Professional Documents
Culture Documents
Pharmaceutical Development
To design a quality product and its
manufacturing process to deliver the
intended performance of the product.
Marketing
Considerations
Clinical Requirements
Patient Population
IP
Manufacturing
Process Considerations
DOSAGE FORM
Use Existing
Equipment/Facilities
Globally
Acceptable
Bioavailable
Stable
Reliable/Rugged
Manufacturing Process
Meets
TPP
Quality by Design
QbD is a systematic approach to pharmaceutical development
that begins with predefined objectives and emphasizes product
and process understanding based on sound science and quality
risk management
QbD Workflow
Labeled Use
Safety and Efficacy
DESIGN Formulation
and Process
TARGET
DESIGN
CONTROL Materials
and Process
IMPLEMENTATION
Target
Minimum
Dosage form
Sterile Solution
Sterile Suspension
Dose Strengths
6.8-7.4
6.0-7.8
NMT 50 ppm
Dosing
Once-a-day
Storage
NLT 18 months at
Room Temperature
Bottles
Bottles
Cardboard Carton
Cardboard Carton
No new inks for labels
pH
Preservative1
Primary Packaging
Secondary Packaging
1Needs
10
Quality Attribute
Dosage form
Dose Strengths
Number of dose Strengths
pH
Preservative1
Acceptable Minimum
Solution or Suspension
0.05 0.2% w/v
NMT 3 strengths for Phase 1
5.5-7.8
Preservative-free
Storage
Primary Packaging
11
Exploitation
Exploration
Product Development
Strategy
Exploration: Existing Knowledge not sufficient to solve the problem identified.
New knowledge needs to be created and acquired to contribute to the existing body
of knowledge
Exploitation: Utilization of existing knowledge for innovative problem solving
Revilla, E., Rodriguez, B., 2011
Technovation (31) 118-127
Regulatory Considerations
Exploratory IND Approach
Bridging Strategy
Target
Dosage form
Solution
Potency (Strength)
0.05-0.1 %
Appearance
Identity
Assay
95 105% at release
90-110% at end of shelf
Impurities
pH
Physiological pH
Isotonicity
280-330 mOsm
APET
Sterility
Particulate Matter
Leachables
Target
Residual Monomer
Molecular Weight
15k to 20k
0.4 to 0.8
Crystallinity
X-ray amorphous
Endotoxin
1. Mixing Time
2. Mixing Speed
3. Process Temperature
1.
2.
Team focused
Risk Assessment
Risk Identification
3.
Risk Analysis
Risk Evaluation
Ri s k Commun ic at ion
Internal consultation
Risk Control
Risk Reduction
Risk Acceptance
1.
R i sk Ma nage ment t ools
unacceptable
Stakeholder involvement
2.
3.
4.
Output / Result of the
Risk Management Process
Risk Review
Review Events
Above risk at an
acceptable level?
What can be done to
reduce or eliminate
risks
Balance between
Benefits, Risks and
Resources
Any new risks
introduced
Risk-based classification
(Risk Evaluation)
FORMULATION
DESIGN SPACE
CONTROL
STRATEGY
PROCESS
DESIGN SPACE
BY UNIT OPERATION
EFPIA Team, P2 Mock Doc
Potential Risk
New polymorph of
DS formed
Probability of
Potential Impact
Occurrence
to Quality
(Lo, Med, Hi)
Med
DS Impurity
New Impurity
generated during
process
optimization
Lo
DP Impurity
Product degrades
during room
temperature storage
Hi
More complex
formulation
needed if dose
strength is
above XX%.
Risk Reduction /
Mitigation
Develop a back-up
formulation
Perform process
optimization earlier in
Qualification of
development (or) plan
new impurity
for a potential tox study
later in development
Refrigerate product until
Reduced
dispensed to patient
product ShelfDevelop back-up
life
formulations
Fishbone Diagram
Batch Size
Solvent Systems
Ionic Strength
(API, reaction products)
Sodium vs Ammonium Salts
Solvent Polarity
Tank Design
Impeller Speed
Impeller Design
Water
Crystal Form
Temperature
Time of Crystallization
Distillation Rate
Seed
Amount/morphology
Seeding Time
Seeding pH
d[pH]/dt
Incoming Materials
Reactor Conditions
Order of
Mixing
addition
pH
Filtration
Filling
Packaging
adjust
Operation
Appearance
Med
Med
Low
Low
Low
Low
Assay
Low
High
High
High
Low
Low
Impurity
Low
Med
High
High
Low
High
pH
Low
Low
Med
Low
Low
Low
Tonicity
Low
Med
High
Med
Low
Low
BAK
Low
Low
Low
High
Low
Low
Sterility
Low
Low
Low
High
High
High
Endotoxin
Low
Low
Low
Low
Low
High
RM Input
Process
Product
Internal Target
Specifications
Continuous Improvement without Regulatory Approval
Adapted from MacGregor J. & Bruwer M. J Pharm Innov (2008) 3:1522
Some Definitions
Design Space
Clinical Relevance
Multi-dimensional space that encompasses combinations of product design, manufacturing
process design, critical manufacturing process parameters and component attributes that
provide assurance of suitable product quality and performance
Control Space
Process Capability
Multi-dimensional space that encompasses process operating parameters and component
quality measurements that assure process or product quality. It is a subset of the design space
Control Strategy
Change Control, Continuous Improvement, Regulatory Considerations
Strategy/Methodology to mitigate risks associated with the batch when the critical and noncritical process parameters fall outside the control space but within the design space
A control strategy is designed to ensure that a product of required quality will be produced
consistently
Design Space
Solubilizer Concentration
1% to 2% w/v
98% to 102%
Buffer Concentration
Tonicity Agent
Mixing Time
Mixing Speed
Temperature
NMT 50 C
Questions / Discussion
Control Strategy
A control strategy is designed to ensure that a product of
required quality will be produced consistently.
A control strategy can include, but is not limited to, the
following:
Control of input material attributes (e.g., drug substance, excipients, primary
packaging materials) based on an understanding of their impact on
processability or product quality;
Product specification(s);
Controls for unit operations that have an impact on downstream processing or
product quality (e.g., the impact of drying on degradation, particle size
distribution of the granulate on dissolution);
In-process or real-time release testing in lieu of end-product testing (e.g.
measurement and control of CQAs during processing);
A monitoring program (e.g., full product testing at regular intervals) for
verifying multivariate prediction models.