Chemical Engineering in the Pharmaceutical Industry Drug Product Design, Development, and Modeling

A guide to the important chemical engineering concepts for the development of new drugs, revised second edition

The revised and updated second edition of Chemical Engineering in the Pharmaceutical Industry offers a guide to the experimental and computational methods related to drug product design and development. The second edition has been greatly expanded and covers a range of topics related to formulation design and process development of drug products. The authors review basic analytics for quantitation of drug product quality attributes, such as potency, purity, content uniformity, and dissolution, that are addressed with consideration of the applied statistics, process analytical technology, and process control. The 2^nd Edition is divided into two separate books: 1) Active Pharmaceutical Ingredients (API’s) and 2) Drug Product Design, Development and Modeling.

The contributors explore technology transfer and scale-up of batch processes that are exemplified experimentally and computationally. Written for engineers working in the field, the book examines in-silico process modeling tools that streamline experimental screening approaches. In addition, the authors discuss the emerging field of continuous drug product manufacturing. This revised second edition:

• Contains 21 new or revised chapters, including chapters on quality by design, computational approaches for drug product modeling, process design with PAT and process control, engineering challenges and solutions
• Covers chemistry and engineering activities related to dosage form design, and process development, and scale-up
• Offers analytical methods and applied statistics that highlight drug product quality attributes as design features
• Presents updated and new example calculations and associated solutions
• Includes contributions from leading experts in the field

Written for pharmaceutical engineers, chemical engineers, undergraduate and graduation students, and professionals in the field of pharmaceutical sciences and manufacturing, Chemical Engineering in the Pharmaceutical Industry, Second Edition contains information designed to be of use from the engineer's perspective and spans information from solid to semi-solid to lyophilized drug products.

Mary T. am Ende, PHD, is Vice President of Process Development at Lyndra Therapeutics, Inc. Previously, she was a Research Fellow at Pfizer, Inc. in Drug Product Design. She has over 25 years' experience in drug product formulation, process development and computational modeling.

David J. am Ende, PHD, is President of Nalas Engineering Services, Inc. Previously, he was Research Fellow at Pfizer Inc. in the Chemical Research & Development department. He has over 25 years experience in chemical process development.

List of Contributors ix

Preface xv

Unit Conversions xvii

Part I Introduction 1

1 Chemical Engineering in the Pharmaceutical Industry: An Introduction 3
David J. am Ende and Mary T. am Ende

Part II Drug Product Design, Development, and Modeling 19

2 Design of Solid Dosage Formulations 21
Kevin J. Bittorf, Tapan Sanghvi, and Jeffrey P. Katstra

3 Powder Process Challenges and Solutions 53
Thomas Baxter and James Prescott

4 Design and Scale-up of Dry Granulation Processes 81
Howard J. Stamato and Omar L. Sprockel

5 Model-based Development of Roller Compaction Processes 119
Gavin Reynolds

6 Wet Granulation Processes 147
Karen P. Hapgood and James D. Litster

7 Toward a Generic Model for Twin-screw Wet Granulation 173
Daan Van Hauwermeiren, Maxim Verstraeten, Michaël Ghijs, Kai Lee, Neil Turnbull, Mary T. am Ende, Pankaj Doshi, David Wilsdon, Thomas De Beer, and Ingmar Nopens

8 Modeling a Dosator Capsule Filling Process for Hard-shell Capsules 187
Peter Loidolt, Eva Faulhammer, and Johannes G. Khinast

9 Powder Compaction: Process Design and Understanding 203
David Wilson, Ron Roberts, and John Blyth

10 Punch Sticking: Factors and Solutions 227
Daryl M. Simmons

11 Spray Atomization Modeling for Tablet Film Coating Processes 245
Alfred Berchielli, Pankaj Doshi, Alberto Aliseda, and Juan C. Lasheras

12 Spray Drying and Amorphous Dispersions 267
Kristin J.M. Ploeger, Pavithra Sundararajan, Pedro C. Valente, Kenneth J. Rosenberg, João G. Henriques, and Paige Adack

13 The Freeze Drying Process: The Use of Mathematical Modeling in Process Design, Understanding, and Scale-up 293
Venkat Koganti, Sumit Luthra, and Michael J. Pikal

14 Sterilization Processes in the Pharmaceutical Industry 311
Piero M. Armenante and Otute Akiti

15 Controlled Release Technology and Design of Oral Controlled Release Dosage Forms 381
Avinash G. Thombre, Xiao Yu (Shirley) Wu, and Mary T. am Ende

16 Process Design and Development for Novel Pharmaceutical Dosage Forms 409
Leah Appel, Joshua Shockey, Matthew Shaffer, and Jennifer Chu

17 Multiscale Modeling of a Pharmaceutical Fluid Bed Coating Process Using CFD/DEM and Population Balance Models to Predict Coating Uniformity 419
Avik Sarkar, Dalibor Jajcevic, Peter Böhling, Peter Toson, Matej Zadravec, Brian Shoemaker, Pankaj Doshi, Johannes Khinast, and Mary T. am Ende

18 Process Design of Topical Semisolids: Application of Fundamental Concepts in Pharmaceutical Engineering to PEG Ointment Development 451
Amanda Samuel, Thean Yeoh, Rolf Larsen, and Avik Sarkar

19 Achieving a Hot Melt Extrusion Design Space for the Production of Solid Solutions 469
Luke Schenck, Gregory M. Troup, Mike Lowinger, Li Li, and Craig Mckelvey

20 Drug Product Process Modeling 489
Mary T. am Ende, William Ketterhagen, Andrew Prpich, Pankaj Doshi, Salvador García-Muñoz, and Rahul Bharadwajh

Part III Continuous Manufacturing 527

21 Continuous Manufacturing in Secondary Production 529
Martin Warman

22 Continuous Direct Compression Using Portable Continuous Miniature Modular & Manufacturing (PCM&M) 547
Daniel O. Blackwood, Alexandre Bonnassieux, and Giuseppe Cogoni

23 Process Control Levels for Continuous Pharmaceutical Tablet Manufacturing 561
Niels Nicolaï, Ingmar Nopens, Maxim Verstraeten, and Thomas De Beer

Part IV Applied Statistics and Regulatory Environment 585

24 Multivariate Analysis for Pharmaceutical and Medical Device Development 587
Frederick H. Long

25 Pharmaceutical Manufacturing: The Role of Multivariate Analysis in Design Space, Control Strategy, Process Understanding, Troubleshooting, and Optimization 601
Theodora Kourti

26 Quality by Design: Pilot to Reality-The Honeymoon Phase to the Stormy Years 631
Mary T. am Ende and Christine B. Seymour

Index 645

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