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TRANSCRIPT
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QbD/DoE in the Development, Production and
Approval of Potent Antibiotic Ceftolozane
September 12, 2016
David L. Waller, Ph.D.
Cubist Manufacturing Process Development
Merck Chemical Commercialization & Technical Operations
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What Chemists Do
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Raw Materials Drug Substance Drug Product
Drug Substance vs. Drug Product
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Drug Substance
What Process Chemists Do
Manufacturing facility, Milan, Italy
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Commercial Launch
Pre-clinical/ Toxicology
Phase I Clinical
Phase II Clinical
Phase III Clinical
Increasing demand in every dimension
QbD/DoE in Process Chemistry
Optimization Regulatory
QbD/DoE serve dual roles in development
Use phase-appropriately, but always with the other(s) in mind
Ceftolozane Sulfate
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Fifth generation cephalosporin antibiotic
Treatment of resistant gram-negative infections
-abdominal, urinary tract, pneumonia
Dose: 6 – 8 grams/day over 14 days
30-40 metric tons/year demand @ peak
22 synthetic steps embedded in ceftolozane
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Amine
Acid
Chloride
TFA Salt Drug Substance
UreaAcid
Stage 1
Stage 2 Stage 3
Stage 1A
7 steps
9 steps
2 steps
90%
90%
50% 74%
-Specialized-High capacity-Unalterable
-Key coupling-Low yield
-Low capacity-5 day cycle time
GMP
Global Process Evaluation
Need for cost of goods reduction
Need for capacity improvement
Stage 2 was a clear target for improvement
-Ceftolozane was acquired in Phase II clinical trials
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Right half (ratio)
Solvent (volume)
Potassium Iodide (ratio)
Base (ratio)
Temperature (C)
Agitation rate (rpm) Eliminated by experimentation
Parameters in DoE study
coupling
Left half Right half Complete drug
Ceftolozane Key Coupling: Parameter Selection
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Final Coupling DoE Parameter Evaluation
Parameter Low High Responses Analytical Method
Right half 1.0 1.4
-Yield-Purity (overall)-Individual impurities-Reaction rate-Downstream effects
-In-situ yield assay-Purity assay(s)-Downstream methods
Solvent 5 7
Potassium Iodide (ratio)
1.6 2.4
Base (ratio) 2.6 4.6
Temperature (C) 23 34
With range setting, go wide.....wider.
Fight the urge to control the outcome.
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Final Coupling DoE Parameter Evaluation
Parameter Low High Responses Analytical Method
Right half 1.0 1.4
-Yield-Purity (overall)-Individual impurities-Reaction rate-Downstream effects
-In-situ yield assay-Purity assay(s)-Downstream methods
Solvent 5 7
Potassium Iodide (ratio)
1.6 2.4
Base (ratio) 2.6 4.6
Temperature (C) 23 34
½ Factorial Design (resolution V) workhorse for chemical processes
One-way and two-way effects are not aliased
Nearly always achieve high quality outcomes
16 design experiments + 4 center points = 20 experiments
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Analysis of Variance
Source DF Adj SS Adj MS F-Value
Model 11 2041.48 185.589 66.31
Linear 5 1820.12 364.023 130.07
Potassium Iodide 1 379.62 379.619 135.64
Right Hand Fragment 1 287.67 287.671 102.79
Solvent 1 17.61 17.608 6.29
Base 1 245.82 245.818 87.84
Reaction Temperature 1 889.40 889.400 317.80
2-Way Interactions 5 220.54 44.108 15.76
Right Hand Fragment*Solvent 1 6.47 6.472 2.31
Right Hand Fragment*Base 1 14.65 14.645 5.23
Right Hand Fragment*Reaction Temperature 1 86.11 86.108 30.77
Solvent*Base 1 77.92 77.922 27.84
Solvent*Reaction Temperature 1 35.39 35.392 12.65
Curvature 1 0.83 0.827 0.30
Error 8 22.39 2.799
Lack-of-Fit 5 10.49 2.097 0.53
Pure Error 3 11.90 3.967
Total 19 2063.87
Model Summary
S R-sq R-sq(adj) R-sq(pred)
1.67291 98.92% 97.42% 93.77%
Source P-Value
Model 0.000
Linear 0.000
Potassium Iodide 0.000
Right Hand Fragment 0.000
Solvent 0.036
Base 0.000
Reaction Temperature 0.000
2-Way Interactions 0.001
Right Hand Fragment*Solvent 0.167
Right Hand Fragment*Base 0.051
Right Hand Fragment*Reaction Temperature 0.001
Solvent*Base 0.001
Solvent*Reaction Temperature 0.007
Curvature 0.601
Error
Lack-of-Fit 0.751
Pure Error
Total
Coupling DoE Execution: Chemical Yield
What we look for:
Standard error magnitude
R2 value
Significance of curvature
Regulatory implications
Chemical mechanism change
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Coupling DoE Execution: Chemical Yield
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Coupling DoE Execution: Chemical Yield
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Right half (ratio)
Solvent (volume)
Potassium Iodide (ratio)
Base (ratio)
Temperature (C)
Agitation rate (rpm) Eliminated by experimentation
Parameters in DoE study
coupling
Left half Right half Complete drug
Ceftolozane Key Coupling: Parameter Selection
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Potassium Iodide 2.4
Solvent 6
Base 3.6
Hold Values
Right Hand Fragment
Reacti
on
Tem
pera
ture
1 .41 .31 .21 .11 .0
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32
30
28
26
24
>
–
–
–
–
–
–
–
–
–
–
<
72 74
74 76
76
56
56 58
58 60
60 62
62 64
64 66
66 68
68 70
70 72
Yield (%)
Chemical
Chemical Yield: Reaction Temperature vs. Right Hand Fragment
Coupling DoE Execution: Chemical Yield
Phase II conditions Residual right
hand fragment not purgeable
Optimum conditions
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Commercial Launch
Pre-clinical/ Toxicology
Phase I Clinical
Phase II Clinical
Phase III Clinical
Increasing demand in every dimension
QbD/DoE in Process Chemistry
Optimization Regulatory
QbD/DoE serve dual roles in development
Use phase-appropriately, but always with the other(s) in mind
Quality By Design at Regulatory Agencies
“quality should be built into a product with a thorough understanding of the product and process”
“a knowledge of the risks involved in manufacturing the product and how best to mitigate those risks”
Pharmaceutical Quality for the 21st Century, US FDA, 2007
“Firms must continue to move from a compliance mindset to quality by design”
Pharmaceutical cGMPs for the 21st Century, US FDA, 2003Manufacturing facility, Milan, Italy
-What came before QbD?
"quality by QC“ or "quality after design"
Pharmaceutical cGMPs for the 21st Century, US FDA, 2003
Restricted flexibility in the manufacturing process
End product testing
Quality By Design at Regulatory Agencies
Quality assured by understanding and controlling manufacturing variables
Vision for pharmaceutical QbD
CQAs of product Process parameters Risk assessment – Likelihood of impacting quality of
product?
Design and implement a control space/strategy
Raw material attributes(purity, particle size, etc.)
Probe operation space via DoE
Quality By Design at Regulatory Agencies
All QbD is upstream of the product’s critical quality attributes (CQAs)
The Regulatory PAR and NOR = Design Space
Normal Operating Range (NOR)-specifications met; low risk
Proven Acceptable Range (PAR)-specifications met; risk high
Knowledge space
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Amine
Acid
Chloride
TFA Salt Drug Substance
UreaAcid
Stage 1
Stage 2 Stage 3
Stage 1A
7 steps
9 steps
2 steps
GMP
Regulatory Hurdles Toward Approval
One major section of new drug applications:
Chemistry, Manufacturing and Controls (CMC)
Task: Establish relationships (PAR/NOR) for all CQAs and all process variables
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Amine
Acid
Chloride
TFA Salt Drug Substance
UreaAcid
Stage 1
Stage 2 Stage 3
Stage 1A
7 steps
9 steps
2 steps
GMP
Regulatory Hurdles Toward Approval
Approach:
1. Divide manufacturing stages into sub-stages (unit operations)
2. Evaluate each parameter for quality impact
3. Design/execute DoE studies
4. Establish NORs/PARs
5. Validate at commercial production scale
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5
7 5
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Age Time 3
Temperature 1 0
Hold Values
Acid amount
So
luti
on
Co
ncen
trati
on
3.53.02.52.01 .5
1 00
90
80
70
60
>
–
–
–
–
–
–
–
–
–
–
<
97.9 98.2
98.2 98.5
98.5
96.7
96.7 96.8
96.8 96.9
96.9 97.0
97.0 97.1
97.1 97.2
97.2 97.3
97.3 97.6
97.6 97.9
Purity
Purity: Solution Concentration vs Acid Amount
>97.6% cutoff
Setting NOR and PAR values
Subtract error(3x )
PAR ranges
NOR ranges
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Putting It All Together
Assembling your regulatory filings:
-Clear description of the approach
-How/why was the study designed?
-Establish comparability to manufacturing outcomes
-Detail your knowledge space (where do excursions lead?)
-Laboratory references
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Putting It All Together
Assembling your regulatory filings:
-Clear description of the approach
-NORs/PARs and relevant controls
Global supporting controlled document
Included in New Drug Application
• 1.5 years• 10 people• 800 pages of supporting reports• 1 regulatory section• 6 manufacturers in 3 countries• >50 approvals worldwide
US FDA: “One of the best applications of DoE/QbD we have seen”