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 Recombinan
"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.
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