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| List of Tables | |
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| List of Figures | |
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| Biopharmaceutical CMC Regulatory Compliance: What is It? | |
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| Defining Our Terms | |
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| What is a 'Biopharmaceutical'? | |
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| What is 'CMC' | |
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| What is 'CMC Regulatory Compliance'? | |
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| Under the Biopharmaceutical Umbrella | |
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| Recombinant DNA-Derived Proteins | |
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| Monoclonal Antibodies | |
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| Gene Therapy | |
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| Animal/Plant Transgenics | |
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| Rapid Pace of Biopharmaceutical Development | |
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| Regulatory Development of Biopharmaceuticals | |
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| The Drug Development Process | |
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| Regulatory Agency Review | |
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| U.S. FDA | |
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| EMEA | |
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| CMC Regulatory Compliance Track Record | |
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| Drugs and Biologics | |
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| Biopharmaceuticals | |
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| Are Biopharmaceuticals Really Different? | |
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| Perception or Reality? | |
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| Five Questions Frequently Asked | |
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| Bottom Line Question | |
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| Regulatory Agencies Speak | |
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| U.S. FDA | |
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| EMEA | |
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| ICH | |
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| Three Unique CMC Challenges for Biopharmaceuticals | |
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| The Use of Living Recombinant Organisms | |
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| The Products Themselves | |
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| The Impact of the Manufacturing Process | |
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| CMC Meetings with the FDA Take on Greater Importance | |
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| CMC Communication with FDA is Critical | |
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| Preparing for the CMC Meeting | |
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| Pre-IND Meeting | |
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| End of Phase 2 (EOP2) Meeting | |
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| Pre-BLA/NDA Meeting | |
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| What About CMC Meetings with EMEA? | |
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| Biopharmaceuticals Need to be Treated Differently | |
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| Developing the Corporate CMC Regulatory Compliance Strategy | |
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| Three Key Elements for a Complete CMC Strategy | |
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| Element 1: The Broad CMC Scope Must Be Considered | |
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| Element 2: Any Unique CMC Issues Must Be Addressed | |
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| Element 3: Must Meet Minimum CMC Regulatory Requirements | |
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| The Minimum CMC Continuum | |
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| Minimum CMC Requirements for Clinical Development | |
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| An Overview | |
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| Phase 1 | |
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| Phase 2 and 3 | |
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| Full CMC Requirements for Dossier Filing | |
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| Comparison of BLA/NDA and CTD CMC Formats | |
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| Adequate Resources Required to Compile the Full CMC Dossier | |
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| Quality of CMC Content Present in Dossier is Critical | |
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| 'Case-By-Case' CMC Strategy Specifics | |
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| Can't Ignore cGMPs | |
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| Not Optional | |
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| What are 'cGMPs'? | |
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| Three main GMP questions | |
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| GMPs for Everything | |
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| For Finished Drug Products | |
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| Required for APIs Also | |
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| Extra GMPs for Biopharmaceuticals | |
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| Where in the Manufacturing Process Should GMP Begin? | |
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| When During Clinical Development Should GMP Begin? | |
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| API Clinical Trial Materials | |
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| Drug Product Clinical Trial Materials | |
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| Consequences of Not Following GMPs | |
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| Issues with Market Approved Biopharmaceuticals | |
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| Issues During Clinical Development | |
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| How to Avoid GMP Difficulties with the FDA | |
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| Strategic CMC Tips for GMP Compliance | |
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| Recombinant Source Material: Master/Working Banks | |
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| Needed: Reliable, Continuous, Stable Genetic Source | |
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| Three Primary CMC Concerns for Banks | |
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| Genetic Construction of a Bank | |
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| So Many Hosts to Choose From | |
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| Bank Terminology | |
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| Choosing the Host | |
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| Drivers to Reach a Decision | |
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| Why Choose Recombinant Cells? | |
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| Why Bioengineered Animals or Plants? | |
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| CMC Guidance on Preparation of a Bank | |
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| Accurate and Thorough Description of Preparation | |
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| Recombinant Cell Banks | |
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| Transgenic Banks | |
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| Why Does The FDA Want So Much CMC Documentation? | |
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| When is Full CMC Documentation Needed? | |
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| What If CMC Documentation is Missing? | |
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| Don't forget GMPs During Preparation of the Bank | |
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| CMC Guidance on Characterization of a Bank | |
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| Appropriate and Sufficient Characterization | |
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| Six Key Elements for a Thorough Characterization | |
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| Recombinant Cell Bank Characterization | |
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| Example of Characterization of a Bacterial Cell Bank | |
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| Example of Characterization of a Mammalian Cell Bank | |
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| How Much Characterization and When? | |
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| Critical Concern for Virus Safety in Banks | |
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| Minimizing the Risk of TSEs | |
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| A Successful CMC Strategy for Banks | |
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| Production: Expansion of the Recombinant Organism and Expression of the Biopharmaceutical | |
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| Goals: Identity, Capacity and Consistency | |
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| Two Major CMC Regulatory Concerns for Production | |
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| Need for High and Consistent Expression of the Biopharmaceutical | |
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| What is a 'Production Process'? | |
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| Types of Bioreactors for Cell-Based Production | |
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| Harvesting Procedures for Biopharmaceuticals | |
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| Production Processes Familiar to the FDA | |
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| Adequate Description of the Production Process | |
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| During Clinical Development | |
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| Phase 1 IND Submission | |
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| Phase 2 IND Submission | |
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| Phase 3 IND Submission | |
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| Preparing the BLA/NDA Submission | |
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| Validation of a Cell-Based Production Process | |
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| When Should Validation of the Production Process Occur? | |
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| Five Major Areas Involved in Validation of the Production Process | |
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| The Production Facility, Utilities and Process Equipment | |
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| Monitoring of Growth Parameters | |
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| In-Process Controls | |
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| Genetic Stability | |
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| Cleaning Validation | |
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| Final Comments on Process Validation | |
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| Additional Production Controls and Concerns | |
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| Cell-Based Production Processes | |
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| Cell Culture Media Acceptance Criteria | |
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| Avoidance of Animal- and Human-Derived Raw Materials | |
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| Containment of the Recombinant Organism | |
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| Contamination Control for Aseptic Processing Operations | |
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| Gene Therapy Production Processes | |
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| Control of the Cells | |
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| RAC Review and Approval of the Production Process | |
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| Transgenic Animal Production Processes | |
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| Production Controls | |
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| Protecting the Gene Pool | |
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| Transgenic Plant Production Processes | |
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| 'Pharming' Controls | |
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| USDA/APHIS Protecting the Gene Pool | |
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| What Can Go Wrong | |
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| Strategic CMC Tips for Production | |
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| Purification of the Biopharmaceutical | |
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| Goals: Purity, Recovery and Consistency | |
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| Two Major CMC Regulatory Concerns for Purification | |
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| Need for High Recovery of a Pure Product | |
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| What is a 'Purification Process'? | |
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| Physical Separations Methods for Biopharmaceuticals | |
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| Chromatographic Purification Methods for Biopharmaceuticals | |
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| Purification Processes Familiar to the FDA | |
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| Adequate Description of the Purification Process | |
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| During Clinical Development | |
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| Phase 1 IND Submission | |
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| Phase 2 IND Submission | |
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| Phase 3 IND Submission | |
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| Preparing the BLA/NDA Submission | |
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| Facility and Utility Concerns | |
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| Design and Operation | |
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| Environmental Monitoring | |
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| Purification Process Validation | |
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| When Should Purification Validation Occur? | |
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| Process Validation Concerns for a Chromatographic Step | |
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| Process Validation Concerns for a Filtration Step | |
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| In-Process Controls | |
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| Process-Related Impurity Profile | |
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| Viral Safety Evaluation | |
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| General Study Design | |
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| Justification of the Choice of Viruses | |
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| Calculation of Virus Reduction Factors | |
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| Virus Safety Calculation | |
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| Worth All the Trouble and Cost? | |
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| When Should the Viral Clearance Studies Be Performed? | |
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| Purification Controls for Gene Therapy Processes | |
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| What Can Go Wrong | |
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| Strategic CMC Tips for Purification | |
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| Biopharmaceutical Drug Product Manufacturing | |
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| Three Basic CMC Regulatory Concerns | |
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| Formulation of a Biopharmaceutical | |
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| Formulations Familiar to FDA | |
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| Chemical Modification of API Prior to Formulation | |
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| Biopharmaceutical Manufacturing Processes | |
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| Adequate Description of the Manufacturing Process | |
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| During Clinical Development | |
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| Phase 1 IND Submission | |
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| Phase 2 IND Submission | |
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| Phase 3 IND Submission | |
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| BLA/NDA Submission | |
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| Adequate Control Over the Manufacturing Process | |
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| Regulatory Requirements for Market Approved Products | |
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| Regulatory Expectations During Clinical Development | |
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| What Can Go Wrong | |
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| Strategic CMC Tips for Drug Product Manufacturing | |
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| Physicochemical/Biological Analysis of the Biopharmaceutical Product | |
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| A Challenging Analysis | |
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| Goals: Consistent, Safe, Potent and Pure Product | |
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| Relationship Between Product Characterization and QC Testing | |
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| Unraveling the Molecular Properties | |
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| Molecular Variants for DNA | |
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| Molecular Variants for Proteins | |
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| Plethora of Analytical Methods Available For Proteins | |
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| Characterization of Biopharmaceuticals | |
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| Regulatory Expectations During Clinical Development | |
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| Phase 1 IND Submission | |
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| Phase 2 IND Submission | |
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| Phase 3 IND Submission | |
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| Regulatory Expectations for the BLA/NDA Submission | |
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| Full Characterization of Recombinant Proteins and Monoclonal Antibodies | |
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| What is 'Full' Characterization? | |
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| Host-Dependent Glycosylation | |
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| Host-Dependent Impurities | |
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| Impact of Molecular Variants on Biological Activity | |
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| Characterization of a Gene Therapy Biopharmaceutical | |
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| Applying the Minimum CMC Continuum to Characterization | |
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| Release Testing and Specifications | |
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| Regulatory Expectations During Clinical Development | |
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| Phase 1 IND Submission | |
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| Phase 2 IND Submission | |
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| Phase 3 IND Submission | |
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| Regulatory Expectations for the BLA/NDA Submission | |
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| Appropriate Release Test Methods | |
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| Not All Release Testing is at API or Drug Product Stage | |
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| Elimination of Release Testing by Process Validation | |
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| Test Method Parameters Required for Release: Proteins | |
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| Test Method Parameters Required for Release: DNA Vectors | |
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| The Bioassay--Absolute Requirement for a Biopharmaceutical | |
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| Test Method Validation--How Much and When? | |
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| Regulatory Expectations for Test Method Validation | |
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| Assay Qualification During Clinical Development | |
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| Applying the Minimum CMC Continuum to Test Method Validation | |
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| The Art of Setting a Specification | |
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| Development of a Specification | |
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| Release Versus Shelf-Life Specifications | |
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| Are There Required Purity/Impurity Limits? | |
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| Strategic CMC Tips for Setting Specifications | |
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| Biopharmaceutical Stability and Expiration Dating | |
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| Regulatory Expectations During Clinical Development | |
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| Phase 1 IND Submission | |
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| Phase 2 IND Submission | |
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| Phase 3 IND Submission | |
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| Regulatory Expectations for the BLA/NDA Submission | |
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| Stability-Indicating Test Methods | |
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| Setting an Expiration Date | |
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| How Much Change is Acceptable? | |
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| Applying the Minimum CMC Continuum to Stability | |
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| What Can Go Wrong | |
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| Incomplete Release/Stability Testing Requirements in BLA/NDA Filing | |
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| FDA 483 Inspectional Observations | |
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| Biopharmaceutical Product Recalls | |
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| Misuse in the Clinic | |
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| Strategic CMC Tips for Biopharmaceutical Analysis | |
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| Managing Process Changes--Demonstrating Product Comparability | |
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| Not as Easy as it Seems! | |
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| Regulatory Management of Process Changes | |
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| Pre-IND Stage | |
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| IND Clinical Development Stages | |
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| BLA/NDA Filing Stage | |
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| Post-Approval Market Stage | |
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| Demonstrating Product Comparability | |
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| Guidance Documents on Product Comparability | |
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| A Three-Tiered Testing Hierarchy | |
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| Designing the Comparability Study--Four Major Factors | |
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| Factor 1: Clinical Development Stage for the Change | |
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| Factor 2: Where in the Process the Change is Introduced | |
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| Factor 3: Quality Criteria Considerations | |
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| Factor 4: Suitability of Available Analytical Methods | |
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| Regulatory Agencies Have Final Approval | |
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| If in Doubt, Ask! | |
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| Comparability Protocols | |
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| Case Examples of Biopharmaceutical Comparability | |
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| Comparability Success Stories | |
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| Comparability Surprises | |
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| Not Comparable | |
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| Biopharmaceutical CMC Outsourcing | |
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| Regulatory Expectations for Contracted Work | |
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| Why Outsource? | |
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| Written Quality Agreements Required | |
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| Regulatory Requirements During Clinical Development | |
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| Regulatory Requirements for the BLA/NDA Submission | |
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| Regulatory Requirements Post-Market Approval | |
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| Developing the Intercompany Quality Agreement | |
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| Two Viewpoints | |
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| The Biopharmaceutical Company Seeking to Outsource | |
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| The Contact Manufacturer Offering Outsourcing | |
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| Maximum Leverage | |
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| Contents of an IQA | |
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| Strategic CMC Tips for Outsourcing | |
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| Concluding Thoughts on Biopharmaceutical CMC Regulatory Compliance | |
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| Most Helpful Websites for Biopharmaceuticals | |
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| Website Resources from FDA | |
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| Resources from EMEA | |
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| Resources from Professional Associations | |
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| Conclusion | |
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| References | |