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
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2024 Page 1
`
`

`

`PHARMACEUTICAL
`MANUFACTURING
`HANDBOOK
`
`Production and
`Processes
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2024 Page 2
`
`

`

`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
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2024 Page 3
`
`

`

`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
`form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except
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`Street, Hoboken,
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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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`suitable for your situation. You should consult with a professional where appropriate. Neither the
`publisher nor author shall be liable for any loss of profi t or any other commercial damages, including
`but not limited to special, incidental, consequential, or other damages.
`
`For general information on our other products and services or for technical support, please contact
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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
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2024 Page 4
`
`

`

`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
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2024 Page 5
`
`

`

`x
`
` 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:254) (cid:252)
`(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
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2024 Page 6
`
`

`

`CONTENTS
`
` 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
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2024 Page 7
`
`

`

`FORMULATION DEVELOPMENT
`
`19
`
`heat terminal sterilization, terminal fi ltration coupled with aseptic processing tech-
`niques, ultraviolet (UV) and gamma irradiation, ethylene oxide exposure (for con-
`tainers and packaging only), and electron beam irradiation. While terminal heat
`sterilization is by far the most common sterilization technique, it normally cannot
`readily be utilized for peptide or protein formulations due to the potential effects
`of heat and pressure on the compound ’ s structure [48] . Furthermore, irradiation can
`affect protein stability by cross - linking the sulfur - containing and aromatic residues,
`resulting in protein aggregation [49] .
` To overcome these issues, sterile fi ltration coupled with aseptic processing and
`fi lling is the preferred manufacturing procedure for biopharmaceuticals. Garfi nkle
`et al. refer to aseptic processing as “ those operations performed between the steril-
`ization of an object or preparation and the fi nal sealing of its package. These opera-
`tions are, by defi nition, carried out in the complete absence of microorganisms ” [50] .
`This highlights the importance of manufacturing controls and bioburden monitoring
`during aseptic processes. Newer technologies such as isolator technology have been
`developed to reduce human intervention, thereby increasing the sterility assurance.
`These technologies have the added benefi t of facilitating aseptic processing without
`construction of large processing areas, sterile suites, or gowning areas [50] .
` Even the most robust monitoring programs do not ensure the sterility of the fi nal
`formulation. As such, aseptically processed formulations are traditionally fi ltered
`through a retentive fi nal fi lter, which ensures sterility. Coupled with proper compo-
`nent sterilization, traditionally by autoclaving, these processes ensure product steril-
`ity. However, fi ltration is a complex unit operation that can adversely affect the drug
`product through increased pressure, shear, or material incompatibility. Therefore,
`fi ltration compatibility must be assessed thoroughly to demonstrate both product
`compatibility, and suffi cient contaminant retention [51] . Parenteral Drug Associa-
`tion (PDA) technical report 26 provides a thorough systematic approach to selecting
`and validating the most appropriate fi lter for a sterilizing fi ltration application
` [51] .
`
` 1.1.4.4
`
` Excipient Selection
`
` Pharmaceutical products are typically formulated to contain selected nonactive
`ingredients (excipients) whose function is to promote product stability and enable
`delivery of the active pharmaceutical ingredient(s) to the target site. These sub-
`stances include but are not limited to solubilizers, antioxidants, chelating agents,
`buffers, tonicity contributors, antibacterial agents, antifungal agents, hydrolysis
`inhibitors, bulking agents, and antifoaming agents [45] . The ICH states that “ the
`excipients chosen, their concentration, and the characteristics that can infl uence the
`drug product performance (e.g. stability, bioavailability) or manufacturability should
`be discussed relative to the respective function of each excipient ” [42] . Excipients
`must be nontoxic and compatible with the formulation while remaining stable
`throughout the life of the product. Excipients require thorough evaluation and
`optimization studies for compatibility with the other formulation constituents as
`well as the container/closure system [52] . Furthermore, excipient purity may be
`required to be greater than that listed in the pharmacopeial monograph if a specifi c
`impurity is implicated in potential degradation reactions (e.g., presence of trace
`metals) [48] .
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2024 Page 8
`
`

`

`20
`
`BIOTECHNOLOGY-DERIVED DRUG PRODUCT DEVELOPMENT
`
` One of the critical factors in excipient selection and concentration is the effect
`on preferential hydration of the biopharmaceutical product [53, 54] . Preferential
`hydration refers to the hydration layers on the outer surface of the protein and can
`be utilized to thermodynamically explain both stability enhancement and denatur-
`ation. Typical excipients used in protein formulations include albumin, amino acids,
`carbohydrates, chelating and reducing agents, cyclodextrins, polyhydric alcohols,
`polyethylene glycol, salts, and surfactants. Several of these excipients increase the
`preferential hydration of the protein and thus enhance its stability. Cosolvents need
`to be added in a concentration that will ensure their exclusion from the protein
`surface and enhance stability [54] . A more comprehensive review of excipients uti-
`lized for biopharmaceutical drug products is available elsewhere [48] .
`
`Buffer Selection
` In addition to maintaining solution pH, buffers serve a multitude
`of functions in pharmaceutical formulations, such as contributing toward overall
`isotonicity, preferential hydration of proteins and peptides, and serving as bulking
`agents in lyophilized formulations. The buffer system chosen is especially important
`for peptide and proteins that have sensitive secondary, tertiary, and quaternary
`structures, as the overall mechanisms contributing to conformational stabilization
`are extremely complex [48] . Furthermore, a protein ’ s propensity for deamidation at
`a particular pH can be signifi cant, as illustrated by Wakankar and Borchardt [55] .
`This study illustrated stability concerns with peptides and proteins at physiological
`pH in terms of asparagine (Asn) deamidation and aspartate (Asp) isomerization,
`which can be a major issue with respect to circulating half - life and potential in vivo
`degradation. This study and others also provide insight into predicting potential
`degradative mechanisms based on primary and secondary structural elements allow-
`ing for formulation design with these pathways in mind.
` Selecting the appropriate buffer primarily depends on the desired pH range and
`buffer capacity required for the individual formulation; however, other factors,
`including concentration, effective range, chemical compatibility, and isotonicity
`contribution, should be considered [56] . Some acceptable buffers include phosphate
`(pH 6.2 – 8.2), acetate (pH 3.8 – 5.8), citrate (pH 2.1 – 6.2, p K 3.15, 4.8, and 6.4),
`succinate (pH 3.2 – 6.6, p K 4.2 and 5.6), histidine (p K 1.8, 6.0, and 9.0), glycine
`(pK 2.35 and 9.8), arginine (p K 2.18 and 9.1), triethanolamine (pH 7.0 – 9.0), tris -
` hydroxymethylaminomethane (THAM, p K 8.1), and maleate buffer [48] . Addition-
`ally, excipients utilized solely for tonicity adjustment, such as sodium chloride and
`glycerin, may not only differ in ionic strength but also could afford some buffering
`effects that should be considered [52] .
`
`Preservatives
` In addition to those processing controls mentioned above (Section
` 3.1.4.3 ), the sterility of a product may be maintained through the addition of anti-
`microbial preservatives. Preservation against microbial growth is an important
`aspect of multidose parenteral preparations as well as other formulations that
`require preservatives to minimize the risk of patient infection upon administration,
`such as infusion products [52] . Aqueous liquid products are prone to microbial
`contamination because water in combination with excipients derived from natural
`sources (e.g., polypeptides, carbohydrates) and proteinaceous active ingredients
`may serve as excellent media for the growth [57] . The major criteria for the selection
`of an appropriate preservative include effi ciency against a wide spectrum of micro-
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2024 Page 9
`
`

`

`DRUG PRODUCT STABILITY
`
`21
`
`organisms, stability (shelf life), toxicity, sensitizing effects, and compatibility with
`other ingredients in the dosage form [57] . Typical antimicrobial preservatives include
`m - cresol, phenol, parabens, thimerosal, sorbic acid, potassium sorbate, benzoic acid,
`chlorocresol, and benzalkonium chloride. Cationic agents such as benzalkonium
`chloride are typically not utilized for peptide and protein formulations because they
`may be inactivated by other formulation components and their respective charges
`may induce conformational changes and lead to physical instability of the API.
`Further, excipients intended for other applications, such as chelating agents, may
`exhibit some antimicrobial activity. For instance, the chelating agent ethylenediami-
`netetraacetic acid (EDTA) may exhibit antimicrobial activity, as calcium is required
`for bacterial growth.
` Identifying an optimal antimicrobial preservative is based largely on the effective-
`ness of that preservative at the concentration chosen. In short, it is not enough to
`assess the compatibility of the preservative of choice with the API and formulation
`and processing components. There also needs to be a determination of whether the
`preservative concentration is suffi cient to kill certain standard test organisms. The
`USP presents standard protocols for assessing the relative effi cacy of a preservative
`in a formulation using the antimicrobial effectiveness test (AET) [58] . Briefl y, by
`comparing the relative kill effi ciency of the formulation containing varying concen-
`trations of the preservative, the formulator can determine the minimal concentration
`required for preservative effi cacy and design the formulation accordingly.
`
` 1.1.5
`
` DRUG PRODUCT STABILITY
`
` 1.1.5.1
`
` Defi ning Drug Product Storage Conditions
`
` From a regulatory standpoint, the primary objective of formulation development is
`to enable the delivery of a safe and effi cacious drug product to treat and/or mitigate
`a disease state throughout its proposed shelf life. The effi cacy and in many cases the
`safety of a product are directly related to the stability of the API, both neat and in
`the proposed formulation under processing, storage, and shipping conditions as well
`as during administration. As such, the concept of drug stability for biotechnology -
` derived products does not change substantially from that of small molecules,
`although the level of complexity increases commensurate with the increased com-
`plexity of the APIs in question and the formulation systems utilized for their
`delivery.
` Stability study conditions for biotechnology - derived APIs and their respective
`drug products are not substantially different from those studies conducted for small
`molecules. Temperature and humidity conditions under which to conduct said
`studies are outlined in ICH Q1A(R2), which incorporates ICH Q1F, stability study
`conditions for zones III and IV climactic conditions [59] . Additional guidance spe-
`cifi c to conducting stability studies on biopharmaceutical drug products is given in
`ICH Q5C [1] . However, the intention of ICH Q5C is not to outline alternate tem-
`perature and humidity conditions to conduct primary stability studies; rather it
`provides guidance with respect to the fact that the recommended storage conditions
`and expiration dating for biopharmaceutical products will be different from product
`to product and provides the necessary fl exibility in letting the applicant determine
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2024 Page 10
`
`

`

`276
`
`SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS
`
`12% carbohydrates, and 1% free wax alcohols and stearic esters of fatty acids. It is
`available as granules or sheets which are white in color and possesses a characteristic
`odor. White wax is insoluble in water and melts between 61 and 65 ° C. It has stiffen-
`ing and viscosity - enhancing properties and therefore is used in hydrophobic oint-
`ments and oil - in - water creams. Although it is thermally stable, heating to above
`150 ° C results in reduction of its acid value. White wax is incompatible with oxidizing
`agents. The presence of small quantities of impurities results in hypersensitivity
`reactions in rare occasions. Preparations are stored in well - closed, light - resistant
`containers in a cool, dry place [13] .
`
`Yellow Wax
` Yellow wax, also known as yellow beeswax, is obtained from honey
`combs. It contains about 70% esters of straight - chain monohydric alcohols, 15%
`free acids, 12% carbohydrates, and 1% free wax alcohols and stearic esters of fatty
`acids. It is available as noncrystalline pieces which are yellow in color and possesses
`a characteristic odor. It is practically insoluble in water and melts at 61 – 65 ° C. It is
`used in the preparation of hydrophobic ointments and water - in - oil creams because
`of its viscosity - enhancing properties. Concentrations up to 20% are used for produc-
`ing ointments and creams. It is incompatible with oxidizing agents. Esterifi cation
`occurs while heating to 150 ° C and hence should be avoided during preparation.
`Hypersensitivity reactions sometimes occur on topical application of yellow wax –
` containing ointments and creams due to the presence of some minor impurities.
`These products are preserved in well - closed, light - resistant containers [13] .
` Combinations of bases are sometimes used to acquire better stability. Gelling
`agents such as carbomers and PEG are also included in some ointment and cream
`preparations. Table 3 shows examples of cream bases used in some commercial
`cream preparations.
`
` 4.2.2.3
`
` Preparation and Packaging
`
` In addition to the base and drug, ointments and creams may also contain other
`components such as stabilizers, preservatives, and levigating agents. Usually leviga-
`tion and fusion methods are employed for incorporating these components into the
`base. Levigation involves simple mixing of base and other components over an oint-
`ment slab using a stainless steel ointment spatula. A fusion process is employed only
`when the components are stable at fusion temperatures. Ointments and creams
`containing white wax, yellow wax, paraffi n, stearyl alcohol, and high - molecular -
` weight PEGs are generally prepared by the fusion process. Selection of levigation
`or the fusion method depends on the type base, the quantity of other components,
`and their solubility and stability characteristics.
` Oleaginous ointments are prepared by both levigation and fusion processes.
`Small quantities of powders are incorporated into hydrocarbon bases with the aid
`of a levigating agent such as liquid petrolatum, which helps in wetting of powders.
`The powder component is mixed with the levigating agent by trituration and is then
`incorporated into the base by spatulation. All solid components are milled to fi ner
`size and screened before incorporating into the base to avoid gritty sensation of the
`fi nal product. Roller mills are used for producing large quantities of ointments in
`pharmaceutical industries. Uniform mixing can be obtained by the geometric dilu-
`tion procedure, which usually involves stepwise dilution of solids into the ointment
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2024 Page 11
`
`

`

` TABLE 3
`
` Cream Bases Present in Some Commercial Creams
`
` Commercial Name
`
` Drug
`
` Cream Base (s) Used
`
`OINTMENTS AND CREAMS
`
`277
`
` Anthralin, 0.5%, 1.0%
`
` White petrolatum, cetostearyl alcohol
`
` Propylene glycol, glyceryl monostearate,
`cetostearyl alcohol, glyceryl stearate,
`PEG 100 stearate, white wax
` Petrolatum, propylene glycol, cetyl
`alcohol, carbomer - 934
` White petrolatum USP, isopropyl
`myristate NF, lanolin alcohols NF,
`mineral oil USP, cetostearyl alcohol NF
` Hydrophilic vanishing cream base of
`propylene glycol, stearyl alcohol, cetyl
`alcohol
` Polyethylene glycol 8000, propylene
`glycol, stearyl alcohol
` Carbomer - 940, PEG 400, propylene
`glycol, stearic acid
` Polyethylene and mineral oil gel base
`with PEG 400, PEG 6000, PEG 300,
`PEG 1450
` Petrolatum, stearyl alcohol, propylene
`glycol, carbomer - 934
` Water - miscible base consisting of pegoxol
`7 stearate, peglicol 5 oleate, mineral oil,
`butylated hydroxyanisole
`
` Dritho - Calp,
`Psoriatec
` Temovate E
`
` Eurax
`
` Topicort
`
` Clobetasol propionate,
`0.05%
`
` Crotamiton, 10%
`
` Desoximetasone,
`0.25%
`
` Apexicon, Maxifl or,
`Psorcon
`
` Difl orasone diacetate,
`0.05%
`
` Lidex Cream, Vanos
`
` Carac
`
` Halog
`
` Fluocinonide, 0.05%,
`0.10%
` Fluorouracil, 0.5%,
`1.0%, 5.0%
` Halcinonide, 0.1%
`
` Cortaid, Anusol - Hc,
`Proctosol HC
` Monistat - Derm
`
` Hydrocortisone, 2.5%
`water washable
` Miconazole nitrate,
`2%
`
`base. The fusion method is followed when the drugs and other solids are soluble in
`the ointment bases. The base is liquefi ed, and the soluble components are dissolved
`in the molten base. The mixture is then allowed to congeal by cooling. Fusion is
`performed using steam - jacketed vessels or a porcelain dish. The congealed mixture
`is then spatulated or triturated to obtain a smooth texture. Care is taken to avoid
`thermal degradation of the base or other components during the fusion process.
` Absorption - type ointments and creams are prepared by incorporating large
`quantities of water into hydrocarbon bases with the aid of a hydrophobic emulsify-
`ing agent. Water - insoluble drugs are added by mechanical addition or fusion methods.
`As with oleaginous ointments, levigating agents are also included to improve wetting
`of solids. Water - soluble or water - miscible agents such as alcohol, glycerin, or pro-
`pylene glycol are used if the drug needs to be incorporated into the internal aqueous
`phase. If the drug needs to be incorporated into the external oily phase, mineral oils
`are used as the levigating agent. Incorporation of water - soluble components is
`achieved by slowly adding the aqueous drug solution to the hydrophobic base using
`pill tile and spatula. If the proportion of aqueous phase is larger, inclusion of addi-
`tional quantities of emulsifi er and application of heat may be needed to achieve
`uniform dispersion. Care must be taken to avoid excessive heating as it can result
`in evaporation aqueous phase and precipitation of water - soluble components and
`formation of stiff and waxy product.
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2024 Page 12
`
`

`

`278
`
`SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS
`
` Water - removable ointments and creams are basically hydrophilic - type emulsions.
`They are prepared by fusion followed by mechanical addition approach. Hydr-
`ocarbon components are melted together and added to the aqueous phase that
`contains water - soluble components with constant stirring until the mixture congeals.
`A hydrophilic emulsifying agent is included in the aqueous phase in order to obtain
`stable oil - in - water dispersion. Sodium lauryl sulfate is used in the preparation of
`hydrophilic ointment USP.
` Water - soluble ointments and creams do not contain any oily phase. Both water -
` soluble and water - insoluble components are incorporated into water - soluble bases
`by both levigation and fusion methods. If the drug and other components are water
`soluble, they are dissolved in a small quantity of water and incorporated into the
`base by simple mixing over an ointment slab. If the components are insoluble in
`water, aqueous levigating agents such as glycerin, propylene glycol, or a liquid PEG
`are used. The hydrophobic components are mixed with the levigating agent and then
`incorporated into the base. Heat aids incorporation of a large quantity of hydro-
`phobic components.
` A wide range of machines are available for the large - scale production of oint-
`ments and creams. Each of these machines is designed to perform certain unit
`operations, such as milling, separation, mixing, emulsifi cation, and deaeration.
`Milling is performed to reduce the size of actives and other additives. Various fl uid
`energy mills, impact mills, cutter mills, compression mills, screening mills, and tum-
`bling mills are used for this purpose. Alpine, Bepex, Fluid Air, and Sturtevant are
`some of the manufacturers of these mills. Separators are employed for separating
`materials of different size, shape, and densities. Either centrifugal separators or
`vibratory shakers are used for separation. Mixing of the actives and other formula-
`tion components with the ointment or cream base is performed using various types
`of low - shear mixers, high - shear mixers, roller mills, and static mixers. Mixers with
`heating provisions are also used to aid in the melting of bases and mixing of com-
`ponents. Chemineer, Fryma, Gate, IKA, Koruma (Romaco), Moorhouse - Cowles,
`Ross, and Stokes Merrill are some of the manufacturers of semisolids mixers.
` Creams are produced with the help of low - shear and high - shear emulsifi ers.
`These emulsifi ers are used to disperse the hydrophilic components in the hydropho-
`bic dispersion phase (e.g., water - in - oil creams) or oleaginous materials in aqueous
`dispersion medium (oil - in - water creams). Bematek, Fryma, Koruma (Romaco),
`Lightnin, Moorhouse, and Ross supply various types of emulsifi ers. Entrapment of
`air into the fi nal product due to mixing processes is a common issue in the large -
` scale manufacturing of semisolid dosage forms. Various offl ine and in - line deaera-
`tion procedures are adopted to minimize this issue. Effective deaeration is generally
`achieved by using vacuum vessel deaerators. Some of the recent large - scale machines
`are designed to perform heating, high - shear mixing, scrapping, and deaeration pro-
`cesses in a single vessel. Figure 1 shows the design feature of a semisolid production
`machine manufactured by Ross.
` Various low - and high - shear shifters are used to transfer materials from the pro-
`duction vessel to the packaging machines. In the packaging area, various types of
`holders (e.g., pneumatic, gravity, and auger holders), fi llers (e.g., piston, peristaltic
`pump, gear pump, orifi ce, and auger fi llers), and sealers (e.g., heat, torque, micro-
`wave, indication, and mechanical crimping sealers) are used to complete the unit
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2024 Page 13
`
`

`

`OINTMENTS AND CREAMS
`
`279
`
`FIGURE 1
` Semisolid production machine with heat jacketed vessel, high - shear mixer,
`scrapper, vacuum attachments, and control station. (Courtesy of Ross, Inc.)
`
`operations. These equipments are supplied by various manufacturers, namely Bosch,
`Bonafacci, Erweka, Fryma - Maschinenbau, IWKA, Kalish, and Norden.
` Sterility of ointments, especially those intended for ophthalmic use, is achieved
`by aseptic handling and processing. Improper processing, handling, packing, or use
`of ophthalmic ointments lead to microbial contaminations and eventually result in
`ocular infections. In general, the empty containers are separately sterilized and fi lled
`under aseptic condition. Final product sterilization by moist heat sterilization or
`gaseous sterilization is ineffective because of product viscosity. Dry - heat steriliza-
`tion is associated with stability issues. Strict aseptic procedures are therefore prac-
`ticed when processing ophthalmic preparations. Antimicrobial preservatives such as
`benzalkonium chloride, phenyl mercuric acetate, chlorobutanol, or a combination
`of methyl paraben and propyl paraben are included in ophthalmic ointments to
`retain microbial stability.
`
`Packaging
` An ideal container should protect the product from the external atmo-
`sphere such as heat, humidity, and particulates, be nonreactive with the product
`components, and be easy to use, light in weight, and economic [14] . As tubes made
`of aluminum and plastic meet most of these qualities, they are extensively used for
`packaging semisolids. Aluminum tubes with special internal epoxy coatings are
`commercially available for improving the compatibility and stability of products.
`Various modifi ed plastic materials are used for making ointment tubes. Tubes made
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2024 Page 14
`
`

`

`280
`
`SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS
`
`FIGURE 2
` Custom - designed LDPE containers made by BFS process for packaging topical
`products. (Courtesy of Rommelag USA, Inc.)
`
`of low - density polyethylene (LDPE) are generally soft and fl exible and offer good
`moisture protection. Tubes made of high - density polyethylene (HDPE) are rela-
`tively harder but offer high moisture protection. Polypropylene containers offer
`high heat resistance. Plastic containers made of polyethylene terephthalate (PET)
`are transparent and provide superior chemical compatibility. Ointments meant for
`ophthalmic, nasal, rectal, and vaginal applications are supplied with special applica-
`tion tips for the ease of product administration.
` A recent method known as blow fi ll sealing (BFS) performs fabrication of
`container, fi lling of product, and sealing operations in a single stage and hence is
`gaining greater attention. The products can be sterile fi lled, which makes BFS a
`cost - effective alternative for aseptic fi lling. All plastic materials are suitable for
`BFS processing. In most cases, monolayered LDPE materials are used for making
`small - size containers. If the product is not compatible with the LDPE or sensitive
`to oxygen, barrier layers are added to the container wall by coextrusion methods.
`As the container is formed inside the BFS machine, upstream handling problems
`are avoided. The BFS machine can hand the container off to any secondary packag-
`ing operation that needs to be performed. Typically a secondary overwrap is added
`to the containers prior to cartooning. An additional advantage of BFS containers is
`the integrated design of the applicator into the product container. Figure 2 shows
`some of the custom - designed BFS co