Full Description
"The greater our knowledge increases, the more our ignorance unfolds. " U. S. President John F. Kennedy, speech, Rice University, September 12, 1962 My primary purpose for writing this book was much more than to provide another information source on Chemistry, Manufacturing & Controls (CMC) that would rapidly become out of date. My primary purpose was to provide insight and practical suggestions into a common sense business approach to manage the CMC regulatory compliance requirements for biopharmaceuticals. Such a common sense business approach would need (1) to be applicable for all types of biopharmaceutical products both present and future, (2) to address the needs of a biopharmaceutical manufacturer from the beginning to the end of the clinical development stages and including post market approval, and (3) to be adaptable to the constantly changing CMC regulatory compliance requirements and guidance. Trying to accomplish this task was a humbling experience for this author! In Chapter 1, the CMC regulatory process is explained, the breadth of products included under the umbrella ofbiopharmaceuticals are identified, and the track record for the pharmaceutical and biopharmaceutical industry in meeting CMC regulatory compliance is discussed. In Chapter 2, while there are many CMC commonalities between biopharmaceuticals and chemically-synthesized pharmaceuticals, the significant differences in the way the regulatory agencies handle them are examined and the reasons for why such differences are necessary is discussed. Also, the importance of CMC FDA is stressed.
Contents
1 Biopharmaceutical CMC Regulatory Compliance: What is It?.- 1. Defining Our Terms.- 1.1. What is a 'Biopharmaceutical'.- 1.2. What is 'CMC'.- 1.3. What is 'CMC Regulatory Compliance'.- 2. Under the Biopharmaceutical Umbrella.- 2.1. Recombinant DNA-Derived Proteins.- 2.2. Monoclonal Antibodies.- 2.3. Gene Therapy.- 2.4. Animal/Plant Transgenics.- 2.5. Rapid Pace of Biopharmaceutical Development.- 3. Regulatory Development of Biopharmaceuticals.- 3.1. The Drug Development Process.- 3.2. Regulatory Agency Review.- 3.2.1. U.S. FDA.- 3.2.2. EMEA.- 4. CMC Regulatory Compliance Track Record.- 4.1. Drugs and Biologics.- 4.2. Biopharmaceuticals.- 2 Are Biopharmaceuticals Really Different?.- 1. Perception or Reality.- 1.1. Five Questions Frequently Asked.- 1.2. Bottom Line Question.- 2. Regulatory Agencies Speak.- 2.1. U.S. FDA.- 2.2. EMEA.- 2.3. ICH.- 3. Three Unique CMC Challenges for Biopharmaceuticals.- 3.1. The Use of Living Recombinant Organisms.- 3.2. The Products Themselves.- 3.3. The Impact of the Manufacturing Process.- 4. CMC Meetings with the FDA Take on Greater Importance.- 4.1. CMC Communication with FDA is Critical.- 4.2. Preparing for the CMC Meeting.- 4.3. Pre-IND Meeting.- 4.4. End of Phase 2 (EOP2) Meeting.- 4.3. Pre-BLA/NDA Meeting.- 5. What About CMC Meetings with Emea.- 6. Biopharmaceuticals Need to be Treated Differently.- 3 Developing the Corporate CMC Regulatory Compliance Strateg.- 1. Three Key Elements for a Complete CMC Strategy.- 1.1. Element 1: The Broad CMC Scope Must Be Considered.- 1.2. Element 2: Any Unique CMC Issues Must Be Addressed.- 1.3. Element 3: Must Meet Minimum CMC Regulatory Requirements.- 2. The Minimum CMC Continuum.- 3. Minimum CMC Requirements for Clinical Development.- 3.1. An Overview.- 3.2. Phase 1.- 3.3. Phase 2 and 3.- 4. Full Cmc Requirements For Dossier Filing.- 4.1. Comparison of BLA/NDA and CTD CMC Formats.- 4.2. Adequate Resources Required to Compile the Full CMC Dossier.- 4.3. Quality of CMC Content Present in 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.
