The New Quality Paradigm Introduction

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Risk-based concepts and principles

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Pharmaceutical Development (Q8)

Changed Paradigm

Past:

Data transfer / Variable output

Present: Knowledge transfer / Science based / Consistent output

Quality Risk Management (Q9)

Past: Used, however poorly defined Present: Opportunity to use structured process thinking

Pharmaceutical Quality Systems (Q10)

Past: GMP checklist Future: Quality Systems across product life cycle
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Q9

Science is no longer isolated; it is living

across the lifecycle of the product/process

within a Quality Management System

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The new paradigm emphasize:

1.

Quality must be mainly built in and it will not improve by additional testing and inspection Better utilization of modern science throughout product lifecycle QRM is a key enabler throughout product lifecycle Robust PQS, with appropriate knowledge management, assures quality throughout product life cycle An integrated approach to development, manufacturing and quality for both industry and regulators

2.

3. 4.

5.

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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 companys strategy. Product and process understanding can be updated with the knowledge gained over the product lifecycle.

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What are the elements of QbD?

Product & process design and development
Quality by Design

Define desired product performance upfront; identify product CQAs

Design formulation and process to meet product CQAs

Continually monitor and update process to assure consistent quality

Identify and control sources of variability in material and process

Understand impact of material attributes and process parameters on product CQAs

Risk assessment and risk control

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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

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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

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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)

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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

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Essential Elements in a QbD Approach (Q8R2)

Product profile CQAs

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
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Risk assessment

Design space Control strategy Continual Improvement

Annex II: Potential Applications

ICH Q9 QUALITY RISK MANAGEMENT

Development

Target Product Profile

EXAMPLE

Determination of Cause Effect relationships

(Risk Identification with subsequent Risk Analysis)

Phase 1

Risk-based classification
(Risk Evaluation)

Parameters to investigate (e.g. by DOE)

(Risk Reduction 1. proposal; 2. verified)

FORMULATION DESIGN SPACE Phase 2

Product and process characteristics on the final drug product

PROCESS DESIGN SPACE BY UNIT OPERATION

Review events

CONTROL STRATEGY

Phase 3
EFPIA PAT TG, 2006
July 2006, slide 13

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

Launch

Process understanding Re-evaluation and confirmation

Developm.

Drug substance properties; prior knowledge Proposed formulation and manufacturing process Research

Formulation understanding Operation Re-evaluation and confirmation

Process Development

Control Strategy Development

Continual Improvement of the product

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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

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Definition

Regulatory flexibility
Important to note

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 a change

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

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Consider QTPP in establishing the Design Space Initial determination of CQAs Assess prior knowledge to understand variables and their impact 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
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Scientific principles & historical experience

First-principles approach

Non-mechanistic/empirical approach Scale-up correlations Risk Analysis

statistically designed experiments (DOEs) linear and multiple-linear regression

Combination of experimental data and mechanistic knowledge of chemistry, physics, and engineering to model and predict performance

translate operating conditions between different scales or pieces of equipment

Any combination of the above

determine significance of effects

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100.0 95.0 90.0 85.0 80.0 75.0 70.0 65.0 60.0 55.0 50.0 40

Dissolution (%)

Surface Plot

Contour Plot

1.8 1.6 1.4

Parameter 2

Dissolution (%) 90.0-95.0 85.0-90.0 80.0-85.0 75.0-80.0 70.0-75.0 65.0-70.0 60.0-65.0

1.2 1 0.8

2 50 ram ete r1

Design Space
(non-linear) Design Space
40 42 44 46 (linear ranges) 48 50 52 54 Parameter 1 56

0.6 0.4 0.2 0 58 60

Pa

60 0

er et am ar

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
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A planned set of controls,

The controls can include

derived from current product and process understanding, that assures process performance and product quality. 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).
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Design Space and Quality Control Strategy

Design Space
Input Materials
(or Process Step) Reduced Product Variability

Process

Product (or Intermediate)

Process Variability

Input Process Parameters

Monitoring of Parameters or Attributes

Process Drug Regulations Controls/PAT

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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

Breakout C: Pharmaceutical Quality System

Continual Improvement of the Product

Inputs Manufacturing Experience Deviations / CAPA Performance Monitoring Customer Complaints Management Reviews Material Variance
Product Lifecycle Adjustment

Readily achieved as
Continual Improvement

part of routine feedback Require permanent & substantial process/facility design to improve original concept

Expanded Body of Knowledge

Feed Forward

Product Lifecycle Management

Feedback
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Aspect Overall Pharmaceutical Development

Minimal Approaches Mainly empirical Developmental research often conducted one variable at a Time

Enhanced, Quality by Design Approaches 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

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Process flow:
Characterization range
Acceptable range
Operating range

Screening

Identification of significant parameters Finding parameter ranges

Optimization Finding interactions of parameters Defining models Validation Identification of CPP Identification of noise factors Process/ product Development:
Robust Cost effective Feasible

Set point

Process design space

Defining control strategies

Production

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Continuous monitoring and development

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Aspect Manufacturing Process

Minimal Approaches Fixed Validation primarily based on initial fullscale batches Focus on optimisation and reproducibility

Enhanced, Quality by Design Approaches 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

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Aspect Process Controls

Minimal Approaches In-process tests primarily for go/no go decisions Off-line analysis

Enhanced, Quality by Design Approaches PAT tools utilised with appropriate feed forward and feedback controls Process operations tracked and trended to Support continual improvement efforts postapproval Part of the overall quality control strategy Based on desired product performance with relevant supportive data
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Product Specifications

Primary means of control Based on batch data available at time of registration

Aspect Control Strategy

Minimal Approaches

Enhanced, Quality by Design Approaches

Drug product quality Drug product quality controlled primarily ensured by risk-based by intermediates (in control strategy for well process materials) understood product and and end product process testing Quality controls shifted upstream, with the possibility of real-time release testing or reduced end-product testing Reactive (i.e., problem solving and corrective action) Preventive action Continual improvement facilitated

Lifecycle Management

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Traditional development approaches, as outlined in ICH Q8(R2) part I, are acceptable.

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Why QbD?
Higher level of assurance of product quality for patient
o Improved product and process design and understanding
o Quality risk management in manufacturing

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

Cost saving and efficiency for industry

o o o o Increase efficiency of manufacturing process Minimize/eliminate potential compliance actions Provide opportunities for continual improvement Facilitate innovation

More efficient regulatory oversight

o Streamline post approval manufacturing changes and regulatory processes
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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.

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Culture challenges

Business Challenges

Move from prescriptive approach More sharing of scientific and risk information Business justification Management Support Budgeting silos across business units Collaboration between functions Experience with new concepts Workload and resource limitations

Implementation Challenges

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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.

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Product Profile

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
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CQAs

Risk Assessments

Design Space

Control Strategy Continual Improvement