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.