Freeze Drying of Pharmaceutical Products: 1st Edition (Hardback) book cover

Freeze Drying of Pharmaceutical Products

1st Edition

Edited by Davide Fissore, Roberto Pisano, Antonello Barresi

CRC Press

214 pages | 4 Color Illus. | 66 B/W Illus.

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Hardback: 9780367076801
pub: 2019-11-13
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Freeze Drying of Pharmaceutical Products provides an overview of the most recent and cutting-edge developments and technologies in the field, focusing on formulation developments and process monitoring, and considering new technologies for process development.

This book contains case studies from freeze dryer manufacturers and pharmaceutical companies for readers in industry and academia. It was contributed to by lyophilization experts to create a detailed analysis of the subject matter, presenting in an organic perspective the recent advancements in freeze-drying research and technology. It discusses formulation design, process optimization and control, new PAT monitoring tools, multivariate image analysis, process scale-down and development using small-scale freeze-dryers, use of CFD for equipment design, and development of continuous processes.

This book is aimed at industry professionals including chemical engineers and pharmaceutical scientists.

Table of Contents

1. The freeze-drying of pharmaceutical products: Introduction and basic concepts

Davide Fissore, Roberto Pisano, Antonello A. Barresi

1.1 Introduction

1.2 Freeze-drying equipment

1.3 Process objectives and constraints

1.4 Mathematical modelling and process design

1.5 Open issues

List of References

2. Formulation design and optimization using molecular dynamics

Roberto Pisano, Andrea Arsiccio

2.1 Denaturation stresses during lyophilization

2.2.1 Mechanisms of cryoprotection

2.2.2 Mechanisms of lyoprotection

2.2.3 Role of surfactants

2.3 Current approach to formulation design

2.4 Molecular Dynamics as a tool for formulation development

2.4.1 Use of molecular dynamics to study excipient-protein interactions

2.5 Molecular Dynamics for formulation development: Examples of application

2.5.1 Thermodynamic stabilization: A new interpretation of the preferential exclusion theory

2.5.2 Kinetic stabilization: Role of hydrogen bonds

2.5.3 Kinetics vs Thermodynamics: How to design the optimal formulation

2.5.4 Protein stabilization by surfactants: Evidence of an orientation dependent mechanism

2.6 Conclusions

List of References

3. Established and novel excipients for freeze-drying of proteins

Ivonne Seifert, Wolfgang Friess

3.1 Introduction

3.2 Sugars and polyols

3.2.1 The commonly used sucrose, trehalose, and mannitol

3.2.2 Other small saccharides and polyols

3.2.3 Oligo- and polysaccharides

3.3 Amino acids

3.4 Polymers

3.5 Surfactants

3.6 Buffer

3.7 Others

3.7.1 Proteins

3.7.2 Alcohols

3.7.3 Preservatives

3.8 Expert opinion

List of References

4. Infrared Imaging and Multivariate Image Analysis (MIA): A new PAT for freeze-drying Monitoring and Control

Domenico Colucci, José Manuel Prats-Montalbán, Alberto Ferrer, Davide Fissore

4.1 Infrared imaging

4.2 Process monitoring

4.2.1. Product temperature

4.2.2. Sublimation interface monitoring – End of primary drying estimation

4.2.3. Heat and mass transfer coefficients

4.3. Multivariate Image Analysis for Statistical Process Monitoring

4.4 Conclusions

List of References

5. Through vial impedance spectroscopy (TVIS): A new method for determining the ice nucleation temperature and the solidification end point

Geoff Smith, Yowwares Jeeraruangrattana

5.1 An Introduction to Through Vial Impedance Spectroscopy

5.2 TVIS Applications – An overview

5.3 Temperature calibration of the TVIS system

5.3.1 Liquid temperature calibration

5.3.2 Ice temperature calibration

5.4 Ice formation (nucleation and growth)

5.5 Conclusions


List of References

6. Innovations in freeze-drying control and in-line optimization

Antonello Barresi, Roberto Pisano, Davide Fissore

6.1 Introduction

6.2 Open- and closed-loop control in freeze-drying

6.2.1 Control strategies

6.2.2 Control logics Open loop control.

6.3 Control of freezing and controlled nucleation

6.4 Process monitoring and parameter estimation

6.5 In line optimization

6.6. Cycle development

6.7 Secondary drying optimization and control


List of References

7. Use of a micro freeze-dryer for developing a freeze-drying process

Taylor N. Thompson, Davide Fissore

7.1 Introduction

7.2 Small-scale freeze-dryers

7.3 Process investigation in a micro freeze-dryer

7.4 Model parameters estimation for process optimization

7.5 Conclusions


List of References

8. Continuous manufacturing in lyophilization of pharmaceuticals: current status and perspectives

Roberto Pisano, Luigi C. Capozzi, Jos A.W.M. Corver

8.1 Introduction

8.2 The importance of being continuous

8.3 Regulatory perspectives

8.4 Drawbacks of batch lyophilization

8.4.1 Processing and dead times

8.4.2 Poor control of the freezing process

8.4.3 Primary and secondary drying

8.4.4 Batch-to-batch variability

8.4.5 Cycle scale-up onto GMP equipment

8.5 Continuous lyophilization of pharmaceuticals

8.5.1 The continuous lyophilization of drug products in bulk

8.5.2 Continuous lyophilization in unit doses based on spin freezing and IR-assisted vacuum drying

8.5.3 Continuous lyophilization in unit doses based on convective freezing and radiative drying of a continuous flow of suspended vials

8.6 Conclusion remarks

List of References

9. Use of CFD for the design and optimization of freeze-dryers

Antonello A. Barresi

9.1 Introduction

9.1.1 Use of CFD

9.2 Chamber pressure and estimation of the duct conductance

9.2.1 Design charts

9.2.2 Effect of inert gas on duct conductance

9.3 Evaluation of pressure conditions over shelves

9.3.1 Estimation of the pressure drop along a nominal shelf

9.3.2 Maximum pressure difference and coordinates for maximum pressure

9.3.4 Estimation of the intra-vial variance due to pressure gradients

9.4 Estimation of the chamber resistance and duct entrance effect

9.5 Evaluation of butterfly and mushroom valve conductance


List of References



About the Editors

Davide Fissore is Professor of Chemical Engineering at Politecnico di Torino (Italy). His research activity is mainly focused on process modelling and optimisation, and on the design and validation of model-based tools for process monitoring and control. One of the topics of his research activity is the freeze-drying of pharmaceutical products and foodstuffs. He developed various devices to monitor and optimise in-line (using a control system) or offline (using the design space of the product) the freeze-drying process for a given product. He acted as a consultant of several pharmaceutical companies, focusing on process development and scale-up. Davide Fissore is author or co-author of 89 papers appeared in international peer reviewed journals, 15 book chapters and currently holds 9 patents, issued or pending.

Roberto Pisano is a Professor of Chemical Engineering at Politecnico di Torino (Italy), where he received his Ph.D. in 2009. Professor Pisano’s research focuses on the application of both computational and experimental methods to engineering chemical products and processes, with particular emphasis to pharmaceutical processing and formulation of both small molecules and biologics. He has been visitor researcher at Centre de Ressources Technologiques – Institut Technique Agro-Industriel (Strasbourg, France) in 2008, and at the Department of Chemical Engineering of Massachusetts Institute of Technology (Cambridge, USA) in 2016. He has worked with many pharmaceutical companies in research or consulting. He has published more than 75 papers, 7 book chapters, and currently has 4 patents issued or pending.

Antonello Barresi is currently full professor of Transport Phenomena at Politecnico di Torino, in charge of the course of Process Development and Design. Currently Italian national delegate in the Working Party on Drying of the European Federation of Chemical Engineers. His main research interests in drying include: drying and freeze drying of pharmaceuticals and enzymes, modelling and optimization of freeze-drying processes, control of industrial freeze-dryers. Most recent research is focused on process transfer, scale-up and cycle development, and new approaches for process development and quality control in freeze-drying of pharmaceutical and food products. Author of more than 250 papers (of which about 160 published on international journals or books) and more than 100 Conference presentations.

About the Series

Advances in Drying Science and Technology

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Subject Categories

BISAC Subject Codes/Headings:
MEDICAL / Pharmacology
SCIENCE / Biotechnology