A powerful Approach Quality-by-Design

Presented by: Chattar singh yadav

Outline Quality By Design

Background of Quality By Design DefinitionFDA’s Initiative on Quality by DesignWhy QbD?Recent ICH Quality GuidanceCurrent vs. QbD Approach to Pharmaceutical DevelopmentExample of QbD Approach (Q8R1)

Tools of Quality by Design Across the Product Lifespan Design Space (ICH Q8)Design Space Determination Conceptual framework for product manufacture

Design of Experiments (DOE)DOE Methodology, A Practical Example (Product: Aspasome)

Quality Risk Management Process (Q9)Role of Quality Risk Management in Development &

ManufacturingExample Control Strategy for Real Time Release Testing

Process Analytical Technology (PAT)A desired goal of the PAT frameworkApplication of PAT in Pharma Industry

Concluding remarks References

Background of Quality By Design • Outside of FDA regulated industries, quality by design is not new.

• FMEA (US Military development; combined software available)

• DOE (1920s: factorial designs in agriculture)

• In 1970s, Toyota pioneered used many quality by design concept to improve their early automobiles.

• Since that time many industries - technology, telecommunications and aeronautics are use quality by design.

• In the 1990s, Medical devices began to appear that incorporate many of quality by design concepts.

Background of Quality By Design (Cont…..)

• In mid-2002, the U.S FDA published a concept paper on current GMP practices for 21th century.

• This documents express a desire that companies build quality, safety and efficacy into their new products as early as possible.

• This concept become know as Quality by design.

• By 2004, the FDA coalesced its thinking on quality by design and its and its role in product quality and patient safety

• Shortly afterwards FDA issued the guidance document “PAT – a framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance (Pat doc. discusses many principles of QbD); finalized in 2004

• PAT plays a pivotal role in the QbD process

Message: systemic product

and process development

replaces current trial &

error approach

Definition • Quality is dynamic: continuous improvement• Quality by Design:

“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 QbD frame contains concepts and tools - e.g. design space - to practice QbD in a submission file (design space approval)

• Science and risk-based, holistic and proactive approach to product realization that focuses on patient needs

• Deliberate design effort from product conception through commercialization

• Full understanding of how product attributes and process relate to product quality

• a systemic (multivariate statistics) development and manufacturing by use of prior knowledge.

FDA’s Initiative on Quality by Design

• In a Quality-by-Design system:

The product is designed to meet patient requirement

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

Why QbD?• Systematic approach to development

• Begins with predefined objectives

• Emphasizes product and process understanding and process control

• Based on sound science and quality risk management

• Higher level of assurance of product quality for patient• Cost saving and efficiency for industry

o Increase efficiency of manufacturing processo Minimize/eliminate potential compliance actionso Provide opportunities for continual improvement

• More efficient regulatory oversight From ICH Q8(R1)

FDA reviews QbD submission 63% faster.

Recent ICH Quality Guidance• ICH Q8 – Pharmaceutical Development

– Describes good practices for pharmaceutical product development– Introduces concepts of design space and flexible regulatory approaches

• ICH Q8(R1) – Includes concepts of Quality by Design and

examples of design space• ICH Q9 – Quality Risk Management

– Describes a systematic process for the assessment, control, communication and review of quality risks

– Applies over product lifecycle, Includes principles and examples of tools for quality risk management

• ICH Q10 – Pharmaceutical Quality Systems– Describes systems that facilitate establishment and maintenance of a

state of control for process performance and product quality– Facilitates continual improvement

Current vs. QbD Approach to Pharmaceutical Development

Current Approach• Quality assured by testing and

inspection

• Data intensive submission – disjointed information without “big picture”

• 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

Example of QbD Approach (Q8R1)

Product profile

CQAs

Risk assessment

Design space

Control strategy

ContinualImprovement

Tools of Quality by Design Across the Product Lifespan

Manufacturing

Design space PAT

“Real-time” Quality control

Quality Risk Management

Process

Quality by Design Tools

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

Design Space Determination

First-principles approach• combination of experimental data and mechanistic knowledge of

chemistry, physics, and engineering to model and predict performance

Statistically designed experiments (DOEs) • efficient method for determining impact of multiple parameters and their

interactions

Scale-up correlation• a semi-empirical approach to translate operating conditions between

different scales or pieces of equipment

Conceptual framework for product manufacture

Knowledge Space

Design Space

Control Space

Regulatory Agreement

Specifications for quality attributes (QAs)

Process description including process parameters with proven acceptable ranges (PARs)

“Target” or Normal operating ranges (NORs)*

CQA = critical quality attributePP = process parameter

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 MethodologyA Practical Example (Product: Aspasome)

Fig. 3D-Surface Plot for (A) Partical Size (B)Entrapment Efficiency

Amount of ascorbyl palmitate and cholesterol were selected as two independent variables. Vesicle sizes, entrapment efficiency (EE) were selected as dependent variables.

Quality Risk Management• Risk • Risk is defined as the combination of the probability of occurrence of harm

and the severity of that harm.

• Risk Assessment • A systematic process of organizing information to support a risk decision

to be made within a risk management process. It consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards

Quality Risk Management Process (Q9)

ProcessDevelopment

Control StrategyDevelopment

Continual Improvement

Role of Quality Risk Management inDevelopment & Manufacturing

Manufacturing

Process Scale-up & Tech Transfer

Quality Risk Management

Process Development

Product Development

Product qualitycontrol strategy

RiskControl

RiskAssessment

Process design space

ProcessUnderstanding

Excipient & drug substance

design space

Product/prior Knowledge

RiskAssessment

Continualimprovement

ProcessHistory

RiskReview

Example Control Strategy forReal Time Release Testing

Tablet Compression

Pan CoatingSifting Roller

compactionBlending

Raw materials & API dispensing• Specifications based on product

NIR MonitoringBlend Uniformity

Laser DiffractionParticle Size

Dispensing

NIR Spectroscopy(At-Line) • Identity• Assay • API to Excipient ratio

Process Analytical Technology (PAT)

• Process Analytical Technology(PAT) “A system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in process materials and processes with the goal of ensuring final product quality”.

• The term analytical in PAT is viewed broadly to include chemical, physical, microbiological, mathematical, and risk analysis conducted in an integrated manner.

• ICH Q8(R) identifies one use of PAT as ensuring that the process remains within an established design space.

• PAT tools provide continuous monitoring of CPP to demonstrate that a process is maintained in the design space.

• In process testing of CMA can also be conducted online or inline with PAT tools.

A desired goal of the PAT framework

• Gains in quality, safety and/or efficiency will vary depending on the product and are likely to come from:

• Non-intrusive and non-destructive sampling of RM.

• Reducing production cycle times by using on-, in-, and/or at-line measurements and controls.

• Preventing rejects, scrap, and re-processing.

• Considering the possibility of real time release.

• Increasing automation to improve operator safety and reduce human error.

Application of PAT in Pharma Industry

• Granulation, by image processing• FBD granulation, by NIR• Determination of tablet hardness, by NIR• Determination of formaldehyde induced cross-linking in hard gelatin caps,

by NIR• Determination of CU, Assay, ID by NIR• Rapid Microbiological Testing by NIR• In line moisture measurement, by NIR• Determination of residual moisture in lyophilized protein pharmaceuticals,

by NIR• Determination of polymorph composition in physical mixtures, by NIR

Concluding Remarks• Successful implementation of QbD will require multi-disciplinary and multi-functional

teams– Development, manufacturing, quality personnel– Engineers, analysts, chemists, industrial pharmacists & statisticians working together

• FDA looks forward to working with industry to facilitate the implementation of QbD• Improve success in product approval• More robust, efficient commercial operations • Decreased production failures • Decreased regulatory burden • Improve relation with regulatory bodies

• Increased price control

• Absence of design freeze (no variation issues)

• Less validation burden• Continuous improvement over the total product life cycle (i.e. controlled, patient guided

variability

References • ICH Q8: Pharmaceutical development

• ICH Q9: Quality risk management

• FDA Guideline: Pharmaceutical cGMPs FOR 21st century- a risk based approach

• FDA Guideline: PAT, A framework for innovative pharmaceutical development, manufacturing and quality assurance.

• www.fda.gov, Richard (Rik) Lostritto, Ph.D. Director, DPAMS, Office of New Drug Quality Assessment, CDER/FDA

• Food and Drug Administration CDER. Draft Guidance for Industry and Review Staff: Target Product Profile- A Strategic Development Tool (March 2007).

??!! Thank you