(cid:51)(cid:68)(cid:74)(cid:72)(cid:3)(cid:20)(cid:3)(cid:82)(cid:73)(cid:3)(cid:26)
`
`Capsugel Exhibit 1035
`
`

`

`Copyright CSC Publishing
`
`application roller. After the solution is applied, capillary
`action causes some of it to migrate into the interstitial
`space between the cap and body, thereby sealing—to a
`degree—those surfaces. Next, the capsules are transferred
`to a carrier that moves them through the machine's dry—
`ing section, causing the moist, exposed bands to set up
`before the sealed capsules discharge into a receiver.
`Each manufacturer has its own approach to banding.
`
`Qualicaps. The HiCapSeal 40 operates automatically.
`it applies seals to filled capsules that pass from the hop—
`per through a feed roller, rectifier roller, and the transfer
`roller. The capsules rest in pockets in a conveyor belt
`slat as they move through the process. See the photo on
`page 10.
`
`tant packaging features is required, unless the capsules are
`sealed by a tamper—resistant technology.
`"2. For all other products subject to this requirement,
`including two—piece, hard gelatin capsules that are sealed
`by a tamper—resistant technology, a minimum of one tam—
`per—resistant feature is required."
`And:
`
`“Technologies for sealing two—piece hard gelatin cap—
`sules are available that provide evidence if the capsules
`have been tampered with after filling. Such sealing tech—
`nologies currently in use include sonic welding, banding,
`and sealing techniques employing solvents and/or low
`temperature heating. These examples are not intended to
`rule out the development and use of other capsule sealing
`technologies. Manufacturers may consult with FDA if
`they are considering alternative capsule sealing processes.
`"Sealed capsules are not tamper—resistant packages.
`They are required to be contained within a package sys—
`tem that utilizes a minimum of one [tamper—resistant
`package]."
`The main methods of sealing capsules are banding, liq—
`uid spray, and sonic welding. Table 1 lists the suppliers of
`capsule sealing equipment, and each of the machines is
`described below. [Editor's note; All images and illustrations
`used in this article were provided by the manufacturers
`and are used with their permission]
`
`The slat's cavities are cut at a slight angle (3 degrees
`according to capsule size) from the axis of the slat. As the
`belt moves, the capsules rotate counterclockwise, which
`keeps the cap dome in contact with a cap guide and
`ensures that the capsules are accurately positioned over
`the sealing discs. Their position is controlled by the
`length of the caps, which compensates for any variation
`in the closed (joined) length of the capsule (Figure l).
`The first sealing disc applies a band of sealing solution to
`the circumference of the capsule's cap—body seam, and
`the second sealing disc applies another band to ensure a
`good seal (Figure 2). The sealing solution is maintained at
`a constant temperature and circulates continuously
`between the supply and sealing pans to maintain its uni—
`Capsule banding machines orient filled capsules and
`formity (photo page 12). Next, the machine transfers the
`place them in a carrier slat that exposes the area where
`sealed capsules from the conveyor's slats to carriers that
`the cap and body meet. A roller then applies a solution to
`move them into a drying unit. There, filtered, ambient air
`the cap—body seam. Some machines employ a second
`dries the capsule seals.
`
`
`Banding
`
`TABLE 1
`
`Capsule sealing equipment suppliers
`
`Manufacturer
`or supplier
`
`Ilodel
`
`Sealing method
`
`Ilaximum output
`{upsuleslhr}
`
`Capsule sizes
`
`Other features
`
`Minnie
`
`8-1
`
`l'iCqJSed «mo
`
`Sdmfer
`Technologies
`
`“Active
`
`Caramel
`
`F53 LabStaie
`
`LdJTqJ
`
`DotL Bompaoe
`BD-SDCI}
`
`ST| 0345
`
`Henrietta!
`
`F8 1200
`
`CFS 151]} C
`
`Bald
`
`Bald
`
`Bald
`
`Bald
`
`Band
`
`Bald
`
`timid
`
`Liqu'd
`
`100lo1.0tl1
`
`50.000 {100.000
`win I-iCqJSed
`drying uni)
`3.0“}
`
`100lo1.0tl1
`
`3.0%
`
`001n4
`
`00 in 4
`
`00 In 4
`
`001n4
`
`00 In 4
`
`Bendrtpurl‘ttnamal)
`
`Cmnnerdal-sede LIIit
`
`RED tier-sealer
`
`Bendi-tqaurittmamal)
`
`R00 Marta use with
`In-Cq: (repair. tier
`m1 iquid litg station
`
`15.1110
`
`(I10 to 4
`
`Cunnerdd—suie urit
`
`{50.0th
`In 100.000}
`
`1.243}
`
`1.50:}
`
`0ela‘fl00tu4
`(opim firm}
`and 00030
`
`00el to 4
`
`am In 4
`
`Cmnnerdal—scrdeurit
`
`RED filer-sealer
`
`RD filer-sealer
`win continent
`
`
`
`70.1110 Cunnerdfl-strde urit (I10 In 4
`LEMS 70
`Liqu'd
`
`
`
`(cid:51)(cid:68)(cid:74)(cid:72)(cid:3)(cid:21)(cid:3)(cid:82)(cid:73)(cid:3)(cid:26)
`Page 2 of 7
`
`

`

`Copyright CSC Publishing
`
`The mach ine's production capacity is 40,000 to 50,000
`capsules per hour, but using the company’s HiCapSeal
`100 drying unit (Figure 3) can double the output [6].
`
`
`FIGURE '1
`
`Capsule positioning on HiCapSeal unil
`
`
`Sealing roller
`
`Directionof
`
`
`
`
`FIGURE 2
`
`Banding capsules with HiCapSeal unit
`
`
`GEEK We _.
`
`Qualicaps also offers a lab—scale unit, the F53 LabScale
`(Figure 4) that automatically fills and seals as many as
`3,000 capsules per hour. The machines single disc (for
`the capsule caps) and its segments (for the capsule bod~
`ies) handle capsule sizes of 00 to 4 without using change
`parts. in operationr the body segments lift the capsules to
`the filling nozzles, which prevents low—viscosity liquids
`From splashing and high—viscosity fills from creating
`strings. The sealing section uses the same technology as
`the company’s high—speed equipment. Upon discharge,
`filled and joined capsules are immediately fed into cavi—
`ties in a sealing disc, which band—seals them. The cap—
`sules are then transferred into the drying disc—stacking
`unit (Figure 5). The capsules rotate 10 times within the
`drying disc before dropping to a drying disc. [t cradles
`the capsule while room—temperature, filtered air is blown
`
`
`FIGURE 3
`
`HiCapSeal 40 hand sealing sysmm and HiCapSeal 100
`drying unil
`
`
`HiCapSeaMO
`
`Hi CqJSed 100 dry'ng mil
`
`
`
`
`
`
`
`
`3 Cartel panel
`2 Rectifier roller
`1 Capsule hopper
`6 Drying unil
`5 Double seeing uril
`4 Conveyor hellslels
`'i' Air blows
`a Air flier
`9 Produel discharge chute
`
`
`
`
`
`
`
`@veggbe]!travel
`
`
`
`
`
`
`
`
`Second sealing unit
`First sealing unit
`
`
`
`l-l'rCapSeal sealing slalion
`(cid:51)(cid:68)(cid:74)(cid:72)(cid:3)(cid:22)(cid:3)(cid:82)(cid:73)(cid:3)(cid:26)
`Page 3 of 7
`
`F I G U R E 4
`
`F53 LabScale liquid filling and band sealing machine
`
`
`
`
`
`
`
`
`

`

`Copyright CSC Publishing
`
`across the sealed areas of the capsules to ensure they dry
`before the capsules exit the unit [7]
`
`is a lab~sized capsule
`Schaeter Technologies. The 5—]
`band sealer (also available From Qualicaps). See Figure 6.
`in operationf filled capsules are manually loaded into car—
`rier slats, and those are placed on feed tracks that guide
`them through a band sealing process identical to what
`the company’s commercial—scale machines use. Slats con—
`taining the band—sealed capsules are then transferred to
`the drying rack, where they dry under ambient condi—
`
`
`FIGURE 5
`
`LabScale drying section
`
`
`
`
`
`FIGURE 6
`
`S-1 bench-top capsule band sealer, available from
`Schaefer Technologies (shown) and Qualicaps
`
`
`Slal feed lracks
`
`
`
`
`Gelatin pan
`
`tions [8]. The unit seals 100 to 1,000 capsules per hour,
`depending on the capsule size and change parts [9]
`The CB—IS capsule banding machine automatically
`band—seals as many as 15,000 capsules per hour (photo).
`The hopper introduces the capsules into the rectification
`systemr which orients the capsules in conveyor belt slats
`(similar to the Qualicaps configuration). Banding takes
`place as the capsules pass over two rollers that are par—
`tially immersed in temperature—controlled pans of gelatin
`solution,- the solution contacts only the cap—body joint.
`Once banded, the capsules pass over drying fans as they
`move toward the pull—off station, and they’re discharged
`by vacuum.
`
`
`
`(BB-15 capsule banding machine
`
`The 1313—3000 is an automatic banding machine built in
`Italy by Dott. Bonapace and sold in North America by
`Schaefer Technologies (photo). its top output is 3,000
`sealed capsules per hour. In operation, the liquid—filled cap—
`sules are rectified and positioned into the cavities of a rotat—
`ing disc,- the disc, in turn, transports them to the sealing sta—
`tionI where they're held and rotated three times to ensure
`constant and uniform application of the sealing solution to
`the circumference of the body—cap junction. Once sealedI
`the capsules are transferred in the vertical position, cap
`down, to a second disc, where they dry for 4 minutes. Fans
`that circulate ambient—temperature air facilitate drying. The
`capsules are ejected through a chute. A programmable—logic
`controller handles all operations [10].
`
`
`
`
`
`
`
`
`Capsule slat
`
`I. Sealing discs
`
`
`
`Doll. Bonapaoe BD-BGDD capsule banding machine
`
`(cid:51)(cid:68)(cid:74)(cid:72)(cid:3)(cid:23)(cid:3)(cid:82)(cid:73)(cid:3)(cid:26)
`Page 4 of 7
`
`

`

`Copyright 080 Publishing
`
`piece capsules into one—piece fused capsules (Figure 8). in
`the first stage of the process, a very small amount of seal—
`ing fluid (a water—alcohol solution) is sprayed into the
`filled capsule’s cap—body joint. Capillary action draws the
`fluid into the interstitial space between the cap and the
`body, and a suction device removes excess solution from
`the capsule surface. in the second stage, air heated to
`between 40° and 60°C gently blows across the capsule,
`completely melting and fusing the two gelatin layers and
`providing an impervious seal. in the third and final stage,
`the capsule is allowed to reach room temperature, which
`sets the gelatin [13.].
`Fusion ensures a tamper—evident seal, and its seal
`integrity has been verified by x—ray tomography [13].
`
`
`
`FIGURE 7
`
`Hermetica sealing and drying transport plates
`
`
`iMA. The Hermetica capsule banding machine applies
`a double gelatin band using two rollers, each with inde—
`pendent speed control (photo). By applying the second
`band, the unit eliminates any air bubbles or unevenness in
`the first band. The rollers are housed in separate gelatin
`bowls and you can adjust the gelatin temperature and vis—
`cosity of each bowl independently. A pre—clrying unit
`(photo) guarantees that the gelatin band affixes to the
`capsule quickly, before the capsule moves to the drying
`box (photo) for final drying. Both the sealing and drying
`transport plates contain a double row of capsules (Figure
`7), which reduces the number of pieces to be changed
`and cleaned. A camera—based system can be fitted to the
`unit, allowing you to check 100 percent of the capsules
`and to control and select individual banded capsules [1 I].
`
`Liquid spray
`
`Only one company offers machinery that seals cap—
`sules using a non—gelatin liquid.
`
`Capsugel. The company's technique is called Licaps
`Fusion Technology. it uses a micro—spray to convert two—
`
`
`
`
`Hen'nelica 100 capsule banding machine
`
`Hennelica pre-drying unit
`(cid:51)(cid:68)(cid:74)(cid:72)(cid:3)(cid:24)(cid:3)(cid:82)(cid:73)(cid:3)(cid:26)
`Page 5 of 7
`
`Sealing plate
`
`
`
`
`
`
`
`1.:v_‘.._.‘.-‘-‘a..."v._
`
`{1.1
`
`Hermetica drying box
`
`

`

`Copyright CSC Publishing
`FIGURE 3
`filling pump with dosing accuracy of 0.1 to 1.2 milliliters.
`The CFS 1200 is scalable to commercial size LEMS man—
`
`Licaps three-stage fusing process
`
`
`ufacturing equipment [15, 16].
`
`Stage 1: Spraying
`
`Stage 2: Wanning
`
`Seeing fluid Is W Agenle heal
`sprayed onto gaunt
`applieahon
`between-I em and body.
`completes mailing
`I
`Capillary anion draws
`and fusion
`fiLI'd up between the MM
`Genie heal malls
`omnndthehody.
`lheimlayersmhim
`Suction lemmas
`[use logalher to iann
`newness luid.
`an ingenious seal.
`
`“a
`
`
`
`
`
`Capsules equlibmle 31 room temperature.
`Stage 3: Setting
`
`
`Should someone attempt to open a fusion—sealed Licaps
`capsule, tampering becomes readily apparent and the
`capsule loses its integrity.
`Capsugel also offers Licaps capsules that provide
`secure and robust containment of liquids and semi—solids
`(Figure 9). They differ from standard capsules in their use
`of several proprietary features, such as a larger contiguous
`sealing area that extends along the length of the capsule
`above its midpoint. Other capsules have a narrower
`body—cap junction for applying a capsule band.
`
`
`FIGURE 9
`
`Licaps capsules
`
`
`Well-defined sad zone embles
`100% fusion of cap and body.
`
`Dud-ringsystemprovidlsa
`doubleba'rierbelweenthecqisule
`eontenlsarlilhesedzone.
`
`
`
`
`
`
`/\
`
`Entry clannel for consistent
`implication of seziig fiLI'd
`
`Air vents allow at to escqie on
`clos'ng and maintain the banier ii
`the r'lig system.
`
`
`incorporated into the Licaps capsule are full—circumfer—
`ence rings that not only define the large sealing zone, but
`isolate and contain the liquid within the capsule. The cap—
`sule also includes both a liquid—entry channel that ensures
`consistent sealing conditions and vents that allow air to
`escape rapidly, which is critical for high—speed encapsula—
`tion [14].
`
`Three machines employ the company's spray sealing
`technique: the CFS 1200, CFS 1500 C, and LEMS 70.
`The CFS 1200 (photo) is a bench—top machine suit—
`able for RBID labs and CMP manufacture of clinical sup—
`plies. it combines liquid filling and scaling to produce as
`many as 1,200 capsules per hour. it can handle both liq—
`uids and semisolids using a robust temperature—continued
`(cid:51)(cid:68)(cid:74)(cid:72)(cid:3)(cid:25)(cid:3)(cid:82)(cid:73)(cid:3)(cid:26)
`Page 6 of 7
`
`
`
`CFS 1200
`
`The CFS 1500 C (photo) functions similarly to the
`CPS 1200 but includes containment features that allow
`
`safe liquid filling and capsule sealing when handling
`potent compounds in early—phase clinical trials. The CPS
`1500 C has a top output of
`1,500 capsules per hour
`[17]. it weighs every cap—
`sule to determine whether
`
`to reject or accept it and
`records the result. An intu—
`itive software interface
`
`saves the machine's settings
`and stores method develop—
`ment work for later recall.
`
`
`
`CFS15000
`
`Most important, the ma—
`chine cleans easily because
`of removable parts and a
`verification system that pre—
`vents cleaning fluid from
`entering the working elements of the machine [18].
`The LEMS 70 (photo) is a production—scale sealing sys—
`tem with a top output of 70,000 capsules per hour. Key
`components include high—capacity micro—spray bars and a
`contiguous tumble dryer
`fitted with a rotating air
`lock. it is built with FDA—
`
`ll
`
`in commercial installa— tions, the sealing machine
`
`approved materials, and its
`software complies with 21
`CFR Part 11 requirements.
`The sealing range covers
`viscosities of 30 to 30,000
`centipoise.
`
`LEMSYD
`
`connects to standard cap—
`sule fillers that use a liquid filling head. inspection stations
`would also typically be added [19].
`
`Ultrasonic welding
`
`Rainbow Medical Engineering. The term ultrasonic
`applies to sound waves whose frequencies exceed 20 kilo—
`hertz, and an ultrasonic welding system comprises four
`basic components:
`
`

`

`Copyright CSC Publishing
`
`1. A generator or power supply,-
`2. A transducer that converts electrical energy into
`vertical, low~amplitude mechanical motion (vibration) ,-
`3. A booster that modulates the transducers vibrations,-
`and
`
`4. A sonotrode or horn that applies the vibrations to
`the material being welded.
`Ultrasonic welding involves the application of a
`vibrating sonotrode to a thermoplastic—thermoplastic
`interface, thereby inducing a high degree of localized
`frictional heat that causes the thermoplastics to melt and
`form a molecular bond at the interface. Welding usually
`takes only 0.1 to 1 second, a key element to its success in
`high—speed capsule filling operations.
`Thermoplastic polymers have two properties that
`make them particularly suited to ultrasonic welding: low
`thermal conductivity and melting points between 100°
`and 200°C. Most pharmaceutical polymers—celluloses,
`starches, and biopolymers such as gelatin—have these
`thermoplastic properties. ln fact, these therrnoplastics are
`often molded or extruded into capsule—shaped compo—
`nents for use in a number of drug delivery applications.
`As illustrated in Figure 10, the capsule components are
`positioned in a fixture such that the sonotrode encircles the
`circumference of the cap—body interface. Upon contact with
`the active sonotrode, the capsule parts are mechanically
`vibrated at 20,011) to 40,000 cycles per second. That causes
`localized friction between the two capsule sections that
`leads to molecular melting and the capsule halves fuse [20].
`
`FIGURE 10
`
`Ultrasonic welding
`
`
`SC,- lMA Active, Leominster, MA,- and Rainbow Medical
`Engineering for providing the images and the information
`about their equipment.
`
`References
`
`1. Smith T. The hard capsule with the soft center: The re—emergence of
`liquid—filled hard capsules. Tablets 8L Capsules. January 2004, p. 15.
`2. Lighttoot DK. A rising tide: Liquid-tilled capsules. Tablets Sr
`Capsules._lanuary 2008, p. 72.
`3. Richardson M and Stegemann 5. Filling two-piece hard gelatin cap-
`sules with liquids. Tablets 8L Capsules. January 2007, p. 12.
`4. Kadri BV. Delivering poorly soluble APl‘s in liquid tilled hard cap—
`sules. Tablets 8L Capsules. March 2012, p. 16.
`5. FDA. CFC Sec. 450.500 Tamper—Resistant Packaging Requirements
`for Certain Over—the—Counter Human Drug Products. www.tda.gov/icecif
`compliancemanuaIs/compliancepolicyguidancemanualfucrn074391.htm
`6. Qualicaps. HlCAPSEAL Fully Automatic Hard Capsule Sealing
`Machine 40/] (I). Brochure. 2010.
`
`3’. Qialicaps. Qialicaps Lab—Scale Fillinngealing Machine. Brochure.
`3. Schaeter Technologies. laboratory Model Capsule Banding Machine.
`Operation and service manual, Ver. 10].
`9. Qualicaps. Qualicaps Bench—Top Capsule Band—Sealer: The 5—1.
`Brochure.
`
`10. Dott. Bonapace & C. BD—3000 Hard Celatine Capsule Sealing
`Machine. Brochure.
`
`11. IMA Active Division. Her'metica Capsule Banding Machine.
`Brochure. 201 l.
`
`12. Capsugel. Liquid Filling and sealing of hand capsules CPS 1500 C.
`Brochure. 2010.
`
`13. 5. Robin et al. X—Ray Tomography to Determine Seal Integrity of
`Filled Capsules Sealed on Capsugel LEMS 70 and and CPS 1200
`Equipment. BAS 409.
`14. Capsugel. Licaps. Creenwmd, SC.
`15. Capsugel. Pharmaceutical Online.com CPS 1200 Liquid Capsule
`Filling 8: Sealing Machine. Accessed November 9, 2012. www.pharmaceu—
`ticalonline.corn!'doc.mdeFS—1200—]..iquid—CapsuIe—Filling—and—Sealing—M—
`00132.
`
`16. Capsugel. CPS 1201) Capsule Liquid Filling and Sealing Machine.
`Brochure. 2006.
`
`17. Capsugel. Pharmaceutical Onlinecom New CFS 1500 C Capsule
`filling and Sealing System. Accessed November 9, 2012. www.pharmaceu—
`ticalonline.corn/doc.mdeew—CFS—1500—C—Capsule—Filing—And—Sealing—
`001]].
`
`18. Capsugel. CPS 1500 C Containment. Brochure. 2010.
`19. Capsugel. LEMS 3’0 Production of liquid tilled hard capsules.
`Brochure. 2003.
`
`20. Martini PLC et a]. Ultrasonic welding of solid oral dosage forms:
`capsule based systems. 2012. Report to Donald [ighttoot
`21. Rainbow Medical Engineering. 2m6. Accessed November 9, 2012.
`www.minbow—medicaleufpharrnaceutical.html.
`
`Donald K. Liglatfoot is an independent consultant, 2826 W
`
`Placira Paciente, Tucson, AZ 35742. 'lizl. 520 229 3506. E—
`
`mail.- donald.lightfoot®comcastnet He retiredfrom Glaxo-
`SmitbKline 7 years ago after 46 years of service. As a director
`
`of manufacturing and Rail), be gained extensive production
`experience in capsulefilling and otlaer processes, including gran-
`
`ulation, tablet compression, tablet coating, pellet coating, and
`
`suppository manufacturing. His expertise spans plaarrnaceutical
`manufacturing of both clinical and commercial supplies.
`
`ee-
`
`Sumlmde
`
`Eledmnir: weld area
`
`
`
`
`
`
`
`Once sealed using Rainbow Medical Engineering's ultra—
`sonic method, hard gelatin capsules will show clear evi~
`dence of tampering if the capsule body is separated from
`the cap: The capsule body will break along perforations
`and show tell~tale crescent—shaped edges [21].
`TaC
`
`Acknowledgements
`
`thank Qualicaps, Whitsett, NC,- Schaefer
`l
`Technologies, lndianapolis, 1N,- Capsugel, Greenwood,
`(cid:51)(cid:68)(cid:74)(cid:72)(cid:3)(cid:26)(cid:3)(cid:82)(cid:73)(cid:3)(cid:26)
`Page 7 of 7
`
`