Freeze-drying of Pharmaceuticals and Biopharmaceuticals: Principles and Practice - Hardcover

Franks, Felix; Auffret, Tony

Hardcover

ISBN 10: 0854042687 ISBN 13: 9780854042685

Publisher: Royal Society of Chemistry, 2007

Synopsis

Aimed at product and process developers in the biopharmaceutical industry and academia, this is the first book to describe freeze-drying, as related to the pharmaceutical industry.

About this title

From the Back Cover

Freeze-drying, in the past popular in the food industry, has more recently been adopted by the pharmaceutical industry as a standard method for the production of stable solid preparations. Freeze-drying of Pharmaceuticals and Biopharmaceuticals is the first book to specifically describe this process, as related to the pharmaceutical industry. The emphasis of this book is on the properties of the materials processed, how effective formulations are arrived at, and how they are stored and marketed. Beginning with a historical overview of the process, Freeze-drying of Pharmaceuticals and Biopharmaceuticals briefly describes the processes and equipment involved, including: the physics, chemistry and biochemistry associated with freezing, aspects of formulation development, primary and secondary drying; the economics and engineering of scaling up; and, most importantly, attributes of the dried product. It also discusses in detail the science behind freeze-drying, such as the properties of crystalline and amorphous solids. The book concludes with selected case studies and discusses the future of freeze-drying, advances in alternative drying methods, and concludes with an extensive bibliography. This book, written by a leading expert in the field, is aimed primarily at product and process developers in the biopharmaceutical industry and academia.

Excerpt. © Reprinted by permission. All rights reserved.

Freeze-Drying of Pharmaceuticals and Biopharmaceuticals

Principles and Practice

By Felix Franks

The Royal Society of Chemistry

Copyright © 2007 The Royal Society of Chemistry
All rights reserved.

ISBN: 978-0-85404-268-5

Contents

Chapter 1 Historical Background, 1, 
Chapter 2 The Process Sequence in Summary, 13, 
Chapter 3 Essential Product and Process Parameters in Summary, 20, 
Chapter 4 Essential Physics of Low Temperature and Freezing, 28, 
Chapter 5 Essential Chemistry and Biochemistry Associated with Low Temperature and Freezing, 54, 
Chapter 6 Physical Properties of Crystalline and Amorphous Solids, 78, 
Chapter 7 Excipients: Their Role in Rational Formulation Design, 89, 
Chapter 8 Primary Drying: The Sublimation of Ice, 105, 
Chapter 9 Secondary Drying: The Removal of Unfrozen Water, 121, 
Chapter 10 Some Practical Aspects, 130, 
Chapter 11 The Dried Product, 141, 
Chapter 12 Case Histories, 171, 
Chapter 13 Beyond Freeze-Drying, 182, 
Acknowledgements, 187, 
Bibliography, 190, 
Subject Index, 201, 

CHAPTER 1

Historical Background

1.1 History of Drying as a Preservation Method

The recognition that all organic matter on this planet is either water soluble, or at least water sensitive, can be taken as a starting point of almost everything that is discussed in this book. Following on from this bald statement is the unfortunate fact that aqueous solutions of many organic substances, as well as water-sensitive solids containing even relatively low amounts of absorbed water, tend to be subject to chemical, microbial and/or physical changes, most of which are perceived to be undesirable, perhaps even hazardous or lethal. This realisation goes back many centuries: sailors who travelled on exploratory journeys to faraway places learned early on to pickle their meat and other food supplies in concentrated brine solution, so as to inhibit the growth and proliferation of toxic principles that were known to lead to painful or even incurable diseases.

In more modern times, refrigeration and frozen storage have superseded the ancient pickling processes and other, more refined methods have been devised to render foods stable, safe and acceptable for extended periods. Among such methods, drying takes pride of place, insofar as it does not reduce the perceived eating quality of a product. The advent of "instantisation" technology has led to a wide range of products that bear witness to the successes achieved by controlled drying of aqueous solutions, or of solids that contain appreciable amounts of water. Where desirable, solid states so obtained can be readily reconstituted with only minor losses in eating quality. What is not universally appreciated is that freezing as such, is in fact a drying process. As liquid water is converted into crystalline ice from the original aqueous solution or solid substrate, the residue becomes increasingly dehydrated. Upon rewarming, the ice melts and, ideally, the dehydrated product can be reconstituted into its original state, undamaged by the dehydration/ rehydration cycle.

The discovery of freezing as a means of drying was chronicled in detail by one Gerrit de Veer, who was born in Amsterdam some time between 1564 and 1577. As a young man, he accompanied the famous seafarers Willem Barents and Jacob van Heemskerk on two of their journeys in 1595 and 1596. Although his job appears to have been that of an ordinary seaman, with little seafaring experience, he kept a detailed log of the expeditions. Barents' and van Heemskerk's aim was to find a navigable passage around the north of the Asian continent, all the way to China. Barents made several such attempts, all of them unsuccessful, and he died in the Arctic during the 1596 expedition.

According to de Veer's log, a supply base had been established in 1595 on one of the islands close to "Nova Zembla" in the Arctic Ocean, where food and drink were stored for the following year's expedition -the one that proved to become Barents' final attempt to reach China and from which he did not return alive. When the 1596 expedition reached the supply base, the sailors were surprised to find that the beer barrels, which had been left there from the previous year, had not only split open, but that they contained large quantities of ice which, upon thawing, did not taste like beer. At the bottom of the barrels, they found a creamy, unfrozen substance that tasted of yeast and proved to be quite intoxicating. The seafarers had in fact stumbled on the process that is nowadays referred to as "freeze-concentration" and which forms the first stage of freeze-drying and of frozen storage in general.

At about the same time, a more targeted, almost hi-tech application of freeze-drying was already being practised by some South American Indians, who were able to convert several selected potato varieties into "white chuño". This was the name given to a product that does not contain bitter glycoalkaloids, is light, easy to transport and can be stored for extended periods. To produce freeze-dried chuño, the Andean Indians froze potato tubers overnight and then warmed them in the sun, but without direct exposure to the sun's rays. In this manner, the ice was removed by sublimation. Next they trampled the semi-dried product to slough off the skins and squeeze out residual water. Finally the tubers were soaked in cold water for several weeks and sun-dried for a week. The chuño, so obtained, formed a white crust, possessing the desirable storage properties of a freeze-dried, stable potato product, which was first described by chroniclers who accompanied the Spanish invaders of the Inca Kingdom.

1.2 Advent of Industrial Freeze-Drying

In reality, the consequences of freezing and thawing are usually more complex than those described by de Veer, or as performed by the South American Indians. For example, the removal of water from complex solid substrates, such as fish or meat, is accompanied by an irreversible aggregation of muscle tissue, which is then unable to reintegrate enough water into the muscle tissues after thawing, giving rise to what is known as "drip loss". Other deleterious processes that may occur during drying include the rupture of cell membranes (e.g. soft fruit) or enhanced lipid oxidation, leading to off-flavour and rancidity (e.g. fish). Nevertheless, the controlled drying of food, leading either to the so-called intermediate- or low-moisture products or to "instantisable" products has made great strides and has established itself as an important branch of food process development. Although frozen distribution and storage of food is still widely practised, freeze-drying, i.e. the sublimation of ice from a previously frozen product, has been largely superseded by other, more economical drying methods. Its current use is limited mainly to the production of high-value products, e.g. Japanese fish specialities, or products where losses of volatiles would seriously impair quality. The place of freezing and freeze-drying in food process technology, as it existed in the 1970s and how it was predicted to change during the 1980s, is well summarised by the contributions presented at a Royal Society Discussion in 1974. With the benefit of hindsight, the reader is left to decide to what extent the predictions actually came true.

The situation is totally different in the pharmaceutical industry, where freeze-drying has gradually established itself as the standard method for rendering aqueous (or even some non-aqueous) solutions of bioactive substances into solid, stable states. An important difference between food and drug processing lies in the contribution of processing towards the total cost. In the case of food production, the various processing stages account for an appreciable contribution towards the total cost, whereas in the pharmaceutical industry the cost of downstream processing, although appreciable, is usually only a minor factor, compared to the cost of the purified bioactive raw material, the drug substance. Another reason is that the regulatory requirements in the food industry are less stringent than those which govern purity, sterility and stability criteria, applied to pharmaceutical preparations, and in particular to parenteral products.

Yet another important difference between dried food products and pharmaceutical preparations is that the former are usually sold by weight, almost irrespective of quality, whereas the value of the latter is measured in the so-called international units of activity (IU). Thus, for enzymes, the IU measures the amount of substrate that is turned over in unit time by unit weight of enzyme, at a given temperature. Hence, freeze-dried coffee, even when of a somewhat indifferent quality, will find its way onto the supermarket shelf, where it can be labelled and sold as "coffee". The same is not true for, say, an industrial or a therapeutic enzyme. Any losses in specific enzyme activity, incurred during downstream processing, including the final freeze-drying operation, downgrade the value of the finished product, since this is not measured as kg (or mg) of enzyme, but as IU of enzyme activity per kg (or mg).

The choice of a particular drying method is also partly dictated by the scale of the operation. Where it is necessary to remove vast quantities of water from a very dilute solution, e.g. for purposes of waste water purification, freeze-drying is completely unrealistic. On the other hand, the method has been successfully used to dry valuable books and documents in libraries that have suffered flood damage.

Since we are here concerned mainly with pharmaceutical and, especially, biopharmaceutical freeze-drying, processing costs are of secondary importance. Care must however be taken that limited freeze-drying capacity does not give rise to production problems. Thus, where the total drier capacity threatens to become the limiting factor in the production cycle, the best remedy is to examine whether, and how the cycle length might be reduced, commensurate with the maintenance of an acceptable product quality. This is a problem to which we shall return several times.

Probably the first comprehensive monograph on freeze-drying was published in 1949. It traces the early development of the technique, going back as far as 1813, when William Hyde Wollaston, in a lecture to the Royal Society, demonstrated the relation between vapour pressure and temperature, and the cooling effect of evaporation. Wollaston called the procedure "sublimation", which he defined as the process in which a solid (ice) is converted into a gaseous state and then recondensed as a solid, thereby totally avoiding the intervention of a liquid state during the process.

The actual freeze-drying process was first tested and used in 1890 in Leipzig, Germany. It became of practical importance during World War II, when the Canadian Red Cross had to make weekly deliveries of up to 2000 units of human blood plasma. With the help of several US companies, a peak production of 100,000 units per week was eventually achieved. At about the same time, R.I.N. Greaves, working at the University of Cambridge, began the development of more advanced equipment, which was later employed in the first commercial production of antibiotics. During the 1950s, freeze-drying began to be routinely used by the food and drug industries. The rapid development of the technology can best be judged by the number of publications in the field, which grew from 10 in pre-1930, to 350 over the period 1930-1945. When freeze-drying first became an important process technology in the pharmaceutical industry, the number of publications began to climb rapidly, reaching ca. 600 in the year 2000. The first patent was issued in 1934, and the number of US-granted patents during the period 1945-2003 exceeds 400; although references to freeze-drying, as a manufacturing process, feature in many more food and pharmaceutical patents, although not always as the inventive step.

It is interesting to chart the importance attached to the various aspects of the technology at different periods. Thus, during the 1970s, emphasis was placed on modelling the process in terms of heat transfer through frozen layers, and the problems of "collapse" received intensive study. During the following decade, emphasis shifted to the development of electronic devices to control the process. Investigations also commenced on additives and "bound water". The freeze-drying of blood derivatives (oxyhaemoglobin, albumin and clotting factors) became of commercial importance. The decade also witnessed the publication of numerous studies by M.J. Pikal (sometimes referred to, and rightly so, as "the king of freeze-drying"), dealing with more advanced and realistic models of heat and mass transfer. A particular strength of Pikal's contributions derives from his often-expressed philosophy that experimental tests need to be applied to validate all theoretical results. During the 1990s, several reports appeared analysing the economics of large-scale batch freeze-drying. This is a subject to which we shall return later. Product formulation issues also received attention, and the significance of amorphous states vis-à-vis crystalline states began to dawn on the pharmaceutical industry, especially when related to biopharmaceutical products that cannot be crystallised. At the same time, regulatory hurdles became of importance, reining back the more adventurous product developers. Although freeze-drying of foods had declined during the second half of the 20th century, the appearance of probiotics and other "nutroceutical" products regenerated interest in the freeze-drying of bacterial cultures, particularly lactic acid bacteria, where it soon became apparent that isolated molecules are easier to stabilise against deterioration than living species. Even more ambitious attempts have included the long-term stabilisation of freeze-dried mammalian blood cells, embryos, spermatozoa and even organs. The informed reader is left to differentiate between success and failure.

The past two decades have also witnessed the publication of several texts on freeze-drying, some of them focused, allegedly, on the food and pharmaceutical industries. They range from single-author mono-graphs to edited volumes, with contributions by several authors,and international conference proceedings, which, for various reasons, are least satisfactory, unless carefully edited for linguistic problems. Central topics such as engineering principles of heat and mass transfer, reviews of available equipment, its correct use and maintenance, simple physical principles associated with freezing and drying, and good manufacturing practice and registration issues are more or less adequately addressed. However, the recent realisation of the overriding importance of product formulation and the thermophysical properties of water-soluble amorphous products are largely ignored in the available monographs, although they figure quite largely in the current scientific literature. It is one of the chief aims of this volume to restore the balance and to place the topics of product composition and formulation centre stage, where they rightfully belong. In other words, they are discussed in terms of "Food Polymer Science", a term coined as far back as 1988.

The products that appear in this book fall mainly into the following categories:

• Drugs (conventional and biopharmaceuticals)

• Microbial/yeast cultures

• Mammalian cell cultures

• Blood products

• Human and veterinary vaccines

• Diagnostic constructs

• Research enzymes/nucleotides/lipid and glyco-conjugates

• Industrial enzymes

1.3 Elements of Stability

According to perceived wisdom, the solid, dry state of otherwise labile pharmaceutical materials can be equated with "stability", defined by an extended shelf life, with reference to specified storage conditions. Let us consider the exact meaning of "stability", although even the more basic word "dry", as used, often somewhat carelessly, in freeze-drying parlance, has led to lengthy arguments between judges, advocates and the so-called expert witnesses in courts of law. In the Oxford Dictionary, "dry" is denned as "devoid of all natural moisture", or in more technical terms, "anhydrous". However, as mentioned earlier, in our ecosphere, even under low relative humidity conditions, anhydrous organic materials have no existence. We must therefore look for another, more practical definition of "dry".

In purely pharmaceutical terms, the meaning of "stability" is clear: it relates to the maintenance of the exact molecular identity of a given drug substance. Chemical instability can arise by different routes, which include hydrolysis, oxidation, isomerisation, condensation, racemisation and reactions with other components in solution. This subject is discussed in more detail in Chapter 5. A particularly troublesome group of reactions is common in the processed food industry. These non-enzymatic Maillard or "browning" reactions occur between peptides and reducing sugars, especially in semi-dry environments. They are of only minor significance in pharmaceutical processing, and the interested reader is referred to one of the many monographs that deal with this particular problem.

In the vast majority of chemical destabilisation/bioinactivation processes, water acts either as a catalyst or it participates as a reactant and/or product. It therefore seems logical to conclude that the removal of water should eliminate many causes of chemical instability. The situation is not quite so clear however in the case of physical instability. Processes of concern that can take place in the solid state include polymorphic solid/ solid transitions and the compaction of powders. Even low levels of water vapour sorption may lead to other undesirable changes, e.g. solid/liquid phase separations, recrystallisation in the solid state or polymorphic transitions. Since all these processes occur only in the solid state, it follows that they cannot necessarily be eliminated by drying. The important factors in physical and mechanical stabilisation are the actual state of the solid produced by drying, the level of residual water and the temperature and pressure employed during processing and storage.

(Continues...)

Excerpted from Freeze-Drying of Pharmaceuticals and Biopharmaceuticals by Felix Franks. Copyright © 2007 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
Excerpts are provided by Dial-A-Book Inc. solely for the personal use of visitors to this web site.

Edition details

• Publisher: Royal Society of Chemistry
• Publication date: 2007
• Language: English
• ISBN 10: 0854042687
• ISBN 13: 9780854042685
• Binding: Hardcover
• Edition number: 1
• Number of pages: 218