analytical elements of module 3 for biopharmaceutical ... · 4. qualification of all test methods...
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Analytical Elements of Module 3 for Biopharmaceutical Products: Beyond S.4 and P.5
Nadine M. Ritter, Ph.D.President and Sr. Analytical Advisor
Global Biotech Experts, LLCNadine.Ritter@GlobalBiotechExperts.com
To do this, their control strategy is based on:
ICH Q6B: Specifications; Test Procedures and Acceptance Criteria or Biotechnological/Biological Products (August 1999)
Capabilities of the analytical methods
© N.M. Ritter, Ph.D. 2019 2
Capabilities of the manufacturing process
Stability of the bulk substance and final product
Nature of pre‐clinical and clinical batches
Biopharmaceutics are molecularly complex and heterogeneous
Their heterogeneity must be characterized and controlled
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ONE Process, MANY Methods!
MULTIPLE ORTHOGONAL analytical methods are needed to measure all critical physical and functional characteristics
of a biological Drug Substance or Drug Product
© 2018 N. Ritter, Ph.D. © N.M. Ritter, Ph.D. 2019 3
Albrecht Dürer, “Rhinoceros” (1514)
© 2018 N. Ritter, Ph.D. © N.M. Ritter, Ph.D. 2019 4
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11 (12) CMC Analytical Data Packages =The Biomolecular “Story” of Each Rhino
1. Compositional, Conformational and Functional Characterization of Target Protein
© N.M. Ritter, Ph.D. 2019 5
CMC Analytical Data Packages =The Biomolecular “Story” of Each Rhino
1. Compositional, Conformational and Functional Characterization of Target Protein2. Characterization of Impurities (Product Impurities and Process Residuals)
© N.M. Ritter, Ph.D. 2019 6
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CMC Analytical Data Packages =The Biomolecular “Story” of Each Rhino
1. Compositional, Conformational and Functional Characterization of Target Protein2. Characterization of Impurities (Product Impurities and Process Residuals)3. Establishment and Bridging of Product Reference Standards
© N.M. Ritter, Ph.D. 2019 7
CMC Analytical Data Packages =The Biomolecular “Story” of Each Rhino
1. Compositional, Conformational and Functional Characterization of Target Protein2. Characterization of Impurities (Product Impurities and Process Residuals)3. Establishment and Bridging of Product Reference Standards4. Qualification of All Test Methods (e.g. establish linearity, precision, accuracy,
specificity, etc…)
© N.M. Ritter, Ph.D. 2019 8
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CMC Analytical Data Packages =The Biomolecular “Story” of Each Rhino
1. Compositional, Conformational and Functional Characterization of Target Protein2. Characterization of Impurities (Product Impurities and Process Residuals)3. Establishment and Bridging of Product Reference Standards4. Qualification of All Test Methods (e.g. establish linearity, precision, accuracy,
specificity, etc…)5. Validation of cGMP Test Methods (e.g. confirmation of above parameters, plus
addition of data for method robustness and stability‐indicating capability)
© N.M. Ritter, Ph.D. 2019 9
CMC Analytical Data Packages =The Biomolecular “Story” of Each Rhino
1. Compositional, Conformational and Functional Characterization of Target Protein2. Characterization of Impurities (Product Impurities and Process Residuals)3. Establishment and Bridging of Product Reference Standards4. Qualification of All Test Methods (e.g. establish linearity, precision, accuracy,
specificity, etc…)5. Validation of cGMP Test Methods (e.g. confirmation of above parameters, plus
addition of data for method robustness and stability‐indicating capability)6. DP Formulation development (excipient selection, formulation stability)
© N.M. Ritter, Ph.D. 2019 10
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CMC Analytical Data Packages =The Biomolecular “Story” of Each Rhino
1. Compositional, Conformational and Functional Characterization of Target Protein2. Characterization of Impurities (Product Impurities and Process Residuals)3. Establishment and Bridging of Product Reference Standards4. Qualification of All Test Methods (e.g. establish linearity, precision, accuracy,
specificity, etc…)5. Validation of cGMP Test Methods (e.g. confirmation of above parameters, plus
addition of data for method robustness and stability‐indicating capability)6. DP Formulation development (excipient selection, formulation stability)7. DS and DP Batch release data (manufacturing consistency and product quality)
© N.M. Ritter, Ph.D. 2019 11
CMC Analytical Data Packages =The Biomolecular “Story” of Each Rhino
1. Compositional, Conformational and Functional Characterization of Target Protein2. Characterization of Impurities (Product Impurities and Process Residuals)3. Establishment and Bridging of Product Reference Standards4. Qualification of All Test Methods (e.g. establish linearity, precision, accuracy,
specificity, etc…)5. Validation of cGMP Test Methods (e.g. confirmation of above parameters, plus
addition of data for method robustness and stability‐indicating capability)6. DP Formulation development (excipient selection, formulation stability)7. DS and DP Batch release data (manufacturing consistency and product quality)8. Extractable and Leachable Studies (risk assessment for DS; confirmation for DP)
© N.M. Ritter, Ph.D. 2019 12
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CMC Analytical Data Packages =The Biomolecular “Story” of Each Rhino
1. Compositional, Conformational and Functional Characterization of Target Protein2. Characterization of Impurities (Product Impurities and Process Residuals)3. Establishment and Bridging of Product Reference Standards4. Qualification of All Test Methods (e.g. establish linearity, precision, accuracy,
specificity, etc…)5. Validation of cGMP Test Methods (e.g. confirmation of above parameters, plus
addition of data for method robustness and stability‐indicating capability)6. DP Formulation development (excipient selection, formulation stability)7. DS and DP Batch release data (manufacturing consistency and product quality)8. Extractable and Leachable Studies (risk assessment for DS; confirmation for DP)9. Degradation evaluation (establishment of stability profile, validate stability
methods, characterize degradants, assess comparability/similarity)
© N.M. Ritter, Ph.D. 2019 13
CMC Analytical Data Packages =The Biomolecular “Story” of Each Rhino
1. Compositional, Conformational and Functional Characterization of Target Protein2. Characterization of Impurities (Product Impurities and Process Residuals)3. Establishment and Bridging of Product Reference Standards4. Qualification of All Test Methods (e.g. establish linearity, precision, accuracy,
specificity, etc…)5. Validation of cGMP Test Methods (e.g. confirmation of above parameters, plus
addition of data for method robustness and stability‐indicating capability)6. DP Formulation development (excipient selection, formulation stability)7. DS and DP Batch release data (manufacturing consistency and product quality)8. Extractable and Leachable Studies (risk assessment for DS; confirmation for DP)9. Degradation evaluation (establishment of stability profile, validate stability
methods, characterize degradants, assess comparability/similarity)10. ICH Stability testing (accelerated and ongoing real‐time/real conditions)
© N.M. Ritter, Ph.D. 2019 14
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CMC Analytical Data Packages =The Biomolecular “Story” of Each Rhino
1. Compositional, Conformational and Functional Characterization of Target Protein2. Characterization of Impurities (Product Impurities and Process Residuals)3. Establishment and Bridging of Product Reference Standards4. Qualification of All Test Methods (e.g. establish linearity, precision, accuracy,
specificity, etc…)5. Validation of cGMP Test Methods (e.g. confirmation of above parameters, plus
addition of data for method robustness and stability‐indicating capability)6. DP Formulation development (excipient selection, formulation stability)7. DS and DP Batch release data (manufacturing consistency and product quality)8. Extractable and Leachable Studies (risk assessment for DS; confirmation for DP)9. Degradation evaluation (establishment of stability profile, validate stability
methods, characterize degradants, assess comparability/similarity)10. ICH Stability testing (accelerated and ongoing real‐time/real conditions)11. DS and DP Comparability assessment (during clinical development and post‐
approval)
© N.M. Ritter, Ph.D. 2019 15
ProcessA
ProcessB
ProcessC
CMC Analytical Data Packages =The Biomolecular “Story” of Each Rhino
1. Compositional, Conformational and Functional Characterization of Target Protein2. Characterizatiompurities (Product Impurities and Process Residuals)3. Establishment and Bridging of Product Reference Standards4. Qualification of All Test Methods (e.g. establish linearity, precision, accuracy,
specificity, etc…)5. Validation of cGMP Test Methods (e.g. confirmation of above parameters, plus
addition of data for method robustness and stability‐indicating capability)6. DP Formulation development (excipient selection, formulation stability)7. DS and DP Batch release data (manufacturing consistency and product quality)8. Extractable and Leachable Studies (risk assessment for DS; confirmation for DP)9. Degradation evaluation (establishment of stability profile, validate stability
methods, characterize degradants, assess comparability/similarity)10. ICH Stability testing (accelerated and ongoing real‐time/real conditions)11. DS and DP Comparability assessment (during clinical development and post‐
approval)BIOSIMILAR PRODUCTS ONLY:12. Analytical Similarity – Comparison of Biosimilar product to Originator Product
© N.M. Ritter, Ph.D. 2019 16
ProductA
ProductB
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CMC Analytical Data Packages =The Biomolecular “Story” of Each Rhino
1. Compositional, Conformational and Functional Characterization of Target Protein2. Characterization of Impurities (Product Impurities and Process Residuals)3. Establishment and Bridging of Product Reference Standards4. Qualification of All Test Methods (e.g. establish linearity, precision, accuracy,
specificity, etc…)5. Validation of cGMP Test Methods (e.g. confirmation of above parameters, plus
addition of data for method robustness and stability‐indicating capability)6. DP Formulation development (excipient selection, formulation stability)7. DS and DP Batch release data (manufacturing consistency and product quality)8. Extractable and Leachable Studies (risk assessment for DS; confirmation for DP)9. Degradation evaluation (establishment of stability profile, validate stability
methods, characterize degradants, assess comparability/similarity)10. ICH Stability testing (accelerated and ongoing real‐time/real conditions)11. DS and DP Comparability assessment (during clinical development and post‐
approval)BIOSIMILAR PRODUCTS ONLY:12. Analytical Similarity – Comparison of Biosimilar product to Originator Product
© N.M. Ritter, Ph.D. 2019 17
The Harmonized CMC “Story Board”
• ICH Guidance M4Q(R1) (September 2002)
– Module 3 Quality (CMC)
– 3.2.S. Drug Substance
– 3.2.P. Drug Product
– 3.2.A. Appendices
– 3.2.R. Regional Information
• ICH M4Q Q&A (July 2003)
– The majority of clarifications and additions were on analytical issues associated with 3.2.S. and 3.2.P. sections
– Some Q&As add substantial details to the analytical ‘story’
© N.M. Ritter, Ph.D. 2019 18
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3.2.S. Drug Substance 1. General Information
1.1 Nomenclature
1.2 Structure
1.3 General Properties
2. Manufacture
2.1 Manufacturer
2.2 Manufacturing Process and Controls
2.3 Control of Materials
2.4 Control of Critical Steps and Inter.
2.5 Process Validation
2.6 Process Development
3. Characterization
3.1 Structure and Characteristics
3.2 Product and Process Impurities
4. Control of Drug Substance
4.1 Specifications
4.2 Analytical Procedures
4.3 Validation of Analytical Procedures
4.4 Batch Analyses
4.5 Justification of Specification
5. Reference Standards
6. Container Closure System
7. Stability
7.1 Summary and Conclusions
7.2 Post Approval Commitment
7.3 Stability Data
© N.M. Ritter, Ph.D. 2019 19
My name is Rhino
I am big and the analytical data say that overall I look like this:
3.2.S. Drug Substance 1. General Information
1.1 Nomenclature
1.2 Structure
1.3 General Properties
2. Manufacture
2.1 Manufacturer
2.2 Manufacturing Process and Controls
2.3 Control of Materials
2.4 Control of Critical Steps and Inter.
2.5 Process Validation
2.6 Process Development
3. Characterization
3.1 Structure and Characteristics
3.2 Product and Process Impurities
4. Control of Drug Substance
4.1 Specifications
4.2 Analytical Procedures
4.3 Validation of Analytical Procedures
4.4 Batch Analyses
4.5 Justification of Specification
5. Reference Standards
6. Container Closure System
7. Stability
7.1 Summary and Conclusions
7.2 Post Approval Commitment
7.3 Stability Data
© N.M. Ritter, Ph.D. 2019 20
Here are the analytical labs that do QC release and stability testing of my DS
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3.2.S. Drug Substance 1. General Information
1.1 Nomenclature
1.2 Structure
1.3 General Properties
2. Manufacture
2.1 Manufacturer
2.2 Manufacturing Process and Controls
2.3 Control of Materials
2.4 Control of Critical Steps and Intermed.
2.5 Process Validation
2.6 Process Development
3. Characterization
3.1 Structure and Characteristics
3.2 Product and Process Impurities
4. Control of Drug Substance
4.1 Specifications
4.2 Analytical Procedures
4.3 Validation of Analytical Procedures
4.4 Batch Analyses
4.5 Justification of Specification
5. Reference Standards
6. Container Closure System
7. Stability
7.1 Summary and Conclusions
7.2 Post Approval Commitment
7.3 Stability Data
© N.M. Ritter, Ph.D. 2019 21
Here are the analytics used to control my DS raw materials and US/DS intermediates
3.2.S. Drug Substance 1. General Information
1.1 Nomenclature
1.2 Structure
1.3 General Properties
2. Manufacture
2.1 Manufacturer
2.2 Manufacturing Process and Controls
2.3 Control of Materials
2.4 Control of Critical Steps and Inter.
2.5 Process Validation
2.6 Process Development
3. Characterization
3.1 Structure and Characteristics
3.2 Product and Process Impurities
4. Control of Drug Substance
4.1 Specifications
4.2 Analytical Procedures
4.3 Validation of Analytical Procedures
4.4 Batch Analyses
4.5 Justification of Specification
5. Reference Standards
6. Container Closure System
7. Stability
7.1 Summary and Conclusions
7.2 Post Approval Commitment
7.3 Stability Data
© N.M. Ritter, Ph.D. 2019 22
Here are the analytical comparability studies done to check my DS process changes
ProcessA
ProcessB
ProcessC
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3.2.S. Drug Substance 1. General Information
1.1 Nomenclature
1.2 Structure
1.3 General Properties
2. Manufacture
2.1 Manufacturer
2.2 Manufacturing Process and Controls
2.3 Control of Materials
2.4 Control of Critical Steps and Inter.
2.5 Process Validation
2.6 Process Development
3. Characterization
3.1 Structure and Characteristics
3.2 Product and Process Impurities
4. Control of Drug Substance
4.1 Specifications
4.2 Analytical Procedures
4.3 Validation of Analytical Procedures
4.4 Batch Analyses
4.5 Justification of Specification
5. Reference Standards
6. Container Closure System
7. Stability
7.1 Summary and Conclusions
7.2 Post Approval Commitment
7.3 Stability Data
© N.M. Ritter, Ph.D. 2019 23
Here are the analytical data that prove my structure and function
3.2.S. Drug Substance 1. General Information
1.1 Nomenclature
1.2 Structure
1.3 General Properties
2. Manufacture
2.1 Manufacturer
2.2 Manufacturing Process and Controls
2.3 Control of Materials
2.4 Control of Critical Steps and Inter.
2.5 Process Validation
2.6 Process Development
3. Characterization
3.1 Structure and Characteristics
3.2 Product and Process Impurities
4. Control of Drug Substance
4.1 Specifications
4.2 Analytical Procedures
4.3 Validation of Analytical Procedures
4.4 Batch Analyses
4.5 Justification of Specification
5. Reference Standards
6. Container Closure System
7. Stability
7.1 Summary and Conclusions
7.2 Post Approval Commitment
7.3 Stability Data
© N.M. Ritter, Ph.D. 2019 24
Here are the analytical data that prove which degradants and impurities I could have
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3.2.S. Drug Substance 1. General Information
1.1 Nomenclature
1.2 Structure
1.3 General Properties
2. Manufacture
2.1 Manufacturer
2.2 Manufacturing Process and Controls
2.3 Control of Materials
2.4 Control of Critical Steps and Inter.
2.5 Process Validation
2.6 Process Development
3. Characterization
3.1 Structure and Characteristics
3.2 Product and Process Impurities
4. Control of Drug Substance
4.1 Specifications
4.2 Analytical Procedures
4.3 Validation of Analytical Procedures
4.4 Batch Analyses
4.5 Justification of Specification
5. Reference Standards
6. Container Closure System
7. Stability
7.1 Summary and Conclusions
7.2 Post Approval Commitment
7.3 Stability Data
© N.M. Ritter, Ph.D. 2019 25
Here are the analytical controls to keep my DS consistent
3.2.S. Drug Substance 1. General Information
1.1 Nomenclature
1.2 Structure
1.3 General Properties
2. Manufacture
2.1 Manufacturer
2.2 Manufacturing Process and Controls
2.3 Control of Materials
2.4 Control of Critical Steps and Inter.
2.5 Process Validation
2.6 Process Development
3. Characterization
3.1 Structure and Characteristics
3.2 Product and Process Impurities
4. Control of Drug Substance
4.1 Specifications
4.2 Analytical Procedures
4.3 Validation of Analytical Procedures
4.4 Batch Analyses
4.5 Justification of Specification
5. Reference Standards
6. Container Closure System
7. Stability
7.1 Summary and Conclusions
7.2 Post Approval Commitment
7.3 Stability Data
© N.M. Ritter, Ph.D. 2019 26
Here how the QC methods used to measure my DS are conducted
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3.2.S. Drug Substance 1. General Information
1.1 Nomenclature
1.2 Structure
1.3 General Properties
2. Manufacture
2.1 Manufacturer
2.2 Manufacturing Process and Controls
2.3 Control of Materials
2.4 Control of Critical Steps and Inter.
2.5 Process Validation
2.6 Process Development
3. Characterization
3.1 Structure and Characteristics
3.2 Product and Process Impurities
4. Control of Drug Substance
4.1 Specifications
4.2 Analytical Procedures
4.3 Validation of Analytical Procedures
4.4 Batch Analyses
4.5 Justification of Specification
5. Reference Standards
6. Container Closure System
7. Stability
7.1 Summary and Conclusions
7.2 Post Approval Commitment
7.3 Stability Data
© N.M. Ritter, Ph.D. 2019 27
Here is proof of how they can perform reliably and accurately
3.2.S. Drug Substance 1. General Information
1.1 Nomenclature
1.2 Structure
1.3 General Properties
2. Manufacture
2.1 Manufacturer
2.2 Manufacturing Process and Controls
2.3 Control of Materials
2.4 Control of Critical Steps and Inter.
2.5 Process Validation
2.6 Process Development
3. Characterization
3.1 Structure and Characteristics
3.2 Product and Process Impurities
4. Control of Drug Substance
4.1 Specifications
4.2 Analytical Procedures
4.3 Validation of Analytical Procedures
4.4 Batch Analyses
4.5 Justification of Specification
5. Reference Standards
6. Container Closure System
7. Stability
7.1 Summary and Conclusions
7.2 Post Approval Commitment
7.3 Stability Data
© N.M. Ritter, Ph.D. 2019 28
Here is the gold standard rhino against which other rhinos are analytically compared
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3.2.S. Drug Substance 1. General Information
1.1 Nomenclature
1.2 Structure
1.3 General Properties
2. Manufacture
2.1 Manufacturer
2.2 Manufacturing Process and Controls
2.3 Control of Materials
2.4 Control of Critical Steps and Inter.
2.5 Process Validation
2.6 Process Development
3. Characterization
3.1 Structure and Characteristics
3.2 Product and Process Impurities
4. Control of Drug Substance
4.1 Specifications
4.2 Analytical Procedures
4.3 Validation of Analytical Procedures
4.4 Batch Analyses
4.5 Justification of Specification
5. Reference Standards
6. Container Closure System
7. Stability
7.1 Summary and Conclusions
7.2 Post Approval Commitment
7.3 Stability Data
© N.M. Ritter, Ph.D. 2019 29
Here are the analytical data showing I am stable over time
1. Description and Composition2. Pharmaceutical Development
2.1 Components2.2 Drug Product2.3 Manufacturing Process Development2.4 Container Closure System2.5 Microbiological Attributes2.6 Compatibility
3. Manufacture3.1 Manufacturer3.2 Batch Formula3.3 Descr of Process and Process Controls3.4 Control of Critical Steps and Ints3.5 Process Validation
4. Control of Excipients5. Control of Drug Product
5.1 Specifications5.2 Analytical Procedures5.3 Validation of Analytical Procedures5.4 Batch Analyses5.5 Characterization of Impurities5.6 Justification of Specification
6. Reference Standards7. Container Closure System8. Stability
8.1 Summary and Conclusions8.2 Post Approval Commitment8.3 Stability Data
© N.M. Ritter, Ph.D. 2019 30
3.2.P. Drug Product
Here is my DP form
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1. Description and Composition2. Pharmaceutical Development
2.1 Components2.2 Drug Product2.3 Manufacturing Process Development2.4 Container Closure System2.5 Microbiological Attributes2.6 Compatibility
3. Manufacture3.1 Manufacturer3.2 Batch Formula3.3 Descr of Process and Process Controls3.4 Control of Critical Steps and Ints3.5 Process Validation
4. Control of Excipients5. Control of Drug Product
5.1 Specifications5.2 Analytical Procedures5.3 Validation of Analytical Procedures5.4 Batch Analyses5.5 Characterization of Impurities5.6 Justification of Specification
6. Reference Standards7. Container Closure System8. Stability
8.1 Summary and Conclusions8.2 Post Approval Commitment8.3 Stability Data
© N.M. Ritter, Ph.D. 2019 31
3.2.P. Drug Product
Here are the analytical comparability studies done to check my DP process changes
ProcessA
ProcessB
ProcessC
1. Description and Composition2. Pharmaceutical Development
2.1 Components2.2 Drug Product2.3 Manufacturing Process Development2.4 Container Closure System2.5 Microbiological Attributes2.6 Compatibility
3. Manufacture3.1 Manufacturer3.2 Batch Formula3.3 Descr of Process and Process Controls3.4 Control of Critical Steps and Ints3.5 Process Validation
4. Control of Excipients5. Control of Drug Product
5.1 Specifications5.2 Analytical Procedures5.3 Validation of Analytical Procedures5.4 Batch Analyses5.5 Characterization of Impurities5.6 Justification of Specification
6. Reference Standards7. Container Closure System8. Stability
8.1 Summary and Conclusions8.2 Post Approval Commitment8.3 Stability Data
© N.M. Ritter, Ph.D. 2019 32
3.2.P. Drug Product
Here are the analytical data showing the potential for leachablesforming in the DP
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1. Description and Composition2. Pharmaceutical Development
2.1 Components2.2 Drug Product2.3 Manufacturing Process Development2.4 Container Closure System2.5 Microbiological Attributes2.6 Compatibility
3. Manufacture3.1 Manufacturer3.2 Batch Formula3.3 Descr of Process and Process Controls3.4 Control of Critical Steps and Ints3.5 Process Validation
4. Control of Excipients5. Control of Drug Product
5.1 Specifications5.2 Analytical Procedures5.3 Validation of Analytical Procedures5.4 Batch Analyses5.5 Characterization of Impurities5.6 Justification of Specification
6. Reference Standards7. Container Closure System8. Stability
8.1 Summary and Conclusions8.2 Post Approval Commitment8.3 Stability Data
© N.M. Ritter, Ph.D. 2019 33
3.2.P. Drug Product
Here are the analytical labs that do QC release and stability testing of my DP
1. Description and Composition2. Pharmaceutical Development
2.1 Components2.2 Drug Product2.3 Manufacturing Process Development2.4 Container Closure System2.5 Microbiological Attributes2.6 Compatibility
3. Manufacture3.1 Manufacturer3.2 Batch Formula3.3 Descr of Process and Process Controls3.4 Control of Critical Steps and Ints3.5 Process Validation
4. Control of Excipients5. Control of Drug Product
5.1 Specifications5.2 Analytical Procedures5.3 Validation of Analytical Procedures5.4 Batch Analyses5.5 Characterization of Impurities5.6 Justification of Specification
6. Reference Standards7. Container Closure System8. Stability
8.1 Summary and Conclusions8.2 Post Approval Commitment8.3 Stability Data
© N.M. Ritter, Ph.D. 2019 34
3.2.P. Drug Product
Here are the analytics used to control my DP formulation and filling steps
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1. Description and Composition2. Pharmaceutical Development
2.1 Components2.2 Drug Product2.3 Manufacturing Process Development2.4 Container Closure System2.5 Microbiological Attributes2.6 Compatibility
3. Manufacture3.1 Manufacturer3.2 Batch Formula3.3 Descr of Process and Process Controls3.4 Control of Critical Steps and Ints3.5 Process Validation
4. Control of Excipients5. Control of Drug Product
5.1 Specifications5.2 Analytical Procedures5.3 Validation of Analytical Procedures5.4 Batch Analyses5.5 Characterization of Impurities5.6 Justification of Specification
6. Reference Standards7. Container Closure System8. Stability
8.1 Summary and Conclusions8.2 Post Approval Commitment8.3 Stability Data
© N.M. Ritter, Ph.D. 2019 35
3.2.P. Drug Product
Here are the analytics used to control my DP excipients
1. Description and Composition2. Pharmaceutical Development
2.1 Components2.2 Drug Product2.3 Manufacturing Process Development2.4 Container Closure System2.5 Microbiological Attributes2.6 Compatibility
3. Manufacture3.1 Manufacturer3.2 Batch Formula3.3 Descr of Process and Process Controls3.4 Control of Critical Steps and Ints3.5 Process Validation
4. Control of Excipients5. Control of Drug Product
5.1 Specifications5.2 Analytical Procedures5.3 Validation of Analytical Procedures5.4 Batch Analyses5.5 Characterization of Impurities5.6 Justification of Specification
6. Reference Standards7. Container Closure System8. Stability
8.1 Summary and Conclusions8.2 Post Approval Commitment8.3 Stability Data
© N.M. Ritter, Ph.D. 2019 36
3.2.P. Drug Product
Here are the analytical controls to keep my DP consistent
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1. Description and Composition2. Pharmaceutical Development
2.1 Components2.2 Drug Product2.3 Manufacturing Process Development2.4 Container Closure System2.5 Microbiological Attributes2.6 Compatibility
3. Manufacture3.1 Manufacturer3.2 Batch Formula3.3 Descr of Process and Process Controls3.4 Control of Critical Steps and Ints3.5 Process Validation
4. Control of Excipients5. Control of Drug Product
5.1 Specifications5.2 Analytical Procedures5.3 Validation of Analytical Procedures5.4 Batch Analyses5.5 Characterization of Impurities5.6 Justification of Specification
6. Reference Standards7. Container Closure System8. Stability
8.1 Summary and Conclusions8.2 Post Approval Commitment8.3 Stability Data
© N.M. Ritter, Ph.D. 2019 37
3.2.P. Drug Product
Here how the QC methods used to measure my DP are conducted
1. Description and Composition2. Pharmaceutical Development
2.1 Components2.2 Drug Product2.3 Manufacturing Process Development2.4 Container Closure System2.5 Microbiological Attributes2.6 Compatibility
3. Manufacture3.1 Manufacturer3.2 Batch Formula3.3 Descr of Process and Process Controls3.4 Control of Critical Steps and Ints3.5 Process Validation
4. Control of Excipients5. Control of Drug Product
5.1 Specifications5.2 Analytical Procedures5.3 Validation of Analytical Procedures5.4 Batch Analyses5.5 Characterization of Impurities5.6 Justification of Specification
6. Reference Standards7. Container Closure System8. Stability
8.1 Summary and Conclusions8.2 Post Approval Commitment8.3 Stability Data
© N.M. Ritter, Ph.D. 2019 38
3.2.P. Drug Product
Here is proof of how they can perform reliably and accurately
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1. Description and Composition2. Pharmaceutical Development
2.1 Components2.2 Drug Product2.3 Manufacturing Process Development2.4 Container Closure System2.5 Microbiological Attributes2.6 Compatibility
3. Manufacture3.1 Manufacturer3.2 Batch Formula3.3 Descr of Process and Process Controls3.4 Control of Critical Steps and Ints3.5 Process Validation
4. Control of Excipients5. Control of Drug Product
5.1 Specifications5.2 Analytical Procedures5.3 Validation of Analytical Procedures5.4 Batch Analyses5.5 Characterization of Impurities5.6 Justification of Specification
6. Reference Standards7. Container Closure System8. Stability
8.1 Summary and Conclusions8.2 Post Approval Commitment8.3 Stability Data
© N.M. Ritter, Ph.D. 2019 39
3.2.P. Drug Product
Here are analytical data on the DP degradants and impurities that I could have
1. Description and Composition2. Pharmaceutical Development
2.1 Components2.2 Drug Product2.3 Manufacturing Process Development2.4 Container Closure System2.5 Microbiological Attributes2.6 Compatibility
3. Manufacture3.1 Manufacturer3.2 Batch Formula3.3 Descr of Process and Process Controls3.4 Control of Critical Steps and Ints3.5 Process Validation
4. Control of Excipients5. Control of Drug Product
5.1 Specifications5.2 Analytical Procedures5.3 Validation of Analytical Procedures5.4 Batch Analyses5.5 Characterization of Impurities5.6 Justification of Specification
6. Reference Standards7. Container Closure System8. Stability
8.1 Summary and Conclusions8.2 Post Approval Commitment8.3 Stability Data
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3.2.P. Drug Product
Here is the analytical gold standard DP rhino (if different from DS gold standard)
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1. Description and Composition2. Pharmaceutical Development
2.1 Components2.2 Drug Product2.3 Manufacturing Process Development2.4 Container Closure System2.5 Microbiological Attributes2.6 Compatibility
3. Manufacture3.1 Manufacturer3.2 Batch Formula3.3 Descr of Process and Process Controls3.4 Control of Critical Steps and Ints3.5 Process Validation
4. Control of Excipients5. Control of Drug Product
5.1 Specifications5.2 Analytical Procedures5.3 Validation of Analytical Procedures5.4 Batch Analyses5.5 Characterization of Impurities5.6 Justification of Specification
6. Reference Standards7. Container Closure System8. Stability
8.1 Summary and Conclusions8.2 Post Approval Commitment8.3 Stability Data
© N.M. Ritter, Ph.D. 2019 41
3.2.P. Drug Product
Here are the analytical data proving I am stable over time
Any additional drug substance and/or drug product information specific to each region should be provided. Consult the appropriate regional guidance and/or regulatory authorities for additional guidance.
BIOSIMILAR PRODUCTSAnalytical data packages comparing Biosimilar Product to Reference Product
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3.2.R. Regional Information
Here are the analytical similarity data comparing a biosimilar rhino product to the reference rhino product
PRODUCTA
PRODUCTB
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Phase 1 CommercialPre‐ClinicalQUALIFY R&DMETHODS
QUALIFIED R&DMETHODS
QUALIFIED R&DMETHODS
QUALIFIED R&DMETHODS
PH 1 VALIDATEMETHODS
INITIAL PRODUCTCHARACTERIZATION
1ST REFERENCE STDCHARACTERIZATION
NEW REFERENCE LOTQUALIFICATIONS
PROCESS CHANGECOMPARABILITY
PROCESS CHANGECOMPARABILITY
PROCESS CHANGECOMPARABILITY
LOT RELEASE –DP LOTS
LOT RELEASE –DP LOTS
LOT RELEASE –DP LOTS
LOT RELEASE –DP LOTS
PRELIMINARYFORMULA TOX LOTS
STABILITY – INITIALFORMULATION
STABILITY – LEAD FORMULATIONS
STABILITY – FINALFORMULATION
STABILITY ‐ DP1 ANNUAL LOT
LOT RELEASE –DS LOTS
LOT RELEASE ‐ DSPHASE II LOTS
LOT RELEASE –DS LOTS
LOT RELEASE –DS LOTS
DS STABILITYTOX LOTS
STABILITY –DS CLIN LOTS
STABILITY –DS CLIN LOTS
STABILITY –DS CLIN LOTS
STABILITY ‐ DS1 ANNUAL LOT
PRIMARY/WORKNGREFERENCE LOTS
NEW REFERENCE LOTQUALIFICATION
PH 3 VALIDATEMETHODS
PH 2 VALIDATE METHODS
RE‐VALIDATEMETHODS
FORMULATIONSCREENING STUDY
DP STABILITYTOX LOTS
FORMULATIONSELECTION STUDY
PROCESS CHANGECOMPARABILITY
SELECT QCDS and DP METHODS
EXT & LEACHSTUDY
FORM or C/C CHANGERE‐DO E&L
SELECT R&DDS and DP METHODS
Phase 2 Phase 3
COMMERCIALSPECIFICATIONS
PHASE 3 CLIN LOTSPECIFICATIONS
PHASE 2 CLIN LOTSPECIFICATIONS
PHASE 1 CLIN LOTSPECIFICATIONS
PRECLIN LOTSPECIFICATIONS
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LOT RELEASE –DP TOX LOTS
LOT RELEASE –DS TOX LOTS
ICH ACCELERATEDSTABILITY DATA
VALIDATESTABILITY METHODS
FORCED DEGRADATIONSTUDY DATA
RE‐VALIDATESTABILITY METHODS
© N.M. Ritter, Ph.D. 2019
Initial Clinical CommercialPre‐Clinical
VALIDATEMETHODS
VALIDATE QCMETHODS
RE‐VALIDATEQC METHODS
ICH ACCELERATEDSTABILITY DATA
1ST REFERENCE STDCHARACTERIZATION
REFERENCE STDBRIDGING
NEW REFERENCE LOTQUALIFICATIONS
PROCESS CHANGECOMPARABILITY
PROCESS CHANGECOMPARABILITY
LOT RELEASE –DP LOTS
LOT RELEASE –DP LOTS
LOT RELEASE –DP LOTS
STABILITY – INITIALFORMULATION
STABILITY – FINALFORMULATION
STABILITY ‐ DP1 ANNUAL LOT
LOT RELEASE –DS LOTS
LOT RELEASE –DS LOTS
LOT RELEASE –DS LOTS
DS STABILITYTOX LOTS
STABILITY –DS CLIN LOTS
STABILITY –DS CLIN LOTS
STABILITY ‐ DS1 ANNUAL LOT
PRIMARY/WORKNGREFERENCE LOTS
FORCED DEGSTABILITY METHODS
RE‐VALIDATESTABILITY METHODS
FORMULATIONOPTIMIZATION STUDY
DP STABILITYPRECLIN LOTS
PROCESS CHANGECOMPARABILITY
EXT & LEACHSTUDY
FORM or C/C CHANGERE‐DO E&L
SELECT QCDS and DP METHODS
Add’l Clinical
COMMERCIALSPECIFICATIONS
ADD’L CLIN LOTSPECIFICATIONS
INITIAL CLIN LOTSPECIFICATIONS
PRECLIN LOTSPECIFICATIONS
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LOT RELEASE –DP TOX LOTS
LOT RELEASE –DS TOX LOTS
BIOSIMILARITY
ANALYITCALSIMILARITYSTUDIES:• PRIMARY• SECONDARY• TERTIARY• HOS• FUNCTIONAL
ANALYSES• ACCELERATED
STABILITY• SIDE BY SIDE
FORCED DEGRADED
SIMILARITYSPECIFICATIONS
QUALIFY R&DMETHODS
CHARACTERIZEREFERENCE PRODUCT
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The CMC dossier should tell each Rhino’s complete analytical story:
“Here is evidence proving my complexity and heterogeneity*, and here is how it is controlled
and maintained consistently over time”
© N.M. Ritter, Ph.D. 2019
*Each biosimilar Rhino’s analytical story includes:“Here is evidence of how my complexity and heterogeneity compares to their complexity
and heterogeneity”
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THANK YOU!
© N.M. Ritter, Ph.D. 2019
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