The New Quality Paradigm Introduction

Drug Regulations 1

Q8 Q9Q10

Q 11

“Risk-based”concepts and

principles

Drug Regulations 2

Pharmaceutical Development (Q8)Pharmaceutical Development (Q8)

Past: Data transfer / Variable output

Present: Knowledge transfer / Science based / Consistent output

Pharmaceutical Quality Systems (Q10)Pharmaceutical Quality Systems (Q10)

Past: GMP checklist

Future: Quality Systems across product life cycle

Quality Risk Management (Q9)Quality Risk Management (Q9)

Past: Used, however poorly defined

Present: Opportunity to use structuredprocess thinking

ChangedParadigm

Q8

Q9 Q

10

Drug Regulations 3

Science is no longer isolated; it is

living across the lifecycle of the

product/process within a Quality

Management System

Drug Regulations 4

The new paradigm emphasize:

1. Quality must be mainly built in and it will not improve by additional testing and inspection

2. Better utilization of modern science throughout product lifecycle

3. QRM is a key enabler throughout product lifecycle

4. Robust PQS, with appropriate knowledge management, assures quality throughout product life cycle

5. An integrated approach to development, manufacturing and quality for both industry and regulators

Drug Regulations 5

A more systematic approach to development can include, for example, incorporation of◦ Prior knowledge, ◦ Results of studies using design of experiments, ◦ Use of quality risk management, and ◦ Use of knowledge management (see ICH Q10) throughout the

lifecycle of the product. Such a systematic approach can enhance achieving the

desired quality of the product and help the regulators to better understand a company’s

strategy. Product and process understanding can be updated with

the knowledge gained over the product lifecycle.

Drug Regulations 6

What are the elements of QbD?

Define desired product

performance upfront;

identify product CQAs

Design formulation and process to meet

product CQAs

Understand impact of material

attributes and process parameters

on product CQAs

Identify and control sources of

variability in material and

process

Continually monitor and

update process to assure consistent

quality Risk assessment and risk control

Product & process design and development

Qualityby

Design

Drug Regulations 7

Quality◦ The suitability of either a drug substance or a

drug product for its intended use. This term includes such attributes as the identity, strength, and purity (ICH Q6A)

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

Drug Regulations 8

In all cases sufficient development has to be done, so that a product can be released to the market◦ Defining Quality Target Product Profile◦ Identifying critical quality attributes of the drug

product◦ Determining quality attributes of the starting

materials (drug substance, excipients)◦ Selecting an appropriate manufacturing process◦ Defining a control strategy

Drug Regulations 9

Systematic approach to development Begins with predefined objectives Emphasizes product and process

understanding and process control Based on sound science and quality risk

management

from ICH Q8(R2)

Drug Regulations 10

A systematic evaluation understanding and refining formulation and manufacturing process◦ Identifying the material attributes and process

parameters that can have an effect on product CQAs

◦ Determining the functional relationships that can link material attributes and process parameters to product CQAs

◦ Establishing an appropriate control strategy◦ Continual improvement and life cycle

management

Drug Regulations 11

• Quality Target product profile

• Determine critical quality attributes (CQAs)

• Risk assessment: Link raw material attributes and process parameters to CQAs

• Develop a design space.(Optional not required)

• Design and implement a control strategy

• Manage product lifecycle, including continual improvement

Product profile

CQAs

Risk assessme

nt

Design space

Control strategy

ContinualImprovemen

t

Essential Elements in a QbD Approach (Q8R2)

Drug Regulations 12

Annex II: Potential Applications

prepared by some members of the ICH Q9 EWG for example only; not an official policy/guidance

July 2006, slide 13

ICH Q9 QUALITY RISK MANAGEMENTTarget Product Profile

Drug substance properties; prior knowledge

Proposed formulation and manufacturing process

Determination of Cause – Effect relationships

(Risk Identification with subsequent Risk Analysis)

Risk-based classification (Risk Evaluation)

Parameters to investigate (e.g. by DOE)(Risk Reduction 1. proposal; 2. verified)

FORMULATION FORMULATION DESIGN SPACEDESIGN SPACE

PROCESS PROCESS DESIGN SPACE DESIGN SPACE

BY UNIT OPERATIONBY UNIT OPERATIONCONTROL CONTROL STRATEGYSTRATEGY

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Product and process characteristics on the

final drug product

Review events

Development

Develo

pm

.O

peratio

n

Research

Phase 1

Phase 2

Phase 3

Launch

EXAMPLE

EFPIA PAT TG, 2006

ProcessDevelopment

Control StrategyDevelopment

Continual Improvement of the product

Drug Regulations 14

Describes systematic processes for the assessment, control, communication and review of quality risks

Applies over product lifecycle: development, manufacturing and distribution

Includes principles, methodologies and examples of tools for quality risk management

Assessment of risk to quality should:◦ Be based on scientific knowledge◦ Link to the protection of the patient ◦ Extend over the lifecycle of the product

Drug Regulations 15

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

Regulatory flexibility◦ Working within the design space is not

considered a change Important to note

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

Drug Regulations 16

Consider QTPP in establishing the Design Space Initial determination of CQAs Assess prior knowledge to understand variables and

their impact◦ Scientific principles & historical experience

Perform initial risk assessment of manufacturing process relative to CQAs to identify the high risk manufacturing steps (->CPPs)

Conduct Design of Experiments (DoE) Evaluate experimental data Conduct additional experiments/analyses as needed

Drug Regulations 17

First-principles approach◦ Combination of experimental data and mechanistic

knowledge of chemistry, physics, and engineering to model and predict performance

Non-mechanistic/empirical approach ◦ statistically designed experiments (DOEs)◦ linear and multiple-linear regression

Scale-up correlations◦ translate operating conditions between different scales or

pieces of equipment Risk Analysis

◦ determine significance of effects Any combination of the above

Drug Regulations 18

40

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Surface Plot Contour Plot

Design Space(non-linear)

Design Space(linear ranges)

• Design space proposed by the applicant• Design space can be described as a mathematical function

or simple parameter range

• Operation within design space will result in a product meeting the defined quality attributes

Drug Regulations 19

A planned set of controls,◦ derived from current product and process

understanding, ◦ that assures

process performance and product quality. The controls can include

◦ parameters and attributes related to drug substance, drug product materials , components, facility , equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and

control (ICH 10).

Drug Regulations 20

Design Space and Quality Control Strategy

Process (or Process Step)

Design Space

Monitoring ofParameters

or Attributes

Process Controls/PAT

InputProcess

Parameters

Input Materials

Product (or Intermediate)

ProductVariability

ReducedProductVariability

ProcessVariability

Drug Regulations 21

ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

slide 22

Breakout C: Pharmaceutical Quality System

Inputs

• Manufacturing Experience

• Deviations / CAPA

• Performance Monitoring

• Customer Complaints

• Management Reviews

• Material Variance

Product Lifecycle Adjustment

• Readily achieved as part of routine feedback

• Require permanent & substantial process/facility design to improve original concept

Continual

Improvement

Expanded

Body of Knowledge

Feed Forward

Feedback

Product Lifecycle Management

Continual Improvement of the Product

Drug Regulations

Aspect Minimal Approaches

Enhanced, Quality by Design Approaches

OverallPharmaceuticalDevelopment

• Mainly empirical• Developmental

research often conducted one variable at a Time

• Systematic, relating mechanistic understanding of material attributes and process parameters to drug product CQAs

• Multivariate experiments to understand product and process

• Establishment of design space

• PAT tools utilised

Drug Regulations 23

Process flow:

Screening

Optimization

Validation

Identification of significant parametersFinding parameter ranges

Finding interactions of parametersDefining models

Production

Identification of CPP

Continuous monitoring and development

Characterization range

Acceptable range

Operating range

Process design space

Set point

Identification of noise factorsProcess/ product Development:

RobustCost effectiveFeasible

Defining control strategies

Drug Regulations 24

Aspect Minimal Approaches Enhanced, Quality by Design Approaches

ManufacturingProcess

• Fixed• Validation primarily

based on initial full-scale batches

• Focus on optimisation and reproducibility

• Adjustable within design space

• Lifecycle approach to validation and, ideally,

• continuous process verification

• Focus on control strategy and robustness

• Use of statistical process control methods

Drug Regulations 25

Aspect Minimal Approaches Enhanced, Quality by Design Approaches

ProcessControls

• In-process tests primarily for

• go/no go decisions• Off-line analysis

• PAT tools utilised with appropriate feed

• forward and feedback controls

• Process operations tracked and trended to

• Support continual improvement efforts postapproval

ProductSpecifications

• Primary means of control

• Based on batch data available at time of registration

• Part of the overall quality control strategy

• Based on desired product performance with relevant supportive data

Drug Regulations 26

Aspect Minimal Approaches Enhanced, Quality by Design Approaches

Control Strategy

• Drug product quality controlled primarily by intermediates (in process materials) and end product testing

• Drug product quality ensured by risk-based control strategy for well understood product and process

• Quality controls shifted upstream, with the possibility of real-time release testing or reduced end-product testing

LifecycleManagement

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

• Preventive action• Continual improvement

facilitated

Drug Regulations 27

Traditional development

approaches, as outlined in ICH Q8(R2) part I,

are acceptable.

Drug Regulations 28

Why QbD?• Higher level of assurance of product quality for

patiento Improved product and process design and

understandingo Quality risk management in manufacturing

o Monitoring, tracking and trending of product and processo Continual improvement

• Cost saving and efficiency for industryo Increase efficiency of manufacturing processo Minimize/eliminate potential compliance actionso Provide opportunities for continual improvemento Facilitate innovation

• More efficient regulatory oversighto Streamline post approval manufacturing changes and

regulatory processesDrug Regulations 29

Why QbD?

• Depending on the level of development (scientific understanding) achieved and an adapted quality system in place, opportunities exist to develop more flexible regulatory approaches, for example, to facilitate:• Risk-based regulatory decisions (reviews and

inspections);• Manufacturing process improvements, within the

approved design space described in the dossier, without further regulatory review;

• Reduction of post-approval submissions;• Real-time release testing, leading to a reduction of end

product release testing.

Drug Regulations 30

Culture challenges ◦ Move from prescriptive approach◦ More sharing of scientific and risk

information Business Challenges

◦ Business justification◦ Management Support◦ Budgeting silos across business units

Implementation Challenges◦ Collaboration between functions ◦ Experience with new concepts◦ Workload and resource limitations

Drug Regulations 31

The development approach should be adapted based on the complexity and specificity of product and process.

FDA encourages applicants are encouraged to contact regulatory authorities regarding questions related to specific information to be included in their application.

Using the Quality by Design (QbD) approach does not change regional regulatory requirements but can provide opportunities for more flexible approaches to meet them. In all cases, good manufacturing practice (GMP) compliance is expected.

Drug Regulations 32

Quality Target Product Profile (QTPP)

Determine “potential” critical quality attributes (CQAs)

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

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle, including continual improvement

CQA’s

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual Improvement

Drug Regulations 33