Integrated Pharmaceutics : Applied Preformulation, Product Design, and Regulatory Science

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  • Edition: 1st
  • Format: Hardcover
  • Copyright: 2/4/2013
  • Publisher: Wiley
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Focusing on the application of physical pharmacy, drug design, and drug regulations as they relate to produce effective dosage forms for drug delivery, Integrated Pharmaceutics provides a comprehensive picture of pharmaceutical product design, describing the science and art behind the concepts of dosage form development. Combining physical pharmacy, product design, and regulatory affairs issues in a single book, the authors address topics governing drug regulations of United States, European, and Japanese agencies and detail new regulatory guidelines, including quality by design, design space analysis, and blend sample uniformity.

Author Biography

ANTOINE AL-ACHI, PhD, CT (ASCP), is Associate Professor of Pharmaceutics in the College of Pharmacy & Health Sciences at Campbell University. He is also the former head of the Formulation Development Division of Campbell's Pharmaceutical Sciences Institute (CUPSI).

MALI RAM GUPTA, PhD, is Associate Professor of Pharmaceutical Sciences and Director of Pharmaceutical Education & Research Center (PERC) in the College of Pharmacy & Health Sciences. Prior to joining the faculty at Campbell University, he spent twenty-five years in various positions at Revlon, including director of quality control and assurance.

WILLIAM CRAIG STAGNER, PhD, RPh, is Professor of Pharmaceutical Sciences and Director of Campbell University's Center for Analysis of Pharmaceutical Biomaterials. Prior to joining the faculty at Campbell, he established the Pharmaceutics Department at Glaxo Research Institute.

Table of Contents






1 Mathematical Concepts

1.1 Introduction

1.2 The Simple Linear Relationship

1.3 Exponential Rules

1.4 The Logarithmic Rules

1.5 Differential Equations

1.6 Expanding and Reducing Formulas

References for Chapter 1

Glossary for Chapter 1

2 Thermodynamics

2.1 Introduction

2.2 The Zeroth Law of Thermodynamics

2.3 The First Law of Thermodynamics

2.4 The Second Law of Thermodynamics

2.5 The Third Law of Thermodynamics

2.6 Polymorphism

2.7 Physical Stability of Crystal Forms

2.8 Solubility

References for Chapter 2

Glossary for Chapter 2

3 Solubility and Dissolution

3.1 Introduction

3.2 Concentration Units

3.3 What Should Be Done when Alcohol is Prescribed in a Formulation?

3.4 The Partition Coefficient

3.5 Disintegration and Dissolution

3.6 Concluding Remarks

References for Chapter 3

Glossary for Chapter 3

4 Biological Aspects of Formulations

4.1 Introduction

4.2 Bioavailability and Bioequivalence

4.3 Protocols for Determining Bioequivalence

4.4 Bioequivalence Procedure

4.5 FDA Approved Methods for Bioequivalence Studies

4.6 Approaches for Improving Bioavailability

References for Chapter 4

Glossary for Chapter 4

5 Interfacial Properties

5.1 Introduction

5.2 Liquid-Solid Interface

5.3 Dosage Form Applications

References for Chapter 5

Glossary for Chapter 5

6 Adsorption Phenomenon

6.1 Introduction

6.2 Adsorption on Filters

6.3 Adsorption of Proteins

References for Chapter 6

Glossary for Chapter 6

7 Rheological Principles

7.1 Introduction

7.2 Newtonian Systems

7.3 Non-Newtonian Systems

7.4 Viscoelasticity

7.5 Reynolds Number

7.6 Concluding Remarks

References for Chapter 7

Glossary for Chapter 7

8 Chemical Stability and Shelf-life Determination

8.1 Introduction

8.2 Shelf-Life Determination

8.3 Stability of Biotechnology Products

References for Chapter 8

Glossary for Chapter 8

9 Particle Science

9.1 Introduction

9.2 Particle Size Estimation and Distribution

9.3 Micronization

9.4 Particle Size Preparation and Reduction for Pulmonary Delivery

9.5 Polymeric Particulate Matter

9.6 Nanoparticles

9.7 Segregation of Particles

References for Chapter 9

Glossary for Chapter 9

10 Basic Statistics and Design of Experiment Concepts

10.1 Descriptive Statistics

10.2 Inferential Statistics

10.3 Statistical Applications in Quality Control Testing

10.4 Design of Experiment (DOE)

References for Chapter 10

Glossary for Chapter 10

11 Formulation Development Concepts

11.1 Preformulation

11.2 Scale-up Considerations

11.3 Combination Products

11.4 Rate-controlled Drug Delivery

11.5 Drug Delivery Technologies for Improving Oral Delivery

11.6 Drug Delivery Technologies for Improving Transmucosal Delivery

11.7 Drug Delivery Technologies for Transdermal Delivery

11.8 Special Considerations for Biotechnology and Protein Delivery Systems

11.9 Drug/Excipient and Excipient/Excipient Interactions

11.10Presence of Contaminants in Formulation

11.11Other Considerations

References for Chapter 11

Glossary for Chapter 11


12 Introduction to Product Design

12.1 Formulation Design

12.2 Process Design

12.3 Container Closure System (CCS) Design

References for Chapter 12

Glossary for Chapter 12

Appendix 12.1 FDA Route of Administration Nomenclature

Appendix 12.2 FDA Drug Dosage Form Nomenclature

Appendix 12.3 USP Dosage Form Nomenclature

Appendix 12.4 FDA Package Type Nomenclature

Appendix 12.5 USP Packaging Nomenclature

Appendix 12.6 USP Packaging Fabrication Materials and Closure Types

13 Tablet Product Design

13.1 Introduction

13.2 Formulation Design

13.3 Process Design

13.4 Container Closure System (CCS) Design

13.5 Risk Management

13.6 Attribute Tests

13.7 New Drug Application (NDA) Stability Assessment

References for Chapter 13

Glossary for Chapter 13

Appendix 13.1 Hygroscopicity Classification System

Appendix 13.2 Diluents and Direct Compression Binders

Appendix 13.3 Wet Granulation Binders

Appendix 13.4 Hot Melt Excipients

Appendix 13.5 Disintegrants

Appendix 13.6 Lubricants

Appendix 13.7 Antiadherants and Antisticking Agents

Appendix 13.8 Glidants and Flow-aids

Appendix 13.9 Wetting Agents

Appendix 13.10 Nominal Screen Mesh Number and Sieve Opening in Microns

14 Capsule Product Design

14.1 Introduction

14.2 Hard-shell Capsules

14.3 Soft-shell Capsules

14.4 Formulation and Process Optimization

14.5 Container Closure System

14.6 Risk Management

14.7 Attribute Tests

14.8 New Drug Application (NDA) Stability Assessment

References for Chapter 14

Glossary for Chapter 14

Appendix 14.1 Aldehyde Levels in Commonly Used Capsule Excipients

Appendix 14.2 Aldehyde Levels in Commonly Used Liquid-Fill Capsule Excipients

Appendix 14.3 Capsule Liquid-Fill Excipients

15 Dispersed System Product Design

15.1 Introduction

15.2 Formulation Design

15.3 Process Design

15.4 Container Closure System Design

15.5 Risk Management

15.6 Attribute Tests

15.7 New Drug Application (NDA) Stability Assessment

References for Chapter 15

Glossary for Chapter 15

Appendix 15.1 Suspending, Viscosity Enhancing, and Structural Modifying Agents

Appendix 15.2 Sweetening Agents

Appendix 15.3 Flocculating Agents and Buffers

Appendix 15.4 Emulsifying Agents

Appendix 15.5 Required HLB (RHLB) for Oils and Waxes  

16 Aerosol Product Design

16.0 Introduction

16.1 Formulation Design

16.2 Container Closure System Design

16.3 Risk Management

16.4 Attribute Tests

16.5 New Drug Application (NDA) Stability Assessment

References for Chapter 16

Glossary for Chapter 16

Appendix 16.1 Aerosol Excipients

17 Sterile Injectable Product Design

17.1 Introduction

17.2 Formulation Design

17.3 Process Design

17.4 Container Closure System Design

17.5 Risk Management

17.6 Attribute Tests

17.7 New Drug Application (NDA) Stability Assessment

References for Chapter 17

Glossary for Chapter 17

Appendix 17.1 Injectable Solvents and Cosolvents

Appendix 17.2 Injectable Surfactants, Solubilizing, Emulsifying, and Thickening  Agents

Appendix 17.3 Injectable Buffers and pH Adjusting Agents

Appendix 17.4 Injectable Antimicrobial Preservatives

Appendix 17.5 Injectable Antioxidants

Appendix 17.6 Stability Constants for Selected Sequestering Agents

Appendix 17.7 Injectable Bulking Agents, Protectants, and Tonicity Adjusting Agents

Appendix 17.8 Eutectic Temperatures for Selected Compounds

Appendix 17.9 Glass Collapse Temperate, Tgc, Maximally Freeze-Concentrated Glass  Transition Temperature, T?g, and Material Glass Transition Temperature, Tg, for Selected Excipients

18 Ophthalmic Product Design

18.1 Introduction

18.2 Formulation Design

18.3 Process Design

18.4 Container Closure System Design

18.5 Attribute Tests

18.6 New Drug Application (NDA) Stability Assessment

References for Chapter 18

Glossary for Chapter 18

Appendix 18.1 Ophthalmic Excipients

19 Transdermal Product Design

19.1 Introduction

19.2 Formulation Design

19.3 Conclusion

References for Chapter 19

Glossary for Chapter 19

Appendix 19.1 Transdermal Excipients

20 Oral Modified-Release Product Design

20.1 Introduction

20.2 Coatings

20.3 Matrix Systems

20.4 Gastroretentive Devices

20.5 Osmotic Controlled Release

20.6 Conclusion

References for Chapter 20

Glossary for Chapter 20

Appendix 20.1 FDA Nomenclature for Oral Modified Release Dosage Forms


21 Regulatory Practices and Guidelines

21.1 Worldwide Regulatory Agencies

21.2 Good Manufacturing Practice

21.3 FDA Inspection and Regulatory Actions

References for Chapter 21

Glossary for Chapter 21

22 Compounding Pharmacy Regulations

22.1 Introduction

22.2 Compounding Guidelines

22.3 FDA Compliance Policy Guides

22.4 Good Compounding Practices

22.5 Stability Criteria and Beyond-Use-Dating of Compounded Preparations

22.6 Verification

22.7 Patient Counseling

22.8 Pharmacy Compounding Accreditation

References for Chapter 22

Glossary for Chapter 22

Appendix 22.1 List of Compounding Drugs that were Withdrawn or Removed from the Market for Safety Reasons

Appendix 22.2 List of Bulk Drug Substances for Compounding and Subsequent Use in Animals to which CVM would not Ordinarily Object

Appendix 22.3 Formulation Record

Appendix 22.4 Compounding Record

23 IND and NDA Phase Appropriate New Drug Development Process

23.1 Introduction

23.2 Preclinical Development Overview

23.3 Phase Appropriate Clinical Trials Overview

23.4 Investigational New Drug (IND)

23.5 NDA Review Process

References for Chapter 23

Glossary for Chapter 23

24 Generics, Biosimilars, and OTCs

24.1 Generic Drugs

24.2 Biosimilar Drugs

24.3 OTC Drugs

References for Chapter 24

Glossary for Chapter 24

Appendix 24.1 Office of Generic Drugs QbR Quality Overall Summary Outline

25 Accelerated New Drug Approval & Expedited Access of New Therapies

25.1 Background

25.2 Expedited Review and Approval of New Therapies

25.3 Expanded Access to New Therapies

25.4 Orphan Drugs

25.5 Pediatric Drugs

25.6 Pediatric Drug Development and the Orphan Drug Act Incentives

25.7 Common EMEA/FDA Application for Orphan Medicinal Product Designation

References for Chapter 25

Glossary for Chapter 25

26 Post Drug Approval Activities

26.1 Postmarket Requirements and Commitments

26.2 Post Approval Manufacturing Changes

26.3 Clinical Phase 4 Studies: Postmarketing Surveillance & Risk Assessment

26.4 Prescription Drug Advertising and Promotional Labeling Direct-to-Consumers

References for Chapter 26

Glossary for Chapter 26

Appendix 26.1 MedWatch

27 Drug Master Files & EU Dossiers

27.1 Drug Master Files

27.2 European Marketing Authorization Dossiers

References for Chapter 27

Glossary for Chapter 27

28 Commissioning & Qualification

28.1 Regulatory Requirements

28.2 Preliminary C & Q Activities

28.3 Commissioning

28.4 Qualification & Validation

28.5 Qualification Protocols

28.6 Process Validation (PV)

28.7 Cleaning Validation

28.8 Computer Systems Validation

28.9 Change Control

28.10 Revalidation

References for Chapter 28

Glossary for Chapter 28

29 Quality Sytems & Controls

29.1 Pharmaceutical Quality System

29.2 Quality Systems Approach to CGMP Regulations

29.3 Inspection of Pharmaceutical Quality Control Laboratories

29.4 Pharmacopoeias

29.5 Analytical Instrument Qualification (AIQ)

29.6 Validation of Analytical Procedures

29.7 Stability Testing of New Drug Substances and Products

References for Chapter 29

Glossary for Chapter 29

Appendix 29.1 Application of Process Performance and Product Quality Monitoring System throughout the Product Lifecycle

Appendix 29.2 Application of Corrective Action and Preventative Action System throughout the Product Lifecycle

Appendix 29.3 Application of Change Management System throughout the Product Lifecycle

Appendix 29.4 Application of Management Review of Process Performance and Product Quality throughout the Product Lifecycle

Appendix 29.5 21 CFR CGMP Regulations Related to Management Responsibilities

Appendix 29.6 21 CFR CGMP Regulations Related to Resources

Appendix 29.7 21 CFR CGMP Regulations Related to Manufacturing Operations

Appendix 29.8 21 CFR CGMP Regulations Related to Evaluation Activities

Appendix 29.9 Pharmacopoeias Comparison

Appendix 29.10 Recommended Validation Characteristics of the Various Types of Tests

Appendix 29.11 Forced Degradation Parameters for Drug Substance (API)

Appendix 29.12 Decision Flow Chart for Photostability Testing Of Drug Products

Appendix 29.13 Stability Studies Test

Appendix 29.14 Decision Tree for Data Evaluation for Retest Period or Shelf Life Estimation for Drug Substances or Product (Excluding Frozen Products)

30 Safety, Toxicology, & Pharmacogenomics

30.1 Nonclinical Safety Studies

30.2 Safety Pharmacology Studies

30.3 Carcinogenicity Studies of Pharmaceuticals

30.4 Genotoxicity Testing

30.5 Immunotoxicity Studies

30.6 Safety Reporting Requirements

30.7 Pharmacogenomics

References for Chapter 30

Glossary for Chapter 30

Appendix 30.1 Selection of Maximum Recommended Starting Dose for Drugs Administered Systematically to Normal Volunteers

Appendix 30.2 Conversion of Animal Doses to Human Equivalent Doses Based on Body Surface Area

Appendix 30.3 Recommended Duration of Repeated-Dose Toxicity Studies to Support the Conduct of Clinical Trials

Appendix 30.4 Recommended Duration of Repeated-Dose Toxicity Studies to Support Marketing

31 Regulatory Science Initiatives for Advancing Public Health

31.1 Advancing Regulatory Science for Public Health ? The Promise of Regulatory Science

31.2 Advancing Regulatory Science at FDA ? Strategic Plan for Regulatory Science

31.3 A Collaborative Implementation Framework

References for Chapter 31

Glossary for Chapter 31


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