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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
Fo
rmu
lation
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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
50
600
1
250.055.060.065.070.075.0
80.085.0
90.0
95.0
100.0
Dis
solu
tion
(%)
40 42 44 46 48 50 52 54 56 58 600
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
Dissolution (%)
Parameter 1
Param
eter 2
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
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