Sterile Pharmaceutical
`Products
`
`Process
`Engineerin.g
`Applications
`
`Drug Manufacturing
`Technology Series
`
`Edited by
`Kenneth E. Avis
`
`Nexus Ex. 1029
`1 of 48
`
`

`

`Sterile Pharmaceutical
`Products
`
`Process
`Engineering
`Applications
`
`Drug Manufacturing
`Technology Series
`
`Kenneth E. Avis, Editor
`
`Interp,harm Press, Inc.
`Buffalo Grove, IL
`
`Nexus Ex. 1029
`2 of 48
`
`

`

`·ed
`hnology and regulatory
`thors
`boOks focused upon ap~h e I~ec ou are considering writ-
`.
`Invitation to Au
`lnterpharm p~s pub::~re Manufacturers wor~-:,:!c~uJcal, biotechnol_ogy, med(cid:173)
`'1111 affairs impa~tin~ Hea a book applicable to th~ p manufacturing industries, please
`t;9 ing or contnbutillg to u·c or veterinary rned1one
`f Publications.
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`,
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`Interpharm titles are regularl~ sent to ev( f;~es to faculty and students in ad(cid:173)
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`/
`
`Lib ary Of Congress Cataloging-in-Publication Data
`.
`.
`r
`•
`· g applications
`Sterile pharmaceutical products: process engmeenn
`Kenneth E. Avis, editor.
`P·
`.
`cm.
`Includes bibliographic references and index.
`ISBN 0-935184-80-5
`1. Sterilization. 2. Pharmaceutical technology. 3. Oean rooms.
`I. Avis, KeMeth E., 1918-
`RS199.S73S75
`1995
`614.4' .7-dc20
`
`95-24999
`CIP
`
`109 8 7 65 4 32
`
`ISBN: 0-935184-81-3
`Copyright© 1995 by lnterphann Press, Inc. All rights reserved.
`All rights reserved. This book is protected by copyright. No part of it may be reproduced,
`stored in a retrieval system, or transmitted in any form or by any means, electronic, mechani·
`cal, photocopying, recording, or otherwise, without written permission from the publisher.
`Printed in the United States of America.
`Where a product trademark, registration mark or other protected mark is made in the text,
`ownership of the mark remains with the lawful owner of the mark. No claim, intentional or
`otherwise, is made by reference to any such marks in this book.
`While every effort has been made by Interpharm Press, Inc., to ensure the accuracy of the
`information contained in this book, this organization accepts no responsibility for errors or
`omissions.
`
`lnterpharm Press, Inc.
`1358 Busch Parkway
`Buffalo Grove, IL 60089, USA
`Phone: + 1 + 708 + 459-8480
`+ l + 708 + 459-6644
`Fax:
`
`Nexus Ex. 1029
`3 of 48
`
`

`

`CONTENTS
`
`Foreword
`
`1. Introduction
`
`Kenneth E. Avis
`Chapter Contents
`
`xi
`
`1
`
`2
`
`7
`
`7
`
`2. Engineering Control of the Aseptic
`Filling Environment
`Howard R. Leary
`Objective and Introduction
`Creating and Maintaining Aseptic
`Environments for Phannaceutical Filling
`The Enclosure
`Particulate Control
`Ingress to and Egress from the Controlled
`Environment
`11
`Machine Design Issues in Aseptic Packaging
`13
`Asepsis: A Hostile Environment for Filling Equipment 13
`Designing to Protect the Machinery
`16
`Designing to Enhance Bwburden Control
`23
`Designing/or Particulate Control
`32
`Conclusion
`34
`References
`35
`
`9
`1 O
`11
`
`iii
`
`Nexus Ex. 1029
`4 of 48
`
`

`

`iv
`
`Contents
`
`3. Air Handling Systems for
`cteanroom Control
`Brian D. Moore
`
`General Design Guidelines
`
`cost Effectiveness
`Characteristics of Phannaceutical Clean Rooms
`Air Qjlality Standards and Guidelines
`Cleanroom Attributes
`Operational Cleanroom Classifications
`Air Distribution to the Clean Room
`Tenninal HEPA Filters
`Cleanroom Return Air
`Air Distribution to Product IJxposure Areas
`General Cleanroom HVAC System Concepts
`System Configuration
`'Equipment Sizing and Selection
`Aseptic Area Pressuriza,tion
`Mechanical Space Location
`Air Handling Units
`Air Handling Unit Construction
`Air Handling Unit Design
`Ductwork Design and Construction
`Ductwork Design
`Ductwork Construction
`HVAC System Controls
`Temperature and Humidity Control
`Pressure Control
`Details
`System Testing, Commissioning, and Validation
`Testing
`Commissioning
`Validation
`The Future
`References
`
`37
`
`37
`
`38
`
`39
`40
`43
`46
`46
`46
`49
`54
`58
`59
`65
`66
`66
`71
`71
`72
`74
`74
`75
`77
`77
`78
`83
`83
`84
`84
`85
`86
`
`87
`
`Nexus Ex. 1029
`5 of 48
`
`

`

`4. High Speed, Automated Filling
`of Sterile Liquids and Powders
`F. William Rahe
`
`Scope
`Hir)t Speed, Automated Filling
`Aseptic Processing
`Containers
`Small Volume Liquids and Powders
`Trends
`General Machine Features
`Common Design Issues
`Dose Control
`Cleanliness
`Sterilizable Parts
`Materials of Construction
`Validatwn
`Machine Capacity Sizing
`Liquid Filling
`Metering
`Container Handling
`Powder Filling
`Why Powder Filling?
`Pneumatic Cylinder and Piston Wheel
`Totally Enclosed Pneumatic Pump
`Volumetric Compression
`Auger Filling
`Future Developments
`Recommended Readings
`
`5. Engineering Considerations for
`CIP/SIP Systems
`Dale A. Seiberling
`Alfred J Ratz
`Historical Review, Evolution, and
`Applicable Criteria
`
`Contents
`
`v
`
`89
`
`89
`89
`90
`90
`90
`90
`91
`92
`92
`94
`94
`95
`95
`97
`99
`99
`111
`113
`113
`113
`119
`123
`126
`131
`132
`
`135
`
`135
`
`Nexus Ex. 1029
`6 of 48
`
`

`

`136
`136
`136
`137
`139
`
`140
`141
`144
`144
`144
`144
`148
`
`processes
`·dates
`naceuttcal
`oeftned
`cJP p/,an IP Tech1iolog>lt Are GIP Candi
`cIP and s ptnent '(ha,J GIP Equipment
`rypes ~ffiEq"~e oesig,t 0
`'terlafior
`'terltt or
`en 'JP procedure
`ts and en
`'[lie ~ . ,,al C<J11'Ponen
`Add•tiOrptJrattng S~ GIP Process
`11,co
`,view OJ a
`Design ~ Defined
`onents
`GIP sys
`111 CoIIlP
`CIP Syste
`.
`in Units
`C'IP Rearculat g 1 .1-attons
`· :g GolfS't,U"'' ·
`tion
`Reuse opera
`. l
`d
`Engineenn
`Single-Use v~~~ for p}iannaceutica an
`Desirable Gnte
`tems
`. ... ,Attn" Units and
`Biotech GIP sys
`.
`.r GIP Recircmu-
`-o
`LocatttJn -~ Feed Equipment
`trol Systems
`Chemic
`GIP Program g~ta Acquisition
`GIP Program
`eanability
`GIP Data Logger
`r
`Summary ~eportsle u·on and A1'fllicatton
`k fi
`Device Se c
`S
`pra_y oifthe Pharmaceutical Tan
`-or
`Design
`Cleaning
`Effective Spray
`D Drug Process
`An F.xample of a GIP 1"
`.
`.
`aP Supply/Return System Criteria
`GIP Supply/Return Pipi~g C~cepfs
`GIP Supply/Return Engineering
`Return Flow Motivation
`Return Pump Selection
`Eductor Return Systems
`Unifomi F1ow Rates
`Automation of the Phannaceutical or
`Biotech Process
`GIP Air-Operated Values
`Automated Process Piping Design
`Air-Operated Valve Pulsing and Sequencing
`U-Bend Transfer Panels
`Integrated Process/GIP Piping with U-Bend
`Transfer Panels in a Hypothetical Process
`Integrated Process/GIP Piping in a Biotech Process
`Integrated_ Process/GIP Piping with Transfer
`Panels in the Pharmaceutical Process
`
`152
`
`156
`158
`162
`162
`164
`164
`
`166
`169
`172
`174
`176
`179
`181
`181
`182
`
`182
`182
`186
`188
`190
`
`196
`199
`
`200
`
`Nexus Ex. 1029
`7 of 48
`
`

`

`viii
`
`l.,,(,ITl~I• -
`
`248
`2So
`2So
`259
`259
`266
`267
`
`269
`
`270
`273
`273
`274
`275
`276
`277
`280
`
`ti " Resources
`.
`outside Valida o_ and Storage
`Docm11enJ Hand,,,1tidation Seque11ce-An .Example
`d ~ case Histories
`11u: start-Up a1J
`-U Concerns an
`Start P
`,_..,e Maintenance
`System Preve1t .. Jv,
`Conclusion
`References
`Engineering Considerations in
`7. Sterile Powder Processes
`Alpaslan Yaman
`Sterilu.ation of the Bulk Drug Substance
`Packaging of the Bulle Drug Substance
`CC111fai11er Considerations
`Characterization of the Bulle Drug Process
`Powder Density
`Angle of Repose
`Partfcle Size Distribution
`Crystal History
`Aseptic lransfer of Raw Material to the
`Fi11ing Room
`Factors Affecting Filling Rate
`Single Venus Double Stroke Filling
`Multiple Powder Fill
`Aseptic Milling and Blending
`Double Shot Filli'ng
`d lb .
`Environmental Conceni
`on Finished Produ,.. Chs an
`etr Effects
`"'"
`aracte · •
`HumM~
`nsti~
`Electrostatic Discharge
`O.tygen Control
`Dust Containment
`Pariiculate Matte
`A,.,,._
`r
`'-1\UOWledgements
`References
`
`281
`281
`281
`286
`287
`292
`
`295
`296
`296
`297
`298
`298
`302
`304
`
`Nexus Ex. 1029
`8 of 48
`
`

`

`Contents
`
`ix
`
`305
`
`305
`305
`
`8. Engineering Considerations in
`Sterile Filtration Processes
`Holly Haughney
`Introduction to Membrane Filters Used in
`Sterile Filtration Processes
`Filtration Mechanisms
`Membrane Filter Ratings for Particulate
`Removal Filters
`Sterilizing Grade Membrane Filter Ratings
`and Integrity Tests
`Membrane Filter Construction
`Filter Assemblies Used in Processes
`Sterile Liquid Filtration Design and
`312
`Operational Considerations
`312
`Design Considerations for a Filtration Process
`Operational Considerations for a Filtration Process 329
`Integrity Testing Design and Operation
`Considerations
`Sterile Gas Filtration Process Design and
`348
`Operational Considerations
`Considerations for Sterile Filtration of Fermenter Air 3 48
`Considerations for Sterile Tank Vent Filters
`349
`Summary
`353
`References
`353
`
`3 06
`
`307
`308
`311
`
`338
`
`9. The Development of Integrated,
`Automated Filling and Packaging
`Equipment Using Hybrid Robotics
`Hans W. Trechsel
`Understanding httegrated, Automated
`Manufacturing: 11ie Integration Process
`The Challenges of Designing a Processing System
`Processing Requirements
`Machine Design
`Robotic Design
`
`357
`
`359
`360
`360
`361
`362
`
`Nexus Ex. 1029
`9 of 48
`
`

`

`Co11te11ts
`
`X
`
`367
`369
`369
`3 7.3
`
`365
`Processing a Product
`Batch p,.ocessi11g
`1,,dex Mofio,r Process1i1g-Sing/e '!f' Multiple Stations 365
`Collhituuus Motion Flow Pr~cessing
`Process Lttyout-Rotar:r, In-L-me, or Reverse In-Line
`Ro,u Adva11ce Processing
`The Handling of Parts (Bottles, Syringes,
`stoppers, Caps, Etc.)
`An Integrated, Automated Liquid Filling
`Processing Line
`User Requirements for tlte Representative System
`Design Approach
`Integration o f Processes
`Prefeeding
`Wt.Mkti,g
`Sleriluation and Depyrogenation
`Accumulatinl7'f)ow,1-Bottle Reject
`In-Feed Line Conveyor a n d Slarwh { /
`ee
`No Vial-No Fill
`Ta_re Wetgking
`Nitrogen Flushing
`Ftllin17Ckeckweig1tinP
`o
`Sfoppen·
`Nitrogen~
`f
`Ca_ppin17se:f'n;g and Seating of Sloppe,s
`Re;ect o f Bad Parts
`TrayfoadinP n
`? r.t..Jloplti1izing)
`Label.
`tn!YFtnal htspectio
`11/Packaging
`Material Selection
`Product Contact
`&posed Aretzy Areas,
`Enclosed Are4r
`
`374
`375
`377
`379
`378
`378
`379
`
`379
`3Bo
`3Bo
`3Bo
`389
`389
`390
`39J
`391
`39J
`392
`392
`392
`393
`
`395
`
`398
`
`Nexus Ex. 1029
`10 of 48
`
`ValJJe hideg
`
`llbiectbid~
`
`

`

`FOREWORD
`
`The question, "But, how do we do it?" or its essence, is often asked
`by ~-e people responsible for activating the principles embodied in
`dec1S10ns made by committees, administrators, or others involved in
`the decision-making process. Those who make decisions in the con(cid:173)
`ference room or office are often quite removed from the "real world,.
`of design, fabrication, and formulation at the bench or in the plant
`Even if plans are made with a good measure of realism, there is
`much insightful planning and development work needed to convert
`an idea into an applied, working model of the pharmaceutical prod(cid:173)
`uct. Textbooks and other references in the field of pharmaceutical
`processing technology may not be very helpful to the practitioner
`since the theory and principles involved often fall short in giving
`practical direction on how the principles can be applied in actual
`pharmaceutical processing situations. To help to fill this gap in tech(cid:173)
`nical, applied information, the Drug Manufacturing Technology
`Series of books was born.
`The objective of this series is to call upon outstanding experts in
`select fields to distill their knowledge and write very practical infor(cid:173)
`mation that will assist professionally trained chemists, biologists,
`engineers, pharmacists, and other practitioners to solve problems as(cid:173)
`sociated with the preparation of high quality pharmaceutical prod(cid:173)
`ucts. The technology required for or supportive of the production of
`a wide range of pharmaceutical products will be considered for in(cid:173)
`clusion in the series, with appropriate grouping and organization
`Particular attention will be given to new, innovative, or emerging
`technologies. However, sometimes the solution to a need or prob(cid:173)
`lem is simply a new application of a well-known technology. Such
`applications will be included and discussed, and assistance will be
`given in developing insights into the application of basic principles
`to problem solving.
`It should be apparent that there is a great body of experiential
`knowledge in the field that lies largely untapped. It is to be recog(cid:173)
`nized that some such knowledge must remain confidential, but
`
`xi
`
`Nexus Ex. 1029
`11 of 48
`
`

`

`be shared. such sharing will reduce th
`iS .much that can by reducing unnecessary duplicatio e cost
`~er:pa.riJlg producy unproductiVe trial-and-error efforts n of el,
`, 'Which
`o tkiental wals . an roved product quality. Although ph
`%:nttibute~ to a:;:;:foiogy is continuously changing, m:::Uaceuti,
`sooner or later, become good manuf;y of the
`cal processwg
`oeW _deve!0PIDf,11~eneral pharmaceutical acceptance orb a~Iing
`practice, ~er !eptance by the FDA of a new deveJopm Y edict by
`e acd manufacturing practice. 1berefore all ent esta~
`the FD-:1-
`Jishes 1ht oasu15°:e undertaken carefully with thorough qu ~~"elon..
`•d
`·
`alific
`.rnents s
`·t
`·
`t'.
`and/or validation before cons1 enng 1 as an llllprovement and cltion
`'Wor,
`. .
`.
`thy of acceptance.
`Reducing this technology to •wnting m a formalized
`book will help to establis~ the be~t as good manufactllrin reference
`Furth_er., at I~ast some of 1t~ by bemg_ refluxed through In~ ~ractice.
`plicat1ons, will become refined and rmproved. Thus it .
`ltipJe aP(cid:173)
`that these books will not only help to solve probie~ 15 e~ected
`be a catalyst for future improvements in the technolo now, but 'Will
`gy addressed.
`
`KennethE
`S
`· Avis
`epktnber, 1995
`
`Nexus Ex. 1029
`12 of 48
`
`

`

`7
`
`ENGINEERING
`coNSIDERATIONS IN STERILE
`poWDER PROCESSES
`
`Alpaslan Yaman
`R. w. Johnson Pharmaceutical Research Institute
`
`Sterile powder filling is .p~arily used for an~~iotics (specifically
`cephalosporins and perucillins) that are sensitive to hydrolysis.
`Because these drug substances are antibiotics, the risk of bacterio(cid:173)
`logic contamination is less than would be for those drug substances
`that do not inhibit the growth of bacteria. However, this type of raw
`material does not have an inherent propensity to retard the forma(cid:173)
`tion of particulate matter or counter the existence of pyrogens.
`Thus, the process engineer must minimize or eliminate the risk of
`such contamination to the raw material during production, packag(cid:173)
`ing, and shipment.
`Ule most commonly occurring types of microbiological organ(cid:173)
`isms found in the parenteral facility will be gram positive. These or(cid:173)
`ganisms have a high sensitivity to this class of drug substance, but
`they do not form the most potent pyrogens. The pyrogen-forming
`organisms of greatest concern are gram negative; the usual source
`of this type of contamination is standing water or human contact.
`Both of these sources of contamination can be controlled by the
`proper training of personnel Further discussion and information
`about pyrogens can be found in Technical Report Number 7 (PDA
`1985). The sterile preparation of the bulk drug substance and the
`subsequent manufacture of the pharmaceutical drug product are
`processed under aseptic processing conditions. The formulation of a
`
`269
`
`Nexus Ex. 1029
`13 of 48
`
`

`

`270
`
`Sterile Pharmaceutical Products
`
`slerilc injeclable powder ls the bulk drug substance
`.
`izauon is 1he responsibility of the drug substance ;;ict 1ts steru
`There is no true formulation or compounding that take:nufaqllrer(cid:173)
`place With
`this type of product.
`
`STERILIZATION OF THE BULK DRUG SUBSTANce
`This section will focus primarily on the final steps in the p
`of the bulk sterile powder. In the bulk chemical produc/eParauon
`
`substanc~ has been synth~~~ed, a solution of 1~ is filtered. The ~g
`fm~
`filtration 1S through a sterihzmg filter and the filtrate is coll
`
`the drug substance is produced under tight controls rot~~ f~cility
`duction of particulate mat~er and con~amin~tion. Once th: llltro(cid:173)
`a recrystallizer located in a cleanroom environment that is ~ctf d lI1
`from the rest of the facility. The personnel in this room ::0 atect
`gowned, as are those in a Class 100 f~g room of a parent! o/lly
`cility. Following crystallization, the dried powder is then pac~ fa(cid:173)
`into presterilized containers. The type of containers available Wilf ~d
`discussed later. The crystal type, shape, and size are critical in the
`manufacture of the pharmaceutical finished product. Rheol e
`must be addressed first in the production of the drug substance ~
`then in the acceptance of the raw material into the pharmaceutical
`manufacturing facility. A flowchart outlining the manufacture of
`sterile bulk drug substance can be seen in Figure 7.1.
`a
`The hydrate or solvate form of the drug crystal is dependent on
`solvent selection. This factor will not be the focus of the discussion
`here since it is usually a variable that bas been preset during devel(cid:173)
`opment. LikeWise, crystal shape is primarily dependent on the in(cid:173)
`herent crystal type and is not a variable that lends itself to
`manipulation. Thus, the process engineer is left with the variable of
`particle size. fn the production of drug substances for use in non(cid:173)
`sterile products, particle size is usually critical for solid and semi(cid:173)
`solid dosage forms. ln these cases particle size is controlled after
`synthesis by milling. The drug substance is milled and sized
`through a predetermined screen, resulting in a particular particle
`size distribution. Such a step is generally not done for sterile prod(cid:173)
`ucts due to the risk of microbial contamination and the introduction
`of particulate matter. Yet, sterile milling can be employed in the
`process of sterile blending for multiple powder pharmaceutical
`products. Therefore, if milling is generally not a usable method for
`particle size control, the process engineer is left with only one alter(cid:173)
`native, to control crystal growth rate and nucleation. These two pa(cid:173)
`rameters indirectly affect the overall particle size of the crystal.
`
`Nexus Ex. 1029
`14 of 48
`
`

`

`. ring Considerati,ons in Sterile Powder Processes
`e,iginee
`
`271
`
`,:g--,
`
`·s of orug Substance
`synthes1
`
`crystallization
`
`Collection of Sterile
`Filtrate in Evaporator
`
`Filling/Sealing of Bulk Raw
`Material in Presterilized Cans or Bags
`
`QA
`Release
`
`Figure 7. 1. Processing flowchart illustrating the manufacture of
`sterile bulk drug substance.
`
`When nucleation is minimized and crystal growth is maximized,
`the finaJ outcome will be a raw material with large crystals. While
`this may be the desired effect in the general chemical industry, in
`the manufacture of a dry powder drug product to be filled asepti(cid:173)
`cally, a powder consisting of an even particle size distribution with
`~ averag~ p~cle size of approximately ~0~-120 µm ~desired. A
`
`s~r pa~cle stze _may hinder consistent fillmg of t,11~ vial, thus re(cid:173)
`
`b ting tn fill weight variation throughout the foushed product
`hatch. Too small a particle size may result in compaction within the
`feci:r ~~ dosing wheel of the filling machine, which also will af-
`e filling accuracy within the batch of the finished product.
`
`Nexus Ex. 1029
`15 of 48
`
`

`

`272
`
`t ril Plttmnac ittical Proditcls
`
`I n an b de ribed as the sustained t
`Nu I
`·tal that
`·ur l
`• super aturation Jncreases A 0(lllation
`f
`m ved, u ually by evaporation or vacuum the st 1e soJve11~ _'-lllit
`lu L dher and b gin to form an "embryo" th moJecuJes 0f te.
`l 980, 494- 496); however, over ~ lllay rediss the
`(F u t et al.
`reaches a level of stability, which fonns a crystal nuc~ the en:iblve
`u th solvent is removed and supersaturation pers· us. ~eret tyo
`re formed and crystallization increases. As one c:its, U~t crys~:~·
`I u·
`th
`y ue . o nuc ea on, _ e outcome wut'
`· aril d
`see if
`<qJs
`·
`liz ti
`t
`crystal.
`a on is prLm:
`raw matenal with a relatively small particle size, cons·
`. be a solid
`1sting of many
`distinct unit cells (crystals).
`Crystal growth rate can be described by the growth
`ular unit cell. The relative number of distinct crystals is I of a Pclnic(cid:173)
`nucleation; the process of crystallization involves the ess than by
`each crystal. Crystal growth has been described as poss·f ~0wth of
`ring at "dislocations on the surface" of the crystal and .. ~ Y chccur(cid:173)
`tion is self-perpetuating, and the crystal grows in a spiral ~ sloca(cid:173)
`of surface forces" (Foust et al. 1980, 494-496). Therefore wh a result
`tallization is carried out under low supersaturation conditio en crys.
`tal growth and particle size can be maximized.
`ns, crys-
`To attain a particle size distribution within a particular ran
`the rate of crystal growth and the amount of nucleation must b b~'
`anced. The balance of these two variables is the primary par~
`·
`that the process engineer must control in a bulk drug substance ete~
`der tight particle size distribution control.
`un
`Crystallization occurs after the sterile filtration step, using a re(cid:173)
`crystallizer located in . an aseptic en~oi:unent Recrystallizers vary
`by the exact mechamsm of crystallization. Recrystallizers can be
`grouped into three basic functional types :
`
`1. Precipitation by cooling a hot concentrated solution
`2. Precipitation by evaporation
`
`3. Precipitation by adiabatic evaporation and cooling
`This third form is the most prevalent in smaller-scale applications,
`such as the pharmaceutical industry.
`The basic structure of a recrystallizer is a source of heat and an
`exit for the solvent, if the mechanism is by evaporation. On the
`other hand, if the process involves cooling, then a h~at exch'.311geeJ
`extracts heat. One such device that could be used IS an a~itat
`batch crystallizer, which is ideal for smaller or batch-processmg 0~
`
`erations. This crystalhzer is cone shaped at the bott~ID :t
`
`equipped with an agitator and a cooling coil. An added reqwrei;;sed
`for this application is that all product contact surfaces be comp
`
`Nexus Ex. 1029
`16 of 48
`
`

`

`. considerations in Sterile Powder Processes
`uilieermg
`f,tiz,·
`
`273
`
`in1 5 steel. The recrystallizers need not be as large as
`316L sta
`e!.ndard ones in the chemical industry; but they do
`~[ se of the clized between each batch of raw material. 1bis would
`11~d 10 be st; cili' ·ty and recrystallizer to be capable of conducting
`I
`.
`11
`I
`(C
`)
`ne
`the ia
`(SIP) as we
`IP procedures.
`equir~
`as c ean-m-p ace
`1
`~teafll-i.fl-~ ace design should eliminate crevices and convolutions
`Rec!Ystallizer chemical and microbial contamination.
`that can uap
`
`PACKAGING OF THE BULK DRUG SUBSTANCE
`
`container Considerations
`two primary packaging materials: a can (which can be alu-
`11~ere ar~r stainless steel) and a plastic bag. The Triple Seal Bag®,
`aun~rn ed and patented by ACS Dobfar (Milan, Italy), is such a con(cid:173)
`d~ve ;~e latter is especially useful in the case of shipping blended
`t~~ple powders for use in sterile powder filling operations.
`mu The aluminum can is probably the most prevalent container
`sed 10 ship sterile powders to powder filling facilities. The cans are
`~ghtweight and can be easily transported to the pharmaceutical fa(cid:173)
`cility for the production of finished product. Aluminum cans can be
`washed, depyrogenated, and sterilized prior to use. Once the pow(cid:173)
`der is crystallized, the sterile drug substance is filled into the sterile
`aluminum cans and sealed. The can is sealed with a rubber gasket
`and a crimped aluminum cap. The seal on the aluminum can can be
`validated for seal integrity just as a vial or ampoule may be validated
`by media challenge or dye ingress, although the dye test is less
`prevalent Another test tO measure the effectiveness of the seal or
`the possibility of a leak is the vacuum hold test This determines the
`can's capability to maintain a particular vacuum level The Triple
`Se~ B~g® is, as the name implies, three bags where the raw mater(cid:173)
`ial 15 filled into the inner layer and the three layers are then sealed
`under a vacuum. 1bis vacuum sealing results in a powder "brick"
`that:oes not allow for any movement of the contents.
`egardless of which container one chooses the key factors that
`one _must consider are the ease of transport ~aintenance of pack-
`age mte
`·
`th
`'
`tra.nst ~ty, e effect of shipment on the raw material, the ease of
`the ris~ 0 f the ~aw material into the sterile filling environment, and
`Pensin \ Particulate material upon opening the container and dis(cid:173)
`the ca! ·t !i drug . substance into the filling machine. In most cases
`e:ictend !;tted directly onto the filling machine hopper and acts to
`sc?Pic and 0close off th_e_ hopper. This situation is ideal for hygro(cid:173)
`Pru:na.cy co xygen-sensltive powders. With the Triple Seal Bag® the
`ncem wou,d be seal integrity and the transport of
`
`Nexus Ex. 1029
`17 of 48
`
`

`

`274
`
`terile pJum11acctttical Products
`
`moisture Into the raw material, due to. the penneabilit
`, •nus woukl have to be validated through shi
`n,. 1
`.Y of pt,~ .
`Id
`PPm
`•
`"-'tic
`1ut •
`1
`0 11c would assume that a ummum wou be a bette
`g stur1,
`r lllat • ~es
`xh.b.
`t.. : h
`.t.
`those dn1g substances u ,at e.
`it a lUg propensity for etlal fo;
`i
`Uon at very low levels of moisture and thus are sens· . degrad
`. 1
`.
`ttive t
`a-
`ck
`h
`moisture gainS throug pa ag~g matena due to enviro o slllaU
`humidity experienced during shipment
`Ilrnentai
`
`CHARACTERIZATION OF THE BULK DRUG SUBst
`For the process engineer ~esponsibl~ for the development anANCE
`dation of a dry powder filling operauon, knowledge of the hi d vau.
`the raw material is important. for the ~reduction of the ~t~ry of
`pharmaceutical product. The library of information that th lilishect
`ngi-
`neer develops on a particular raw material will have two be e
`ne ts·
`1. control of the incoming raw material and the develo
`·
`Pmen1
`of raw material specifications
`2. Problem solving for future technical service questions
`By developing and maint~ g a complete file on the physical
`characteristics of the raw matenal, one can further develop nee
`sary filling parameter controls for the filling machine, to main~s(cid:173)
`tight control of the o~erall ~g accuracy and minimize waste an~
`rejects in the producuon of fmal product.
`The key parameters that will be defined and discussed in this
`section are particle size distribution, angle of repose, bulk and tap
`density, and the crystal history of the raw material. These parame(cid:173)
`ters are all interrelated in defming the flowability of the bulk drug
`substance and are commonly referred to as the powder rheology.
`Rheology can be defined as the science of flow and is the study of
`how the materials behave under stress and what deformations oc(cid:173)
`cur, both elastic and flow (Wood 1986, 123-145). This defmitionand
`explanation can, in principle, be applied equally to liquids, semi(cid:173)
`solids, and powders. The parameters stated above, assessed collec(cid:173)
`tively, define the inherent flow capability of a particular powder. An
`understanding of these parameters gives the process engineer the
`insight into what should be done to enhance the flow of the powder
`during the filling operation. It is these characteristics that the filling
`machine vendor will need to determine to see if a particular powder
`can be processed on the machine at hand or if modifications to the
`machine are warranted.
`d
`The effects of each of these parameters cannot be separate
`from each other in the assessment of their respective effectS on
`
`6e
`
`I ' .. ! ..... ' ........... ' .... ' I '
`-.. _. ·.· i . ·.-.·I:-:-
`.
`·...... . . . . . . . . .
`.. .' ..... ·1· ...... -. -. .
`,
`. . . . . . . . . . ... ·1· ... · 1 · . . . I
`. .
`· I
`:-:•:•:• ,:-:-:•:•: :-:-:•:•:• •:•:-:•:•::-:-:.:-::::::~:::~:I:::>>-:~:---:••: •:-•-:::: .:-: •-:
`: . : -: .
`.
`Nexus Ex. 1029
`18 of 48
`
`' •
`
`,""i'
`
`

`

`. ,eering Const'derations in Sterile Powder Proces.
`ses
`f,1tf,t,1
`
`275
`
`fl w· however, they can each be easily determ1n d thr
`0
`~tic and practical test methods to develop e
`ough
`!llateria!
`basic, siJJl~·"g ~f the flowability and compactibility of a anp o~er
`1I
`arucu ar
`derstaJlUJJ'
`ufl
`Owder.
`p
`.
`powder oensity
`fir t physical parameter that will be addressed is the po d
`
`1a
`
`'fhe ·t/ It can be subdivided into bulk and tap densities. Dens:y ~;
`de: d as the ratio of mass to the volume occupied by that mass
`de a:s per cubic centimeter). Bulk density (pb) is the apparent den(cid:173)
`!y of a powder an~ is related to bu~k volume. Therefore, bulk den-
`
`. can be determmed by measunng the volume occupied by a
`~~wn mass (or_ w~ight) of powder p~aced in a graduated cylinder.
`'l1lus, bulk density 1S th_e ~pace oc°:1p1ed by a given weight of parti(cid:173)
`cles lying in clo~e proXlilllty to therr n~arest neighbor. Tap density
`(p) can be descnbed as the space occupied by the particles of a pow(cid:173)
`d;r in relative space to the nearest neighbor minus the air pockets
`that may exist as a barrier between the particles. Tap density is also
`defined as mass per unit volume, but is arrived at by physically re(cid:173)
`moving air gaps or pockets between particles. The USP describes fill(cid:173)
`ing a graduated cylinder with a known amount of powder and
`tapping at a specific rate of taps per minute for a specified time or
`number of taps (e.g., 1000 taps). Then the volume of the powder in
`the cylinder is recorded, constituting tap density. The initial density
`prior to tapping would be the bulk density. This method lends itself
`to variation between trials and operators (Marshall 1986, 66-99). A
`more accurate method to determine the bulk and tap density would
`be achieved using a Hosokawa Powder Tester (Figure Z2). This ap(cid:173)
`paratus determines the tap density by weight; tapping is performed
`by a device that is preset for taps per minute. This gives the engi(cid:173)
`neer a consistent measure of the tap and bulk density for a powder
`that is reproducible day to day and operator to operator. Knowledge
`of the bulk and tap density can lead one to determine the com(cid:173)
`pr~ssibility ( C~ of the powder, which is an indicator of its flow prop(cid:173)
`erties. Compressibility can be determined by the following equation:
`
`C1= fl - p,lpbJ X 100
`2 The compressibility of a powder should generally not be above
`l 5 percent. This means that the closer the tap density of a powder
`s to ~e bulk density the better the flow of the powder. 11lis para-
`.thin th
`meter lS dir
`'
`.
`po d
`_ectly related to the particle size distribuuon wt
`e
`Wi~r, which directly affects the quantity of air that can be trapped
`or between particles of a particular powder.
`
`Nexus Ex. 1029
`19 of 48
`
`

`

`276
`
`Sterile Phan11aceutical Products
`
`Figure 7 .2. Hosokawa Micron Powder Characteristic Tester~
`PT-N. (Courtesy of Hosokawa Micron Powder Systems, Summi~, ~J)
`
`Angle of Repose
`
`The angle of repose is defined as the tangent angle of twice the
`height divided by the diameter of a mound of powder. This can be
`noted by the following equation (Marshall 1986, 66-99) :
`tan 0 = 2h/D
`The angle of repose can simply be measured by dropping a quantity
`of powder through a funnel onto a flat surface. Once all the powder
`has been collected on the flat surface, a cone can be fitted over the
`mound or powder bed. The tangent of the angle made with the _hor(cid:173)
`izontal gives the angle of repose. This is a very simple and stra1g_ht(cid:173)
`forward test that can be performed easily at the manufa~tunng
`facility. In Figure Z2 one can see the angle of repose deterrrunauo~
`station of the Hosokawa Tester. The angle of repose can be defin~5
`as_ a ~elationship of the mound of powder (wher_e ~e powder ;:all
`within the cone) to the horizontal plane on which 1t ~ests ~he fric·
`1_986, 66-99). Thus, this would represent the