07 The Case Study
07 The Case Study
07 The Case Study
Case Study
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Disclaimer
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Organization of content
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Technical Examples
Process focus Quality attribute focus
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• QTPP: 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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Quality Target Product Profile (QTPP)
Safety and Efficacy Requirements
Translation into
Characteristics /
Tablet Quality Target Product Profile
Requirements
(QTPP)
Dose 30 mg Identity, Assay and Uniformity
QTPP may evolve during lifecycle – during development and commercial manufacture - as new knowledge is
gained e.g. new patient needs are identified, new technical information is obtained about the product etc.
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Tablet Formulation
Pharmacopoeial
or other
compendial
specification
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Compression
Coating
HPMC , Macrogol 6000
titanium oxide Film coating
iron sesquioxide
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CQA
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Initial Risk Assessment
Process Steps
• Focus on
Impact to
CQA’s CQA
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Hydrolysis Degradation
O
O
H2 O
R'
R O OH
R OH + R'
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Crystallization Process
• For Risk Assessment (FMEA)
- Only crystallization parameters
considered, per scientific rationale
in risk assessment
- All relevant parameters considered
based on first principles
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Experimental Setup -
Hydrolysis Degradation
• Crystallization Process Requirements
- API feed solution held at 60ºC, to maintain solubility of product, allows for
passage through extraneous matter filters.
- Batch fed to crystallizer slowly (to ensure particle size control). If fed too slowly
(over too much time), hydrolysis degradate can form in crystallizer feed.
- Batch will contain some level of residual water (thermodynamics)
- No rejection of hydrolysis degradate seen in crystallization (prior
knowledge/experience)
• Process Constraints
- Factory process can control well within +/- 10ºC. 70ºC is easily the worst case
temperature
- The batch must be held hot during the entire feed time (~ 10 hours), including
time for batch heat up and time for operators to safely start up the crystallization.
A total hold time of 24 hours at temperature is the worst case.
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Experimental Plan –
Hydrolysis Degradation (contd.)
• Univariate experiments justified
- Only upper end of ranges need to be tested, as first principles dictates this is worst
case for degradation rate
- Lower water content, temperature and hold times will not increase hydrolytic
degradation
- Upper end of range for batch temperature and hold time can be set based on
capabilities of a typical factory
- Therefore, only the water content of the batch needs to be varied to establish the
design space
• Experimental Setup
- Set maximum batch temperature (70ºC)
- Set maximum batch feed time (include heat up time, hold time, etc.) = 24 hours
- Vary residual water level
- Monitor degradation rate with criteria for success = max 0.3% degradate (qualified
limit)
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0.1% 0.04%
0.5% 0.16%
1.0% 0.27%
2.0% 0.52%
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Particle Size Distribution Control -
Process History (contd.)
• Changes to crystallization process
• Develop semi-continuous crystallization to
better control PSD (narrow the distribution)
and control agglomeration
• Add air attrition milling of seed to lower the
final API PSD
• API Particle Size Distribution Specification:
5 to 20 micron D90
• Risk Assessment
• Charge ratios/agitation/temperature/
seed characteristics have potential to
affect PSD
• Based on data in a previous filing
and experience with this technology.
• Per prior knowledge, other unit
operations (including filtration and
drying) do not affect PSD.
• Lab data and piloting experience
demonstrate that growing crystals
are sensitive to shear (agitation) in
the crystallizer, but not during
drying.
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Risk Assessment:
Particle Size Distribution (PSD) Control
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Risk Assessment:
Particle Size Distribution (PSD) Control
To be investigated
in DOE
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For purposes of this case study, an acceptable “squared off” design space can be chosen
Temperature = 20 to 30ºC
Seed charge = 1 to 2 wt%
Agitation = 1.1 to 2.5 m/s
Feed Rate = 5 to 15 hr (limit of knowledge space)
Monte Carlo analysis ensures that model uncertainty will be effectively managed throughout the range
Since the important variables affecting PSD are scale independent, model can be confirmed at scale with
“center point” (optimum) runs
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The large square represents the ranges tested in the DOE. The red area represents points of
failure. The green area represents points of success.
The boxes represent simplified design spaces within the points of success
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The large square represents the ranges tested in the DOE. The red area represents points of
failure. The green area represents points of success.
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API Crystallization:
Design Space & Control Strategy
• Control Strategy should address:
- Parameter controls
- Distillative solvent switch achieves target water content
- Crystallization parameters are within the design space
- Testing
- API feed solution tested for water content
- Final API will be tested for hydrolysis degradate
- Using the predictive model, PSD does not need to be routinely tested
since it is consistently controlled by the process parameters
• Quality systems
- Should be capable of managing changes within and to the design space
- Product lifecycle can result in future design space changes
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API Crystallization:
Design Space & Control Strategy
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• Verify that the crystallization parameters are within the design space
- Temperature = 20 to 30º C
- Seed charge = 1 to 2 wt%
- Agitation = 1.1 to 2.5 m/s
- Feed time = 5 to 15 hr
- API feed solution water content < 1 wt%
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Description and hardness Robust tablet able to withstand transport and handling.
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- Dissolution
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Tablet Formulation
Pharmacopoeial or
other compendial
specification.
May have additional
requirements for
Functionality Related
Characteristics
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Focus of
Story
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Example 1:
Real Time Release Testing (RTRT)
for Dissolution
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Developing Product and Process
Understanding: DOE Investigation of factors affecting Dissolution
Multifactorial DOE study of Exp No
1
Run Order
1
API
0.5
MgSt
3000
LubT
1
Hard
60
Diss
101.24
2 14 1.5 3000 1 60 87.99
variables affecting dissolution 3 22 0.5 12000 1 60 99.13
4 8 1.5 3000 10 60 86.03
• Factors: 5 18 0.5 12000 10 60 94.73
-
6 9 1.5 12000 10 60 83.04
API particle size [API] 7 15 0.5 3000 1 110 98.07
unit: log D90, microns 8
9
2
6
0.5
1.5
12000
12000
1
1
110
110
97.68
85.47
- Mg-Stearate Specific Surface Area 10
11
16
20
0.5
1.5
3000
3000
10
10
110
110
95.81
84.38
[MgSt] 12 3 1.5 12000 10 110 81
unit: cm2/g 13 10 0.5 7500 5.5 85 96.85
• Response: 18
19
4
5
1
1
7500
7500
10
5.5
85
60
88.9
92.37
- % API dissolved at 20 min [Diss] 20
21
11
12
1
1
7500
7500
5.5
5.5
110
85
90.95
91.95
• DOE design: 22
23
13
23
1
1
7500
7500
5.5
5.5
85
85
90.86
89
- RSM design
Note: A screening DoE may be used first to identify
- Reduced CCF (quadratic model) which of the many variables have the greatest effect
- 20+3 center point runs
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in-vitro dissolution:
-
-2
%
(= CQA of API) -4
-5
-
-6
Lubrication time has a
small influence
MgSt*LubT
Hard
MgSt
API
LubT
API Mg Lubrication Tablet Mg St*LubT
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Example 2:
Real Time Release Testing (RTRT)
for Assay and Content Uniformity
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3 10 varied 2 30 V type 40
4 5 varied 16 30 V type 5
5 6 varied 2 10 Drum type 40
6 1 varied 16 10 Drum type 5
7 8 varied 2 30 Drum type 5
8 11 varied 16 30 Drum type 40
9 3 standard 9 20 V type 20
10 12 standard 9 20 Drum type 20
11 9 standard 9 20 V type 20
12 4 standard 9 20 Drum type 20
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Control Strategy
• Input materials meet specifications and are tested
- API PSD
- Magnesium stearate specific surface area
• Assay calculation
- Verify (API assay of blend by HPLC) X (tablet weight)
- Tablet weight by automatic weight control (feedback loop)
- For 10 tablets per sampling point, <2% RSD for weights
• Content Uniformity
- On-line NIR criteria met for end of blending (blend homogeneity)
- Tablet weight control results checked
• Dissolution
- Predictive model using input and process parameters for each batch calculates
whether dissolution meets acceptance criteria
- Input and process parameters are all within the filed design space
- Compression force is controlled for tablet hardness
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API
API PSD API PSD API PSD model
Crystallization
Lubricant Lubricant
Mg stearate SSA
amount
Lubrication
Lubrication time Lubrication time Lubrication time
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Conclusions
• Better process knowledge is the outcome of QbD development
• Provides the opportunity for flexible change management
• Use Quality Risk Management proactively
• Multiple approaches for experimental design are possible
• Multiple ways of presenting Design Space are acceptable
- Predictive models need to be confirmed and maintained