The Challenge of CMC Regulatory Compliance for Biopharmaceuticals

Dossier is Critical.- 5. 'Case-by-Case' CMC Strategy Specifics.- 4 Can't Ignore cGMP.- 1. Not Optional.- 1.1 What are 'cGMPs'.- 1.2 Three main GMP questions.- 2. GMPS for Everything.- 2.1. For Finished Drug Products.- 2.2. Required for APIs Also.- 2.3. Extra GMPs for Biopharmaceuticals.- 3. Where in the Manufacturing Process Should GMP Begin.- 4. When During Clinical Development Should GMP Begin.- 4.1. API Clinical Trial Materials.- 4.2. Drug Product Clinical Trial Materials.- 5. Consequences of not Following GMPS.- 5.1. Issues with Market Approved Biopharmaceuticals.- 5.2. Issues During Clinical Development.- 5.3. How to Avoid GMP Difficulties with the FDA.- 6. Strategic CMC Tips for GMP Compliance.- 5 Recombinant Source Material: Master/Working Bank.- 1. Needed: Reliable, Continuous, Stable Genetic Source.- 1.1. Three Primary CMC Concerns for Banks.- 1.2. Genetic Construction of a Bank.- 2. So Many Hosts to Choose From.- 2.1. Bank Terminology.- 2.2. Choosing the Host.- 2.2.1. Drivers to Reach a Decision.- 2.2.2. Why Choose Recombinant Cells.- 2.2.3. Why Bioengineered Animals or Plants.- 3. CMC Guidance on Preparation of a Bank.- 3.1. Accurate and Thorough Description of Preparation.- 3.1.1. Recombinant Cell Banks.- 3.1.2. Transgenic Banks.- 3.2. Why Does The FDA Want So Much CMC Documentation.- 3.3. When is Full CMC Documentation Needed.- 3.4. What If CMC Documentation is Missing.- 3.5. Don't forget GMPs During Preparation of the Bank.- 4. CMC Guidance on Characterization of a Bank.- 4.1. Appropriate and Sufficient Characterization.- 4.1.1. Six Key Elements for a Thorough Characterization.- 4.1.2. Recombinant Cell Bank Characterization.- 4.1.3. Example of Characterization of a Bacterial Cell Bank.- 4.1.4. Example of Characterization of a Mammalian Cell Bank.- 4.2. How Much Characterization and When.- 4.3. Critical Concern for Virus Safety in Banks.- 4.4. Minimizing the Risk of TSEs.- 5. A Successful CMC Strategy for Banks.- 6 Production: Expansion of the Recombinant Organism and Expression of the Biopharmaceutica.- 1. Goals: Identity, Capacity and Consistency.- 1.1. Two Major CMC Regulatory Concerns for Production.- 1.2. Need for High and Consistent Expression of the Biopharmaceutical.- 1.3. What is a 'Production Process'.- 1.3.1. Types of Bioreactors for Cell-Based Production.- 1.3.2. Harvesting Procedures for Biopharmaceuticals.- 1.4. Production Processes Familiar to the FDA.- 2. Adequate Description of the Production Process.- 2.1. During Clinical Development.- 2.1.1. Phase 1 IND Submission.- 2.1.2. Phase 2 IND Submission.- 2.1.3. Phase 3 IND Submission.- 2.2. Preparing the BLA/NDA Submission.- 3. Validation of a Cell-Based Production Process.- 3.1. When Should Validation of the Production Process Occur.- 3.2. Five Major Areas Involved in Validation of the Production Process.- 3.2.1. The Production Facility, Utilities and Process Equipment.- 3.2.2. Monitoring of Growth Parameters.- 3.2.3. In-Process Controls.- 3.2.4. Genetic Stability.- 3.2.5. Cleaning Validation.- 3.3. Final Comments on Process Validation.- 4. Additional Production Controls and Concerns.- 4.1. Cell-Based Production Processes.- 4.1.1. Cell Culture Media Acceptance Criteria.- 4.1.2. Avoidance of Animal- and Human-Derived Raw Materials.- 4.1.3. Containment of the Recombinant Organism.- 4.1.4. Contamination Control for Aseptic Processing Operations.- 4.2. Gene Therapy Production Processes.- 4.2.1. Control of the Cells.- 4.2.2. RAC Review and Approval of the Production Process.- 4.3. Transgenic Animal Production Processes.- 4.3.1. Production Controls.- 4.3.2. Protecting the Gene Pool.- 4.4. Transgenic Plant Production Processes.- 4.4.1. 'Pharming' Controls.- 4.4.2. USDA/APHIS Protecting the Gene Pool.- 5. What Can Go Wrong.- 6. Strategic CMC Tips For Production.- 7 Purification of the Biopharmaceutical.- 1. Goals: Purity, Recovery and Consistency.- 1.1. Two Major CMC Regulatory Concerns for Purification.- 1.2. Need for High Recovery of a Pure Product.- 1.3. What is a 'Purification Process'.- 1.3.1. Physical Separations Methods for Biopharmaceuticals.- 1.3.2. Chromatographic Purification Methods for Biopharmaceuticals.- 1.4. Purification Processes Familiar to the FDA.- 2. Adequate Description of the Purification Process.- 2.1. During Clinical Development.- 2.1.1. Phase 1 IND Submission.- 2.1.2. Phase 2 IND Submission.- 2.1.3. Phase 3 IND Submission.- 2.2. Preparing the BLA/NDA Submission.- 3. Facility and Utility Concerns.- 3.1. Design and Operation.- 3.2. Environmental Monitoring.- 4. Purification Process Validation.- 4.1. When Should Purification Validation Occur.- 4.2. Process Validation Concerns for a Chromatographic Step.- 4.3. Process Validation Concerns for a Filtration Step.- 5. In-Process Controls.- 6. Process-Related Impurity Profile.- 7. Viral Safety Evaluation.- 7.1. General Study Design.- 7.2. Justification of the Choice of Viruses.- 7.3. Calculation of Virus Reduction Factors.- 7.4. Virus Safety Calculation.- 7.5. Worth All the Trouble and Cost.- 7.6. When Should the Viral Clearance Studies Be Performed.- 8. Purification Controls for Gene Therapy Processes.- 9. What Can Go Wrong.- 8 Biopharmaceutical Drug Product Manufacturing.- 1. Three Basic CMC Regulatory Concerns.- 2. Formulation of a Biopharmaceutical.- 2.2. Formulations Familiar to FDA.- 2.3. Chemcial Modification of API Prior to Formulation.- 3. Biopharmaceutial Manufacturing Processes.- 4. Adequate Description of the Manufacturing Process.- 4.1. During Clinical Development.- 4.1.1. Phase 1 IND Submission.- 4.1.2. Phase 2 IND Submission.- 4.1.3. Phase 3 IND Submission.- 4.2. BLA/NDA Submission.- 5. Adequate Control Over the Manufacturing Process.- 5.1. Regulatory Requirements for Market Approved Products.- 5.2. Regulatory Expectations During Clinical Development.- 6. What Can Go Wrong.- 7. Strategic CMC Tips for Drug Product Manufacturing.- 9 Physicochemical/Biological Analysis of the Biopharmaceutical Produc.- 1. A Challenging Analysis.- 1.1. Goals: Consistent, Safe, Potent and Pure Product.- 1.2. Relationship Between Product Characterization and QC Testing.- 2. Unraveling the Molecular Properties.- 2.1. Molecular Variants for DNA.- 2.2. Molecular Variants for Proteins.- 2.3. Plethora of Analytical Methods Available For Proteins.- 3. Characterization of Biopharmaceuticals.- 3.1. Regulatory Expectations During Clinical Development.- 3.1.1. Phase 1 IND Submission.- 3.1.2. Phase 2 IND Submission.- 3.1.3. Phase 3 IND Submission.- 3.2 Regulatory Expectations for the BLA/NDA Submission.- 3.3. Full Characterization of Recombinant Proteins and Monoclonal Antibodies.- 3.3.1. What is 'Full' Characterization.- 3.3.2. Host-Dependent Glycosylation.- 3.3.3. Host-Dependent Impurities.- 3.3.4. Impact of Molecular Variants on Biological Activity.- 3.4. Characterization of a Gene Therapy Biopharmaceutical.- 3.5. Applying the Minimum CMC Continuum to Characterization.- 4. Release Testing and Specifications.- 4.1. Regulatory Expectations During Clinical Development.- 4.1.1. Phase 1 IND Submission.- 4.1.2. Phase 2 IND Submission.- 4.1.3. Phase 3 IND Submission.- 4.2. Regulatory Expectations for the BLA/NDA Submission.- 4.3. Appropriate Release Test Methods.- 4.3.1. Not All Release Testing is at API or Drug Product Stage.- 4.3.2. Elimination of Release Testing by Process Validation.- 4.3.3. Test Method Parameters Required for Release: Proteins.- 4.3.4. Test Method Parameters Required for Release: DNA Vectors.- 4.4. The Bioassay - Absolute Requirement for a Biopharmaceutical.- 4.5. Test Method Validation - How Much and When.- 4.5.1. Regulatory Expectations for Test Method Validation.- 4.5.2. Assay Qualification During Clinical Development.- 4.5.3. Applying the Minimum CMC Continuum to Test Method Validation.- 4.6. The Art of Setting a Specification.- 4.6.1. Development of a Specification.- 4.6.2. Release Versus Shelf-Life Specifications.- 4.6.3. Are There Required Purity/Impurity Limits.- 4.6.4. Strategic CMC Tips for Setting Specifications.- 5. Biopharmaceutical Stability and Expiration Dating.- 5.1. Regulatory Expectations During Clinical Development.- 5.1.1. Phase 1 IND Submission.- 5.1.2. Phase 2 IND Submission.- 5.1.3. Phase 3 IND Submission.- 5.2. Regulatory Expectations for the BLA/NDA Submission.- 5.3. Stability-Indicating Test Methods.- 5.4. Setting an Expiration Date.- 5.5. How Much Change is Acceptable.- 5.6. Applying the Minimum CMC Continuum to Stability.- 6. What Can Go Wrong.- 6.1. Incomplete Release/Stability Testing Requirements in BLA/NDA Filing.- 6.2. FDA 483 Inspectional Observations.- 6.3. Biopharmaceutical Product Recalls.- 6.4. Misuse in the Clinic.- 7. Strategic Cmc Tips For Biopharmaceutical Analysis.- 10 Managing Process Changes - Demonstrating Product Comparabilit.- 1. Not As Easy as it Seems.- 2. Regulatory Management of Process Changes.- 2.1. Pre-IND Stage.- 2.2. IND Clinical Development Stages.- 2.3. BLA/NDA Filing Stage.- 2.4. Post-Approval Market Stage.- 3. Demonstrating Product Comparability.- 3.1 Guidance Documents on Product Comparability.- 3.2. A Three-Tiered Testing Hierarchy.- 3.3. Designing the Comparability Study - Four Major Factors.- 3.3.1. Factor 1: Clinical Development Stage for the Change.- 3.3.2. Factor 2: Where in the Process the Change is Introduced.- 3.3.3. Factor 3: Quality Criteria Considerations.- 3.3.4. Factor 4: Suitability of Available Analytical Methods.- 3.4. Regulatory Agencies Have Final Approval.- 3.5 If in Doubt, Ask.- 4. Comparability Protocols.- 5. Case Examples of Biopharmaceutical Comparability.- 5.1. Comparability Success Stories.- 5.2. Comparability Surprises.- 5.3. Not Comparable.- 11 Biopharmaceutical CMC Outsourcing.- 1. Regulatory Expectations for Contracted Works.- 1.1. Why Outsource.- 1.2. Written Quality Agreements Required.- 1.3. Regulatory Requirements During Clinical Development.- 1.4. Regulatory Requirements for the BLA/NDA Submission.- 1.5. Regulatory Requirements Post-Market Approval.- 2. Developing the Intercompany Quality Agreement.- 2.1. Two Viewpoints.- 2.1.1. The Biopharmaceutical Company Seeking to Outsource.- 2.1.2. The Contact Manufacturer Offering Outsourcing.- 2.1.3. Maximum Leverage.- 2.2. Contents of an IQA.- 3. Strategic CMC Tips for Outsourcing.- 12 Concluding Thoughts on Biopharmaceutical CMC Regulatory Compliance.- 1. Most Helpful Websites for Biopharmaceuticals.- 2. Website Resources from FDA.- 3. Resources from Emea.- 4. Resources from Professional Associations.- 5. Conclusion.- References.