Figure 6.1Basic operations common to all filling machines. (Courtesy of IMA ACTIVE division, Bologna, Italy.)
Separation
The diameter of the upper bushing or housing is larger than the diameter of the capsule body bushing; therefore, the capsule cap is retained within the upper bushing while the body is pulled into the lower bushing by vacuum. Once the capsule is opened/separated, the upper and lower housing or bushing is separated to position the capsule body for filling.
Filling
The open capsule body is then dosed with the medicament. The various types of filling mechanisms are described in detail in “Capsule Filling Machine Dosing Systems” section.
Joining and Ejection
The cap and body housings or bushings are then realigned for capsule closing. An upper plate or pin will hold the cap stationary in the housing while lower closing shaft rods will push the bodies upward into the caps until the capsules are completely joined, engaging the locking mechanism of the capsule shell. The lower closing rod or shaft will ascend, ejecting the capsule from the housing or bushing into an exit chute. Compressed air nozzles are frequently used to assist the ejection of capsules from the machine, particularly with fully automatic filling machines.
Capsule Filling Machine Dosing Systems
Capsule filling machines employ a variety of mechanisms to handle the various dosage ingredients. In every case, the dosing systems are based on volumetric fills governed by the capsule size and capacity of the capsule body. The empty capsule manufacturers provide reference tables (e.g., Table 6.13) that indicate the volume capacity of their capsule body and the maximum fill weight for each capsule size based on the density of the fill material.
Capsule Size | Body Volume (mL) | Powder Density | |||
|---|---|---|---|---|---|
Capsule Capacity (mg) | |||||
0.6 g/mL | 0.8 g/mL | 1.0 g/mL | 1.2 g/mL | ||
000 | 1.37 | 822 | 1096 | 1370 | 1644 |
00el | 1.02 | 612 | 816 | 1020 | 1224 |
00 | 0.91 | 546 | 728 | 910 | 1092 |
0 | 0.78 | 468 | 624 | 780 | 936 |
1el | 0.54 | 324 | 432 | 540 | 648 |
1 | 0.50 | 300 | 400 | 500 | 600 |
2el | 0.41 | 246 | 328 | 410 | 492 |
2 | 0.37 | 222 | 296 | 370 | 444 |
3 | 0.30 | 180 | 240 | 300 | 360 |
4 | 0.21 | 126 | 168 | 210 | 252 |
5 | 0.13 | 78 | 104 | 130 | 156 |
Source: Capsugel. Coni-Snap Hard Gelatin Capsules. 2011. Brochure: Data obtained from p. 16.
Powders
When calculating maximum fill weights for powder fills, the tapped density values for the specified powder should be used. The following dosing methods are employed.
Auger Fill Method
The auger fill method (Figure 6.24) is employed by most of the semiautomatic capsule filling machines. A rotating auger blade at the discharge of the drug hopper forces the powder through a feed shoe into the open capsule bodies housed in a rotating ring beneath the drug hopper. The filling of the capsule is primarily volumetric.5 The factors controlling the dosing volume are the rotation speed of the body ring, the rotation speed and design or pitch of the auger, and the level of powder within the drug hopper reservoir.
Figure 6.2Auger fill method. (From Warner Lambert Co. Capsugel Division. Operation and Maintenance of the Type 8 Capsule Filling Machine. Capsugel Publication. Morris Plains, NJ; 1989.)
Mechanical Vibration Filling Method
The mechanical vibration method (Figure 6.36) is employed specifically by Qualicaps filling machines. A level sensor located in the powder supply chute maintains a stable powder layer that fills directly into the capsule body facilitated by a vibration plate. The accuracy of the filled powder is improved by the use of an adjustable spring plunger that removes air from the powder, creating uniform density. A scraper removes any excess fill material before capsule joining.
Figure 6.3(See color insert.) Mechanical vibration filling method. (From Qualicaps. LIQFIL super 40. Brochure. Whitsett, NC; 2011.)
Dosator Method
The dosator principle (Figure 6.4) is employed by numerous fully automatic capsule filling machines. The dosator consists of a hollow metal tube with a spring-loaded adjustable piston that is volumetrically adjusted to capture the powder dose. The dosator descends into a rotating dosing bowl of powder that is being maintained at a constant level. Once the dosator reaches the bottom of the powder bed, the powder dose is pre-compressed and then the piston moves downward, compressing the powder to form a plug. The dosator moves out of the powder bed and then aligns over the open capsule body. The piston descends to the bottom of the dosing tube, discharging the dosage plug into the capsule body.7 In the case of the IMA ACTIVE dosator system, the rotary dosing bowl can be configured with a patented vacuum system for pre-compacting fine powders to create a uniform powder bed density.8
Figure 6.4(See color insert.) Dosator method. (Courtesy of IMA ACTIVE division, Bologna, Italy.)
Tamping Pin/Dosing Disc Method
The tamping pin/dosing disc principle (Figure 6.59) was originally developed by Höfliger and Karg and is now utilized on numerous fully automatic, intermittent motion capsule filling machines. The method consists of a rotating steel dosing disc mounted at the base of a dosing bowl. The dosing disc has six sets of precisely bored holes. The powder is metered into the dosing bowl via an auger from a powder supply hopper to maintain a consistent powder level above the dosing disc. As the rotating dosing disc indexes the holes beneath five sets of spring-loaded tamping pins, the powder is compressed in the bores, forming a powder plug. A stationary tamping ring seated below the dosing disc retains the powder in the holes during the compaction of the powder plug. After five tamps, a deflector isolates the powder from the disc as the holes index directly over the open capsule bodies. A set of transfer pins push the powder plug out of the holes into the capsule bodies.10 Weight control on a tamping pin machine is controlled by three basic steps: (1) selecting the proper thickness of the dosing disc for the density and fill weight of the powder being run, (2) proper tamping penetration station settings, and (3) the height of the powder within the dosing bowl.
Figure 6.5Tamping pin/dosing disc method. (From Harro Hofliger Packaging Systems. Modular filling and closing machine for capsules. Modu-C Mid-Speed (MS). 2010. Brochure.)
Drum Filler Method
The dose of powder is metered by dosing bores in a vacuum drum, which is rotating at the base of a powder bed (Figure 6.69). A scraper blade removes any excess powder on the drum surface as it exits the powder bed. The powder dose is retained in the dosing bores by vacuum until it is discharged into the capsule body. This method is employed by the Harro Höfliger capsule filling machines for dosing powders in the micro-dose filling range with a fill amount of 1 mg and upward.
Figure 6.6(See color insert.) Drum filler method. (From Harro Hofliger Packaging Systems. Modular filling and closing machine for capsules. Modu-C Mid-Speed (MS). 2010. Brochure.)
Compression Filling Method
The compression filling method (Figure 6.711) is employed by certain models of Qualicaps filling machines. It is a modified version of the Tamping Pin/Dosing Disc method that employs four subhoppers, tapping rods, and a powder molding plate. In the first subhopper, a powder stirring agitator feeds the powder into the bores of the molding plate. In the second and third subhoppers, tapping rods compress the filling powder into the molding plate, forming a powder slug. In the fourth subhopper, a weight adjustment pusher raises the molded slug to a set height above the plate, and the excess powder is scraped away. At the fifth section, a transfer rod places the finished slug into the capsule body.12
Figure 6.7Compression filling method. (From Qualicaps. LIQFIL super 40. Brochure. Whitsett, NC; 2010.)
Beads and Granules/Pellets
When calculating maximum fill weights for beads and granules fills, bulk density values should be used.
Direct Fill
The direct fill method is employed by most of the semiautomatic capsule filling machines. The beads/granules flow from a drug hopper (with the auger blade removed) through a feed shoe into the open capsule bodies housed in a rotating ring beneath the feed shoe. The factors controlling the dosing are the aperture of the feed shoe and the rotation speed of the body ring.
Vacuum Dosator Method
The vacuum dosator method (Figure 6.813) is employed by Imatic and Zanasi capsule filling machines, which are manufactured by the IMA ACTIVE division. The dosator descends partway into the pellet layer in the dosing bowl, picking up the pellets with an aspiration vacuum. Excess pellets on the dosator tip are removed by either a brush or an air-jet. The pellet product is then dosed into the capsule body by reducing the vacuum and lowering the dosator piston.13 This system is also used in the dosing of microtablets.
Figure 6.8(See color insert.) Vacuum dosator method. (From IMA ACTIVE. IMATIC High Speed Capsule Filling Machine. 2011. Brochure.)
Dosing Chamber
The dosing chamber principle (Figure 6.9) is employed by numerous fully automatic capsule filling machines. It consists of various configurations of vertical or horizontal adjustable chambers that pre-measure the dose volume of beads/pellets or granules and discharge them into the capsule body.
Figure 6.9Dosage chamber. (Courtesy of Robert Bosch GmbH Packaging Technology, Waiblingen, Germany.)
Dosing Disc Method
Dosing pellets using the dosing disc method was developed by Bosch Packaging Technology and is similar to the powder dosing disc method, except the tamping pins are removed, and a slide gate (Figure 6.10) is installed below the dosing disc. Pellets flow into the dosing disc holes, the slide gate opens between indexes, and the pellets drop into the open capsule bodies with the assistance of the transfer pins that purge the pellets from the disc bores.14
Figure 6.10Slide gate. (Courtesy of Robert Bosch GmbH Packaging Technology, Waiblingen, Germany.)
Tablet and Capsule Overencapsulation
Overencapsulation is the most widely used method of blinding clinical supplies, performed by placing the product or products (i.e., tablets, caplets, or capsules) into an opaque capsule. This prevents the clinical investigators and subjects from differentiating between the active, placebo, or comparator drug within double-blind studies.15 Overencapsulation is also used in the manufacture of combination products.
Capsules
When overencapsulating a filled capsule, the receiving capsule shell should be two capsule sizes larger.
Tablets
There are different types of capsule filling machine dosing units used to handle single tablets, multiple tablets, or microtablets. The basic design of the tablet dosing units (Figure 6.1116) consists of a feed tube or flexible spring attached to the base of the tablet feed hopper. The tablets drop into a bushing, which transfers the tablet into the capsule body. An electromechanical device, or sensor, verifies proper dosing of the tablet within the capsule body. To assure proper handling by the dosing mechanisms, tablets should ideally be spherical or have beveled edges and coated to avoid dusting. Also, the overall tablet dimensions and hardness specifications should be kept within strict tolerances.17
Figure 6.11Tablet dosing unit. (From IMA ACTIVE division. Zanasi Low-medium speed capsule filling machines. 2011. Brochure.)
Liquids/Semisolids
There has been a re-emergence of liquid-filled capsules for several reasons: They can be used for active ingredients with low melting points; they are effective for compounds that are unstable when exposed to moisture or oxygen18; they enhance the content uniformity of low dose drugs; they address safety concerns when handling highly potent APIs such as cytotoxins; they allow formulations with fewer excipients; they reduce manufacturing and plant infrastructure costs19; they overcome poor aqueous solubility; and they improve oral bioavailability.20 To note, about 60% of compounds in development exhibit poor solubility.21
When calculating maximum fill volume for liquid/semisolid fills, use a target of 85–90% of the capsule body volume.
Liquid dosing systems (Figure 6.12) employ piston pumps or a series of pumping syringes. Precise volumetric dosing is accomplished by drawing liquid from the product container and pushing it into the capsule bodies utilizing a series of slide valves. Liquid containers may be fitted with a mixer and a heating and temperature control system for thixotropic or thermosetting products.22
Figure 6.12Liquid dosing system. (From IMA ACTIVE Division. ZANASI LAB. 2011. Brochure.)
Multicomponent Dosing
Many capsule filling machines can be equipped with more than one type of dosing unit to provide for filling different dosage combinations into a capsule as illustrated in Figure 6.13.23
Figure 6.13Multicomponent dosing. (From Warner-Lambert Company, Capsugel Division. All About the Hard Gelatin Capsule. Capsugel Publication. Morris Plains, NJ; 1991. Report No. CAP 126E.)
Capsule Filling Machinery
The commercially available capsule filling machines are summarized in Table 6.2. Capsule filling machines can be categorized by their level of automation or their special filling capabilities described in this section.
Manufacturer | Machine Type/Motion | Model | Maximum Hourly Output (capsules per hour) | Method of Dosing | Other Dosing Capabilities | Other | |
|---|---|---|---|---|---|---|---|
Powder | Granules | ||||||
ACG-pam ACG Worldwide Mumbai, India | Intermittent | AFT Lab | 6,000 | Tamping pin | Dosing chamber | Tablets, microtablets, capsule/softgel in capsule | |
Intermittent | AF 25T | 25,000 | Tamping pin | Dosing chamber | Tablets, microtablets, capsule/softgel in capsule | ||
Intermittent | AF 40T | 40,000 | Tamping pin | Dosing chamber | Tablets, microtablets, capsule/softgel in capsule | ||
Intermittent | AF 40D | 40,000 | Dosator | Dosing chamber | Tablets, microtablets, capsule/softgel in capsule | ||
Intermittent | AF 90T | 90,000 | Tamping pin | Dosing chamber | Tablets, microtablets, capsule/softgel in capsule | ||
Intermittent | AF 150T | 150,000 | Tamping pin | Dosing chamber | Tablets, microtablets, capsule/softgel in capsule | ||
Intermittent | AF 200T | 200,000 | Tamping pin | Dosing chamber | Tablets, microtablets, capsule/softgel in capsule | ZRM technology | |
Bosch Packaging Technology Waiblingen, Germany | Automatic/ Intermittent | GKF 700 | 42,000 | Tamping pin | – | – | Designed for nutraceuticals |
Automatic/ Intermittent | GKF 702 | 42,000 | Tamping pin, dosator | Dosing chamber/dosing disk/dosator | R&D mini-bowl, tablets, liquids, micro-dosing, combinations | Mini-bowl, lab kit | |
Automatic/ Intermittent | GKF 1400 | 84,000 72,000—liquids | Tamping pin | Dosing chamber/dosing disk | Tablets, liquids, combinations | GKF 1400L liquid | |
Automatic/ Intermittent | GKF HiProTect 1700 | 100,000 72,000—tablets | Tamping pin | Dosing disk or dosing chamber | Tablets, liquids, combinations | Containment for processing potent substances | |
Automatic/ Intermittent | GKF Capsylon 705 1505 3005 | 42,000 92,000 175,000 | Tamping pin | Dosing disk | Powder or pellets | Designed for nutraceuticals | |
Automatic/ Intermittent | GKF 2000 | 150,000 | Tamping pin | Dosing chamber | Powders/pellets | ||
Automatic/ Intermittent | GKF 2500 | 150,000 | Tamping pin | Dosing chamber/dosing disk | Tablets, combinations, liquids, micro-dosing | ||
Automatic/ Intermittent | GKF 2500ASB | 150,000 | Tamping pin | Dosing chamber/dosing disk | Tablets, combinations, liquids, micro-dosing | Automatic troubleshooting | |
Automatic/ Intermittent | GKF 2500 ABS IPK | 150,000 | Tamping pin | Dosing chamber/dosing disk | Tablets, combinations, liquids, micro-dosing | In-process statistical weight control | |
Automatic/ Intermittent | GKF 2500 ASB 100% | 150,000 | Tamping pin | Dosing chamber/dosing disk | Tablets, combinations, liquids, micro-dosing | Integrated checkweigher | |
Automatic/ Intermittent | GKF 3000 | 175,000 | Tamping pin | Dosing disk | – | – | |
Capsugel Greenwood, South Carolina USA | Semiautomatic | Cap8 | Up to 29,000 Dependent on capsule size | Auger | Direct fill Feed shoe | Tablets, capsules (using TFR 8) | |
Semiautomatic | Ultra 8 II | Up to 33,000 Dependent on capsule size | Auger | Direct fill Feed shoe | Tablets, capsules (using TFR 8) | ||
Semiautomatic | Xcelodose 120 | 200 | “Pepper-pot” | n/a | Other small dose containers | Precise dosing of drug substance weights from 100 μg to 100+ mg | |
Automatic | Xcelodose 600 | 600+ | “Pepper-pot” | n/a | Capsules only | Precise dosing of drug substance weights from 100 μg to 100+ mg | |
Automatic | CFS1200 | 1,200 | n/a | n/a | Liquids | Benchtop unit Filler and sealer | |
Automatic | CFS 1500C | 1,500 | n/a | n/a | Liquids | Floor standing machine designed for containment Filler and sealer | |
Manual | ProFiller 100 | 2,000–3,000 | Manual | Manual | |||
Manual | ProFill DB Overencapsulation | 1,000–1,500 | Manual | Manual | Overencapsulation of tablets, caplets, capsules | Designed specifically for filling DB caps capsules for double-blind studies | |
Semiautomatic | Xcelolab | 200 | “Pepper-pot” | n/a | Small dose containers | ||
Manual | ProFiller 3000 | 4,500–9,000 | Manual | Manual | |||
Harro Höfliger Packaging Systems Doylestown, Pennsylvania, USA | Automatic/Intermittent | Modu-C LS (low speed) | 24,000 | Dosator Tamping pin Drum filler | Dosing chamber | Microtablets, tablets, capsules, liquids, combinations | Laboratory operations and production Quick-changeable (trolleys) for powder, pellets, and tablets |
Automatic/Intermittent | Modu-C MS (mid speed) | 100,000 | Dosator Tamping pin Drum filler | Dosing chamber | Microtablets, tablets, capsules, liquids, combinations | Quick-changeable (trolleys) for powder, pellets and tablets Optional weight checking system for determination of the total and net weight | |
Automatic Intermittent | Modu-C HS (high speed) | 200,000 | Dosator Tamping pin Drum filler | Dosing chamber | Microtablets, tablets, capsules, liquids, combinations | Quick-changeable (trolleys) for powder, pellets and tablets Optional weight checking system for determination of the total and net weight | |
Semiautomatic Intermittent | OmniDose | 100–300 | Dosator Drum filler | Lab use Mounted on interchangeable trolleys | |||
IMA Active Bologna, Italy | Intermittent | Zanasi Lab 8 Zanasi Lab 16 | 8,000 16,000 | Dosators or tamping pin | Dosators (vacuum) | Liquids, microtablets, combinations | R&D production |
Intermittent | Zanasi 6 E Zanasi 12 E | 6,000 12,000 | Dosators | Dosators (vacuum) | Liquids, tablets, combinations | Statistic weight checking unit for production monitoring | |
Intermittent | Zanasi 25E/F Zanasi 40/EF | 25,000 40,000 | Dosators | Dosators (vacuum) | Liquids, tablets, combinations | E-versions are equipped with a statistic weight checking unit for production monitoring | |
Intermittent | Zanasi Plus 48 Zanasi Plus 70 Zanasi Plus 85 | 48,000 70,000 85,000 | Dosators | Dosators (vacuum) | Liquids, tablets, microtablets, combinations | Statistical weight check and adjustment 100% in-line net weight control for powders (compaction force measurement) | |
Intermittent | Zanasi 70C | 55,000 | – | – | Gelatin-coated tablet | Exclusively used for production of Press-Fit and XPress-Fit Gelcaps | |
Continuous | IMATIC 100 IMATIC 150 IMATIC 200 | 100,000 150,000 200,000 | Dosators | Dosators (vacuum) | The machine can be fitted with a wide range of devices, allowing operator unattended production | ||
Intermittent | ADAPTA 100 ADAPTA 200 | 100,000 200,000 | Dosators | Dosators (vacuum) | Liquids, tablets, microtablets, capsules, combinations (up to 3–5 products) | Interchangeable dosing units make for flexible configuration Total in-process control: 100% control of gross and/or net weight | |
MG2 Bologna, Italy | Continuous motion—intermittent (depending on the type of dosing unit installed) | “Labby” | 3,000 | Dosators (standard and low dosage) or dosing disk | Dosing chamber | Liquids, tablets, microtablets, capsules, caplets, micro-dosing | R&D capsule filler (single dosing station) |
Continuous motion—intermittent (depending on the type of dosing unit installed) | “FlexaLab” | 3,000 | Dosators (standard and low dosage) or dosing disk | Dosing chamber | Liquids, tablets, microtablets, capsules, caplets, micro-dosing, combinations | R&D capsule filler Up to two dosing units can be fitted on machine Potent compound Containment option | |
Continuous motion | Planeta | 6,000–50,000 | Dosators (standard and low dosage) | Dosing chamber (up to 4 types) | Liquids, tablets, microtablets, capsules, caplets, micro-dosing, combinations | Up to two dosing units can be fitted on machine Can be fitted with “MG2 Nett Weight” control systems Lights-out version available | |
Continuous motion | Planeta 100 | 100,000 | Dosators (standard and low dosage) | Dosing chamber (up to 4 types) | Liquids, tablets, microtablets, capsules, caplets, micro-dosing, combinations | Up to two dosing units can be fitted on machine Can be fitted with “MG2 Nett Weight” control systems Lights-out version available | |
MG2 Bologna, Italy | Continuous motion | Planeta 100 Pre-weight | 100,000 | Dosators (low dosage) | Dosing chamber (up to 4 types) | Liquids, tablets, microtablets, capsules, caplets, micro-dosing, combinations | Can be fitted with “MG2 Multi-Nett Weight” control systems |
Intermittent motion | Alterna70 | 70,000 | Tamping pin | Dosing chamber | Tablets | Up to three dosing stations | |
Intermittent motion | Alternova | 105,000–180,000 | Tamping pin | Dosing chamber | Tablets | Up to three dosing stations | |
Continuous motion | G-70 G-140 | 70,000 140,000 | Dosators (standard and low dosage) | Dosing chamber | Tablets, microtablets, combinations | Can be fitted with MG2 “Nett Weight” control systems Lights-out version available | |
Continuous motion | G-250 | 200,000 | Dosators (standard and low dosage) | Dosing chamber (up to 2 types) | Tablets (2 types), microtablets, combinations | Can be fitted with MG2 “Nett Weight” control systems Lights-out version available | |
Continuous motion | MultiFlexa | 250,000 | Dosators (standard and low dosage) | Dosing chamber (up to 2 types) | Containment for processing potent substances WIP/CIP Can be fitted with MG2 “Multi-Nett Weight” control systems Lights-out version available | ||
Qualicaps Whitsett, North Carolina, USA | Automatic/ Intermittent | FS3 | 3,000 | – | – | Liquids | Liquid filler and sealer |
Automatic/ Intermittent | LIQFIL Super LABO | 1,000–2,600 | Dosing disk | Dosing chamber | Liquids, tablets | Lab unit for drug formulation | |
Automatic/ Intermittent | F-5 | 5,000 | Compression/tamping | Dosing chamber | Liquids, tablets, microtablets, capsules, combinations | ||
Automatic/ Intermittent | F-40 | 40,000 | Compression/tamping Dosing disk Vibration | Dosing chamber | Liquids, tablets, microtablets, capsules, combinations | ||
Automatic/ Intermittent | JCF-40 | 40,000 | Auger | Auger | – | ||
Automatic/ Intermittent | F-80 | 80,000 | Compression/tamping Dosing disk | Dosing chamber | Liquids, tablets, microtablets, capsules, combinations | ||
Automatic/ Intermittent | F-100 | 100,000 | Vibration | Vibration | |||
Automatic/ Intermittent | F-120 | 120,000 | Compression/tamping Dosing disk | Dosing chamber | Liquids, tablets, microtablets, capsules, combinations | ||
Automatic/ Intermittent | F-150 | 150,000 | Compression/tamping | Dosing chamber | Liquids, tablets, microtablets, capsules, combinations | ||
Romaco S.r.l. Bologna, Italy | Automatic/ Intermittent | Macofar CD25 | 25,000 | Vacuum dosators | Dosing chamber | Tablets | Double station of capsule opening Optional statistical weight control (SWC) |
Automatic/ Intermittent | Macofar CD40 | 40,000 | Vacuum dosators | Dosing chamber | Tablets | ||
Automatic/ Intermittent | Macofar CD60 | 60,000 | Vacuum dosators | Dosing chamber | Tablets | Double station of capsule opening Automatic adjustment of powder/pellet dosing with feedback from SWCl | |
Schaefer Technologies Indianapolis, Indiana, USA | Semiautomatic | Model 8 S | 15,000 | Auger | Direct fill Feed shoe | Tablets, capsules (using insertion ring) | |
Semiautomatic | STI Model 10 | 25,000 | Auger | Direct fill Feed shoe | Tablets, capsules (using insertion ring) | ||
Semiautomatic | STI LF10 | 10,000–25,000 Dependent on capsule size/formulation | n/a | n/a | Designed for liquid filling | 8 L heated hopper Will fill products with viscosities 100–1000 cps | |
Automatic | Dott.Bonapace IN-CAP | 3,000 | Tamping pin Dosator | Dosing chamber | Tablets, liquids | ||
Automatic | Dott.Bonapace IN-CAP HS | 7,000 | Tamping pin | Dosing chamber | |||
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