Lyophilized Biologics and Vaccines: Modality-Based Approaches

Lyophilized Biologics and Vaccines

Dushyant Varshney • Manmohan Singh

Editors

Lyophilized Biologics

and Vaccines

Modality-Based Approaches

ISBN 978-1-4939-2382-3           ISBN 978-1-4939-2383-0 (eBook)

DOI 10.1007/978-1-4939-2383-0

Library of Congress Control Number: 2015938701

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© Springer Science+Business Media New York 2015

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Editors

Dushyant Varshney

Novartis Vaccines and Diagnostics

Holly Springs

North Carolina

USA

AND

Director, Manufacturing Assessment, MS&T

Hospira

Lake Forest

Illinois

USA

Manmohan Singh

Novartis Vaccines and Diagnostics

Holly Springs

North Carolina

USA

v

Preface

Lyophilization has become a popular approach for stabilization of the biologics.

In the recent years, advances in biotechnology have resulted in various modali￾ties of antibodies, antigens, and cancer drugs being explored in the development

of therapeutic proteins, effective drugs, and vaccines. Diverse forms of antibodies

(e.g., monoclonal, domain, fused), complex biologics (e.g., antibody drug conju￾gate, PEGylated proteins), peptides (e.g., cyclic peptides), and vaccines (e.g., com￾bination type, inactivated virus, recombinant protein based) are being stabilized in

the lyophilized form. Recent advances in lyophilization equipment, formulation,

analytical instrumentation, delivery devices (e.g., cartridges), and manufacturing

processes are being explored to overcome challenges posed by differences in the

biophysical and chemical stability of each modality. The book “Lyophilized Biolog￾ics and Vaccines—Modality-Based Approaches” covers advances in lyophilization

theories, product and process development approaches, and delivery approaches

based on new modalities of biologics and vaccines. Recent advances in alternate

drying methods and bulk lyophilization are also discussed in depth. The book is

composed of four major sections having a total of 17 chapters, presented by expert

and world renowned authors from academia, industry, and regulatory agencies.

Part I—Lyophilization History and Fundamentals is covered in five chapters.

First a detail account of the historical development of lyophilization is discussed

followed by recent advances in the understanding of heterogeneity of protein envi￾ronment in the frozen or dried state, new developments in understanding buffer be￾havior and instrumental analysis of lyophilized biologics or vaccines is described.

Special focus is given on recent advances in controlled ice nucleation with a spe￾cific discussion on VERISEQ® nucleation technology.

Part II—Lyophilized Biologics and Vaccines—Modality Considerations are dis￾cussed in five chapters. First an overview of the challenges and developments in ly￾ophilized formulations for different modalities of biologics or vaccines is presented.

Next, recent advances in quality by design (QbD) and process analytical technology

(PAT) approaches for process scale-up of therapeutic protein are discussed in depth.

The chapter on lyophilized vaccine provides a complete and detailed overview of

a typical vaccine product and process development, from scale-up to optimization.

vi Preface

A special highlight on advances in stabilization of plasmid DNA and lipid-based

therapeutics as dehydrated formulations is covered.

Part III—Advances in Alternate Drying methods is covered in four chapters. A

detailed account of alternate drying methods compared to traditional vial lyophili￾zation is discussed. Some of these include sterile spray drying, sterile powder fill￾ing, vacuum drying and drying on a fiber matrix. Chapters on recent advances in the

spray drying, bulk freeze drying and crystallization provide an in-depth understand￾ing of technology, challenges, and advantages, with nicely illustrated case studies.

Part IV—Regulatory, Packaging, and Technology Transfer Considerations is

discussed in three important chapters, providing the latest regulatory perspective

on lyophilized biologics, recent trends in lyophilized delivery devices, and pack￾aging. The chapter on lyophilization technology transfer process provides critical

considerations with case studies in detail for successful process scale-up to process

validation and launch of lyophilized biologics and vaccines.

Dushyant Varshney

Manmohan Singh

vii

Contents

Part I Lyophilization History and Fundamentals

History of Lyophilization 3

Dushyant Varshney and Manmohan Singh

Heterogeneity of Protein Environments in Frozen Solutions and

in the Dried State 11

Maya Salnikova, Dushyant Varshney and Evgenyi Shalaev

Advance Understanding of Buffer Behavior during Lyophilization 25

Cindy Wu, Sheri Shamblin, Dushyant Varshney and Evgenyi Shalaev

Advances in Instrumental Analysis Applied to the Development

of Lyophilization Cycles 43

William J. Kessler, Puneet Sharma and Mircea Mujat

New Developments in Controlled Nucleation: Commercializing

VERISEQ® Nucleation Technology 73

Joseph Brower, Ron Lee, Eugene Wexler, Steven Finley, Monica Caldwell

and Peter Studer

Part II Lyophilized Biologics and Vaccines – Modality Considerations

Lyophilized Biologics 93

Byeong S. Chang, Michael Reilly, and Hana Chang

Lyophilization of Therapeutic Proteins in Vials: Process

Scale-Up and Advances in Quality by Design 121

Bingquan (Stuart) Wang, Timothy R. McCoy, Michael J. Pikal and

Dushyant Varshney

viii Contents

Advances in Process Analytical Technology in Freeze-Drying 157

Bingquan (Stuart) Wang and Timothy R. McCoy

Process Scale-Up and Optimization of Lyophilized Vaccine Products 179

Jeffrey T. Blue, Jessica R. Sinacola and Akhilesh Bhambhani

Stabilization of Plasmid DNA and Lipid-Based Therapeutics as

Dehydrated Formulations 211

Marion dC. Molina, Nicole M. Payton and Thomas J. Anchordoquy

Part III Advances in Alternate Drying

Alternatives to Vial Lyophilization 257

Jim Searles and Mathew Cherian

Spray-Drying of Biopharmaceuticals 273

Grace A. Ledet, Richard A. Graves, Levon A. Bostanian and

Tarun K. Mandal

Current Trends and Advances in Bulk Crystallization and

Freeze-Drying of Biopharmaceuticals 299

Hiten Gutka and Krishna Prasad

Case Studies and Examples of Biopharmaceutical Modalities

Processed by Bulk Crystallization or Bulk Freeze-Drying 319

Hiten Gutka and Krishna Prasad

Part IV Regulatory, Packaging and Technology Transfer Considerations

Lyophilization of Biologics: An FDA Perspective 341

David Awotwe-Otoo and Mansoor A. Khan

Recent Trends in Lyophilized Delivery Devices and Packaging 361

Renaud Janssen

Lyophilization Process Technology Transfer Towards Product Launch 381

Madhav Kamat and Dushyant Varshney

Index 399

ix

Contributors

Thomas J. Anchordoquy School of Pharmacy, University of Colorado Denver,

Aurora, CO, USA

David Awotwe-Otoo Division of Product Quality Research, Office of Testing

and Research, Office of Pharmaceutical Sciences, Center for Drug Evaluation and

Research, U.S. Food and Drug Administration, Silver Spring, MD, USA

Akhilesh Bhambhani Greater Philadelphia Area, USA

Jeffrey T. Blue Telford, USA

Levon A. Bostanian College of Pharmacy, Center for Nanomedicine and Drug

Delivery, Xavier University of Louisiana, New Orleans, LA, USA

Joseph Brower IMA Life, Tonawanda, NY, USA

Monica Caldwell Linde Gases, Murray Hill, NJ, USA

Byeong S. Chang Integrity Bio, Inc., Camarillo, CA, USA

Hana Chang Integrity Bio, Inc., Camarillo, CA, USA

Mathew Cherian Hospira, Inc. One 2 One® Research and Development, Lake

Forest, IL, USA

Steven Finley Linde Gases, Murray Hill, NJ, USA

Richard A. Graves College of Pharmacy, Center for Nanomedicine and Drug

Delivery, Xavier University of Louisiana, New Orleans, LA, USA

Hiten Gutka Thermalin Diabetes LLC, Cleveland, OH, USA

Renaud Janssen Datwyler Pharma Packaging International NV, Alken, Belgium

Madhav Kamat Kamat Pharmatech LLC, North Brunswick, NJ, USA

x Contributors

William J. Kessler Physical Sciences Inc., Andover, MA, USA

Mansoor A. Khan Division of Product Quality Research, Office of Testing and

Research, Office of Pharmaceutical Sciences, Center for Drug Evaluation and

Research, U.S. Food and Drug Administration, Silver Spring, MD, USA

Grace A. Ledet College of Pharmacy, Center for Nanomedicine and Drug

Delivery, Xavier University of Louisiana, New Orleans, LA, USA

Ron Lee Linde Gases, Murray Hill, NJ, USA

Tarun K. Mandal College of Pharmacy, Center for Nanomedicine and Drug

Delivery, Xavier University of Louisiana, New Orleans, LA, USA

Timothy R. McCoy Technical Development, Genzyme Ireland Ltd. IDA

Industrial Park, Waterford, Ireland

Marion dC. Molina Independent Pharmaceutical Consultant, Ashland, MA, USA

Mircea Mujat Physical Sciences Inc., Andover, MA, USA

Nicole M. Payton School of Pharmacy, University of Colorado Denver, Aurora,

CO, USA

Michael J. Pikal Department of Pharmaceutical Sciences, University of

Connecticut, Storrs, CT, USA

Krishna Prasad Julphar Pharmaceuticals, Ras Al Khaimah, United Arab

Emirates

Michael Reilly Integrity Bio, Inc., Camarillo, CA, USA

Maya Salnikova Novartis Vaccines and Diagnostics, Holly Springs, NC, USA

Jim Searles Hospira, Inc. One 2 One® Research and Development, McPherson,

KS, USA

Evgenyi Shalaev Allergan, Irvine, CA, USA

Sheri Shamblin Pfizer, Groton, CT, USA

Puneet Sharma Genentech Inc., South San Francisco, CA, USA

Jessica R. Sinacola Collegeville, USA

Manmohan Singh Novartis Vaccines and Diagnostics, Holly Springs, NC, USA

Peter Studer Linde Gases, Murray Hill, NJ, USA

Dushyant Varshney Novartis Vaccines and Diagnostics, Holly Springs, NC, USA

MS & T Hospira, Inc., Lake Forest, IL, USA

Contributors xi

Bingquan (Stuart) Wang Late Stage Process Development, Genzyme, A Sanofi

Company, Framingham, MA, USA

Protein Formulation Development, Biogen Idec, Cambridge, MA, USA

Eugene Wexler Linde Gases, Murray Hill, NJ, USA

Cindy Wu Allergan, Irvine, CA, USA

Part I

Lyophilization History and Fundamentals

3

History of Lyophilization

Dushyant Varshney and Manmohan Singh

© Springer Science+Business Media New York 2015

D. Varshney, M. Singh (eds.), Lyophilized Biologics and Vaccines,

DOI 10.1007/978-1-4939-2383-0_1

D. Varshney ()

MS & T Hospira, Inc., 275 N. Field Drive Lake Forest, Lake Forest, IL 60045, USA

e-mail: [email protected]

D. Varshney · M. Singh

Novartis Vaccines and Diagnostics, Holly Springs, NC 27540, USA

Introduction

Lyophilization also known as freeze-drying is a process known from the ancient

times, since 1250 BC, for preserving material by dehydrating the sample, which

includes first freezing the sample and then drying under a vacuum (or low pres￾sures) at very low temperatures [1–4]. The term lyophilization or lyophilisation

literally means “solvent-loving process” or “process for loving dry state.” The term

has the origin from the ancient Greek root word, λύω/leo meaning “to break up,

to dissolve,” φιλέω/phileo meaning “to love, to kiss, to have tenderness for,” and

πίλναμαι/pilnamai meaning “contact, approach” [5]. The term lyophilization, as

we know, is mostly attributed to Rey LR’s work in 1976 described by taking into

account the porous nature of the dried product and its “lyophil” characteristic to

rapidly reabsorb the solvent and restore the substance [6]. Lyophilization (noun)/

ly·oph·i·li·za·tion/(li-of″ĭ-lĭ-za′shun), transitive verb form is lyophilize, where lyo￾phile or lyophilic in chemistry terms means—noting a colloid the particles of which

have a strong affinity for the liquid in which they are dispersed. The suffix –ize or

-ise, meaning—to cause to become [7].

Freeze-drying is in fact a sublimation process where the frozen liquid transforms

to gaseous state directly without going through a liquid phase. Lyophilization is

a dehydration process to preserve material and make lighter for transportation, a

popular freeze-dried ice-cream treat for space astronauts [8]. Interestingly, lyophi￾lization is also defined based on its applications [7]. For example, lyophilization

(noun) is a method of drying food or blood plasma or pharmaceuticals or tissue

without destroying their physical structure; material is frozen and then warmed in a

vacuum so that the ice sublimes. Lyophilization also defined as the process of iso-

4 D. Varshney and M. Singh

lating a solid substance from solution by freezing the solution and then evaporating

the ice under vacuum [7].

In this chapter, we have attempted to cover some of the key historical events

that led to the development of modern day freeze-drying or lyophilization, and its

widespread applications expanding from basic food needs to biotechnology prod￾ucts. Special consideration is given to lyophilization process, and the history of

lyophilized vaccines and biopharmaceuticals.

Historical Events in Development of Lyophilization

Prehistoric Events

The method of freeze-drying, although not claimed as named “freeze-drying,” has

been utilized from ancient time since 1250 BC. Freeze-drying procedure can be

traced back to prehistoric times of Eskimos, who preserved the fish in the cold

temperatures of artic by dehydration [1–4]. In 1250–850 BC, ancient Peruvian Incas

placed their potatoes and crops above Machu Picchu that caused freezing of their

produce. They did not realize that low pressure at the high altitudes vaporized or

sublimed the water from the produce and basically freeze-dried it [3, 9]. Although

this process was relatively slow, but during drying the quality of the food was pre￾served due to its final frozen state. Interestingly, South Americans living in the

Andes used a primitive freeze-drying method to preserve potatoes. They carried the

tubers high into the mountains where temperatures drop below the freezing point

of water and atmospheric pressure is low [3]. It is also known that monks living on

Koya, the famous Buddhist sacred mountains, were packing tofu in snow on moun￾tain sides that were conducive for drying due to high altitudes and extremely cold

winds [3]. Vikings freeze-dried their favorite food, cold fish, by utilizing the local

cold and dry conditions [10]. Such dehydration occurs under a vacuum, where the

plant or animal product is solidly frozen during the process. The shrinkage of prod￾uct is minimized or eliminated that result in a good preservation and long lasting.

Realization of Freeze-Drying Process: Early 1900s

In 1890, Altman reported that he was able to obtain dry tissue, at subatmospheric

pressures, at a temperature of approximately −20°C [1, 11]. The report in the litera￾ture does not easily reveal who named or first called the equipment as freeze-dryer.

In 1905, Benedict and Manning reported the drying of animal tissue at pressures

less than 1 atm by means of a chemical pump [11]. Shackell independently redis￾covered the technique in 1909 for the preservation of biologicals, and was the first

one to realize that the material had to be frozen before commencing the drying

process, hence freeze-drying [12]. In 1910, Shackell took the basic design of Bene-

History of Lyophilization 5

dict and Manning, and to produce the necessary vacuum he utilized an electrically

driven vacuum pump instead of displacement of air with ethyl ether [12].

In the 1920s, lyophilization was established as a stabilizing process for heat￾liable materials [13]. Interestingly, in 1925 the Dry Ice Corporation of America first

trademarked the name Dry Ice [9]. In 1927, the first US patent was issued to Tival

which made a reference to the drying of frozen materials under vacuum conditions

[13]. The industrial applications of freeze-drying do not appear to have been ap￾preciated prior to patents of Tival in 1927. In 1934, a US patent was issued to Elser

who described drying equipment that replaced Shackell’s sulfuric acid desiccating

system with a cold trap chilled with dry ice.

Development and Popularity of Lyophilization in Food Products

In 1938, the freeze-dried coffee was first manufactured, which led to the develop￾ment of powdered food product [9]. The 1940s marked great development. The first

commercial use of the freeze-drying was reported. Equipment and techniques were

developed to supply blood plasma and penicillin to the armed forces during World

War II [14]. Greaves was the first to show scientific insight into the drying process

by identifying the key operating parameters [15].

From 1950s to 1960s, with increasing popularity of lyophilized food products,

further development in freeze-drying process was realized. In 1960, the coining of

the term lyophilization is generally attributed to LR Rey who described the porous

nature of the dried product and its “lyophil” characteristics to rapidly reabsorb the

solvent and restore the substance to its original state [6, 11].

Freeze-drying which requires the use of special equipment, is called a freeze￾dryer or lyophilizer. It contains a large chamber for freezing and a vacuum pump for

removing moisture or sublimation of ice. Since the 1960s, more than 400 different

types of freeze-dried foods have been commercially manufactured. Lettuce and wa￾termelon are considered the two worst candidates for freeze-drying, not surprising,

due to its very high water content [9].

Freeze-dried coffee is the best-known freeze-dried product. Nestle company in￾vented freeze-dried coffee, when asked by Brazil to find a solution to their coffee

surpluses. Nescafe, first introduced in Switzerland, was Nestlé’s own freeze-dried

coffee product. After Nescafe, the Taster’s Choice Coffee, another famous freeze￾dried product is derived from the patent issued to James Mercer. During 1966–1971,

Mercer at Hills Brothers Coffee Inc. in San Francisco led the development of a

continuous freeze-drying capability and was granted 47 US and foreign patents [9].

It was after the World War II that drying was converted into an industrial meth￾od utilizing the tray-type lyophilizer to improve the shelf life for pharmaceuticals.

Also, for instant coffee granules, the tray-type freeze-dryer was used for the subli￾mation of the water.

In 1968, Whirlpool Corporation under contract from NASA for the Apollo mis￾sions developed the freeze-dried ice cream, well known as astronaut’s ice cream