PHARMACEUTICAL
`MANUFACTURING
`HANDBOOK
`Production and
`Processes
`
`SHAYNE COX GAD, PH.D., D.A.B.T.
`Gad Consulting Services
`Cary, North Carolina
`
`A JOHN WILEY & SONS, INC., PUBLICATION
`
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`Copyright © 2008 by John Wiley & Sons, Inc. All rights reserved
`
`Published by John Wiley & Sons, Inc., Hoboken, New Jersey
`Published simultaneously in Canada
`
`No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any
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`
`Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts
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`or completeness of contents of this book and specifi cally disclaim any implied warranties of
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`Library of Congress Cataloging-in-Publication Data is available.
`
`ISBN: 978-0-470-25958-0
`
`Printed in the United States of America
`
`10 9 8 7 6 5 4 3 2 1
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`CONTENTS
`
`PREFACE
`
`SECTION 1 MANUFACTURING SPECIALTIES
`
`1.1 Biotechnology-Derived Drug Product Development
`Stephen M. Carl, David J. Lindley, Gregory T. Knipp, Kenneth R. Morris,
`Erin Oliver, Gerald W. Becker, and Robert D. Arnold
`
`1.2 Regulatory Considerations in Approval on Follow-On Protein
`Drug Products
`Erin Oliver, Stephen M. Carl, Kenneth R. Morris, Gerald W. Becker, and
`Gregory T. Knipp
`
`1.3 Radiopharmaceutical Manufacturing
`Brit S. Farstad and Iván Peñuelas
`
`SECTION 2 ASEPTIC PROCESSING
`
`2.1
`
`Sterile Product Manufacturing
`James Agalloco and James Akers
`
`SECTION 3 FACILITY
`
`3.1
`
`From Pilot Plant to Manufacturing: Effect of Scale-Up on
`Operation of Jacketed Reactors
`B. Wayne Bequette
`
`xiii
`
`1
`
`3
`
`33
`
`59
`
`97
`
`99
`
`137
`
`139
`
`ix
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` CONTENTS
`
`3.2 Packaging and Labeling
`Maria Inês Rocha Miritello Santoro and Anil Kumar Singh
`
`3.3 Clean-Facility Design, Construction, and Maintenance Issues
`Raymond K. Schneider
`
`SECTION 4 NORMAL DOSAGE FORMS
`
`4.1
`
`4.2
`
`Solid Dosage Forms
`Barbara R. Conway
`
`Semisolid Dosages: Ointments, Creams, and Gels
`Ravichandran Mahalingam, Xiaoling Li, and Bhaskara R. Jasti
`
`4.3 Liquid Dosage Forms
`Maria V. Rubio-Bonilla, Roberto Londono, and Arcesio Rubio
`
`SECTION 5 NEW DOSAGE FORMS
`
`5.1 Controlled-Release Dosage Forms
`
`Anil Kumar Anal
`
`5.2 Progress in the Design of Biodegradable Polymer-Based
`Microspheres for Parenteral Controlled Delivery of Therapeutic
`Peptide/Protein
`Shunmugaperumal Tamilvanan
`
`
`
`5.3 Liposomes and Drug Delivery
`Sophia G. Antimisiaris, Paraskevi Kallinteri, and Dimitrios G. Fatouros
`
`5.4 Biodegradable Nanoparticles
`Sudhir S. Chakravarthi and Dennis H. Robinson
`
`5.5 Recombinant Saccharomyces cerevisiae as New Drug Delivery
`System to Gut: In Vitro Validation and Oral Formulation
`Stéphanie Blanquet and Monique Alric
`
`5.6 Nasal Delivery of Peptide and Nonpeptide Drugs
`Chandan Thomas and Fakhrul Ahsan
`
`5.7 Nasal Powder Drug Delivery
`(cid:252)
`(cid:254) (cid:252)
`
`Jelena Filipovi -Gr i and Anita Hafner
`
`5.8 Aerosol Drug Delivery
`
`Michael Hindle
`
`5.9 Ocular Drug Delivery
`Ilva D. Rupenthal and Raid G. Alany
`
`5.10 Microemulsions as Drug Delivery Systems
`Raid G. Alany and Jingyuan Wen
`
`159
`
`201
`
`233
`
`235
`
`267
`
`313
`
`345
`
`347
`
`393
`
`443
`
`535
`
`565
`
`591
`
`651
`
`683
`
`729
`
`769
`
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`CONTENTS
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` xi
`
`5.11 Transdermal Drug Delivery
`C. Scott Asbill and Gary W. Bumgarner
`
`5.12 Vaginal Drug Delivery
`José das Neves, Maria Helena Amaral, and Maria Fernanda Bahia
`
`SECTION 6 TABLET PRODUCTION
`
`6.1 Pharmaceutical Preformulation: Physicochemical Properties of
`Excipients and Powers and Tablet Characterization
`Beom-Jin Lee
`
`
`
`6.2 Role of Preformulation in Development of Solid Dosage Forms
`Omathanu P. Perumal and Satheesh K. Podaralla
`
`6.3 Tablet Design
`Eddy Castellanos Gil, Isidoro Caraballo, and Bernard Bataille
`
`6.4 Tablet Production Systems
`Katharina M. Picker-Freyer
`
`6.5 Controlled Release of Drugs from Tablet Coatings
`Sacide Alsoy Altinkaya
`
`6.6 Tablet Compression
`Helton M. M. Santos and João J. M. S. Sousa
`
`6.7 Effects of Grinding in Pharmaceutical Tablet Production
`Gavin Andrews, David Jones, Hui Zhai, Osama Abu Diak, and
`Gavin Walker
`
`6.8 Oral Extended-Release Formulations
`Anette Larsson, Susanna Abrahmsén-Alami, and Anne Juppo
`
`SECTION 7 ROLE OF NANOTECHNOLOGY
`
`7.1 Cyclodextrin-Based Nanomaterials in Pharmaceutical Field
`Erem Bilensoy and A. Attila Hincal
`
`7.2 Nanotechnology in Pharmaceutical Manufacturing
`
`Yiguang Jin
`
`7.3 Pharmaceutical Nanosystems: Manufacture, Characterization,
`and Safety
`D. F. Chowdhury
`
`7.4 Oil-in-Water Nanosized Emulsions: Medical Applications
`
`Shunmugaperumal Tamilvanan
`
`INDEX
`
`793
`
`809
`
`879
`
`881
`
`933
`
`977
`
`1053
`
`1099
`
`1133
`
`1165
`
`1191
`
`1223
`
`1225
`
`1249
`
`1289
`
`1327
`
`1367
`
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`1.1
`
` BIOTECHNOLOGY - DERIVED DRUG
`PRODUCT DEVELOPMENT
`
` Stephen M. Carl, 1 David J. Lindley, 1 Gregory T. Knipp, 1
` Kenneth R. Morris, 1 Erin Oliver, 2 Gerald W. Becker, 3 and
` Robert D. Arnold 4
`1 Purdue University, West Lafayette, Indiana
`2 Rutgers, The State University of New Jersey, Piscataway, New Jersey
`3 SSCI, West Lafayette, Indiana
`4 The University of Georgia, Athens, Georgia
`
` Contents
`
` 1.1.3
`
` 1.1.4
`
` 1.1.1 Introduction
` 1.1.2
` Formulation Assessment
` 1.1.2.1
` Route of Administration and Dosage
` 1.1.2.2
` Pharmacokinetic Implications to Dosage Form Design
` 1.1.2.3
` Controlled - Release Delivery Systems
` Analytical Method Development
` 1.1.3.1
` Traditional and Biophysical Analytical Methodologies
` 1.1.3.2
` Stability - Indicating Methodologies
` 1.1.3.3
` Method Validation and Transfer
` Formulation Development
` 1.1.4.1
` Processing Materials and Equipment
` 1.1.4.2
` Container Closure Systems
` 1.1.4.3
` Sterility Assurance
` 1.1.4.4
` Excipient Selection
` Drug Product Stability
` 1.1.5.1
` Defi ning Drug Product Storage Conditions
` 1.1.5.2
` Mechanisms of Protein and Peptide Degradation
` 1.1.5.3
` Photostability
` 1.1.5.4
` Mechanical Stress
` 1.1.5.5
` Freeze – Thaw Considerations and Cryopreservation
` 1.1.5.6
` Use Studies
` 1.1.5.7
` Container Closure Integrity and Microbiological Assessment
` 1.1.5.8
` Data Interpretation and Assessment
`
` 1.1.5
`
`Pharmaceutical Manufacturing Handbook: Production and Processes, edited by Shayne Cox Gad
`Copyright © 2008 John Wiley & Sons, Inc.
`
`3
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`4
`
` 1.1.6
`
` 1.1.7
`
`BIOTECHNOLOGY-DERIVED DRUG PRODUCT DEVELOPMENT
`
` Quality by Design and Scale - Up
` 1.1.6.1
` Unit Operations
` 1.1.6.2
` Bioburden Considerations
` 1.1.6.3
` Scale - Up and Process Changes
` Concluding Remarks
` References
`
` 1.1.1
`
` INTRODUCTION
`
` Although the origins of the fi rst biological and/or protein therapeutics can be
`traced to insulin in 1922, the fi rst biotechnology - derived pharmaceutical drug
`product approved in the United States was Humulin in 1982. In the early stages
`of pharmaceutical biotechnology, companies that specialized primarily in the devel-
`opment of biologicals were the greatest source of research and development in
`this area. Recent advances in molecular and cellular biological techniques and
`the potential clinical benefi ts of biotechnology drug products have led to a sub-
`stantial increase in their development by biotechnology and traditional pharma-
`ceutical companies . In terms of pharmaceuticals, the International Conference on
`Harmonization (ICH) loosely defi nes biotechnology - derived products with biologi-
`cal origin products as those that are “ well - characterized proteins and polypeptides,
`their derivatives and products of which they are components, and which are
`isolated from tissues, body fl uids, cell cultures, or produced using rDNA tech-
`nology ” [1] . In practical terms, biological and biotechnology - derived pharmaceuti-
`cal agents encompass a number of therapeutic classes, including cytokines,
`erythropoietins, plasminogen activators, blood plasma factors, growth hormones
`and growth factors, insulins, monoclonal antibodies, and vaccines [1] . Additionally,
`short interfering and short hairpin ribonucleic acids (siRNA, shRNA) and anti-
`sense oligonucleotide therapies are generally characterized as biotechnology -
` derived products.
` According to the biotechnology advocacy group, The Biotechnology Industry
`Organization (BIO), pharmaceutical - based biotechnology represents over a $ 30
`billion dollar a year industry and is directly responsible for the production of
`greater than 160 drug therapeutics and vaccines [2] . Furthermore, there are more
`than 370 biotechnology - derived drug products and vaccines currently in clinical
`trials around the world, targeting more than 200 diseases, including various cancers,
`Alzheimer ’ s disease, heart disease, diabetes, multiple sclerosis, acquired immuno-
`defi ciency syndrome (AIDS), and arthritis. While the clinical value of these
`products is well recognized, a far greater number of biotechnology - derived drug
`products with therapeutic potential for life - altering diseases have failed in
`development.
` As the appreciation of the clinical importance and commercial potential for bio-
`logical products grows, new challenges are arising based on the many technological
`limitations related to the development and marketing of these complex agents.
`Additionally, the intellectual property protection of an associated agent might not
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`INTRODUCTION
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`5
`
`provide a suffi cient window to market and regain the costs associated with the dis-
`covery, research, development, and scale - up of these products. Therefore, to prop-
`erly estimate the potential return on investment, a clear assessment of potential
`therapeutic advantages and disadvantages, such as the technological limitations in
`the rigorous characterization required of these complex therapeutic agents to gain
`Food and Drug Administration (FDA) approval, is needed prior to initiating
`research. Clearly, research focused on developing methodologies to minimize these
`technological limitations is needed. In doing so we hypothesize the attrition rate
`can be reduced and the number of companies engaged in the development of bio-
`technology - derived products and diversity of products will continue to expand.
` Technological limitations have limited the development of follow - on, or generic
`biopharmaceutical products that have lost patent protection. In fact, the potential
`pitfalls associated with developing these compounds are so diverse that regulatory
`guidance concerning follow - on biologics is relatively obscure and essentially notes
`that products will be assessed on a case - by - case basis. The reader is encouraged to
`see Chapter 1.2 for a more detailed discussion concerning regulatory perspectives
`pertaining to follow - on biologics.
` Many of the greatest challenges in producing biotechnology - derived pharmaceu-
`ticals are encountered in evaluating and validating the chemical and physical nature
`of the host expression system and the subsequent active pharmaceutical ingredient
`(API) as they are transferred from discovery through to the development and mar-
`keting stages. Although this area is currently a hotbed of research and is progressing
`steadily, limitations in analytical technologies are responsible for a high degree of
`attrition of these compounds. The problem is primarily associated with limited
`resolution of the analytical technologies utilized for product characterization. For
`example, without the ability to resolve small differences in secondary or tertiary
`structure, linking changes to product performance or clinical response is impossible.
`The biological activity of traditional small molecules is related directly to their
`structure and can be determined readily by nuclear magnetic resonance (NMR),
`X - Ray crystallography (X - ray), mass spectrometry (MS), and/or a combination of
`other spectroscopic techniques. However, methodologies utilized for characterizing
`biological agents are limited by resolution and reproducibility. For instance, circular
`dichroism (CD) is generally considered a good method to determine secondary
`structural elements and provides some information on the folding patterns (tertiary
`structure) of proteins. However, CD suffers from several limitations, including a
`lower resolution that is due in part to the sequence libraries used to deconvolute
`the spectra. To improve the reliability of determining the secondary and tertiary
`structural elements, these databases need to be developed further. An additional
`example is the utility of two - dimensional NMR (2D - NMR) for structural determi-
`nation. While combining homonuclear and heteronuclear experimental techniques
`can prove useful in structural determination, there are challenges in that 2D - NMR
`for a protein could potentially generate thousands of signals. The ability to assign
`specifi c signals to each atom and their respective interactions is a daunting task.
`Resolution between the different amino acids in the primary sequence and their
`positioning in the covalent and folded structures become limited with increasing
`molecular weight. Higher dimensional techniques can be used to improve resolu-
`tion; however, the resolution of these methods remains limited as the number of
`amino acids is increased.
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`6
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`BIOTECHNOLOGY-DERIVED DRUG PRODUCT DEVELOPMENT
`
` Understanding the limitations of the analytical methodologies utilized for product
`characterization has led to the development of new experimental techniques as well
`as the refi ned application of well - established techniques to this emerging fi eld. Only
`through application of a number of complementary techniques will development
`scientists be able to accurately characterize and develop clinically useful products.
`Unfortunately, much of the technology is still in its infancy and does not allow for
`a more in - depth understanding of the subtleties of peptide and protein processing
`and manufacturing. For instance, many of the analytical techniques utilized for
`characterization will evaluate changes to product conformation on the macroscopic
`level, such as potential denaturation or changes in folding, as observed with CD.
`However, these techniques do not afford the resolution to identify subtle changes
`in conformation that may either induce chemical or physical instabilities or unmask
`antigenic epitopes.
` Further limiting successful product development is a lack of basic understanding
`as to critical manufacturing processes that have the potential to affect the structural
`integrity and activity of biopharmaceuticals. As with traditional small molecules,
`stresses associated with the different unit operations may affect biopharmaceutical
`products differently. In contrast to traditional small molecules, there is considerable
`diffi culty in identifying potentially adverse affects, if any, that a particular unit opera-
`tion may have on the clinically critical structural elements of a drug. Considering
`that many proteins exhibit a greater potential for degradation from shear stress, it
`is particularly important to assess any negative effects of mixing, transport through
`tubing, fi ltration, and fi lling operations. Essentially all unit operations for a given
`manufacturing process could create enough shear stress to induce minor structural
`changes that could lead to product failure. The diffi culty is establishing what degree
`of change will have an impact on the stability, bioactivity, or immunogenic potential
`of the compound. Unfortunately, unless exhaustive formulation development studies
`are conducted, coupled with a comprehensive spectrum of analytical methodologies,
`these effects may not be readily evident until after scale - up of the manufacturing
`process or, worse yet, in the clinical setting. Moreover, modeling shear and stress
`using fl uid dynamic structurally diverse molecules is a foreboding task. Extending
`these models to validate process analytical technologies (PAT) and incorporate
`critical quality by design (QbD) elements in the development process for a collec-
`tion of biopharmaceuticals would be largely hindered by the daunting nature of the
`task at hand.
` The use of biological systems to produce these agents results in additional vari-
`ability. Slight changes in nutrient profi le could affect growth patterns and protein
`expression of cultured cells. Furthermore, microbial contamination in the form of
`viruses, bacteria, fungi, and mycoplasma can be introduced during establishment of
`cell lines, cell culture/fermentation, capture and downstream processing steps, for-
`mulation and fi lling operations, or drug delivery [3] . Therefore, establishing the
`useful life span of purifi cation media and separation columns remains a critical issue
`for consistently producing intermediates and fi nal products that meet the defi ned
`quality and safety attributes of the product [4] . In short, understanding the proper
`processability and manufacturing controls needed has been a major hurdle that has
`kept broader development of biopharmaceutical products relatively limited.
` Notwithstanding the many technological hurdles to successfully develop a phar-
`maceutically active biotechnology product, they offer many advantages in terms of
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`FORMULATION ASSESSMENT
`
`7
`
`therapeutic potency, specifi city, and target design (not generally limited to a particu-
`lar class or series of compounds). This is an iterative approach, whereby every new
`approved compound, new lessons, and applications to ensure successful product
`development are realized, thereby adding to our knowledge base and facilitating
`the development of future products. This chapter will discuss some of the funda-
`mental issues associated with successful biopharmaceutical drug product develop-
`ment and aims to provide an understanding of the subtleties associated with their
`characterization, processing, and manufacturing.
`
` 1.1.2
`
` FORMULATION ASSESSMENT
`
` In order to select the most appropriate formulation and route of administration for
`a drug product, one must fi rst assess the properties of the API, the proposed thera-
`peutic indication, and the requirements/limitations of the drug and the target patient
`population. Development teams are interdisciplinary comprised of individuals with
`broad expertise, for example, chemistry, biochemistry, bioengineering, and pharma-
`ceutics, that can provide insight into the challenges facing successful product devel-
`opment. As such, knowledge gained through refi nement of the API manufacturing
`process through to lead optimization is vital to providing an initial starting point
`for success. Information acquired, for example, in the way of analytical development
`and API characterization, during drug discovery or early preclinical development
`that can be applied to fi nal drug product development may contribute to shorter
`development times of successful products.
` The host system utilized for API production is critical to the production of the
`fi nal product and will determine the basic and higher order physicochemical char-
`acteristics of the drug. Typically biopharmaceuticals are manufactured in Escherichia
`coli as prokaryotic and yeast and Chinese hamster ovary (CHO) cells as eukaryotic
`expression systems [5] . While general procedures for growth condition optimization
`and processing and purifi cation paradigms have emerged, differences in posttrans-
`lational modifi cations and host – system related impurities can exist even with rela-
`tively minor processing changes within a single production cell line [5] . Such changes
`have the potential to alter the biopharmaceutical properties of the active compound,
`its bioactivity , and its potential to elicit adverse events such as immunogenic reac-
`tions. These properties will be a common theme as they could potentially play a
`major role in both analytical and formulation development activities.
` During the process of lead optimization, characterization work is performed that
`would include a number of parameters that are critical to formulation and analytical
`development scientists. The following information is a minimalist look at what
`information should be available to support product development scientists:
`
` • Color
` • Particle size and morphology (for solid isolates)
` • Thermoanalytical profi le (e.g., Tg for lyophiles)
` • Hygroscopicity
` • Solubility with respect to pH
` • Apparent solution pH
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`8
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`BIOTECHNOLOGY-DERIVED DRUG PRODUCT DEVELOPMENT
`
`䊊
`
`䊊
`
`䊊
`
`䊊
`
` • Number and p Ka of ionizable groups
` • Amino acid sequence
` • Secondary and tertiary structural characteristics
` • Some stability parameters with respect to
`䊊 pH
` Temperature
` Humidity
` Light
` Mechanical stress
` Oxygen sensitivity
`• Impurity profi le
`䊊 Misfolded/misaligned active
` Potential isoforms
` Expression system impurities
`• Potency [median inhibitory concentration (IC 50 )]
`• Animal Pharmacokinetic/Pharmacodynamic (PK/PD) and Tox profi les
`
`䊊
`
`䊊
`
`䊊
`
` All of the above information will prove invaluable in determining the potential
`methods for rational drug delivery. Particular attention should be paid to the rela-
`tive hygroscopicity of the API, of course, any stability information, as well as the
`impurity profi le and ADMET (absorption, distribution, metabolism, excretion, and
`toxicity) information. In short, the more information that is available when develop-
`ment activities are initiated, the easier it is to avoid common pitfalls and make
`development decisions more rationally.
`
` 1.1.2.1
`
` Route of Administration and Dosage
`
` Biologics are traditionally very potent molecules that may require only picomolar
`blood concentrations to elicit a therapeutic effect. Given that the amount of drug
`required per dosage will be commensurate with the relative potency of the molecule,
`small concentrations are generally required for any unit dose. Biopharmaceuticals
`typically have large molecular weights relative to conventional pharmaceutical
`agents, which may be increased further by posttranslational modifi cations. The phar-
`macokinetics (ADMET) of biotechnology products have been reviewed elsewhere
` [6] , but generally they have short circulating half - lives [7] . As such, biological prod-
`ucts are most often delivered parenterally and formulated as solutions, suspensions,
`or lyophilized products for reconstitution [8, 9] . However, one must fi rst ascertain
`the potential physiological barriers to drug delivery and effi cacy before assessing
`potential routes of administration. These barriers may include actual physical bar-
`riers, such as a cell membrane, that could restrict the drug from reaching its site of
`action or chemical barriers, including pH or enzymatic degradation. Based on
`current drug delivery approaches, the proteinaceous nature of biological products
`limits their peroral delivery due to their susceptibility to proteases and peptidases
`present in the gastrointestinal tract as well as size limitations for permeating through
`absorptive enterocytes [10] .
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`FORMULATION ASSESSMENT
`
`9
`
` Diffi culties in peroral delivery have stimulated researchers to explore alternate
`delivery mechanisms for biologics, such as through the lungs or nasal mucosa [11,
`12] . Further, advances in technology and our understanding of the mechanisms
`limiting oral delivery of biotechnology products have led to innovative drug delivery
`approaches to achieve suffi cient oral bioavailability. However, no viable products
`have successfully reached the market [13] . As a result of the technological limita-
`tions inherent in biopharmaceutical delivery, these compounds are largely delivered
`parenterally through an injection or implant.
` When assessing the potential routes of administration, one must consider the
`physicochemical properties of the drug, its ADMET properties, the therapeutic
`indication, and the patient population, some of which are discussed below. Table 1
`provides a list of some of those factors that must be addressed when determining
`the most favorable route of administration and the subsequent formulation for
`delivery. Ideally the route of administration and subsequent formulation will be
`optimized after identifying critical design parameters to satisfy the needs of patients
`and health care professionals alike while maintaining the safety and effi cacy of the
`product.
` Parenteral administration is the primary route of delivering biopharmaceutical
`agents (e.g., insulin); however, issues associated with patient compliance with admin-
`istration of short - acting molecules are a challenge. Yet, the risk - to - benefi t ratio must
`be weighed when determining such fundamental characteristics of the fi nal dosage
`form. For instance, a number of biopharmaceutical compounds are administered
`subcutaneously, but this route of parenteral administration exhibits the highest
`potential for immunogenic adverse events due to the presence of Langerhans cells
` [14] . A compound ’ s immunogenic potential is related to a host of factors, both
`
` Factors That Determine Route of
` TABLE 1
`Administration
`
` Site of action
` Therapeutic indication
` Dosage
` Potency/biological activity
` Pharmacokinetic profi le
`
` Absorption time from tissue vs. IV
`
` Circulating half - life
`
` Distribution and elimination kinetics
` Toxicological profi le
` Immunogenic potential
` Patient population characteristics
`
` Disease state
`
` Pathophysiology
`
` Age
` Pharmacodynamic profi le
`
` Onset and duration of action
`
` Required clinical effect
` Formulation considerations
`
` Stability
`
` Impurity profi le
`
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`BIOTECHNOLOGY-DERIVED DRUG PRODUCT DEVELOPMENT
`
`patient and treatment related; however, if an alternate, potentially safer route of
`administration is available, it may be prudent to consider it. Other factors, such as
`the frequency of dosing (especially into an immune organ such as the skin) and the
`duration of treatment, can also dramatically increase the potential for immunogenic
`reactions [14] . Many of the factors that contribute to the immunogenic potential of
`biopharmaceuticals, such as impurities, degradation products, and native antigenic
`epitopes, can be mitigated through altering the physicochemical properties of the
`drug (e.g., pegylation [15, 16] , acylation [17, 18] , increased glycosylation to mask
`epitopes [19] ) or changing the characteristics of the formulation [20, 21] . In reality,
`the pharmaceutical industry has done a good job of recognizing the potential impli-
`cations of immunogenic reactions and readily embraced technologies that can either
`mask or eliminate potential antigenic epitopes. However, additional research is
`needed to further identify and remove immunogenic epitopes.
`
` 1.1.2.2
`
` Pharmacokinetic Implications to Dosage Form Design
`
` Biological agents are generally eliminated by metabolism into di - and tripeptides,
`amino acids, and smaller components for subsequent absorption as nutrients or
`clearance by the kidney, liver, or other routes. Renal elimination of peptides and
`proteins occur primarily via three distinct mechanisms. The fi rst involves the glo-
`merular fi ltration of low - molecular - weight proteins followed by reabsorption into
`endocytic vesicles in the proximal tubule and subsequent hydroysis into small peptide
`fragments and amino acids [22] . Interleukin 11 (IL - 11) [23] , IL - 2 [24] , insulin [25] ,
`and growth hormone [26] have been shown to be eliminated by this method. The
`second involves hydrolysis of the compound at the brush border of the lumen and
`subsequent reabsorption of the resulting metabolites [6] . This route of elimination
`applies to small linear peptides such as angiotensin I and II, bradykinin, glucagons,
`and leutinizing hormone releasing hormone (LHRH) [6, 27, 28] . The third route of
`renal elimination involves peritubular extraction from postglomerular capillaries
`and intracellular metabolism [6] . Hepatic elimination may also play a major role in
`the metabolism of peptides and proteins; however, reticuloendothelial elimination is
`by far the primary elimination route for large macromolecular compounds [29] .
` Biopharmaceutical drug products are subject to the same principles of pharma-
`cokinetics and exposure/response correlations as conventional small molecules [6] .
`However, these products are subject to numerous pitfalls due to their similarity to
`nutrients and endogenous proteins and the evolutionary mechanisms to break them
`down or prevent absorption. The types of pharmacokinetic - related problems that a
`biotechnology drug development team may encounter range from lack of specifi city
`and sensitivity of bioanalytical assays to low bioavailability and rapid drug elimina-
`tion from the system [6] . For example, most peptides have hormone activity and
`usually short elimination half - lives which can be desirable for close regulation of
`their endogenous levels and function. On the other hand, some proteins such as
`albumin or antibodies have half - lives of several days and formulation strategies
`must be designed to account for these extended elimination times [6] . For example,
`the reported terminal half - life for SB209763, a humanized monoclonal antibody
`against respiratory syncytial virus, was reported as 22 – 50 days [30] . Furthermore,
`some peptide and protein products that persist in the bloodstream exhibit the
`potential for idiosyncratic adverse affects as well as increased immunogenic poten-
`
`IPR2020-00770
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`Page 13 of 102
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`ANALYTICAL METHOD DEVELOPMENT
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`11
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`tial. Therefore, the indication and formulation strategy can prove crucial design
`parameters simply based on clearance mechanisms.
`
` 1.1.2.3
`
` Controlled - Release Delivery Systems
`
` Given that the majority of biopharmaceutical products are indicated for chronic
`conditions and may require repeated administrations, products may be amenable to
`controlled - release drug delivery systems. Examples include Lupron Depot (leupro-
`lide acetate), which is delivered subcutaneously in microspheres [31] , and Viadur,
`which is implanted subcutaneous