New Quality Paradigm Focuses on Built-In Quality

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
Visit www.drugregulations.org for the latest in Pharmaceuticals.

 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

7
RTRT
CPP
Control
StrategyDesign
Space
PAT
RTRT
QbD
CMA CQA
23-09-2015

“Risk-based”
concepts and
principles
823-09-2015

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

Science is no longer isolated; it is living
across the lifecycle of the product/process
within a Quality Management System
1023-09-2015

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

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

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

16
CQA’s
Product Profile
Risk Assessments
Design Space
Control Strategy
Continual
Improvement
23-09-2015

• Quality Target product profileProduct
profile
CQAs
Risk
assessment
Design
space
Control
strategy
Continual
Improvement
Approach (Q8R2)
1723-09-2015

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

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

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

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

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

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

(CQAs)
Product
profile
CQAs
Risk
assessment
Design
space
Control
strategy
Continual
Improvement
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

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

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

(CQAs)
CQAs
Product
profile
CQAs
Risk
assessment
Design
space
Control
strategy
Continual
Improvement
Approach (Q8R2)
2823-09-2015

 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

 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

Process
(or Process Step)
Input
Process
Parameters
Input
Materials
Product
(or Intermediate)
Process
Variability
3123-09-2015

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

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

Process
Materials
Design
Manufacturing
Distribution
Patient
Facilities
Opportunities to
impact risk using
quality risk
management
3423-09-2015

Q10Q8
Process
Materials
Design
Manufacturing
Distribution
Patient
Facilities
Opportunities to
impact risk using
quality risk
management
Q9
3523-09-2015

 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

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

Process
Development
Control Strategy
Development
Continual
Improvement
of the product
3823-09-2015

 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

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

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

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

(CQAs)
CQAs
• Develop a design space.(Optional not required)
Product
profile
CQAs
Risk
assessment
Design
space
Control
strategy
Continual
Improvement
Approach (Q8R2)
4323-09-2015

 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

 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

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

Process
(or Process Step)
Design
Space
Input
Process
Parameters
Input
Materials
Product
(or Intermediate)
Process
Variability
4723-09-2015

 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

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

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

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

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

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

Traditional
development
approaches, as
outlined in ICH
Q8(R2) part I,
are acceptable.
5723-09-2015

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

 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

 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

 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

 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

New Quality Paradigm Focuses on Built-In Quality

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New Quality Paradigm Focuses on Built-In Quality