2nd Edition

Active Pharmaceutical Ingredients Development, Manufacturing, and Regulation, Second Edition

Edited By Stanley Nusim Copyright 2010
    456 Pages 35 B/W Illustrations
    by CRC Press

    To successfully bring an Active Pharmaceutical Ingredient (API) to market, many steps must be followed to ensure compliance with governmental regulations. Active Pharmaceutical Ingredients is an unparalleled guide to the development, manufacturing, and regulation of the preparation and use of APIs globally.

    Topics include:

    • Safety, efficacy, and environmental/regulatory requirements
    • Analysis of the recent movement of API manufacturing from the U.S. and Europe to countries such as India and China
    • The FDA’s intensified foreign inspection program
    • Multi-use and flexible design facilities
    • The shift from maintenance scheduling to built-in reliability

    This second edition focuses on the quality control regulations for APIs that have been added or amended since the first edition. These updates help ensure that pharmaceutical professionals and drug manufacturers meet the established and required guidelines set forth by the United States and international regulatory agencies.

    Preface
    Contributors

    Introduction, Stanley H. Nusim
    Consolidation and Integration
    Quality
    Potency
    Computer Control and Automation
    Summary

    Bulk Drugs: The Process Development Task,
    Carlos B. Rosas
    Introduction
    The Bulk Drug Process as Part of the Drug Development Program
    From the Bench to the Pilot Plant and Beyond
    The Physicochemical Attributes of the Bulk Drug
    The Process Body of Knowledge
    New Trends and Their Probable Impact on Bulk Drug Process Development
    Processing Responsibility in Bulk Drug Process Development
    Outsourcing in Bulk Drug Process Development
    In Closing
    References

    Bulk Drugs: Process Design, Technology Transfer, and First Manufacture,
    Carlos B. Rosas
    Introduction
    The Process Design Task in Bulk Drugs
    Technology Transfer of the Bulk Drug Process and First Manufacture
    In Closing—The Processing Technologies of Bulk Drugs
    References

    Design and Construction of API Manufacturing Facilities,
    Steven Mongiardo
    Introduction
    Project Scope Development
    Preliminary Scope Development
    GMP Considerations
    Safety and Environmental Considerations
    Design Strategy and Detailed Design
    Design Development
    Sterile Process Facilities Design
    Construction Management
    Conclusions
    References

    Regulatory Affairs: Requirements and Expectations,
    John Curran
    Introduction
    High-Level Requirements for Submission of Regulatory CMC Documents
    Contents of Regulatory Submissions—API Sections
    Registration Samples
    The Review and Approval Process
    Preapproval Inspections
    Postapproval Change Evaluations

    Regulatory Affairs: Guidelines, Evolving Strategies, and Issues,
    John Curran
    Introduction
    Guidelines Issued by the International Conference on Harmonisation
    Regulatory Agency Guidelines
    Evolving Strategies and Issues
    The Future

    Validation of Active Pharmaceutical Ingredients,
    James Agalloco and Phil DeSantis
    History
    Definition of Validation
    Regulations
    Application of Validation
    Life Cycle Model
    Validation of New Products
    Validation of Existing Products
    Implementation
    Bulk Pharmaceutical Chemical Validation
    In-Process Controls
    Cleaning Validation
    Computerized Systems
    Procedures and Personnel
    Validation of Sterile Bulk Production
    Conclusion
    References

    Quality of Active Pharmaceutical Ingredients,
    Michael C. Vander Zwan and Carlos Yuraszeck
    Introduction
    The Product
    The Process
    The Facilities
    The People
    The Quality Management Department
    The Regulatory Authorities
    The Regulations
    Part I: Defining and Ensuring the Quality of the Active Pharmaceutical Ingredient
    Part II: The Regulations for Quality
    Q7 Section I: ‘‘Introduction’’
    Q7 Section 2: ‘‘Quality Management’’
    Q7 Section 3: ‘‘Personnel’’
    Q7 Section 4: ‘‘Buildings and Facilities’’
    Q7 Section 5: ‘‘Process Equipment’’
    Q7 Section 6: ‘‘Documents and Records’’
    Q7 Section 7: ‘‘Materials Management’’
    Q7 Section 8: ‘‘Production and In-Process Controls’’
    Q7 Section 9: ‘‘Packaging and Identification Labeling of APIs and Intermediates’’
    Q7 Section 10: ‘‘Storage and Distribution’’
    Q7 Section 11: ‘‘Laboratory Controls’’
    Q7 Section 12: ‘‘Validation’’
    Q7 Section 13: ‘‘Change Control’’
    Q7 Section 14: ‘‘Rejection and Reuse of Materials’’
    Q7 Section 15: ‘‘Complaints and Recalls’’
    Q7 Section 16: ‘‘Contract Manufacturers (Including Laboratories)’’
    Q7 Section 19: ‘‘APIS for Use in Clinical Trials’’
    Part III. The Quality Control and Quality Assurance Department

    Environmental Control,
    Bruce Wallington
    Introduction
    License to Operate
    Environmental Management Systems
    Environmental Scoping
    Permit Project Schedules
    Environmental Profile
    Environmental Dossier
    Applicable Regulatory Requirements
    Control Equipment Plan
    Operational Flexibility
    Management of Change
    Sustainability
    Green Chemistry Initiatives
    Conclusions
    References

    Thermochemical Process Safety—An Introduction,
    Carlos B. Rosas
    Preamble
    Hazards, Risks, and Consequences—Definitions and an Actual Thermochemical Example
    Thermochemical Events and Their Basis—Energy
    Thermochemistry, Heat Effects in Chemical Reaction Processing, and Calorimetry
    Thermochemical Hazards and Their Assessment
    Exothermic Reactions—Runaways and Unintended Reactions
    Thermochemical Hazard Avoidance, Prevention, and Risk Reduction
    In Closing
    References

    Design and Operating Practices for Safety,
    Stanley S. Grossel
    Introduction
    Flammable/Combustible Liquids Storage and Handling
    Toxic Gas Storage and Handling
    Water-Reactive Chemicals
    Cyanides Storage and Handling
    Handling and Containment of APIs
    Reactor Design and Operation
    Presure Relief and Effluent Handling
    Fire and Explosion Protection
    References

    Plant Operations,
    Stanley H. Nusim
    Plant Organization
    Batch Versus Continuous Operations
    Dedicated Versus Shared Manufacturing Facilities
    Shift Operations
    Clean Room
    Cost Control
    Employee Safety

    Sterile Bulk Active Pharmaceutical Ingredient Production,
    James Agalloco and Phil DeSantis
    Introduction
    Typical Sterile Bulk Active Pharmaceuticals Ingredients and Excipients
    Sterile Synthesis Steps
    Considerations for Sterile Bulk Pharmaceutical Chemical
    Buildings and Facilities
    Personnel Training and Qualification
    Container-Closure Systems
    Time Limitations
    Aseptic Processing Simulation
    Sterilization
    Laboratory Controls
    Sterile Excipients
    In-Process Sterilization of Bulk APIs and Excipients
    Other Attributes
    Conclusion
    References

    Biological Production of Active Pharmaceutical Intermediates,
    Max J. Kennedy, Randolph L. Greasham, and Stephen W. Drew
    Introduction
    Microorganisms
    Bioreactors
    Fermentor Design
    Regulation of Microbial Metabolism and Product Formation
    Growth Media
    Medium Components
    Medium Sterilization
    Growth Kinetics
    Seed Train
    Reducing Variability and Throughput Time in Inoculum Development
    Downstream Processing
    Solvent Processing
    Scale-Up to Manufacturing
    Strategies for Process Development and Scale-Up of Biological Products
    Bioanalytics
    Production of a Recombinant Vaccine in Saccharomyces Cerevisiae
    Triggering Immune Response
    Estimates of Capital and Operating Costs for Manufacture from Fermentation or Cell Culture
    Contract Manufacturers for API from Fermentation or Cell Culture
    Contract Development Organizations and Contract Manufacturing Organizations for Fermentation and Cell Culture Biological Products
    What Happens if the Fermentation or Cell Culture Does not Perform as You Expect?
    References

    Supply Management,
    Victor J. Catalano
    Introduction to Supply Management
    Production Planning
    Inventory Management
    Purchasing/Supply Management
    Distribution/Transportation
    Information Technology
    Quality Management
    Reference
    Further Reading

    Equipment Maintenance and Reliability,
    Kaizad P. Sunavala
    Introduction
    Strategic Plan (2)
    Reliability Fundamentals Program
    Summary
    References
    Index

    Biography

    Stanley Nusim