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Trevor Schoerie
Guidelines
Please contribute and ask questions
Please relax and enjoy yourself Phone on silent / mute? Native presentation can be emailed.
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Agenda
The what, who, why, where, when but not the how of QbD 1 What is QbD? 2 Who is driving QbD? 3 Why are we talking about QbD? 4 Where will QbD be applicable? 5 When will we need to adopt QbD? 6 How do we do QbD?
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What is QbD?
The quality by design (QbD) principle can be simply stated as follows:
Once a system has been tested to the extent that the test results are predictable, further testing can be replaced by establishing that the system was operating within a defined design space.
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Quality Targeted Product Profiles QTPP Design of experiments DOE Product Lifecycle
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Design space
QbD
Control strategy
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1987 | 2000
|2002
| 2004
| 2006
2013
ICH Q8
ASTM E250007
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What is QbD?
Quality by Design (QbD) is a concept first outlined by Juran
ICH - concepts 1. Quality by Design 2. Design Space 3. Design of Experiments 4. Critical Quality Attributes (CQA) 5. Critical Process Parameters (CPP) 6. Control Strategy
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FDA PV Stages
Stage 1 Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities. Stage 2 Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing. Stage 3 Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control.
[FDA Guidance for Industry Process Validation: General Principles and Practices, Jan 2011]
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FDA Stage 1
Stage
Process design
Intent
Typical activities
To define the A combination of product and process commercial process on design (Quality by Design) knowledge gained through development Product development activities and scale up activities Experiments to determine process parameters, The outcome is the variability and necessary design of a process controls suitable for routine manufacture that will Risk assessments consistently deliver product that meets its Other activities required to define the critical quality commercial process attributes Design of Experiment testing
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FDA Stage 2
Stage
Process Qualification
Intent
Typical activities
To confirm the process Facility design design as capable of reproducible Equipment & utilities qualification commercial manufacturing Process Performance qualification (PPQ)* Strong emphasis on the use of statistical analysis of process data to understand process consistency and performance
* Note: The term Process Performance Qualification or PPQ has been carried over from the 1987 guidance. This term is analogous with the traditional concept of process validation, as multiple batches of product made at commercial scale under commercial manufacturing conditions. It is not the same as the concept of equipment performance qualification.
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FDA Stage 3
Stage
Continued Process Verification
Intent
To provide ongoing assurance that the process remains in a state of control during routine production through quality procedures and continuous improvement initiatives.
Typical activities
Product review
Quality by Design for ANDAs: An example for Modified Release Dosage Forms Dec 2011
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugA pplicationANDAGenerics/UCM286595.pdf
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ICH
ICH Q8, Q9, Q10 & Q11are designed as separate but linked in a series of documents exploring pharmaceutical products lifecycle
ICH Q8 Pharmaceutical Development ICH Q9 Quality Risk Management ICH Q10 Pharmaceutical Quality System ICH Q11 - Development and Manufacture of Drug Substances
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ICH Q8 Concepts
Critical Process Parameter (CPP) Control strategy
CQA Variable 1
Design Space
CQA Variable 4 Design Space CDQ Variable 3 CQA Variable 2
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Investigational products
PQS elements
Management review
Enablers
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Enhanced approach
Risk management & science. process parameters and unit operations that impact on CQA Further studies, design space & control strategies over the lifecycle.
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ICH Q11 Example Linking Material Attributes & process parameters to a Drug CQA
hydrolysis_impurity
hydrolysis_impurity
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ICH Q11 Example Linking Material Attributes & process parameters to a Drug CQA
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ICH Q11 Example Linking Material Attributes & process parameters to a Drug CQA
Traditional Approach: Set a proven acceptable range for % water and time that achieves the acceptance criteria for the hydrolysis impurity of 0.30% in intermediate F. Dry Intermediate E to a water content < 1.0%. Target reflux time of 1.5 hours and a maximum reflux time of 4 hours
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ICH Q11 Example Linking Material Attributes & process parameters to a Drug CQA
Enhanced Approach:
[H20] o
M=[F]o/ [H20] o to
XF
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ICH Q11 Example Linking Material Attributes & process parameters to a Drug CQA
Summary: While both the traditional and enhanced approach provide ranges of water content and time to control the formation of the hydrolysis impurity, the enhanced approach allows more manufacturing flexibility.
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Control Strategy
Planned set of controls, derived from current product and process understanding that assures process performance and product quality A control strategy can include, but is not limited to, the following: Material attributes (raw materials, starting materials, intermediates, reagents, primary packaging materials) Controls are implicit in the design of the manufacturing process In-process controls Controls on drug substance
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Organic Purity
Design space of the reflux unit operation composed of a combination of % water in Intermediate E and the reflux time in step 5 that delivers Intermediate F with Hydrolysis Impurity 0.30% (3.2.S.2.2)
Process parameters step 4 (3.2.S.2.2) P(H2) 2 barg T <50C Specs for starting material D (3.2.S.2.3)
Yes/Yes
Yes/Yes
Any individual unspecified impurity NMT 0.10% Total impurities NMT 0.50% Enantiomeric purity S-enantiomer NMT 0.50% Residual Solvent Ethanol Slide 36 NMT 5000 ppm
Yes/Yes
Yes/Yes Specs for starting material D (3.2.S.2.3) S-enantiomer 0.50% Stereocentre is shown not to racemize; (3.2.S.2.6) In-process results correlated to test results on drug substance No/No
In-process test during drying after final purification step (3.2.S.2.4) LOD 0.40%
No/Yes
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/Abbreviat edNewDrugApplicationANDAGenerics/UCM304305.pdf
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Module 1
Nonclinical Overview Quality Overall Summary
Module 2
The CTD
Quality
Module 3
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Module 4
Module 5
Thanks
http://au.linkedin.com/in/schoerie
1. 2. 3. 4. 5. 6.
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What is QbD? Who is driving QbD? Why are we talking about QbD? Where will QbD be applicable? When will we need to adopt QbD? How do we do QbD?