Active Pharmaceutical Ingredients: Development, Manufacturing, and Regulation, Second Edition, 2nd Edition (Hardback) book cover

Active Pharmaceutical Ingredients

Development, Manufacturing, and Regulation, Second Edition, 2nd Edition

Edited by Stanley Nusim

CRC Press

456 pages | 35 B/W Illus.

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pub: 2009-12-23
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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.

Table of Contents



Introduction, Stanley H. Nusim

Consolidation and Integration



Computer Control and Automation


Bulk Drugs: The Process Development Task, Carlos B. Rosas


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


Bulk Drugs: Process Design, Technology Transfer, and First Manufacture, Carlos B. Rosas


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


Design and Construction of API Manufacturing Facilities, Steven Mongiardo


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



Regulatory Affairs: Requirements and Expectations, John Curran


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


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


Definition of Validation


Application of Validation

Life Cycle Model

Validation of New Products

Validation of Existing Products


Bulk Pharmaceutical Chemical Validation

In-Process Controls

Cleaning Validation

Computerized Systems

Procedures and Personnel

Validation of Sterile Bulk Production



Quality of Active Pharmaceutical Ingredients, Michael C. Vander Zwan and Carlos Yuraszeck


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


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


Green Chemistry Initiatives



Thermochemical Process Safety—An Introduction, Carlos B. Rosas


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


Design and Operating Practices for Safety, Stanley S. Grossel


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


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


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


Laboratory Controls

Sterile Excipients

In-Process Sterilization of Bulk APIs and Excipients

Other Attributes



Biological Production of Active Pharmaceutical Intermediates, Max J. Kennedy, Randolph L. Greasham, and Stephen W. Drew




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


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?


Supply Management, Victor J. Catalano

Introduction to Supply Management

Production Planning

Inventory Management

Purchasing/Supply Management


Information Technology

Quality Management


Further Reading

Equipment Maintenance and Reliability, Kaizad P. Sunavala


Strategic Plan (2)

Reliability Fundamentals Program




About the Series

Drugs and the Pharmaceutical Sciences

Learn more…

Subject Categories

BISAC Subject Codes/Headings:
MEDICAL / Pharmacology
SCIENCE / Chemistry / General