Professional Documents
Culture Documents
Chris Potter
Chris Potter
2
Concepts Included
Risk-based classification
(Risk Evaluation)
5
Target Product Profile
6
Proposed Formulation and
Manufacturing Process
Key Formulation Design Decisions
DirectU
Compression High bulk density
Wet Granulation
U
Lactose Primary amine
Mannitol
7
Proposed Manufacturing Process
Fluidized Bed
Dryer
Dispensing Granulation
Scale
Air
Blending
Tableting
Unit Operations
Packaging
8
Cause and Effect Process
Drying Analytical
Temp
RH
Tooling P.S.
Plant Feed P.S.
Scrape Down
Factors Frame LOD
Chopper Speed Other
Compressing
Mixer Speed Lubricant
Disintegrant
Endpoint Raw
Binder
Materials
Power
Granulation
Time
9
Initial Classification of Importance of Unit
Operation to Have an Impact on Quality
• Write down, what you know already
Unit operation
Quality Attributes
Example of Formulation
Development DOE (3.2.P.2.2.1)
Previous knowledge
Potential Formulation
DOE
16.00
14.00
12.00
Crushing Strength (Kp)
10.00
8.00
6.00
4.00
2.00
0.00
0 5 10 15 20 25 30 35
Compression Force (kN)
12
Dissolution Profiles made with
Different Lubricant Levels
120
100
Mean % dissolution
80
1% Mg St
60 2% Mg St
3% Mg St
40
20
0
0 5 10 15 20 25 30 45
Tim e (m inutes)
13
Magnesium Stearate
Design Space
• One dimension – univariate range
• No edge of failure
• Maybe not useful in this case as a formulation
variable
• Does help conclude a robust formulation
• Risk of failure of dissolution, disintegration,
hardness at blending step significantly
reduced
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Key Process Variables for Wet
Granulation
Wet granulation parameters Input material attributes
Mixing speed API particle size
Water addition rate Mannitol particle size
Mixing time
Series1
0
Drug Substance Mannitol PS Mixing Speed Water Amount Wet Mixing Time Compression Force
-1
-2
-3
16
Effect of Water Addition Rate and Mixer Speed on
Disintegration (red does not meet quality requirements)
Disintegration
Faster
Mixer speed
17
Examplain: Drying Operation
Inlet Temp Bed Temp
Outlet RH
Air flow
Outlet Temp
Fluid Bed Drier
colour code: Red - input variables; Green - derived parameters; Blue - on-line measurements
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Process Variables and Quality Attributes for the
Fluid Bed Drying Operation
Process variables
Drying parameters Input material attributes
Inlet air temperature Water content
Inlet air humidity Granule particle size distribution
Air flow rate
Fill level
Filter sock cycle
Heating rate
Cooling rate
Quality attributes
Dried granule Tablet
Particle size distribution (fines) Disintegration
Water content Dissolution
Degradation (des-ethyl Weight uniformity
examplain)
Content uniformity
19
Effect of inlet temperature and air flow on degradation and
generation of fines, as shown by the DOE (red = does not
meet quality requirements) (1 kg scale)
Degradation Fines
Inlet temperature
Inlet temperature
20
Interaction of Inlet Temperature and Air
Flow for Combination of Failure Modes
(Red = Does Not Meet Quality
Requirements)
Air flow
21
Examplain Design Space –
Graphical Description
(1 kg Scale)
18.5%
17.5% Regions of uncertainty
Known edge of failure due to fines
%
Known edge of failure due to degradation
H2O
Drying time
22
Process Trajectories for 5 Batches
Manufactured at 25 Kg Scale
18.5%
17.5%
ICH registration stability batches
Test batches (see text)
%
H2O
Drying time
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Summary: Design Space for Fluid
Bed Drying
• Multivariate for degradation, disintegration,
uniformity of content
– Inlet temperature
– Air flow
– Drying time
• Trajectory for water content, a critical
parameter
• Change of scale understood
• Areas of failure found in this case
• Clear control strategy
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Use of Design Space for Fluid Bed Drying
Manufacturing changes
– Change of fluidised bed dryer
– Allows change of packaging within pre-defined criteria
26
Determination of Design Space –
Conclusions
• Requires experimentation or prior knowledge
– But not necessarily formalised designs such as
factorials
• Can be a very simple or more complex concept
– May require multi-factorial approaches using PAT
tools
– Could (will) be multidimensional
• Per definition, quality attributes of the finished
product are achieved when operating within the
Design Space
• As a consequence, any process modification within
design space should be acceptable without any
further regulatory approval
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