmanufacturing through

TIMELY measurements (i.e., during processing) ofCRITICAL quality and performance ATTRIBUTESof raw and in-process materials and processeswith the goal of ensuring final product quality.

= Continuous Quality Assurance paradigm that canimprove our ability to ensure quality was built-in or wasby design - ultimate realization of the true spirit of

cGMP!


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WHY PAT? Greater insight and understanding of processes

At/On/In-line measurement of performance attributes

Real-time or rapid feedback controls Potential for significant reduction in production and development

cycle time

Minimize risks of poor process quality and reduce (regulatory)

concerns

PAT Tools

Near Infra Red technology for RM identification, moisture

measurement, blend uniformity, CU of tablets. Torque sensor for endpoint granulation

Focused Beam Reflectance Measurement (FBRM) for PSmeasurements

Imaging systems for process controls and process monitoring invarious applications.


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Example QbD Approach - Q8(R1)

Target the quality product profile (QTPP)

Determine critical quality attributes (CQAs)

Link raw material attributes and process parameters to CQAsand perform risk assessment

application of common risk management tools (e.g. Failure Mode

and Effects Analysis (FMEA) ) Develop a design space = understand the relative impact of

input variables (process steps, process parameters, and rawmaterials) on CQAs.

Design and implement a control strategy

Manage product lifecycle, including continual improvement


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QbD - Risk Based Development Use sound scientific principles

in the design of the product andProcess

Identify the critical attributes(CAs) for the raw materials

Identify the process criticalcontrol points for the processes

(PCCPs)

Employ the proper analyses andPAT concepts for processunderstanding and control

Tie it all together with theappropriate informatics to feed theinformation forward andbackwards for QbD and

continuous improvement andinnovation = reduced risk

Were the principles appropriatelyapplied?

How were the CAs identified and

the formula designed?

Ditto for the PCCPs

What were the bases for analyses

selection?

What are the supporting data forall of the above?

Product Development History

Ken Morris


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QbD - Risk Based Development

(1) Choose experimentaldesign(i.e., full factorial)

Experiment FactorA

FactorB

Factor C

1 + - -

2 - + -

3 + + +

(3) Analyze data (4) Create multidimensionalsurface model (for optimization orcontrol)

(2) Conduct randomized experiment


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How do you know when you have

understood the process?

All critical sources of variability are identified andexplained

Can you explain the variability from batch to batch? Product quality attributes can be accurately and reliably

predicted

Can you predict a good run from a bad run? The ability to predict reflects a high degree of

process understanding.

Variability is managed by the process

Process Understanding inversely proportional to riskFDA PAT GUIDANCE


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Generics QbD Principles

Target product qualityprofile

well defined such asdissolution, purity,

uniformity, and stability

Extensive formulation

and manufacturingexperience for many

generic manufacturers

Biopharmaceutical propertiesof drugs already knownsuch as polymorphism,

absorption, and pharmacokineticsinformation

OBJECTIVE:

understand attributes of theformulation and

manufacturing process thathave the potential to changethe bioavailability of aparticular active ingredient.


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Generics QbD Principles

API Polymorphism

Particle size Stability

Excipients Polymers to control

release (properselection)

Compatibility to API Flow Compression

characteristics

Process Compression ranges

Physicalcharacteristics Blend uniformity

Finished product Formulation

Optimization

Stability Drug Release Packaging


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Quality by Design for ANDAs: An

Example for Immediate-Release DosageForms

Pharmaceutical Development Report

Example QbD for IR Generic Drugs

Draft Apri l 26, 2011

How to move toward implementation of quality by design


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QbD for ANDAs: An Example for IR DF

Product development outline: Analysis of the reference listed drug (RLD) product

Defining Quality Target Product Profile (QTPP)

Identification of Critical Quality Attributes (CQAs) for the drug product

(DP) Identification and prioritization of potential risks for each unit operation

(Risk assessment)

Screening and optimization of formulation (DOE for high risk

components) including a development PK study Development of a robust process (DOE for high risk parameters)

Blending / Roller compaction / Lubrication/ Compression

Scale up and manufacture of the exhibit batch

Establishment of control strategies Input material

Unit operations - process controls and monitoring, design spacesaround individual or multiple unit operations

Blending/ Roller compaction and milling/ Lubrication/ Tablet compression Finished product specifications


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QbD for ANDAs: An Example for IR DF

Blending

Attribute or Parameter Range Type of Control

Mixing Speed 8 rpm Operating range

Number of Revolutions 128-256 PAR

Online NIR monitoring

Blend Uniformity NMT 6.5% In-process control

A near IR online tool for monitoring the blend uniformity was developed andis used to terminate the blending when sufficient uniformity is reached

CONTROL STRATEGYA risk matrix table for the blending operation demonstrates that the identified risk t

the quality Attributes = control of API, lactose and MCC particle size and monitoriof blend uniformity.


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WHERE DOES INDUSTRY STAND?

Level of maturity and drug type of examined companiesFullyGroup Novice Pilot Rollout implemented Total

New Rx 22% 33% 22% 22% 100

Gx 40% 20% 40% --- 100

Biologics17% 67% 17% --- 100

Novice: Company is skeptical about the value QbD can bring. Utilizes conventionaldevelopment.Pilot: Company is trying QbD, but still on the fence about the potential value. Tends toapply QbD to a small subset of projects and processes and has implemented limited.Rollout: Company is convinced about impact of QbD and is beginning to see some ofthe benefits. Uses QbD techniques regularly, but not universally. May engage in somelifecycle management with integrated platform and network strategy.Fully implemented: Company is completely convinced about the positive impact ofQbD and is realizing the benefits. Uses QbD in almost every development program andalmost every production step. Additionally, has a systematic, comprehensive review andre-design of in-line products.

FDA, December 2009

lack of beliefin the

business case

lack oftechnology to

execute


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Obstacles to Implementing QbD

Internal misalignment within a company around if and how toimplement is a key adoption challenge and can take several forms.

1. Misalignment horizontally across the organization. (i.e.,Disconnect between cross functional areas, e.g., R&D andmanufacturing or quality and regulatory)Potential for confusion: How could R&D define attributes outside of itsdomain and area of practice, that were critical to quality?

2. Disconnect between leadership and middle management.

Clearly state the specific benefits the organization wants to getfrom QbD and how those benefits will be realized.

3. Culture of conservatism.4.Amount of change required within company is not feasible.

Many companies will have to redesign certain aspects of theiroperating model.

5. For some, QbD remains low on the priority list.


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Obstacles to Implementing QbD

Lack of belief in the business case. $$$ for more extensive characterization and development Financial payback is over the lifetime of the product, but requires

investment early in development

Moheb Nasr


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CONCLUSION Application of QbD principles facilitate development of quality products

and their assessment throughout their lifecycle, and ultimately, resultin greater patient benefit.

QbD readiness assessment

Clearly define the strategic objective

Assessment of organization and culture

QbD is relatively new: will require original thinking,

organizational re-training/hiring and learning Process goals must be communicated across all business unitsRight-first-time culture, where quality means continuouslycreating more value

Operational assessment

Process development : Individual unit operations/entiremanufacturing process.

Challenges to Regulatory agencies


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"The World According to Peter Drucker :

In my view, he said, the future has already

happened. The task we must take up is to look at allthat has already happened, but has yet to have an

impact.

THANK YOU.

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Dr KyQUALITY by DESIGN:From Theory to Practice