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The New Quality Paradigm
Introduction
1
Presentation prepared by Drug Regulations – a not for
profit organization. Visit www.drugregulations.org for
the latest in Pharmaceuticals.
23-09-2015
 This presentation is compiled from freely
available resource like the website of FDA, EMA
and ICH .
 “Drug Regulations” is a non profit organization
which provides free online resource to the
Pharmaceutical Professional.
 Visit http://www.drugregulations.org for latest
information from the world of Pharmaceuticals.
9/23/2015 2
Drug Regulations : Online
Resource for Latest Information
 Quality
3
Visit www.drugregulations.org for the latest in Pharmaceuticals. 23-09-2015
 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)
423-09-2015
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 Quality by Design
523-09-2015
 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
623-09-2015
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7
RTRT
CPP
Control
StrategyDesign
Space
PAT
RTRT
QbD
CMA CQA
23-09-2015
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“Risk-based”
concepts and
principles
823-09-2015
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Pharmaceutical Development (Q8)
Past: Data transfer / Variable output
Present: Knowledge transfer / Science
based / Consistent output
Pharmaceutical Quality Systems (Q10)
Past: GMP checklist
Future: Quality Systems across product
life cycle
Quality Risk Management (Q9)
Past: Used, however poorly defined
Present: Opportunity to use structured
process thinking
Changed
ParadigmQ9
923-09-2015
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Science is no longer isolated; it is living
across the lifecycle of the product/process
within a Quality Management System
1023-09-2015
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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
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
1123-09-2015
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CQA’s
Product Profile
Risk Assessments
Design Space
Control Strategy
Continual
Improvement
12
Identify
CQA
Identify
CMA &
CPP
Quality
Target
Product
Profile
What is
critical to
the
Patient
QRM
PAT
Design space Control Strategy
SOP PAT
PAT ,
RTRT
PAT RTRT
23-09-2015
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
Quality
by
Design
1323-09-2015
• 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
assessment
Design
space
Control
strategy
Continual
Improvement
Essential Elements in a QbD
Approach (Q8R2)
1423-09-2015
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Product
Distribution
Product
Quarantine
Fixed
Packaging
Process
Fixed, Batch
Manufacturing
Process
Product
Development
Release Testing,
Document
Integrity
In-process
Testing,
Documentation
In-process
Testing,
Documentation
Fixed
Parameters,
Ranges
PatientProduction
System
Quality
System
As-Is: Traditional Pharmaceutical Product Supply System
Product
Distribution
Variable Pkg
Process
Variable Batch
or Continuous
Mfg Process
Product
Development
Real-time
Release
Maintain in Design Space
(PAT, etc.)
Design Space,
Variable
Parameters
PatientProduction
System
Quality
System
To-Be: QbD Pharmaceutical Product Supply System
Product
Distribution
Product
Quarantine
Fixed
Packaging
Process
Fixed, Batch
Manufacturing
Process
Product
Development
Release Testing,
Document
Integrity
In-process
Testing,
Documentation
In-process
Testing,
Documentation
Fixed
Parameters,
Ranges
PatientProduction
System
Quality
System
As-Is: QbT Pharmaceutical Product Supply System
Product
Distribution
Responsive Pkg
Process
Responsive
Batch or
Continuous
Mfg Process
Product
Development
Real-time
Release
Control Strategy: Maintain
in Design Space (PAT, etc.)
Design Space
PatientProduction
System
Quality
System
To-Be: QbD Pharmaceutical Product Supply System
15
23-09-2015
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16
CQA’s
Product Profile
Risk Assessments
Design Space
Control Strategy
Continual
Improvement
23-09-2015
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• Quality Target product profileProduct
profile
CQAs
Risk
assessment
Design
space
Control
strategy
Continual
Improvement
Essential Elements in a QbD
Approach (Q8R2)
1723-09-2015
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18
Dissolution ?
Dose ?
Content
Uniformity ? Hardness ?
Appearance ?
Quality Target Product Profile
Identify what is
critical to the patient
and
link this to the drug
product
23-09-2015
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A prospective summary of
the quality characteristics of
a drug product that ideally
will be achieved to ensure the
desired quality, taking into
account safety and efficacy of
the drug product : ICH Q8
(R2)
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20
By beginning with the end in
mind, the result of development
is a robust formulation and
manufacturing process with an
acceptable control strategy that
ensures the performance of the
drug product
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QTPP Element Target Justification
Dosage Form MR Tablet Pharmaceutical equivalence
requirement: Same dosage form
Route of Administration Oral Pharmaceutical equivalence
requirement: Same route of
administration
Dosage Strength 10 mg Pharmaceutical equivalence
requirement: Same strength
Pharmacokinetics Fasting Study and
Fed Study
90 % confidence
interval of the PK
parameters, AUC0-
2, AUC2-24,
AUC0-∞ and
Cmax, should fall
within
bioequivalence
limits
Bioequivalence requirement
Initial plasma concentration through
the first two hours that provides a
clinically significant therapeutic
effect followed by a sustained plasma
concentration that maintains the
therapeutic effect
2123-09-2015
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QTPP Element Target Justification
Stability At least 24-month
shelf-life at room
temperature
Equivalent to or better than RLD
shelf-life
Drug product quality
attributes
Physical attributes
Pharmaceutical equivalence
requirement: Meeting the same
compendial or other applicable
(quality) standards (i.e., identity,
assay, purity, and quality)
Identification
Assay
Content Uniformity
Degradation products
Residual solvents
Drug release
Microbial Limits
Water Content
2223-09-2015
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QTPP Element Target Justification
Container Closure System Suitable container
closure system to
achieve the target
shelf-life and to
ensure tablet
integrity during
shipping
HDPE bottles with Child Resistant
(CR) Caps are selected based on
similarity to the RLD packaging. No
further special protection is needed
due to the stability of drug substance
Z.
Administration/concurrence
with labeling
A scored tablet
can be divided into
two 5 mg tablets. Information is provided in the RLD
labeling
The tablet can be
taken without
regard to food (no
food effect).
Alternative methods of
administration
None
None are listed in the RLD labeling.
2323-09-2015
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• Quality Target product profile
• Determine critical quality attributes
(CQAs)
Product
profile
CQAs
Risk
assessment
Design
space
Control
strategy
Continual
Improvement
Essential Elements in a QbD
Approach (Q8R2)
2423-09-2015
 A CQA is a physical, chemical, biological, or
microbiological property or characteristic that
should be within an appropriate limit, range, or
distribution to ensure the desired product
quality. (ICH Q 8 R2)
 CQAs are generally associated with the
◦ Drug substance,
◦ Excipients,
◦ Intermediates (in-process materials) and
◦ Drug product.
2523-09-2015
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26
Q T P P
Potential
Impact to
Safety
Efficacy &
Quality?
Non - Critical
Severity@ Critical
Low Risk
High risk
Continual Improvement iteration
@ A Severity Scale is used to assess
relative magnitude of impact. A
change in criticality only occurs w/
a change in severity.
No
Yes
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27
QTPP
Safety&Efficacy
Identity
Others
Purity
Potency
POTENTIAL
QUALITY
ATTRIBUTES
• Appearance
• Assay
• Crystallinity
• C U
• Degradation
• Disintegration
• Dissolution
• IR / MR
• Microbiology
• Sterility
Criticalityassessment
C
Q
A
s
23-09-2015
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• Quality Target product profile
• Determine critical quality attributes
(CQAs)
• Risk assessment: Link raw material
attributes and process parameters to
CQAs
Product
profile
CQAs
Risk
assessment
Design
space
Control
strategy
Continual
Improvement
Essential Elements in a QbD
Approach (Q8R2)
2823-09-2015
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 Material: raw materials, starting materials, reagents,
solvents, process aids, intermediates, APIs, and packaging
and labelling materials, ICH Q7A
 Attribute: A physical, chemical, biological or
microbiological property or characteristic
 Material Attribute: Can be an excipient CQA, raw material
CQA, starting material CQA, drug substance CQA etc
◦ A Material Attribute can be quantified
◦ Typically fixed
◦ Can sometimes be changed during further processing (e.g. PSD–
milling)
◦ Examples of material attributes: PSD, Impurity profile, porosity,
specific volume, moisture level, sterility
2923-09-2015
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 A process parameter whose variability has an impact
on a critical quality attribute and therefore should be
monitored or controlled to ensure the process
produces the desired quality (Q8R2)
 CPPs have a direct impact on the CQAs
 A process parameter (PP) can be measured and
controlled (adjusted)
◦ Examples of CPPs for small molecule: Temperature,
addition rate, cooling rate, rotation speed
◦ Examples of CPPs for large molecule: Temperature, pH,
Agitation, Dissolved oxygen, Medium constituents, Feed
type and rate
3023-09-2015
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Process
(or Process Step)
Input
Process
Parameters
Input
Materials
Product
(or Intermediate)
Process
Variability
3123-09-2015
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Critical
Material
Attributes
MA 1
MA2
Critical Process
Parameters
CPP 1
CPP 2
Critical Quality
attributes
CQA 1
CQA 2
CQA 3
Understand & control the variability of
Material attributes and critical process
parameters to meet Product CQA’s.
3223-09-2015
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Two primary principles:
The evaluation of
the risk to quality
should be based on
scientific knowledge
and ultimately link
to the protection
of the patient
The level of effort,
formality and
documentation
of the quality risk
management process
should be
commensurate with the
level of risk
ICH Q9
3323-09-2015
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Process
Materials
Design
Manufacturing
Distribution
Patient
Facilities
Opportunities to
impact risk using
quality risk
management
3423-09-2015
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Q10Q8
Process
Materials
Design
Manufacturing
Distribution
Patient
Facilities
Opportunities to
impact risk using
quality risk
management
Q9
3523-09-2015
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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
3623-09-2015
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Risk Review
RiskCommunication
Risk Assessment
Risk Evaluation
unacceptable
Risk Control
Risk Analysis
Risk Reduction
Risk Identification
Review Events
Risk Acceptance
Initiate Quality
Risk Management Process
Output / Result of the Quality
Risk Management Process
RiskManagementtools
 Failure Mode Effects Analysis (FMEA)
◦ Break down large complex processes into manageable steps
 Failure Mode, Effects and Criticality Analysis (FMECA)
◦ FMEA & links severity, probability & detectability to criticality
 Fault Tree Analysis (FTA)
◦ Tree of failure modes combinations with logical operators
 Hazard Analysis and Critical Control Points (HACCP)
◦ Systematic, proactive, and preventive method on criticality
 Hazard Operability Analysis (HAZOP)
◦ Brainstorming technique
 Preliminary Hazard Analysis (PHA)
◦ Possibilities that the risk event happens
 Risk ranking and filtering
◦ Compare and prioritize risks with factors for each risk
CONSIDERATIONS
3723-09-2015
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Process
Development
Control Strategy
Development
Continual
Improvement
of the product
3823-09-2015
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 A material attribute or process parameter is
critical when a realistic change in that
attribute or parameter can significantly
impact the quality of the output material
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40
• A Process Parameter is a
Critical Process Parameter
when it has a high impact
on a CQA
• CPPs are responsible for
ensuring the right CQA
• CPPs are identified from a
list of potential CPPs, (i.e.
PPs) using risk assessment
and experimental work
CPP
PP
PP
High Impact
Low Impact
CQA
23-09-2015
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Drug Substance Attributes
Drug
Product
C Q A
Solid
State
Form
P S D Hygrosc
opicity
Solubil
ity
Mois
ture
Cont
ent
Residual
Solvent
Process
Impurit
ies
Chemi
cal
stabili
ty
Flow
prop
Assay Low Med Low Low Low Low Low High Med
C U Low High Low Low Low Low Low Low High
Dissolution High High Low High Low Low Low Low Low
Degradation
products
Med Low Low Low Low Low Low High Low
4123-09-2015
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Drug Substance
Attributes
Drug Product
CQA’s
Justification
Solid state form
Assay Drug substance solid state form does not affect tablet
assay. The risk is low.
Content
Uniformity
Drug substance solid state form does not affect tablet
CU. The risk is low.
Dissolution Different polymorphic forms of the drug substance
have different solubility and can impact tablet
dissolution. The risk is high.
Acetriptan polymorphic Form III is the most stable form
and the DMF holder consistently provides this form. In
addition, pre-formulation studies demonstrated that
Form III does not undergo any polymorphic conversion
under the various stress conditions tested. Thus,
further evaluation of polymorphic form on drug product
attributes was not conducted.
Degradation
Products
Drug substance with different polymorphic forms may
have different chemical stability and may impact the
degradation products of the tablet. The risk is medium
4223-09-2015
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• 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)
Product
profile
CQAs
Risk
assessment
Design
space
Control
strategy
Continual
Improvement
Essential Elements in a QbD
Approach (Q8R2)
4323-09-2015
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 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
4423-09-2015
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 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
4523-09-2015
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40
50
600
1
2
50.0
55.0
60.0
65.0
70.0
75.0
80.0
85.0
90.0
95.0
100.0
Dissolution(%)
Parameter 1
Param
eter 2
40 42 44 46 48 50 52 54 56 58 60
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
Dissolution (%)
Parameter 1
Parameter2
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
4623-09-2015
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Process
(or Process Step)
Design
Space
Input
Process
Parameters
Input
Materials
Product
(or Intermediate)
Process
Variability
4723-09-2015
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 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).
4823-09-2015
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Design Space and
Quality Control Strategy
Process
(or Process Step)
Design
Space
Monitoring of
Parameters
or Attributes
Process Controls/PAT
Input
Process
Parameters
Input
Materials
Product
(or Intermediate)
Product
Variability
Reduced
Product
Variability
Process
Variability
4923-09-2015
50
Assay (HPLC)
Purity, related
impurities, ((HPLC)
Residual solvent (GC)
Moisture content (KF)
Heavy Metals
Etc…
ID, Assay, CU (HPLC)
Purity, ((HPLC)
Dissolution,
Appearance
Moisture content (KF)
Etc
NIR, at-line (id
raw materials)
NIR, on-line
(reaction id)
IR, on-line
(purity, assay)
FBRM, on-
line (PSD)
NIR, on-line
(Moisture, purity
NIR, at-line (id raw
materials)
NIR, on-line, blend
homogeneity
NIR, on-line
(assay, CU, ID)
NIR, on-line, blend
homogeneity
ConventionalTesting
23-09-2015
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
slide 51
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
23-09-2015
Aspect Minimal Approaches Enhanced, Quality by Design
Approaches
Overall
Pharmaceutical
Development
• 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
5223-09-2015
Process flow:
Screening
Optimization
Validation
Identification of significant parameters
Finding parameter ranges
Finding interactions of parameters
Defining models
Production
Identification of CPP
Continuous monitoring
and development
Characterization range
Acceptable range
Operating range
Process
design space
Set point
Identification of noise factors
Process/ product Development:
Robust
Cost effective
Feasible
Defining control strategies
5323-09-2015
Aspect Minimal Approaches Enhanced, Quality by Design
Approaches
Manufacturing
Process
• 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
5423-09-2015
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Aspect Minimal Approaches Enhanced, Quality by Design
Approaches
Process
Controls
• 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
Product
Specifications
• 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
5523-09-2015
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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
Lifecycle
Management
• Reactive (i.e.,
problem solving and
corrective action)
• Preventive action
• Continual improvement
facilitated
5623-09-2015
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Traditional
development
approaches, as
outlined in ICH
Q8(R2) part I,
are acceptable.
5723-09-2015
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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 Increase efficiency of manufacturing process
o Minimize/eliminate potential compliance actions
o Provide opportunities for continual improvement
o Facilitate innovation
• More efficient regulatory oversight
o Streamline post approval manufacturing changes and
regulatory processes
5823-09-2015
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.
5923-09-2015
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 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
6023-09-2015
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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.
6123-09-2015
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 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
6223-09-2015
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 This presentation is compiled from freely
available resource like the website of FDA, EMA
and ICH .
 “Drug Regulations” is a non profit organization
which provides free online resource to the
Pharmaceutical Professional.
 Visit http://www.drugregulations.org for latest
information from the world of Pharmaceuticals.
9/23/2015 63
Drug Regulations : Online
Resource for Latest Information

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New Quality Paradigm Focuses on Built-In Quality

  • 1. The New Quality Paradigm Introduction 1 Presentation prepared by Drug Regulations – a not for profit organization. Visit www.drugregulations.org for the latest in Pharmaceuticals. 23-09-2015
  • 2.  This presentation is compiled from freely available resource like the website of FDA, EMA and ICH .  “Drug Regulations” is a non profit organization which provides free online resource to the Pharmaceutical Professional.  Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals. 9/23/2015 2 Drug Regulations : Online Resource for Latest Information
  • 3.  Quality 3 Visit www.drugregulations.org for the latest in Pharmaceuticals. 23-09-2015
  • 4.  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) 423-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 5.  Quality by Design 523-09-2015
  • 6.  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 623-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 9. Pharmaceutical Development (Q8) Past: Data transfer / Variable output Present: Knowledge transfer / Science based / Consistent output Pharmaceutical Quality Systems (Q10) Past: GMP checklist Future: Quality Systems across product life cycle Quality Risk Management (Q9) Past: Used, however poorly defined Present: Opportunity to use structured process thinking Changed ParadigmQ9 923-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 10. Science is no longer isolated; it is living across the lifecycle of the product/process within a Quality Management System 1023-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 11. 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 1123-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 12. CQA’s Product Profile Risk Assessments Design Space Control Strategy Continual Improvement 12 Identify CQA Identify CMA & CPP Quality Target Product Profile What is critical to the Patient QRM PAT Design space Control Strategy SOP PAT PAT , RTRT PAT RTRT 23-09-2015
  • 13. 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 Quality by Design 1323-09-2015
  • 14. • 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 assessment Design space Control strategy Continual Improvement Essential Elements in a QbD Approach (Q8R2) 1423-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 15. Product Distribution Product Quarantine Fixed Packaging Process Fixed, Batch Manufacturing Process Product Development Release Testing, Document Integrity In-process Testing, Documentation In-process Testing, Documentation Fixed Parameters, Ranges PatientProduction System Quality System As-Is: Traditional Pharmaceutical Product Supply System Product Distribution Variable Pkg Process Variable Batch or Continuous Mfg Process Product Development Real-time Release Maintain in Design Space (PAT, etc.) Design Space, Variable Parameters PatientProduction System Quality System To-Be: QbD Pharmaceutical Product Supply System Product Distribution Product Quarantine Fixed Packaging Process Fixed, Batch Manufacturing Process Product Development Release Testing, Document Integrity In-process Testing, Documentation In-process Testing, Documentation Fixed Parameters, Ranges PatientProduction System Quality System As-Is: QbT Pharmaceutical Product Supply System Product Distribution Responsive Pkg Process Responsive Batch or Continuous Mfg Process Product Development Real-time Release Control Strategy: Maintain in Design Space (PAT, etc.) Design Space PatientProduction System Quality System To-Be: QbD Pharmaceutical Product Supply System 15 23-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 16. 16 CQA’s Product Profile Risk Assessments Design Space Control Strategy Continual Improvement 23-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 17. • Quality Target product profileProduct profile CQAs Risk assessment Design space Control strategy Continual Improvement Essential Elements in a QbD Approach (Q8R2) 1723-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 18. 18 Dissolution ? Dose ? Content Uniformity ? Hardness ? Appearance ? Quality Target Product Profile Identify what is critical to the patient and link this to the drug product 23-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 19. A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product : ICH Q8 (R2) 1923-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 20. 20 By beginning with the end in mind, the result of development is a robust formulation and manufacturing process with an acceptable control strategy that ensures the performance of the drug product 23-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 21. QTPP Element Target Justification Dosage Form MR Tablet Pharmaceutical equivalence requirement: Same dosage form Route of Administration Oral Pharmaceutical equivalence requirement: Same route of administration Dosage Strength 10 mg Pharmaceutical equivalence requirement: Same strength Pharmacokinetics Fasting Study and Fed Study 90 % confidence interval of the PK parameters, AUC0- 2, AUC2-24, AUC0-∞ and Cmax, should fall within bioequivalence limits Bioequivalence requirement Initial plasma concentration through the first two hours that provides a clinically significant therapeutic effect followed by a sustained plasma concentration that maintains the therapeutic effect 2123-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 22. QTPP Element Target Justification Stability At least 24-month shelf-life at room temperature Equivalent to or better than RLD shelf-life Drug product quality attributes Physical attributes Pharmaceutical equivalence requirement: Meeting the same compendial or other applicable (quality) standards (i.e., identity, assay, purity, and quality) Identification Assay Content Uniformity Degradation products Residual solvents Drug release Microbial Limits Water Content 2223-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 23. QTPP Element Target Justification Container Closure System Suitable container closure system to achieve the target shelf-life and to ensure tablet integrity during shipping HDPE bottles with Child Resistant (CR) Caps are selected based on similarity to the RLD packaging. No further special protection is needed due to the stability of drug substance Z. Administration/concurrence with labeling A scored tablet can be divided into two 5 mg tablets. Information is provided in the RLD labeling The tablet can be taken without regard to food (no food effect). Alternative methods of administration None None are listed in the RLD labeling. 2323-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 24. • Quality Target product profile • Determine critical quality attributes (CQAs) Product profile CQAs Risk assessment Design space Control strategy Continual Improvement Essential Elements in a QbD Approach (Q8R2) 2423-09-2015
  • 25.  A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. (ICH Q 8 R2)  CQAs are generally associated with the ◦ Drug substance, ◦ Excipients, ◦ Intermediates (in-process materials) and ◦ Drug product. 2523-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 26. 26 Q T P P Potential Impact to Safety Efficacy & Quality? Non - Critical Severity@ Critical Low Risk High risk Continual Improvement iteration @ A Severity Scale is used to assess relative magnitude of impact. A change in criticality only occurs w/ a change in severity. No Yes 23-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 27. 27 QTPP Safety&Efficacy Identity Others Purity Potency POTENTIAL QUALITY ATTRIBUTES • Appearance • Assay • Crystallinity • C U • Degradation • Disintegration • Dissolution • IR / MR • Microbiology • Sterility Criticalityassessment C Q A s 23-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 28. • Quality Target product profile • Determine critical quality attributes (CQAs) • Risk assessment: Link raw material attributes and process parameters to CQAs Product profile CQAs Risk assessment Design space Control strategy Continual Improvement Essential Elements in a QbD Approach (Q8R2) 2823-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 29.  Material: raw materials, starting materials, reagents, solvents, process aids, intermediates, APIs, and packaging and labelling materials, ICH Q7A  Attribute: A physical, chemical, biological or microbiological property or characteristic  Material Attribute: Can be an excipient CQA, raw material CQA, starting material CQA, drug substance CQA etc ◦ A Material Attribute can be quantified ◦ Typically fixed ◦ Can sometimes be changed during further processing (e.g. PSD– milling) ◦ Examples of material attributes: PSD, Impurity profile, porosity, specific volume, moisture level, sterility 2923-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 30.  A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality (Q8R2)  CPPs have a direct impact on the CQAs  A process parameter (PP) can be measured and controlled (adjusted) ◦ Examples of CPPs for small molecule: Temperature, addition rate, cooling rate, rotation speed ◦ Examples of CPPs for large molecule: Temperature, pH, Agitation, Dissolved oxygen, Medium constituents, Feed type and rate 3023-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 31. Process (or Process Step) Input Process Parameters Input Materials Product (or Intermediate) Process Variability 3123-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 32. Critical Material Attributes MA 1 MA2 Critical Process Parameters CPP 1 CPP 2 Critical Quality attributes CQA 1 CQA 2 CQA 3 Understand & control the variability of Material attributes and critical process parameters to meet Product CQA’s. 3223-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 33. Two primary principles: The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk ICH Q9 3323-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 34. Process Materials Design Manufacturing Distribution Patient Facilities Opportunities to impact risk using quality risk management 3423-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 35. Q10Q8 Process Materials Design Manufacturing Distribution Patient Facilities Opportunities to impact risk using quality risk management Q9 3523-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 36.  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 3623-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 37. Risk Review RiskCommunication Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality Risk Management Process RiskManagementtools  Failure Mode Effects Analysis (FMEA) ◦ Break down large complex processes into manageable steps  Failure Mode, Effects and Criticality Analysis (FMECA) ◦ FMEA & links severity, probability & detectability to criticality  Fault Tree Analysis (FTA) ◦ Tree of failure modes combinations with logical operators  Hazard Analysis and Critical Control Points (HACCP) ◦ Systematic, proactive, and preventive method on criticality  Hazard Operability Analysis (HAZOP) ◦ Brainstorming technique  Preliminary Hazard Analysis (PHA) ◦ Possibilities that the risk event happens  Risk ranking and filtering ◦ Compare and prioritize risks with factors for each risk CONSIDERATIONS 3723-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 38. Process Development Control Strategy Development Continual Improvement of the product 3823-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 39.  A material attribute or process parameter is critical when a realistic change in that attribute or parameter can significantly impact the quality of the output material 3923-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 40. 40 • A Process Parameter is a Critical Process Parameter when it has a high impact on a CQA • CPPs are responsible for ensuring the right CQA • CPPs are identified from a list of potential CPPs, (i.e. PPs) using risk assessment and experimental work CPP PP PP High Impact Low Impact CQA 23-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 41. Drug Substance Attributes Drug Product C Q A Solid State Form P S D Hygrosc opicity Solubil ity Mois ture Cont ent Residual Solvent Process Impurit ies Chemi cal stabili ty Flow prop Assay Low Med Low Low Low Low Low High Med C U Low High Low Low Low Low Low Low High Dissolution High High Low High Low Low Low Low Low Degradation products Med Low Low Low Low Low Low High Low 4123-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 42. Drug Substance Attributes Drug Product CQA’s Justification Solid state form Assay Drug substance solid state form does not affect tablet assay. The risk is low. Content Uniformity Drug substance solid state form does not affect tablet CU. The risk is low. Dissolution Different polymorphic forms of the drug substance have different solubility and can impact tablet dissolution. The risk is high. Acetriptan polymorphic Form III is the most stable form and the DMF holder consistently provides this form. In addition, pre-formulation studies demonstrated that Form III does not undergo any polymorphic conversion under the various stress conditions tested. Thus, further evaluation of polymorphic form on drug product attributes was not conducted. Degradation Products Drug substance with different polymorphic forms may have different chemical stability and may impact the degradation products of the tablet. The risk is medium 4223-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 43. • 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) Product profile CQAs Risk assessment Design space Control strategy Continual Improvement Essential Elements in a QbD Approach (Q8R2) 4323-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 44.  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 4423-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 45.  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 4523-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 46. 40 50 600 1 2 50.0 55.0 60.0 65.0 70.0 75.0 80.0 85.0 90.0 95.0 100.0 Dissolution(%) Parameter 1 Param eter 2 40 42 44 46 48 50 52 54 56 58 60 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 Dissolution (%) Parameter 1 Parameter2 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 4623-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 47. Process (or Process Step) Design Space Input Process Parameters Input Materials Product (or Intermediate) Process Variability 4723-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 48.  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). 4823-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 49. Design Space and Quality Control Strategy Process (or Process Step) Design Space Monitoring of Parameters or Attributes Process Controls/PAT Input Process Parameters Input Materials Product (or Intermediate) Product Variability Reduced Product Variability Process Variability 4923-09-2015
  • 50. 50 Assay (HPLC) Purity, related impurities, ((HPLC) Residual solvent (GC) Moisture content (KF) Heavy Metals Etc… ID, Assay, CU (HPLC) Purity, ((HPLC) Dissolution, Appearance Moisture content (KF) Etc NIR, at-line (id raw materials) NIR, on-line (reaction id) IR, on-line (purity, assay) FBRM, on- line (PSD) NIR, on-line (Moisture, purity NIR, at-line (id raw materials) NIR, on-line, blend homogeneity NIR, on-line (assay, CU, ID) NIR, on-line, blend homogeneity ConventionalTesting 23-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 51. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop slide 51 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 23-09-2015
  • 52. Aspect Minimal Approaches Enhanced, Quality by Design Approaches Overall Pharmaceutical Development • 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 5223-09-2015
  • 53. Process flow: Screening Optimization Validation Identification of significant parameters Finding parameter ranges Finding interactions of parameters Defining models Production Identification of CPP Continuous monitoring and development Characterization range Acceptable range Operating range Process design space Set point Identification of noise factors Process/ product Development: Robust Cost effective Feasible Defining control strategies 5323-09-2015
  • 54. Aspect Minimal Approaches Enhanced, Quality by Design Approaches Manufacturing Process • 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 5423-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 55. Aspect Minimal Approaches Enhanced, Quality by Design Approaches Process Controls • 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 Product Specifications • 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 5523-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 56. 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 Lifecycle Management • Reactive (i.e., problem solving and corrective action) • Preventive action • Continual improvement facilitated 5623-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 57. Traditional development approaches, as outlined in ICH Q8(R2) part I, are acceptable. 5723-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 58. 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 Increase efficiency of manufacturing process o Minimize/eliminate potential compliance actions o Provide opportunities for continual improvement o Facilitate innovation • More efficient regulatory oversight o Streamline post approval manufacturing changes and regulatory processes 5823-09-2015
  • 59. 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. 5923-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 60.  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 6023-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 61.  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. 6123-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 62.  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 6223-09-2015 Visit www.drugregulations.org for the latest in Pharmaceuticals.
  • 63.  This presentation is compiled from freely available resource like the website of FDA, EMA and ICH .  “Drug Regulations” is a non profit organization which provides free online resource to the Pharmaceutical Professional.  Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals. 9/23/2015 63 Drug Regulations : Online Resource for Latest Information