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- Herausgeber: Wiley-VCH Verlag GmbH & Co. KGaA
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
A comprehensive source of information about modern drying technologies that uniquely focus on the processing of pharmaceuticals and biologicals
Drying technologies are an indispensable production step in the pharmaceutical industry and the knowledge of drying technologies and applications is absolutely essential for current drug product development. This book focuses on the application of various drying technologies to the processing of pharmaceuticals and biologicals. It offers a complete overview of innovative as well as standard drying technologies, and addresses the issues of why drying is required and what the critical considerations are for implementing this process operation during drug product development.
Drying Technologies for Biotechnology and Pharmaceutical Applications discusses the state-of-the-art of established drying technologies like freeze- and spray- drying and highlights limitations that need to be overcome to achieve the future state of pharmaceutical manufacturing. The book also describes promising next generation drying technologies, which are currently used in fields outside of pharmaceuticals, and how they can be implemented and adapted for future use in the pharmaceutical industry. In addition, it deals with the generation of synergistic effects (e.g. by applying process analytical technology) and provides an outlook toward future developments.
-Presents a full technical overview of well established standard drying methods alongside various other drying technologies, possible improvements, limitations, synergies, and future directions
-Outlines different drying technologies from an application-oriented point of view and with consideration of real world challenges in the field of drug product development
-Edited by renowned experts from the pharmaceutical industry and assembled by leading experts from industry and academia
Drying Technologies for Biotechnology and Pharmaceutical Applications is an important book for pharma engineers, process engineers, chemical engineers, and others who work in related industries.
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Veröffentlichungsjahr: 2020
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Table of Contents
Cover
1 Introduction
Acknowledgement
References
2 A Concise History of Drying
2.1 Introduction
2.2 History of Drying of Pharmaceutical Products
2.3 History of Selected Drying Technologies
2.4 Concluding Remarks
Acknowledgments
References
Note
Part I: Drug Product Development
3 Importance of Drying in Small Molecule Drug Product Development
3.1 Introduction
3.2 Drying Materials and Dryer Types
3.3 Directly Heated (Convective) Dryers
3.4 Indirectly Heated (Conductive) Dryers
3.5 Emerging Drying Technologies
3.6 Summary
References
4 Drying for Stabilization of Protein Formulations
4.1 Protein Stability
4.2 Protein Stability in the Dried State
4.3 How Does the Process Influence Protein Stability?
4.4 Summary
References
5 Vaccines and Microorganisms
5.1 Introduction
5.2 Vaccine Drug Product Development
5.3 Spray Drying: An Alternate to Lyophilization
5.4 Summary and Path Forward
References
Part II: Common Drying Technologies
6 Advances in Freeze Drying of Biologics and Future Challenges and Opportunities
6.1 Introduction
6.2 Where Are We Now?
6.3 Current State
6.4 Current Challenges
6.5 Vision for the Future
6.6 Summary
Acknowledgments
Tributes
References
7 Spray Drying
7.1 Background
7.2 Particle Engineering
7.3 Current Status
7.4 Future Direction: Aseptic Spray Drying
References
Part III: Next Generation Drying Technologies
8 Spray Freeze Drying
8.1 Introduction
8.2 Background
8.3 Spray Freezing and Dynamic Freeze Drying
8.4 Conclusion
References
9 Microwave Drying of Pharmaceuticals
9.1 Fundamentals of Microwave Heating and Drying
9.2 Equipment Used for Microwave Freeze Drying
9.3 Formulation Characterization
9.4 Dehydration Process Using Microwave Freeze Drying
9.5 Advantages and Challenges of Pharmaceutical Microwave Freeze Drying
9.6 Some of the Published Patents for Application of Microwave Freeze Drying
References
10 Foam Drying
10.1 Introduction
10.2 Comparison of Drying Methods
10.3 Foam Drying: Historical Perspective
10.4 The Foam-Drying Process
10.5 Application of Foam Drying to Biostabilization
10.6 Physiochemical Characterization of the Foam-Dried Product
10.7 Conclusions and Future Prospects
References
11 Effects of Electric and Magnetic Field on Freezing
11.1 Introduction
11.2 The Different Stages and Parameters of Freezing
11.3 Effect of Electric Field on Freezing
11.4 Effect of Magnetic Field on Freezing
11.5 Possible Effect of Electric and Magnetic Field on the Sublimation Process
11.6 Future Outlook for Pharmaceutical Application
References
12 Desired Attributes and Requirements for Implementation
12.1 Introduction
12.2 Measuring Dryness
12.3 Process Considerations
12.4 Product Considerations
12.5 Scale-Up Considerations
12.6 Implementation
References
Part IV: Formulation Considerations for Solid Dosage Preparation
13 The Roles of Acid–Base Relationships, Interfaces, and Molecular Mobility in Stabilization During Drying and in the Solid State
13.1 Introduction
13.2 Acid–Base Relationships and Change in Ionization During Freezing and Drying
13.3 Role of Interfaces in Instability During Freeze Drying and Spray Drying
13.4 Influence of Molecular Mobility on Physicochemical Stability
13.5 Fast β-Relaxation in Practice
13.6 Conclusions and Advice to the Formulator
References
Note
Part V: Implementation
14 Challenges and Considerations for New Technology Implementation and Synergy with Development of Process Analytical Technologies (PAT)
References
Part VI: Future Perspectives
15 Future Directions: Lyophilization Technology Roadmap to 2025 and Beyond
15.1 Introduction
15.2 Overview of the Roadmapping Process
15.3 Trends and Drivers
15.4 Lyophilized Products
15.5 Process
15.6 Equipment
15.7 Regulatory Interface
15.8 Workforce Development
References
Index
End User License Agreement
List of Tables
Chapter 3
Table 3.1 Classification of dryers.
Table 3.2 Spray-drying parameters and their importance.
Table 3.3 Overview of the advantages, drawbacks, pharmaceutical applications, an...
Chapter 5
Table 5.1 Potential benefits and limitations of liquid drug product vs. lyophili...
Chapter 7
Table 7.1 Spray-dried inhaled biotherapeutics that have been commercialized or t...
Table 7.2 Investigational spray-dried vaccine formulations.
Chapter 8
Table 8.1 Process challenges/advantages in lyo-production.
Chapter 10
Table 10.1 Examples of process parameters associated with various foam-drying me...
Table 10.2 Physical properties and H1N1 LAIV stability in foam-dried, freeze-dri...
Table 10.3 Process-associated loss and storage stability at 25 °C for freeze-dri...
List of Illustrations
Chapter 1
Figure 1.1 Number of FDA-approved lyophilized drugs by year and decade of ap...
Chapter 2
Figure 1.1 Advertisement of an earlier version of evaporated milk.
Figure 2.2 Sample page of Pen T'Sao.
Figure 2.3 Dover's powder.
Figure 2.4 Black chuño (left) and white chuño (right).
Figure 2.5 Aerogel block being held in a hand.
Chapter 3
Figure 3.1
X-ray powder diffraction
(
XRPD
) patterns of anhydrous trehalose...
Figure 3.2
Differential scanning calorimetry
(
DSC
) heating scans of amorph...
Figure 3.3 A plot showing a linear decrease in order with increase in drying...
Figure 3.4 Schematic summarizing the importance of drying as a unit operatio...
Figure 3.5 Schematic showing reversible binding in erythromycin dihydrate ta...
Figure 3.6 Schematic of a batch fluidized-bed dryer. (1) Fluidizing chamber....
Figure 3.7 Correlation of moisture content as monitored in-line by
microwave
...
Figure 3.8 Effect of risedronate sodium rehydration on tablet thickness upon...
Figure 3.9 DSC traces of frusemide solid forms. (a) Crystalline form I. (b) ...
Figure 3.10 XRPD patterns depicting the effect of pH on the polymorphism of ...
Figure 3.11
Scanning electron microscopy
(
SEM
) micrographs of mannitol spr...
Figure 3.12 Dissolution profiles of different nifedipine formulations in dei...
Figure 3.13 Intensity of the characteristic peaks of anhydrous α-mannitol an...
Figure 3.14 SEM micrographs of paracetamol-containing freeze-dried wafers (a...
Figure 3.15 Phase diagram of carbon dioxide.
Figure 3.16 Diastereomeric resolution of SEDS-crystallized ephedrine mandala...
Figure 3.17 Tablet hardness vs. pressing power (compression force) for granu...
Chapter 4
Figure 4.1 Scheme of possible aggregation mechanisms of proteins. Stress fac...
Figure 4.2 Progression of Maillard reaction in freeze-dried disaccharide mat...
Chapter 7
Figure 7.1 Key elements of the spray-drying process.
Figure 7.2 Example of a cGMP commercial spray-drying system.
Figure 7.3 Computational fluid dynamics modeling results showing dryer cente...
Figure 7.4 Example of a twin-fluid/gas-assisted atomizer.
Figure 7.5 Computational fluid dynamics modeling results in a clinical scale...
Figure 7.6 Pressure-swirl atomizer concept.
Figure 7.7 Calculated particle trajectories in a clinical-scale spray dryer.
Figure 7.8 Computational fluid dynamics modeling results of a clinical scale...
Figure 7.9 The left panel shows the steady state radial concentration profil...
Figure 7.10 Electromicrograph of amorphous protein particles dried at a dryi...
Figure 7.11 Schematic representation of the particle formation process for a...
Figure 7.12 Effect of decreasing the available time for crystallization, Δ
t
c...
Figure 7.13 Schematic representation of the particle formation process for a...
Figure 7.14 The effect of crystallization sequence on the surface compositio...
Figure 7.15 Schematic representation of shell deformation with hole formatio...
Figure 7.16 Process model output in gray (process conditions: drying gas inl...
Figure 7.17 Commercial-scale aseptic spray-drying system.
Chapter 8
Diagram 8.1 Comparison of process chains for existing and proposed process.
Diagram 8.2 Configuration options for spray freeze drying.
Figure 8.1 Droplet formation by controlled laminar jet breakup: stroboscopic...
Figure 8.2 (a) Cross-sectional view of spray freezing tower including top li...
Figure 8.3 Vacuum process chamber housing with rotating double wall drum inc...
Figure 8.4 Spray-freeze-dried microspheres filled into vial from bulk.
Figure 8.5 Schematic view of a production size contained process line with m...
Figure 8.6 Fully contained sterilizable process line in production scale wit...
Figure 8.7 (a) Lab-scale freezing chamber. (b) Lab-scalerotary freeze dryer.
Chapter 9
Figure 9.1 Electromagnetic wave components [1]. Source: Adapted from Coyne a...
Figure 9.2 Continuous “traveling-wave” vacuum microwave dehydration system.
Figure 9.3 Relationship of boiling point and sublimation points of water vs....
Figure 9.4 Typical breakdown electric field responses in air as a function o...
Figure 9.5 Solid, porous, non-shrunken “cakes” left after microwave freeze d...
Figure 9.6 Effect of coating material and dehydration method on the survival...
Chapter 10
Figure 10.1 Sucrose–water state diagram comparing illustrative pharmaceutica...
Figure 10.2 (a) Representative samples of dried product from foam, freeze, a...
Figure 10.3 Comparison of representative foam- and freeze-drying shelf tempe...
Figure 10.4 (a) Foam-drying process conditions for the preservation of live ...
Figure 10.5 Storage stability at 37 °C (a), 25 °C (b), and 4 °C (c) for H1N1...
Figure 10.6 Stability profile of foam-dried formulation for type-B LAIV stra...
Figure 10.7 The process recovery of Ty21a upon foam drying. Bacteria were gr...
Chapter 11
Figure 11.1 The different stages of freezing.
Chapter 13
Figure 13.1 Acidity functions in ethanol–water solvents with 4 mM triethanol...
Figure 13.2 Change in the apparent acidity from solution to lyophile, as qua...
Figure 13.3 The effect of water content on the ionization of bromophenol blu...
Figure 13.4 Pseudo-first-order rate constants of sucrose inversion in PVP (s...
Figure 13.5 A glass can be viewed as a nonequilibrium supercooled liquid.
Figure 13.6 Illustration of dielectric spectra obtained in the broad frequen...
Figure 13.7 Correlations between
T
g
, structural relaxation time (
τ
β
...
Figure 13.8 The influence of β motions on protein stability. (a) Greater sug...
Figure 13.9 Aggregation of a monoclonal antibody
human epidermal growth fact
...
Chapter 15
Figure 15.1 Product-related technology roadmap.
Figure 15.2 Equipment-related technology roadmap.
Figure 15.3 Industry foundation roadmap.
Figure 15.4 Lyophilization roadmap summary table.
Figure 15.5 Pharmaceutical product lifetime stages. IND, Investigational New...
Figure 15.6 Lyophilized drug approvals by FDA from 1990 to 2014.
Figure 15.7 Process-related technology roadmap.
Guide
Cover
Table of Contents
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Drying Technologies for Biotechnology and Pharmaceutical Applications
Edited by
Satoshi Ohtake
Ken-ichi Izutsu
David Lechuga-Ballesteros
Editors
Dr. Satoshi Ohtake
Pfizer, Inc.
Pharmaceutical R&D
875 Chesterfield Parkway West
MO 63017
United States
Dr. Ken-ichi Izutsu
National Institute of Health Sciences
Division of Drugs
Tonomachi 3-25-26
Kawasaki 2109501
Kanagawa
Japan
Dr. David Lechuga-Ballesteros
AstraZeneca Pharmaceuticals, LP
Pharmaceutical Technology and Development
121 Oyster Point Boulevard, South San Francisco
CA 94080
United States
Cover
Cover Images: A multicolored powder explosion © Jag_cz/iStock.com, Vaccination © AlexRaths/iStock.com, Ceramic powder © aytacbicer/iStock.com
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1Introduction
Alex Langford1, Satoshi Ohtake1, David Lechuga-Ballesteros2, and Ken-ichi Izutsu3
1Pfizer BioTherapeutics, Pharmaceutical Sciences, 875 Chesterfield Parkway West, Chesterfield, MO, 63017, USA
2AstraZeneca Pharmaceuticals LP, Pharmaceutical Technology and Development, 121 Oyster Point Boulevard, South San Francisco, CA, 94080, USA
3National Institute of Health Sciences, Division of Drugs, Tonomachi 3-25-26, Kawasaki, 2109501, Kanagawa, Japan
Succeeding the inception of recombinant DNA technology in the 1970s [1], the pharmaceutical industry observed a significant shift from chemically synthesized drugs toward biologics. Biopharmaceuticals or biologics, distinct from small molecule drugs, include a wide variety of therapeutic products derived from living organisms or produced using biotechnology, e.g. recombinant proteins, vaccines, blood components, cellular therapies, and gene therapies. Biopharmaceuticals are characterized by a composition containing biological components or subunits including peptides, proteins, nucleic acids, and cells [2].
Since the US Food and Drug Administration (FDA) approved the first recombinant protein-based biologic in 1982 (recombinant insulin, Humulin®, Eli Lilly and Co., Indianapolis, IN, USA) [3] and monoclonal antibody-based therapy in 1986 [4], there has been continual growth in the number of biopharmaceuticals on the market. There were only nine biopharmaceutical approvals prior to 1990; however, since the mid-1990s, the United States and European Union have seen a combined average of more than 10 new approvals each year (based on Figure 1b of [5]). A survey of biopharmaceuticals published by Walsh [5] in 2014 reported that there were 212 approved biopharmaceutical products on the market in the United States and European Union with biopharmaceuticals making up an estimated 26% of all new drug approvals. The annual sales value of biopharmaceuticals in 2013 was reported to be US$140 billion, a value noted to be greater than the gross domestic product (GDP) of 156 of 214 countries listed in the World Bank GDP database. In 2017, the highest selling biologic was adalimumab (Humira, AbbVie Inc., North Chicago, IL, USA) at over US$18 billion in annual sales [6].
In more recent years, the diversity and complexity of the biopharmaceuticals in development has continued to increase. Protein-based therapeutics remain common, but the breadth of compounds the industry is currently faced with manufacturing has expanded significantly. Some examples of the products currently in development and on the market include antibody drug conjugates (ADCs), multivalent polysaccharide conjugate vaccines, live attenuated vaccines, cellular therapies, and gene therapies.
Figure 1.1 Number of FDA-approved lyophilized drugs by year and decade of approval.
Source: Adapted with permission from Ref. [8].
As the biopharmaceutical industry continues to evolve, advances in technologies will be required to address the challenges of speed to market, reducing developmental costs, improving storage stability, maintaining high product quality, and enhancing end-user convenience. The dehydration of material provides advantages that are able to address some of these challenges. While many biological materials contain high water content (typically ≥80%, w/w), the removal of water confers benefits such as ease of handling and storage, reduction in transportation costs, and improved stability [7]. For these reasons, the number of approved pharmaceutical products requiring lyophilization has significantly increased over the last two decades, as demonstrated by the increasing number of FDA-approved products that are freeze-dried (Figure 1.1). Furthermore, it was reported that the percentage of all approved injectable/infusible drugs that were lyophilized increased from only 12% between 1990 and 1998 to greater than 50% between 2013 and 2015 [8]. An increase in the number of biological therapy approvals by the FDA has been accompanied with a parallel increase in the overall number of approved drugs.
Whether it is the ancient use of sun and air drying as a means of food preservation, a primitive form of lyophilization used by the Incan Empire centuries ago using radiation from the sun and reduced pressure at high altitudes [9], or any advanced drying technology used in modern manufacturing processes across the globe, the basic principles of drying remain the same. Drying is the process of dehydration or the removal of water from a solution or suspension to form a solid. During the drying process, an energy source transfers heat to the solution through conduction, convection, and/or radiation to vaporize water. An aqueous solution is dried by two fundamental processes to remove either bound or unbound water (i.e. bulk water). The first process is the evaporation of surface moisture from the transfer of heat, or other forms of energy, to the wet feed. The second process is the transfer of internal moisture to the product surface where it can then evaporate following the first process [10]. Chapter 2 expands on the various ways in which these principles have been applied throughout history.
Since the dawn of modern engineering, drying has continued to mature, and now hundreds of dryer types are available for industrial applications. Chapter 2 provides a review of the current applications of drying technologies in industries other than pharmaceuticals, such as the food, agriculture, and textile industries. While many drying technologies in these industries are considered well established, the need for significant improvements to existing processes remains with respect to efficiency and control. The process efficiency of dryers has been reported to range from under 5% to approximately 35% on the high side due to (i) the high latent heat of vaporization of water and (ii) the inefficient heat transfer of convection (a common method of heat transfer in industrial dryers) [10]. The rate of drying is largely based on the amount of heat transferred to the wet feed through conduction, convection, and/or radiation. Additionally, it can be altered by changing factors such as the type of energy source used and/or application of forced air or a vacuum.
Traditional methods of commercial drying are limited either by their high production costs (e.g. freeze-drying) or severe reduction in product quality due to long exposure times at high temperatures (e.g. hot air drying). For biopharmaceuticals, the maintenance of high product quality is a crucial consideration for an optimized drying process. In general, a higher drying temperature will negatively impact product quality though reduce overall processing time. Often, loss of a drug substance and/or drug product batch has such a significant impact on developmental cost and/or clinical timelines that very conservative drying temperatures (i.e. lower temperatures) are utilized early in development. These lower drying temperatures often maintain product quality but require significantly longer processing time. In addition, a greater deviation of the processing temperature from ambient typically requires greater energy consumption. Thus, finding the optimum drying temperature is the most common problem encountered in developing an efficient drying process.
Historically within the pharmaceutical industry, engineers and scientists have been very limited in their use of drying technologies. The need to preserve high product quality of labile biomolecules and maintain aseptic processing has severely reduced the number of methods used in the industry. The gold standard for the drying of biopharmaceuticals is freeze-drying as evidenced by the significant number of freeze-dried biomolecule products on the market [11]. Due to its prominence in the field, the first drying technology to be reviewed in this book is freeze-drying (Chapter 6). In addition, there are several supplemental resources on this topic recommended for further reading [12–14]. Even though the freeze-drying process is common and relatively well established, it has several shortcomings, including high energy consumption, long drying times, low process efficiency, formulation limitations (i.e. challenges with low collapse temperature excipients such as salts), and incompatibility with continuous manufacturing. The efficiency of fully loaded laboratory- and production-scale lyophilizers was reported to range from 1.5% to 2% as calculated by Alexeenko [15]. While higher process efficiency is possible through other drying technologies, consideration of alternative drying methods depends on several factors such as the physical properties of the product, application of the product, type of energy source available, container closure system, and scalability of the equipment. Chapter 12 reviews the desired characteristics of a novel drying technology and requirements for implementation into the current manufacturing environment.
As mentioned above, drying can provide significant benefits to the stabilization of labile biomolecules. A liquid drug product formulation is often preferred due to reduced manufacturing costs and end-user convenience (i.e. no reconstitution required); however, sufficient stabilization in the liquid state often cannot be achieved. In an aqueous solution, water serves as a medium that results in significant molecular mobility and conformational perturbations and acts as a catalyst for chemical degradation that can promote instability during storage and shipping [16]. The removal of water through drying significantly retards water-mediated degradation. An early-stage clinical development strategy may be to proceed with a dried formulation as a means of quickly achieving adequate product stability without needing to develop a liquid formulation. This may be a preferred approach since many products do not make it to approval based on clinical results and the consequential reduction of up-front resources may help to reduce the company's developmental costs. That being said, smaller organizations may benefit from developing a stable liquid dosage form due to the increased cost of manufacturing a freeze-dried product. Chapter 13 presents additional details on relevant challenges in the development of liquid dosage forms and the benefits of solid-state stabilization. A drying process cannot be designed as a stand-alone entity, and the characteristics of the molecule to be processed must be considered. Chapters 3, 4, and 5 review the unique considerations when applying drying processes to small molecule active pharmaceutical ingredient (API), proteins, and vaccines, respectively.
Even though a well-designed drying procedure can often sufficiently stabilize biomolecules, drying induces new stresses to a product that are not present in a liquid formulation. From a freeze-drying perspective, these stresses include the ice–water interface, low temperature, cryo-concentration [17], freezing-induced pH shifts [18], and the removal of bulk and bound water during drying [14, 19]. It has been widely reported that the degradation of biomolecules, such as monoclonal antibodies, caused by some of these stresses can be overcome by the use of stabilizing excipients, such as disaccharides [16, 17]. Chapter 13 presents the primary considerations when developing a stable solid-state formulation in addition to discussing the key role of water in the final product. Looking toward the future, as biomolecules continue to increase in complexity (e.g. mammalian cell-based therapies), these drying-induced stresses may prove to be more problematic, and stabilizing excipients alone may not be sufficient to adequately stabilize dried formulations. The formulation scientist may have to consider the unique benefits of next-generation drying technologies to overcome such challenges [20].
Next-generation drying technologies for biological materials include but are not limited to spray freeze-drying (Chapter 8) [21, 22], microwave drying (Chapter 9) [23, 24], foam drying (Chapter 10) [25, 26], and the use of electromagnetic/magnetic waves on freeze-drying (Chapter 11) [27]. While these “novel” drying techniques currently have limited application in the biopharmaceutical industry, many are commonly used in other industries. Benefits such as improved stabilization of biomolecules, compatibility with continuous manufacturing, and improved process efficiency compared with freeze-drying are potential reasons to evaluate these technologies. Microwave-assisted freeze-drying is an example of utilizing a hybrid of two drying methods to significantly reduce drying process time [24, 28]. For these reasons, this book will veer away from established biopharmaceutical development approaches and conventional drying processes, such as freeze-drying and spray drying (Chapter 7), to discuss and evaluate these promising next-generation technologies. Chapter 14 reviews the challenges and considerations for implementing these new technologies into the current manufacturing environment as well as discusses the potential synergy with process analytical technologies (PAT). These novel techniques are presented to the reader in hope that they will consider how to utilize them to overcome new problems and inefficiencies they encounter.
Several resources are currently available to engineers, scientists, and academics that review the fundamentals of drying and its application to various industries. However, there is currently no book that focuses solely on the application of a variety of drying technologies to biopharmaceuticals. The aim of this book is to fill this void by providing a comprehensive resource reviewing the current state and future direction of drying technologies for biopharmaceutical applications. The authors hope that this book will serve scientists and engineers in the pharmaceutical industry as well as academics, particularly in chemical engineering and pharmaceutical sciences, as a single source of information related to pharmaceutical drying technologies. Since this book presents the latest developments related to drying technologies in the field, senior leaders in the industry may find it useful for identifying improvements to current and/or new technologies to implement into their current manufacturing environment. The authors hope that the specific focus of this book on biopharmaceutical applications will enhance its effectiveness in providing a clear vision of the current and future (Chapter 15) landscape of drying in the pharmaceutical industry.
Acknowledgement
The authors along with the other contributors of the book would like to acknowledge the contributions made by Professor Michael J. Pikal to advance our understanding of and technical capability of various drying processes. He sadly passed away prior to the completion of the book and we dedicate this book to Prof. Pikal, who was our friend, colleague, and mentor.
References
1 Berg, P. and Mertz, J.E. (2010). Personal reflections on the origins and emergence of recombinant DNA technology.
Genetics
184 (1): 9–17.
2 Shih, H.H., Miller, P., and Harnish, D.C. (2010). An overview of the discovery and development process for biologics. In:
Pharmaceutical Sciences Encyclopedia
(ed. S.C. Gad). New York, NY: Wiley.
3 Altman, L.K. (1982). A new insulin given approval for use in the U.S.
The New York Times
(30 October).
4 Goswami, S., Wang, W., Arakawa, T., and Ohtake, S. (2013). Developments and challenges for mAb-based therapeutics.
Antibodies
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2A Concise History of Drying
Sakamon Devahastin1,2 and Maturada Jinorose3
1King Mongkut's University of Technology Thonburi, Advanced Food Processing Research Laboratory, Department of Food Engineering, Faculty of Engineering, Bangkok, 10140, Thailand
2The Royal Society of Thailand, The Academy of Science, Dusit, Bangkok, 10300, Thailand
3King Mongkut's Institute of Technology Ladkrabang, Department of Food Engineering, Faculty of Engineering, Bangkok, 10520, Thailand
2.1 Introduction
Drying has been conducted since time immemorial with the main purpose of preserving food and agricultural produce. Although the main objective of drying has not changed since its first application, drying is also used nowadays for a number of other equally important purposes. Among such purposes is the use of drying to produce products that cannot be obtained by other processing means. These range from such ubiquitous products as instant milk, coffee, and other beverages to some household products such as detergent powder to some advanced materials, including pharmaceutical products.
As far as 20 000 BC, humans started to dry meat via the method of sun drying. Some 10 000 years later, fish was noted to be dried in France, while some grains and legumes were dried in the Middle and Near East. Around 9000 BC, salt was made by drying seawater, but it was only 1500 years ago in India that sugar was first dried into a solid form [1]. Development of most drying techniques that are widely in use today started only in the nineteenth century. Around 1800, a dryer made of brick, which can probably be regarded as an early version of a mechanical dryer, was constructed and used to dry grains.
In 1856, Gail Borden Jr., based on his earlier experience producing the so-called meat biscuit [2, 3], which was a dehydrated meat mixed with flour, patented a process for concentrating and preserving milk (Figure 1.1) by “coagulating and rearranging the albuminous particles in combination with the evaporation of the fluid in vacuo.” This represents an early attempt to develop a water-removal process under vacuum. Many other patents on the production of various dried products have been filed afterward. For example, in 1865, Charles A. La Mont patented a process to manufacture dried egg [4]. This probably represents the first attempt to spray-dry a product as the egg can be forced “by means of a powerful blast of air, into a thin spray, which is made to fall through a current of heated air, as aforesaid, and dry in small, fine particles,” among other possible alternatives. Samuel R. Percy, however, was the one credited for the invention of modern spray drying. He was granted in 1872 a patent on the method to improve atomizing and drying liquid substances by the process of atomization [5]. Several advanced designs of spray dryer have emerged during the twentieth century [1, 6]. Some investigator has even declared that it was the invention and continuous development of spray drying that ultimately helped advance the manufacturing technology for solubilizing drug molecules [7].
Figure 1.1 Advertisement of an earlier version of evaporated milk.
Source: https://tshaonline.org/handbook/online/articles/fbo24 (accessed 1 April 2018).
Another important drying technology, especially for such highly heat-sensitive materials as pharmaceutical products, is freeze drying. A technique similar to freeze drying was first noted to be used by the Peruvian Incas to dry potatoes and other crops and by Japanese monks living on a mountain to dry tofu. In such cases, drying materials were carried high into the mountains where temperatures descended below the freezing point of water; atmospheric pressure was also low due to the high altitudes, resulting in the removal of water within the materials [8]. Modern-day freeze drying, however, started only in the late nineteenth century, with Richard Altman in 1890 drying pieces of frozen tissues by placing them in a vacuum desiccator at −20 °C. Freeze drying became more popular during World War II as a means to preserve blood plasma and eventually vaccines and many other biological molecules [9].
In addition to the developments in drying equipment, theoretical developments have also flourished since the beginning of the twentieth century. Warren K. Lewis and Thomas K. Sherwood (of the well-known Sherwood number) were among the first who laid the foundations of modern-day theoretical study of drying [10–12]. Throughout the century, progress has significantly been made by a large number of fine individuals working in both academia and industry. Freeze drying of pharmaceuticals, for example, has been well studied by the late Prof. Michael J. Pikal, to whom this book is dedicated, along with many other researchers.
The history of drying would not be complete without the mentioning of the journal devoted solely to the science and engineering of drying. Drying Technology, which was launched in 1983 under the editorship of the late Prof. Carl W. Hall, now (2019) publishes 16 issues per annum under the editorship of Prof. Arun S. Mujumdar; drying of pharmaceuticals is of course one of the main themes of the journal. Prof. Mujumdar also launched another important knowledge dissemination outlet in 1978 in the form of the International Drying Symposium, which has since uninterruptedly held on a biennial basis and already celebrated its 40th anniversary at the 21st symposium in Valencia, Spain, in 2018. Coincidently or not, it is interesting to note that Prof. Mujumdar started the important aforementioned activity while at McGill University in Canada, the institution where Prof. Sherwood received his first degree in chemical engineering in 1923.
In the next section, a concise history of drying of pharmaceutical products is provided. Brief histories of some popular drying techniques for drugs and other relevant molecules will also be given.
2.2 History of Drying of Pharmaceutical Products
Pharmaceutical products have been dried for millennia, starting in the form of herbs and other medicinal natural products. In fact, the word “drug” is derived from French “drogue,” which means dried herb [13].
Figure 2.2 Sample page of Pen T'Sao.
Source: https://commons.wikimedia.org/wiki/File:Pen_ts%27ao,_woodblock_book_1249-ce.png (accessed 1 April 2018).
The Chinese book on roots and grasses Pen T'Sao (Figure 2.2), written by Emperor Shen Nung as early as 2500 BC, mentioned as many as 365 drugs obtained from dried parts of medicinal plants, many of which are still in use even today such as Rhei rhizoma, camphor, Theae folium, Podophyllum, ginseng, jimson weed, cinnamon bark, and ephedra [14]. Since then a large number of books describing a very wide array of aromatic plants, spices, and plant drugs have been written in other parts of the world, including Egypt, India, the Middle East, and different parts of Asia and Europe. Later, between the sixteenth and eighteenth centuries, compound drugs, which consisted of medicinal plants along with drugs of plant and animal origins, started to receive more attention. From today's technological point of view, this represents more challenges for drying to retain bioactivities of the drugs. These challenges might nevertheless not be well recognized some five centuries ago.
One important dried pharmaceutical product of the eighteenth century was the so-called Dover's powder (Figure 2.3), which was introduced by Thomas Dover. The powder was prescribed as diaphoretics but was aimed for the treatment of gout. The powder was prepared and used, as stated in the section on gout in Dover's book The Ancient Physician's Legacy to his Country,1 by “Tak(ing)e Opium one ounce, Salt-Petre and Tartar vitriolated each four ounces, Ipocacuana one ounce. Put the Salt-Petre and Tartar into a red-hot mortar, stirring them with a spoon until they have done flaming. Then powder them very fine; after that slice in your opium, grind them to a powder, and then mix the other powders with these. Dose from forty to sixty or seventy grains in a glass of white wine Posset, going to bed; covering up warm, and drinking a quart or three pints of the Posset – Drink while sweating.” The compound had become the most widely used opium preparation for the next 150 years [15, 16].
Figure 2.3 Dover's powder.
Source: https://commons.wikimedia.org/wiki/File:Bottle_of_Dover_Powder_Wellcome_L0047580.jpg (accessed 30 March 2018).
The importance of drying on the drug activities was revisited in the late nineteenth century when various investigators started to note that the healing effect of medicinal plants depended on the mode of drying. On a side note, drying was used in 1884 as a means to attenuate the rabies virus by Louis Pasteur; drying of viral infected tissues was noted to help weaken the virus [17]. In the early twentieth century, stabilization methods for fresh medicinal plants started to be proposed. Significant effort has since been made to study the effects of manufacturing conditions on the activities of medicinal plants and drugs. Extensive literature on drying of pharmaceutical and related products has been produced [18, 19], making the field expand very rapidly.
2.3 History of Selected Drying Technologies
2.3.1 Freeze Drying
As mentioned earlier, a process that can be more or less qualified as freeze drying has started to be practiced by the South American natives some centuries ago. Tubers of frost-resistant potato varieties are frozen overnight and later warmed in indirect sun. In this way, the ice is removed by sublimation. The semi-dried product is trampled to remove the skins and eliminate the residual water, which allow for further freezing and drying. The so-called white chuño (or tunta) is made by soaking the partially dried tubers in water for a week (or even several weeks in some cases) prior to sun drying. Black chuño is, on the other hand, obtained from tubers subjected directly to sun drying without prior soaking or washing [20, 21]. Note that white chuño is covered during sun drying by blankets to avoid direct exposure to sunlight; this results in the different appearance of the two chuño (Figure 2.4). As a dried product, chuño has extended shelf life in comparison with unprocessed tubers. Chuño possesses higher contents of some minerals, including calcium and iron, than its unprocessed counterpart. However, chuño has lower contents of phosphorus, potassium, magnesium, and zinc as well as some antioxidants (e.g. phenolic compounds) than unprocessed tubers. This is particularly true in the case of white chuño due to its long exposure to water during processing [22, 23].
In the pharmaceutical industry, freeze drying (or lyophilization) is among the most widely and successfully utilized methods for transforming a wide range of aqueous and nonaqueous solutions of bioactive substances, including antibiotics, bacteria, sera, vaccines, diagnostic medications, protein-containing and biotechnological products, cells and tissues, and chemicals, into a solid, stable state [24].
The development of freeze drying can be traced back to as early as 1811 when Sir John Leslie first demonstrated the process of ice sublimation [25]. Later in 1813, William H. Wollaston, in his lecture to the Royal Society of London, defined such a process in which a solid (ice) is converted into a gaseous state and then recondensed as a solid, thereby completely avoiding the intervention of a liquid state during the process [21]. Neither Leslie nor Wollaston seemed to use the process of sublimation for drying, however. The actual freeze-drying process was first tested by Richard Altman in Leipzig in 1890 for drying pieces of frozen tissues. Later in 1903, Vansteenberghe freeze-dried rabies virus, and in 1906, Jacques-Arsene d'Arsonval removed water at a lower temperature for distillation [26]. The first patent for freeze drying was issued to a French inventor Henri Tival in 1927. Later in 1934, William Elser received a patent for a freeze-drying apparatus that did not supply heat (but rather employed the so-called solid carbon dioxide cold trap) for sublimation [27]. In fact, all related works conducted up to this point involved the use of no heat for drying. Test materials were either vacuum-insulated from the atmosphere or the whole apparatus was placed in a cold room [28].
Figure 2.4 Black chuño (left) and white chuño (right).
Source: Black Chuno: https://commons.wikimedia.org/wiki/File:Chu%C3%B1o.jpg and White Chuno: https://commons.wikimedia.org/wiki/File:Tunta-02.jpg (accessed 1 April 2018).
In 1935, Earl W. Flosdorf and Stuart Mudd were the first to use a high-temperature source to perform freeze drying; human blood serum and plasma were dried for clinical use [28]. Their subsequent efforts led to commercial freeze-drying applications in the United States. Application of the process to food (fruit juices and milk) started in 1935, and a British patent was issued to Franklin Kidd in 1941 for the freeze drying of foods [26, 29]. Due to technological restrictions, however, the process was not often used and was difficult to replicate.
Freeze drying became of practical importance during World War II. Many blood supplies being sent to Europe from the United States for medical treatment spoiled before reaching their destination. Freeze drying, through the research of Flosdorf and Mudd, was then used to produce blood that was chemically stable and viable without requiring refrigeration. Shortly thereafter, the process was also applied to penicillin and bone [30]. At about the same time, freeze-drying applications were developed under the leadership of Ronald I. N. Greaves of Cambridge University, first also to dry blood and later as a means to alleviate the food crisis during World War II. In 1951, the British Ministry of Food Research was established in Aberdeen, Scotland, where a vacuum contact plate freeze dryer that improved the product quality and reduced the time required for rehydration was developed. A continuous process for freeze drying was eventually developed by Greaves in 1960 [26]. By the 1950s, freeze drying has established itself as a common process for drying pharmaceutical products. Toward the end of the twentieth century through to present day, the process has also gained attention for drying probiotics and nutraceutical products [21, 29, 31].
Despite being treated as a gold standard to which alternative drying methods must be compared, freeze drying suffers from a number of limitations, including the lengthy required drying time [31]. An array of alternative drying methods, ranging from bulk freeze drying and foam drying to rather different classes of drying techniques, have therefore been proposed and tested; some of them will be discussed in the latter chapters of the book.
2.3.2 Spray Drying
As mentioned earlier, it was Samuel Percy in 1872 who was credited for the invention of modern spray drying. He indeed described the spray-drying process as “The process of simultaneously atomizing and desiccating fluid and solid substances, and its application to the purpose of the exhaustion of moisture from such substances, and for the prevention of destructive chemical change” [5]. World War II was again the important driving force for the development and adoption of spray drying for continuous production of milk powder. The process has gone through a number of design modifications and is now widely used to convert an array of pumpable liquids into flowing powders of versatile applications [32].
Spray drying is probably the most mature alternative technology to freeze drying and can be applied to the production of many pharmaceutical products, especially when attributes such as particle size, morphology, and stability need to be accurately controlled [33]. Spray drying may be used to produce fine particles for pulmonary and nasal deliveries as well as large agglomerated powers for oral administration [34]; Exubera®, despite its failure, was indeed the first inhaled therapeutics that was manufactured by spray drying [31]. Spray drying owes its advantages to the ability to control the particle size, bulk density, degree of crystallinity, and residual solvent or moisture content of a final powdery product. Micro- and nanocapsules with therapeutic core and biocompatible coating material(s) can be well prepared by spray drying. The technique can also be used to enhance the solubility and dissolution rate of a poorly soluble drug, usually via the formation of inclusion complexes or via the development of solid dispersions.
The first use of spray drying in pharmaceutically related application was probably that of Robert Stauf in the early twentieth century for drying of blood [35]. A sterile version of spray dryer, which was used for drying plasma and serum, was, however, proposed by John F. Wilkinson, Kenneth Bullock, and William Cowen in the 1940s [36]. The technique has since been applied to manufacture infusions, extracts, inorganic medicinal salts, adrenaline, and some vitamins [31, 37–39]. Of particular use of this drying technique is the production of pharmaceutical excipients and active ingredients, which are difficult to crystallize [33].
It is interesting to note here a brief historical development of the three major components of a spray-drying system, namely, a liquid pump, nozzle (or atomizer), and powder collection unit. The first use of pump dated back to as long as 2000 BC in Egypt, and the progress has continued through the whole history, with the inventions of a piston vacuum pump by Otto von Guericke in 1650, packed plunger pump by Sir Samuel Morland in 1674, and screw pump by Revillion in 1830 [40]. However, it was the invention of a steam pump of Henry R. Worthington in 1840 that marked the beginning of a real progress in this area. Spray nozzle was indeed the invention of Stauf in 1901, while the powder collection was first patented in 1906 by Wilhelm F. L. Beth [7].
Spray drying nevertheless suffers some shortcomings. Aseptic processing is clearly more challenging in the case of spray drying when compared with freeze drying. There may also be some difficulties when hygroscopic powders need to be handled. As the material recovery can never reach 100%, high-cost pharmaceutical products may not be suitable to be processed via spray drying.
2.3.3 Fluidized-Bed Drying
The first application of a fluidized bed was probably that of Fritz Winkler in 1922 for coal gasification, while it was not until 1942 that the first production facility using the fluidized-bed concept for catalytic cracking of petroleum feedstock became operational [41]. Since then fluidized bed has found applications in such a wide array of industries as petrochemical, materials processing, food, and pharmaceuticals. Fluidized-bed dryer has become particularly popular in the food industry for drying a large number of particulate materials. Grain kernels such as rice [42] as well as potato granules, peas, and diced vegetables [43] are commonly dried in this type of dryer.
In the pharmaceutical industry, a fluidized bed is used not only for drying but also for blending, pelletizing, and coating [44–46]. Combined drying and granulation are among the common operations that have been conducted in this type of dryer to improve the flowability and compressibility of a pharmaceutical powder.
2.3.4 Supercritical Drying
Baron Charles Cagniard de la Tour was noted in 1822 to be the first person to observe the critical phenomena. By placing a flint ball in a digester that was partially filled with liquid, a splashing sound was generated as the ball penetrated the liquid–vapor interface. Upon heating, the splashing sound ceased above a certain temperature beyond the boiling temperature of the liquid. This marks the discovery of the supercritical fluid phase where the densities of the liquid and gas phases become equal and the distinction between them disappears, resulting in a single supercritical fluid phase. Cagniard de la Tour, however, did not use the term “critical point” to explain his observation. It was Thomas Andrews in 1869 who coined the term. Significant progress has been made since that time; the reader is referred to an excellent review by Berche et al. [47] for the summary of the first 150-year history of the field.
Supercritical drying works in a similar fashion to supercritical fluid extraction, with solvent to be removed as a solute and supercritical fluid as an extraction solvent. Supercritical drying using CO2 (which is the most widely used supercritical solvent) has been applied to produce a number of products, including aerogels (Figure 2.5); high-value dried herbs and spices are also produced by this drying technique [48]. Among the noted advantages of supercritical drying, absence of the vapor–liquid interfaces is of particular interest. Such an absence leads to negligible surface tension and capillary-induced stress that may damage the microstructure of a material being dried [48, 49]. Samuel S. Kistler in the late 1920s was indeed the first who recognized such an advantage of a supercritical fluid when he tried to replace the liquid inside of a jelly without causing any shrinkage. In other words, he was trying to replace a liquid in a gel with a gas, thus creating a substance that was structurally a gel, but without the liquid [50].
Figure 2.5 Aerogel block being held in a hand.
Source: https://en.wikipedia.org/wiki/Aerogel#/media/File:Aerogel_hand.jpg (accessed 1 April 2018).
Another important advantage of supercritical drying is its ability to operate at a lower temperature and hence the ability to dry highly heat-sensitive materials. In the pharmaceutical industry, supercritical fluid-assisted nebulization drying via the so-called Bubble Dryer® was used to prepare various dried powdery protein formulations and protein-loaded microparticles [51]. Supercritical solvents, e.g. supercritical CO2, possess a number of unique properties, making them possible to process bioactive molecules and amorphous polymers without the use of toxic organic solvents. This type of solvent exhibits positive impacts on both micronization and encapsulation of microparticles [52]. Through the use of supercritical solvent for drying, microbial inactivation can also be achieved, thus alleviating concerns on aseptic processing as compared with the case of spray drying [31].
Other alternative technologies can also be applied to the drying of pharmaceutical products. Despite their ubiquity in other industries, namely, food and chemical industries, such technologies as vacuum drying and microwave drying still need to find more of their places in the pharmaceutical industry.
2.4 Concluding Remarks
In this chapter, a concise history of drying in general and pharmaceutical drying in particular is given. Brief histories of some major drying technologies that are in use in the pharmaceutical industry are also reviewed. Knowing the history, even in its brevity as is the case of this chapter, should give the reader a better appreciation (and more enjoyment!) of the exciting scientific and technological details of the various drying technologies applicable for an array of pharmaceutical products that will follow in the latter chapters of this book.
Acknowledgments
Financial support provided by the Thailand Research Fund (TRF) (grant number RTA 6180008), which allowed for the completion of the chapter, is greatly appreciated.
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