U.S. patent application number 11/148919 was filed with the patent office on 2006-01-26 for apparatus and method for pharmaceutical production.
This patent application is currently assigned to SmithKline Beecham Corporation. Invention is credited to Allan J. Clarke, David George Doughty, David R. Rudd, David A. Tainsh.
Application Number | 20060016830 11/148919 |
Document ID | / |
Family ID | 35510312 |
Filed Date | 2006-01-26 |
United States Patent
Application |
20060016830 |
Kind Code |
A1 |
Clarke; Allan J. ; et
al. |
January 26, 2006 |
Apparatus and method for pharmaceutical production
Abstract
An apparatus and method for producing a pharmaceutical and
pharmaceutical-like product is provided. The apparatus and method
dispense a liquid dose onto a carrier substrate. The apparatus and
method provide for continuous movement of the carrier substrates
during the process. The apparatus and method reduce batch dosage
errors and provide real-time release of the product.
Inventors: |
Clarke; Allan J.;
(Collegeville, PA) ; Doughty; David George;
(Harlow, GB) ; Rudd; David R.; (Harlow, GB)
; Tainsh; David A.; (Harlow, GB) |
Correspondence
Address: |
Charles N.J. Ruggiero, Esq.;Ohlandt, Greeley, Ruggiero & Perle, L.L.P.
One Landmark Square, 10th Floor
Stamford
CT
06901-2682
US
|
Assignee: |
SmithKline Beecham
Corporation
|
Family ID: |
35510312 |
Appl. No.: |
11/148919 |
Filed: |
June 9, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60621992 |
Oct 25, 2004 |
|
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60578245 |
Jun 9, 2004 |
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Current U.S.
Class: |
222/95 |
Current CPC
Class: |
A61J 3/00 20130101; C23C
16/52 20130101; A61J 3/10 20130101; G01N 21/359 20130101; B41P
2200/00 20130101; B41P 2200/31 20130101; G01N 21/93 20130101; A61J
3/005 20130101; Y10T 436/12 20150115; G01N 21/9508 20130101; Y10T
436/11 20150115; G01N 2021/6417 20130101; Y10T 436/113332 20150115;
A61J 3/007 20130101; Y10T 436/2575 20150115; G01N 21/3563 20130101;
B05C 11/10 20130101; G01N 21/64 20130101 |
Class at
Publication: |
222/095 |
International
Class: |
B65D 35/28 20060101
B65D035/28 |
Claims
1. An apparatus for producing pharmaceutical product that each has
a carrier substrate and a dosage, the apparatus comprising: a
dispensing module that dispenses the dosage onto each of the
carrier substrates, wherein said dispensing module dispenses the
dosage under pressure.
2. The apparatus of claim 1, wherein said dispensing module has a
positive displacement pump.
3. The apparatus of claim 1, further comprising a holding member
that holds each of the carrier substrates, wherein said dispensing
module moves with respect to said holding member.
4. The apparatus of claim 3, further comprising a conveyor that
moves said holding member along the apparatus.
5. The apparatus of claim 4, wherein said holding member continues
to move along the apparatus as said dispensing module dispenses the
dosage onto each of the carrier substrates.
6. The apparatus of claim 4, wherein said dispensing module moves
along an X-like path.
7. The apparatus of claim 1, further comprising a drying system
that dries the dosage on each of the carrier substrates.
8. The apparatus of claim 7, further comprising a holding member
that holds each of the carrier substrates, wherein said holding
member continues to move along the apparatus as said drying system
dries the dosage on each of the carrier substrates.
9. The apparatus of claim 8, wherein said drying system has an oven
that provides heat and air flow to each of the carrier substrates
to dry the dosage.
10. The apparatus of claim 8, wherein said drying system dries the
dosage by use of infrared radiation.
11. The apparatus of claim 1, further comprising a coating system
that applies a coating over the dosage on each of the carrier
substrates.
12. The apparatus of claim 11, wherein said coating system has a
first pad-printing device that applies said coating to each of the
carrier substrates.
13. The apparatus of claim 11, wherein said coating system has a
spraying device that sprays said coating onto each of the carrier
substrates.
14. The apparatus of claim 12, further comprising a holding member
that holds each of the carrier substrates, wherein said holding
member continues to move along the apparatus as said coating system
applies said coating to each of the carrier substrates.
15. The apparatus of claim 12, further comprising a coating dryer
that dries said coating on each of the carrier substrates.
16. The apparatus of claim 15, further comprising a holding member
that holds each of the carrier substrates, wherein said holding
member continues to move along the apparatus as said coating dryer
dries said coating on each of the carrier substrates.
17. The apparatus of claim 1, further comprising a marking device
that applies an identification marker to each of the carrier
substrates, wherein said marking device is chosen from the group
consisting of a second pad-printing device, a laser marker, an
inkjet device or a rotogravure device.
18. The apparatus of claim 17, further comprising a holding member
that holds each of the carrier substrates, wherein said holding
member continues to move along the apparatus as said marking device
applies said identification marker to each of the carrier
substrates.
19. The apparatus of claim 17, further comprising an ink dryer that
dries said identification marker on each of the carrier
substrates.
20. The apparatus of claim 19, further comprising a holding member
that holds each of the carrier substrates, wherein said holding
member continues to move along the apparatus as said ink dryer
dries said identification marker on each of the carrier
substrates.
21. An apparatus for producing pharmaceutical product that each has
a carrier substrate and a dosage, the apparatus comprising: a
dispensing module; a holding member that holds each of the carrier
substrates; and a conveyor that moves said holding member along the
apparatus, wherein said dispensing module dispenses the dosage onto
each of the carrier substrates, and wherein said holding member
continues to move along the apparatus as said dispensing module
dispenses the dosage onto each of the carrier substrates.
22. The apparatus of claim 21, wherein said dispensing module moves
with respect to said holding member and said conveyor when
dispensing the dosage onto each of the carrier substrates.
23. The apparatus of claim 22, wherein said dispensing module moves
along an X-like path.
24. The apparatus of claim 21, wherein said dispensing module
dispenses the dosage under pressure.
25. The apparatus of claim 21, wherein said dispensing module has a
positive displacement pump.
26. The apparatus of claim 21, further comprising a drying system
that dries the dosage on each of the carrier substrates.
27. The apparatus of claim 26, wherein said holding member
continues to move along the apparatus as said drying system dries
the dosage on each of the carrier substrates.
28. The apparatus of claim 27, wherein said drying system comprises
an oven that provides heat and air flow to each of the carrier
substrates to dry the dosage.
29. The apparatus of claim 27, wherein said drying system dries the
dosage by use of infrared radiation.
30. The apparatus of claim 21, further comprising a coating system
that applies a coating over the dosage on each of the carrier
substrates.
31. The apparatus of claim 30, wherein said coating system has a
coating device that applies said coating to each of the carrier
substrates, and wherein said coating device is chosen from the
group consisting of a first pad-printing device or a spraying
device.
32. The apparatus of claim 30, wherein said holding member
continues to move along the apparatus as said coating system
applies said coating to each of the carrier substrates.
33. The apparatus of claim 30, further comprising a coating dryer
that dries said coating on each of the carrier substrates.
34. The apparatus of claim 33, wherein said holding member
continues to move along the apparatus as said coating dryer dries
said coating on each of the carrier substrates.
35. The apparatus of claim 21, further comprising a marking device
that applies an identification marker to each of the carrier
substrates, wherein said marking device is chosen from the group
consisting of a second pad-printing device, a laser marker, an
inkjet device or a rotogravure device.
36. The apparatus of claim 35, wherein said holding member
continues to move along the apparatus as said marking device
applies said identification marker to each of the carrier
substrates.
37. The apparatus of claim 35, further comprising an ink dryer that
dries said identification marker on each of the carrier
substrates.
38. The apparatus of claim 37, wherein said holding member
continues to move along the apparatus as said ink dryer dries said
identification marker on each of the carrier substrates.
39. An apparatus for producing a batch of pharmaceutical product
that each has a carrier substrate and a dosage of active agent, the
apparatus comprising: a dispensing module that dispenses the dosage
onto each of the carrier substrates, wherein a content uniformity
for the batch is less than 5% RSD where the dosage of active agent
is less than 5 mg, or wherein the content uniformity for the batch
is less than 2% RSD where the dosage of active agent is less than
10 mg.
40. The apparatus of claim 39, wherein said dispensing module
dispenses the dosage under pressure.
41. The apparatus of claim 39, wherein said dispensing module has a
positive displacement pump.
42. The apparatus of claim 39, further comprising a holding member
that holds each of the carrier substrates, wherein said dispensing
module moves with respect to said holding member.
43. The apparatus of claim 42, further comprising a conveyor that
moves said holding member along the apparatus.
44. The apparatus of claim 43, wherein said holding member
continues to move along the apparatus as said dispensing module
dispenses the dosage onto each of the carrier substrates.
45. The apparatus of claim 43, wherein said dispensing module moves
along an X-like path.
46. The apparatus of claim 39, further comprising a drying system
that dries the dosage on each of the carrier substrates.
47. The apparatus of claim 46, further comprising a holding member
that holds each of the carrier substrates, wherein said holding
member continues to move along the apparatus as said drying system
dries the dosage on each of the carrier substrates.
48. The apparatus of claim 47, wherein said drying system comprises
an oven that provides heat and air flow to each of the carrier
substrates to dry the dosage.
49. The apparatus of claim 47, wherein said drying system dries the
dosage by use of infrared radiation.
50. The apparatus of claim 39, further comprising a coating system
that applies a coating over the dosage on each of the carrier
substrates.
51. The apparatus of claim 50, wherein said coating system has a
coating device that applies said coating to each of the carrier
substrates, and wherein said coating device is chosen from the
group consisting of a first pad-printing device or a spraying
device.
52. The apparatus of claim 50, further comprising a holding member
that holds each of the carrier substrates, wherein said holding
member continues to move along the apparatus as said coating system
applies said coating to each of the carrier substrates.
53. The apparatus of claim 50, further comprising a coating dryer
that dries said coating on each of the carrier substrates.
54. The apparatus of claim 53, further comprising a holding member
that holds each of the carrier substrates, wherein said holding
member continues to move along the apparatus as said coating dryer
dries said coating on each of the carrier substrates.
55. The apparatus of claim 39, further comprising a marking device
that applies an identification marker to each of the carrier
substrates, wherein said marking device is chosen from the group
consisting of a second pad-printing device, a laser marker, an
inkjet device or a rotogravure device.
56. The apparatus of claim 55, further comprising a holding member
that holds each of the carrier substrates, wherein said holding
member continues to move along the apparatus as said marking device
applies said identification marker to each of the carrier
substrates.
57. The apparatus of claim 55, further comprising an ink dryer that
dries said identification marker on each of the carrier
substrates.
58. The apparatus of claim 57, further comprising a holding member
that holds each of the carrier substrates, wherein said holding
member continues to move along the apparatus as said ink dryer
dries said identification marker on each of the carrier
substrates.
59. A method of producing pharmaceutical product, the method
comprising: providing a plurality of carrier substrates; providing
a dosage of active agent for each of said plurality of carrier
substrates; and dispensing said dosage onto each of said plurality
of carrier substrates under pressure.
60. The method of claim 59, wherein dispensing said dosage is done
by a positive displacement pump.
61. The method of claim 59, wherein dispensing said dosage is done
while each of said plurality of carrier substrates continues to
move.
62. The method of claim 61, wherein dispensing said dosage is
performed by a dispensing module that moves along an X-like
path.
63. The method of claim 60, further comprising drying said dosage
on each of said plurality of carrier substrates.
64. The method of claim 59, further comprising applying a coating
over said dosage on each of said plurality of carrier
substrates.
65. The method of claim 59, further comprising applying an
identification marker to each of said plurality of carrier
substrates.
66. A method of producing pharmaceutical product comprising:
providing a plurality of carrier substrates; providing a dosage of
active agent for each of said plurality of carrier substrates;
moving said plurality of carrier substrates in a direction; and
dispensing said dosage onto each of said plurality of carrier
substrates while said plurality of carrier substrates continues to
move in said direction.
67. The method of claim 66, wherein dispensing said dosage is done
under pressure.
68. The method of claim 66, wherein dispensing said dosage is done
by a positive displacement pump.
69. The method of claim 66, wherein dispensing said dosage is
performed by a dispensing module that moves along an X-like
path.
70. The method of claim 66, further comprising drying said dosage
on each of said plurality of carrier substrates.
71. The method of claim 66, further comprising applying a coating
over said dosage on each of said plurality of carrier
substrates.
72. The method of claim 66, further comprising applying an
identification marker to each of said plurality of carrier
substrates.
73. A method of producing a batch of pharmaceutical product
comprising: providing a plurality of carrier substrates; providing
a dosage of active agent on each of said plurality of carrier
substrates; and dispensing said dosage onto each of said plurality
of carrier substrates with a content uniformity for the batch being
less than 5% RSD where the dosage of active agent is less than 5 mg
or with the content uniformity for the batch being less than 2% RSD
where the dosage of active agent is less than 10 mg.
74. The method of claim 73, wherein dispensing said dosage is done
under pressure.
75. The method of claim 73, wherein dispensing said dosage is done
by a positive displacement pump.
76. The method of claim 73, wherein dispensing said dosage is done
while each of said plurality of carrier substrates continues to
move.
77. The method of claim 73, wherein dispensing said dosage is
performed by a dispensing module that moves along an X-like
path.
78. The method of claim 73, further comprising drying said dosage
on each of said plurality of carrier substrates.
79. The method of claim 73, further comprising applying a coating
over said dosage on each of said plurality of carrier
substrates.
80. The method of claim 73, further comprising applying an
identification marker to each of said plurality of carrier
substrates.
81. A method of producing pharmaceutical product comprising:
providing a plurality of carrier substrates; providing a dosage of
active agent for each of said plurality of carrier substrates;
producing the pharmaceutical product from said plurality of carrier
substrates and said dosage of active agent using a continuous
process; and providing quality control for the pharmaceutical
product during said continuous process.
82. The method of claim 81, further comprising dispensing under
pressure said dosage on each of said plurality of carrier
substrates.
83. The method of claim 81, further comprising dispensing said
dosage on each of said plurality of carrier substrates by a
positive displacement pump.
84. The method of claim 81, further comprising drying said dosage
on each of said plurality of carrier substrates.
85. The method of claim 81, further comprising applying a coating
over said dosage on each of said plurality of carrier
substrates.
86. The method of claim 81, further comprising applying an
identification marker to each of said plurality of carrier
substrates.
87. The method of claim 81, wherein the pharmaceutical product has
a batch that is produced with a content uniformity for said batch
of less than 5% RSD where the dosage of active agent is less than 5
mg.
88. The method of claim 81, wherein the pharmaceutical product has
a batch that is produced with a content uniformity for said batch
of less than 2% RSD where the dosage of active agent is less than
10 mg.
89. An apparatus for producing pharmaceutical product that each has
a carrier substrate and a dosage, the apparatus comprising: a
dispensing module that dispenses the dosage onto each of the
carrier substrates, wherein said dispensing module dispenses the
dosage via movement of said dispensing module.
90. The apparatus of claim 89, wherein said movement is vibration
of said dispensing module.
91. A method of producing pharmaceutical product, the method
comprising: providing a plurality of carrier substrates; providing
a dosage of active agent for each of said plurality of carrier
substrates; and dispensing said dosage onto each of said plurality
of carrier substrates by vibration.
Description
RELATED APPLICATIONS
[0001] This application is related to, and claims priority in,
co-pending U.S. Provisional Application Ser. No. 60/621,992, filed
Oct. 25, 2004, the disclosure of which is incorporated herein by
reference. This application is also related to, and claims priority
in, co-pending U.S. Provisional Application Ser. No. 60/578,245,
filed Jun. 9, 2004, the disclosure of which is incorporated herein
by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to the manufacture of
pharmaceutical and pharmaceutical-like product. More particularly,
the present invention relates to an apparatus and process for
manufacturing pharmaceutical and pharmaceutical-like product.
[0004] 2. Description of Related Art
[0005] Contemporary tablet manufacturing methods use wet
granulation or direct compression approaches to add the active
ingredient into the tablet ingredients. After mixing to achieve
homogeneity, tablets are produced, which are each intended to have
the required dosage of active ingredient. These types of
contemporary batch manufacturing techniques suffer from drawbacks
due to their inefficiency and inaccuracy.
[0006] Contemporary batch production attempts to homogeneously mix
and equally distribute the active ingredient to each of the tablets
in the batch. When the active ingredient in the batch is not
equally distributed, such as, for example, an unacceptable
concentration, the non-homogeneity of the active ingredient will be
distributed throughout the entire batch rendering all of the
tablets unacceptable. Additionally, inadequate mixing in other
ingredients will be distributed throughout the entire batch rather
than just to individual tablets.
[0007] Contemporary machines that manufacture pharmaceutical
product suffer from the drawback of having a large footprint. These
machines may be broken into a number of different units that handle
different steps of the process. The use of separate units adds
labor and time to the process, such as, for example, requiring the
product to be moved between different machines.
[0008] In addition, the pharmaceutical product is usually stored
for days awaiting availability of machines for the next step of the
process. This delay increases production time and increases
manufacturing costs.
[0009] Contemporary machines and techniques also require a longer
time and added labor to change over to different products, if the
machine is capable of doing so at all. To produce a different
pharmaceutical product, these contemporary machines require
thorough cleaning of the components to avoid contamination of the
next batch from the previous production ingredients.
[0010] Contemporary quality control methods for pharmaceutical and
pharmaceutical-like product involve the use of batch sampling
techniques. The batch-sampling techniques test samples from batches
of the product, such as through the use of wet chemistry, after the
product has been made. Contemporary batch sampling techniques use
frequent and sometimes random batch sampling for various
characteristics of the final product, such as, for example,
quality, concentration and consistency. However, these
batch-sampling techniques suffer from drawbacks because of their
inefficiency and inaccuracy.
[0011] Batch-sampling assumes that all of the product attributes in
a particular batch are normally distributed and have the same or
very similar characteristics as the sampled product from the batch.
Where the chosen samples do not meet the required tolerances, an
entire batch can be discarded or re-processed for additional
sampling and testing. If the chosen unacceptable samples do not
have the same characteristics as other acceptable product in the
batch, then acceptable product may be discarded along with the
rejected samples or at least need to undergo more costly testing.
Batch-sampling can be particularly inaccurate where the error or
flaw in the process is random, non-repeating or of a non-linear
nature. Such flaws or errors in the manufacturing process may
provide for only a fraction of the product of the batch being
unacceptable but result in an entire batch being discarded or
re-tested, as a result of the use of batch sampling.
[0012] Another significant drawback of batch-sampling techniques is
where the chosen samples meet the required tolerances, but where a
fraction of the batch is in fact unacceptable and not represented
in the tested sample. In such a situation, unacceptable product may
be provided to the consumer because of the inherent flaw in the
quality control method.
[0013] An additional drawback in batch-sampling techniques is that
the testing is done at the end of the process and provides little,
if any, information for corrective action to be taken with regard
to the manufacturing process and its various steps. The
batch-sampling technique can provide overall information for
sampled product, but does not indicate at which point or which
particular step in the process that a flaw is occurring, such as,
for example, inadequate dosing or detrimental heating.
[0014] Another drawback of batch-sampling technique is that it is
done off-line of the manufacturing process, which adds time to the
overall manufacturing process, and can also be labor intensive. The
cost in time and labor is increased where more stringent standards
are applied to a particular product so the batch-sampling technique
utilizes a higher portion of samples for testing.
[0015] Accordingly, there is a need for an apparatus and process
for manufacturing pharmaceutical and pharmaceutical-like product
that reduce or eliminate these manufacturing and quality control
drawbacks of the contemporary devices and techniques.
SUMMARY OF THE INVENTION
[0016] It is an object of the present invention to provide a more
efficient process and/or apparatus for manufacturing pharmaceutical
and pharmaceutical-like products.
[0017] It is another object of the present invention to provide
such a process and/or apparatus that provides real-time process
monitoring.
[0018] It is yet another object of the present invention to provide
such a process and/or apparatus that provides real-time feedback
and control of the process and product quality.
[0019] It is yet a further object of the present invention to
provide such a process and/or apparatus that provides monitoring of
each product that is manufactured.
[0020] It is still another object of the present invention to
provide such a process and/or apparatus that minimizes or
eliminates off-line quality control inspection and facilitates
real-time release of the product.
[0021] It is still a further object of the present invention to
provide such a process and/or apparatus that eliminates product
with an incorrect dose.
[0022] It is still another further object of the present invention
to provide such a process and/or apparatus that facilitates change
over to a production of a different product.
[0023] It is a further object of the present invention to provide
such a process and/or apparatus that enhances stability by reducing
excipient interaction with the active pharmaceutical ingredient
(API).
[0024] It is yet another further object of the present invention to
provide a process and/or apparatus that employs Process Analytical
Technology to improve the manufacture of pharmaceutical
product.
[0025] These and other objects and advantages of the present
invention are provided by an apparatus for producing pharmaceutical
product that each have a carrier substrate and a dosage of API. The
apparatus has a dispensing module that dispenses the API dosage
onto each of the carrier substrates.
[0026] In another aspect, an apparatus or machine for producing a
pharmaceutical product is provided where the product each has a
carrier substrate and a dosage. The apparatus has a dispensing
module, a holding member, and a conveyor member. The holding member
holds each of the carrier substrates. The conveyor moves the
holding member along the apparatus. The dispensing module dispenses
the dosage onto each of the carrier substrates. The holding member
moves continually along the apparatus as the dispensing module
dispenses the dosage onto each of the carrier substrates.
[0027] In another aspect, an apparatus is provided for producing a
batch of pharmaceutical product that each have a carrier substrate
and a dosage of active agent. The apparatus has a dispensing module
that dispenses the dosage onto each of the carrier substrates with
a content uniformity for the batch of less than 5% relative
standard deviation (RSD), and preferably less than 2% RSD, for a
dosage of less than 5 mg. Also, the dispensing module dispenses the
dosage onto each of the carrier substrates with a content
uniformity for the batch of less than 2% RSD for a dosage of less
than 10 mg.
[0028] In another aspect, a method of producing pharmaceutical
product is provided. The method includes, but is not limited to,
providing a plurality of carrier substrates, providing a dosage of
active agent for each of the plurality of carrier substrates, and
dispensing the dosage onto each of the plurality of carrier
substrates.
[0029] In another aspect, a method of producing pharmaceutical
product is provided that includes, but is not limited to, providing
a plurality of carrier substrates; providing a dosage of active
agent for each of the plurality of carrier substrates; moving the
plurality of carrier substrates in a direction; and dispensing the
dosage onto each of the plurality of carrier substrates while the
plurality of carrier substrates continues to move in the desired
direction.
[0030] In another aspect, a method of producing a batch of
pharmaceutical product is provided that includes, but is not
limited to, providing a plurality of carrier substrates; providing
a dosage of active agent for each of the plurality of carrier
substrates; and dispensing the dosage onto each of the plurality of
carrier substrates with a content uniformity for the batch of less
than 5% relative standard deviation (RSD), and preferably less than
2% RSD, for a dosage of less than 5 mg; and/or with a content
uniformity for the batch of less than 2% RSD for a dosage of less
than 10 mg.
[0031] In another aspect, a method of producing a pharmaceutical
product is provided that includes, but is not limited to, providing
a plurality of carrier substrates; providing a dosage of active
agent for each of the plurality of carrier substrates; producing
the pharmaceutical product from the plurality of carrier substrates
and the dosage of active agent using a continuous process; and
providing quality control for the pharmaceutical product during the
continuous process.
[0032] The dispensing module may dispense the dosage under
pressure. The apparatus can also have a holding member that holds
each of the carrier substrates, and the dispensing module can move
with respect to the holding member.
[0033] The apparatus may also have a conveyor that moves the
holding member along the apparatus. The holding member can move
continually along the apparatus as the dispensing module dispenses
the dosage onto each of the carrier substrates. The dispensing
module may move along an X-like path.
[0034] The apparatus can also have a drying system that dries or
evaporates solvent from the dosage on each of the carrier
substrates. The holding member may move continually along the
apparatus as the drying system dries the dosage on each of the
carrier substrates. The drying system can have an oven that
provides heat and air flow to each of the carrier substrates to dry
the dosage. The drying system may dry the dosage by use of heated
air, infrared or microwave heating.
[0035] The apparatus can also have a coating system that applies a
coating over the dosage on each of the carrier substrates. The
coating system may have a first pad-printing device or a sprayer
that applies the coating to each of the carrier substrates. The
holding member may move continually along the apparatus as the
coating system applies the coating to each of the carrier
substrates. The apparatus may also have a coating dryer that dries
the coating on each of the carrier substrates. The holding member
can move continually along the apparatus as the coating dryer dries
the coating on each of the carrier substrates.
[0036] The apparatus may also use intermittent, low volume atomized
sprayers to locally apply the coating over the tablet surface where
the dosage has been applied. The sprayer may use volumetric pumps
to intermittently supply coating materials. A two fluid air-liquid
atomization sprayer may also be used to generate a fine spray.
Alternatively, an ultrasonic spray device or ink jet device may be
used to generate a fine spray.
[0037] The apparatus may also have a second pad-printing device
that applies an identification marker to each of the carrier
substrates. The holding member may move continually along the
apparatus as the second pad-printing device applies the
identification marker to each of the carrier substrates. The
apparatus can also have an ink dryer that dries the identification
marker on each of the carrier substrates. The holding member may
move continually along the apparatus as the ink dryer dries the
identification marker on each of the carrier substrates. The
identification marking can also be done by lasermarking, inkjet or
rotogravure.
[0038] This application is related to the following applications
which have been filed contemporaneously herewith and the
disclosures of which are hereby incorporated by reference in their
entirety: APPARATUS AND METHOD FOR PRODUCING A PHARMACEUTICAL
PRODUCT, Ser. No. ______ Atty. Docket No. 0001534USU1;
PHARMACEUTICAL PRODUCT, Ser. No. ______ Atty. Docket No.
0001534USU2; APPARATUS AND METHOD FOR PRODUCING OR PROCESSING A
PRODUCT OR SAMPLE, Ser. No. ______ Atty. Docket No. 0001534USU3;
APPARATUS FOR PRODUCING A PHARMACEUTICAL PRODUCT, Ser. No. ______
Atty. Docket No. 0001534USU4; and METHOD FOR PRODUCING A
PHARMACEUTICAL PRODUCT, Ser. No. ______ Atty. Docket No.
0001534USU5.
[0039] Other and further objects, advantages and features of the
present invention will be understood by reference to the
following:
BRIEF DESCRIPTION OF THE DRAWINGS
[0040] FIG. 1 is a perspective view of a preferred embodiment of a
pharmaceutical manufacturing machine of the present invention;
[0041] FIG. 2 is a schematic representation of the automation
components of the pharmaceutical manufacturing machine of FIG.
1;
[0042] FIG. 2a is a representation of a path of continuous movement
of the dispensing module of the pharmaceutical manufacturing
machine of FIG. 1;
[0043] FIG. 2b is a representation of another path of continuous
movement of the dispensing module of the pharmaceutical
manufacturing machine of FIG. 1;
[0044] FIG. 2c is a perspective view of a dispenser assembly of the
pharmaceutical manufacturing machine of FIG. 1;
[0045] FIG. 2d is a perspective cross-sectional view of the
dispenser assembly of FIG. 2c;
[0046] FIG. 2e is a perspective view of the pump module of the
dispenser assembly of FIG. 2c;
[0047] FIG. 2f is a perspective view of the motor module of the
dispenser assembly of FIG. 2c;
[0048] FIG. 2g is a perspective cross-sectional view of another
embodiment of a nozzle of the pharmaceutical manufacturing machine
of FIG. 1;
[0049] FIG. 2h is a schematic representation of another embodiment
of a dispensing assembly of the pharmaceutical manufacturing
machine of FIG. 1;
[0050] FIG. 2i shows the range of droplets that can be dispensed
from the assembly of FIG. 2h;
[0051] FIG. 2j shows the dispensing assembly of FIG. 2h with
multiple nozzles or apertures;
[0052] FIG. 3 is a plan view of a pharmaceutical product
manufactured by the machine of FIG. 1;
[0053] FIG. 4 is a high speed video image of a dose droplet
dispensed by the pharmaceutical manufacturing machine of FIG.
1;
[0054] FIG. 5 is a process flow diagram for the process performed
by the pharmaceutical manufacturing machine of FIG. 1;
[0055] FIG. 6 is a graph of the dose droplet measurements by video
imaging and processing for a run of 300 tablets;
[0056] FIG. 6a is a graph comparing dose droplet measurements made
by the video imaging, high performance liquid chromatography and
weight;
[0057] FIG. 6b is a graph of the volumetric determinations by the
video imaging and processing compared to drug content measured by
high performance liquid chromatography;
[0058] FIG. 6c is a graph of the amount of active agent as
predicted by the video imaging compared to that measured by high
performance liquid chromatography for a 1 mg dosage;
[0059] FIG. 6d is a graph of the amount of active agent as
predicted by the video imaging compared to that measured by high
performance liquid chromatography for a 2 mg dosage;
[0060] FIG. 6e is a graph of the amount of active agent as
predicted by the video imaging compared to that measured by high
performance liquid chromatography for a 4 mg dosage;
[0061] FIG. 7 is a near-infrared chemical image of a carrier tablet
with the dose droplet as processed by the pharmaceutical
manufacturing machine of FIG. 1;
[0062] FIG. 7a is an alternative near-infrared chemical image of a
carrier tablet with the dose droplet as processed by the
pharmaceutical manufacturing machine of FIG. 1;
[0063] FIG. 7b is a UV induced fluorescence chemical image of a
carrier tablet with the dose droplet as processed by the
pharmaceutical manufacturing machine of FIG. 1;
[0064] FIG. 7c is a luminescence image of a carrier tablet with
only HPC present and no image processing;
[0065] FIG. 7d is a luminescence image of a carrier tablet with an
active agent and HPC present with image processing;
[0066] FIG. 8 is a perspective view of an alternative embodiment of
a pharmaceutical manufacturing machine of the present
invention;
[0067] FIG. 8a is a perspective view of another alternative
embodiment of a pharmaceutical manufacturing machine of the present
invention;
[0068] FIG. 8b is a schematic illustration of an alternative
embodiment of a spectroscopic detection system;
[0069] FIG. 8c is a schematic illustration of one of the control
devices for the spectroscopic detection system of FIG. 8b;
[0070] FIG. 8d is a perspective, assembly view of the transport
system for the spectroscopic detection system of FIG. 8b;
[0071] FIG. 8e is a top plan view of the sample table for the
spectroscopic detection system of FIG. 8b;
[0072] FIG. 8f is a sectioned, side plan view of the sample table
of FIG. 8e;
[0073] FIG. 8g is a partial section, side plan view of the sample
table of FIG. 8e, illustrating the placement of a pharmaceutical
sample in one of the sample table receptacles;
[0074] FIG. 8h is a bottom plan view of the sample table of FIG.
8e;
[0075] FIG. 8i is a partial side plan view of the sample table of
FIG. 8e;
[0076] FIG. 8j is a side plan view of the position table for the
spectroscopic detection system of FIG. 8b;
[0077] FIG. 8k is a partial front plan view of the position table
of FIG. 8j;
[0078] FIG. 8l is a partial top plan view of the transport system
base for the spectroscopic detection system of FIG. 8b;
[0079] FIG. 8m is a partial side plan view of the base of FIG.
8l;
[0080] FIG. 8n is a partial sectioned, side plan view of the
transport system assembly of FIG. 8d;
[0081] FIG. 8o is a schematic illustration of the spectroscopic
detection system of FIG. 8b with associated display device or
means;
[0082] FIG. 9 is a schematic representation of components of the
pharmaceutical manufacturing machine of FIG. 8;
[0083] FIG. 10 is a schematic representation of the communication
between the components of the pharmaceutical manufacturing machine
of FIG. 8;
[0084] FIG. 11 is a plan view of a preferred embodiment of a
carrier tablet of the present invention;
[0085] FIG. 12 is a cross-sectional view of the carrier tablet of
FIG. 11 taken along line 12-12 of FIG. 11 with a dose droplet;
[0086] FIG. 13 is a plan view of an alternative embodiment of a
carrier tablet of the present invention; and
[0087] FIG. 14 is a cross-sectional view of the carrier tablet of
FIG. 13 taken along line 14-14 of FIG. 13 with a dose droplet.
DETAILED DESCRIPTION OF THE INVENTION
[0088] Referring to the drawings, and in particular FIGS. 1 through
3, a preferred embodiment of the pharmaceutical manufacturing
apparatus or machine of the present invention is shown and
generally referred to by reference numeral 10. The machine 10 has a
plurality of components that are operably connected to manufacture
a pharmaceutical product 3000 and preferably a batch of
pharmaceutical product, as will be described later in greater
detail. A batch of pharmaceutical product 3000 is a quantity of
product, which has been produced during a defined cycle of
manufacture, such as, for example, a fixed number or one or more
runs over a fixed time period. The machine 10 has various
components arranged along a straight or substantially straight
line. However, the present invention contemplates other
arrangements and positionings of the various components, such as,
for example, in circular or rectangular paths.
[0089] The arrangement and positioning of the components of machine
10 provide a smaller footprint for space savings, as well as
providing a more efficient and ergonomic machine that facilitates
operation. Machine 10 can have components stacked on each other or
at differing heights to take advantage of vertical space, as well
as facilitating operation, such as, for example, enabling the use
of gravity in the process performed by the machine.
[0090] The machine 10 has a loading system 100, a holding system
200, a conveyor system 300, a drug dispensing system 400, a coating
system 600, a printing system 700, a product acception-rejection
system 800, and a control system 900. Each of these systems 100
through 900 are operably connected to each other to efficiently and
ergonomically provide pharmaceutical product 3000 that is ready for
packaging, and which has each undergone real-time monitoring, and
preferably real-time feedback and adjustment or control.
[0091] The machine 10 delivers the pharmaceutical product 3000,
which is a combination of a carrier tablet or other substrate 1000
and a liquid dose 2000, as shown in FIG. 3. As will be described
later in greater detail, the liquid dose 2000 is dispensed by drug
dispensing system 400 in the form of a dose droplet 2100 (shown in
FIG. 4) that is dispensed onto the carrier tablet 1000. It should
be understood that the liquid dose 2000 can have a variety of
properties, such as, for example, low-viscosity, high-viscosity,
solution or suspension, such that the term liquid is not intended
to be limiting.
[0092] The liquid dose 2000 has an active, active agent or
therapeutic active agent, and is capable of being dispensed by the
machine 10 onto the carrier tablet 1000. The terms active, active
agent or therapeutic active agent include, but are not limited to,
drugs, proteins, peptides, nucleic acids, nutritional agents, as
described herein. These terms include pharmaceutically acceptable
agents, bioactive agents, active agents, therapeutic agents,
therapeutic proteins, diagnostic agents, or drug(s) as defined
herein, and follows the guidelines from the European Union Guide to
Good Manufacturing Practice. Such substances are intended to
furnish pharmacological activity or other direct effect in the
diagnosis, cure, mitigation, treatment, or prevention of disease or
to affect the structure and function of the body. The substance may
also include a diagnostic agent, such as an imaging agent and/or a
radioactive labeled compound. Their use may be in a mammal, or may
be in a human. The pharmacological activity may be prophylactic, or
for treatment of a disease state. The agents herein include both
small molecule therapeutics, as well as peptides and proteins. The
pharmaceutical compositions described herein may optionally
comprise one or more pharmaceutically acceptable active agent,
bioactive agent, active agent, therapeutic agent, therapeutic
protein, diagnostic agent, or drug(s) or ingredients distributed
within, or any combinations thereof.
[0093] It should further be understood that the present invention
is not intended to be limited to the use of any particular active
agents, formulations or resulting pharmaceutical or
pharmaceutical-like product. The liquid dose 2000 can be a solution
or suspension; and the resulting pharmaceutical or
pharmaceutical-like product can be immediate release, slow release,
or controlled release. The liquid dose 2000 can be aqueous,
non-aqueous or mixtures thereof. Non-aqueous solutions or
suspensions include, but are not limited to, organic solvents,
propellants, liquefied gases, volatile silicons, or any
combinations thereof. The terms pharmaceutical or
pharmaceutical-like product are also not intended to be limiting.
The present invention contemplates the use of any active agents
and/or combinations of active agents that are suited for dispensing
by the machine 10.
[0094] Dose droplet 2100 preferably forms a film 2200 upon the
outer surface 1100 or substantially along the outer surface of the
carrier tablet 1000 (shown in FIG. 12). As will be described later,
the liquid dose 2000 is preferably heated so that excess amounts of
liquid are evaporated and the active agent becomes captured in the
film 2200. The carrier tablet 1000, the liquid dose 2000 and
resulting pharmaceutical product 3000 undergo real-time monitoring,
feedback and adjustment, which improves quality control.
[0095] In the preferred embodiment shown in FIG. 1, loading system
100 has a loading container or hopper 110 in communication with a
loading chute 120. Hopper 110 is preferably movable so that carrier
tablets 1000 can be loaded into the hopper and then the hopper can
be moved into communication with the loading chute 120. Loading
chute 120 is in communication with holding system 200 and conveyor
system 300 so that the carrier tablets 1000 can be moved from the
hopper 110 into the holding system 200 for movement along and
through machine 10 by way of conveyor system 300.
[0096] The hopper 110 and loading chute 120 can use various devices
and methods, such as, for example, powered wheels or wedges,
powered belts, or gravity, to move each of the carrier tablets 1000
into their designated positions in holding system 200. In machine
10, a portion of loading system 100 is preferably disposed above a
portion of conveyor system 300 to take advantage of gravity, in
combination with a mechanical loading device.
[0097] In the preferred embodiment, holding system 200 has a
plurality of holding members or trays 210 with tablet positions 220
having a size and shape that allows for holding of each of the
carrier tablets 1000. Preferably, each of the holding trays 210 is
rectangular, and the tablet positions 220 are arranged in an array
of equi-distantly spaced rows and columns. As will be explained
later, this array facilitates operation of the dispensing system
400 in adding the dose droplets 2100 to the carrier tablets 1000.
However, the present invention contemplates the use of other
structures and methods for securing each of the carrier tablets
1000 and the resulting pharmaceutical product 3000 as they travel
along machine 10.
[0098] Preferably, each of the holding trays 210 has two rows of
thirty tablet positions 220. However, alternative sizes, capacities
and shapes of the holding trays 210 and the tablet positions 220
may be used to accommodate different shapes and/or sizes of carrier
tablets 1000 and to increase efficiency.
[0099] Holding system 200 tracks individual carrier tablets 1000 by
their designation in each of the tablet positions 220. This allows
machine 10 to perform various real-time monitoring, feedback and
adjustment activities upon each of the carrier tablets 1000, dose
droplets 2100 and pharmaceutical product 3000, and also to make
determinations as to whether each of the tablets, droplets or
resulting product has met the quality control standards that are
designated for a particular pharmaceutical product. The tracking of
each of the carrier tablets 1000, dose droplets 2100 and/or
pharmaceutical product 3000 throughout the process carried out by
machine 10, allows for acceptance or rejection during the process.
The present invention also contemplates tracking of unacceptable
tablets for removal by acception-rejection system 800 based on the
real-time monitoring.
[0100] Various tracking or identification methods can be used by
holding system 200 for each of the carrier tablets 1000. In the
preferred embodiment of machine 10, holding trays 210 have a bar
code 230 that can be scanned to provide identification and
information to control system 900, and which can also be used to
track and monitor the individual carrier tablets 1000, dose
droplets 2100 and/or pharmaceutical product 3000 throughout the
process. As will be discussed later in greater detail, the data
compiled throughout the process is stored by control system 900.
The data is based upon the individual carrier tablets 1000, dose
droplets 2100 and/or pharmaceutical product 3000, as opposed to
contemporary quality control methods that use batch-sampling.
[0101] In the embodiment of machine 10, holding system 200
positions each of the carrier tablets 1000 so that dispensing
system 400 can add the dose droplet 2100 to the outer surface 1100
(shown in FIG. 11), which is facing away from the holding tray 210.
The present invention contemplates the dispensing system 400 also
adding the dose droplet 2100 to the opposing outer surface 1200 of
the carrier tablet 1000 (shown in FIG. 12). This would allow for a
greater capacity of liquid dose 2000 being carried by the carrier
tablet 1000 (on both of its outer surfaces 1100 and 1200), as well
as providing a more uniform and symmetrical pharmaceutical product
3000.
[0102] Dosing of both sides of the carrier tablet 1000 would also
provide the ability for different liquid doses 2000, e.g.,
different active agents, to be dispensed upon a single tablet, such
as, for example, where the different liquid doses are incompatible
and cannot be mixed together in liquid form or where the different
liquid doses cannot be layered on top of each other. The present
invention contemplates dispensing system 400 adding one or more
different liquid doses 2000 to carrier tablets 1000 through
layering, through depositing on opposing outer surfaces 1100 and
1200, and/or both.
[0103] Machine 10 can also be used to re-process the carrier
tablets 1000 any number of times through the dispensing system 400
in order to add each of the different liquid doses 2000. Machine 10
may have additional dispensing systems 400 in series that will add
each of the different liquid doses 2000 to the carrier tablets
1000.
[0104] Holding system 200 can alternatively provide for dispensing
the liquid dose 2000 (or different liquid doses) on both sides of
the carrier tablets 1000 by providing dispensing system 400 with
access to both sides of the carrier tablet. Examples of such
alternative methods of dispensing include, but are not limited to,
inverting holding tray 210 so that each of the carrier tablets 1000
are transferred into a second holding tray 210 so that the opposing
outer surfaces 1200 are now facing away from the second holding
tray or using a holding tray that holds each of the carrier tablets
around their perimeters or outer circumferences so that both outer
surfaces 1100 and 1200 are simultaneously accessible.
[0105] The flipping or inverting of each of the carrier tablets
1000 or their holding tray 210 can be done near the end of the
process so that the opposing outer surface 1200 is re-processed by
the same components or a second set of components could be added to
machine 10 to continue the process with respect to the opposing
outer surface. Additionally, the inverting of each of the carrier
tablets 1000 or their holding tray 210, can be done by holding
system 200 to allow for other operations or processes to be
performed on opposing outer surface 1200, such as, for example,
coating or printing both sides of the pharmaceutical product
3000.
[0106] Conveyor system 300 provides for movement of holding trays
210 along machine 10 and through the various stages or systems of
the machine. In the preferred embodiment of machine 10, conveyor
system 300 provides for movement of holding trays 210 along a
substantially horizontal path. However, the present invention
contemplates movement of the holding trays 210 in other directions,
such as, for example, in a vertical path, where spacial economy,
the use of gravity or other reasons suggest or dictate such a
direction of movement.
[0107] Conveyor system 300 has a drive conveyor 310. Drive conveyor
310 is controlled by control system 900, shown in FIG. 1, and is
preferably variable speed. Holding trays 210 are preferably
removably connected to drive conveyor 310. Holding trays 210 are
securely connected to the drive conveyor 310 so that each of the
tablet positions 220 remains constant with respect to the drive
conveyor in order to provide accuracy in dispensing and monitoring
of the carrier tablets 1000, dose droplets 2100 and pharmaceutical
product 3000. In the preferred embodiment of machine 10, drive
conveyor 310 is a circulating conveyor belt that traverses the
length of machine 10 and, more preferably, is a serial real-time
communications system drive unit. However, the present invention
contemplates other types and methods of moving the holding trays
210, such as, for example, parallel drive chains, tracks, belts or
wheels to which the holding trays can be removably connected.
[0108] The present invention also contemplates the use of a number
or series of holding trays 210 that are pivotally secured to each
other to form a belt-like structure or tray belt, which can be
operably connected to the drive conveyor 310. Machine 10 can have a
plurality of tray belts with different sizes and/or shapes of
tablet positions 220 to accommodate different sizes and/or shapes
of carrier tablets 1000. The tray belt is a length or line of
holding trays 210 that is connectable at opposing ends to form a
loop. When the holding trays 210 are to be replaced for a different
pharmaceutical product 3000, the tray belt is fed along the drive
conveyor 310 and then secured at its opposing ends to form the belt
along the machine 10. To expedite the connection of the second tray
belt to drive conveyor 310, the second tray belt can preferably be
connected to the end of the first tray belt that is being removed,
as that first tray belt is driven along and off of the drive
conveyor.
[0109] The present invention also contemplates the use of any
number of drive conveyors 310. For example, different systems of
machine 10 can have independent drive conveyors 310 that allow for
independent control of the speed of the drive conveyors, such as,
for example, to more rapidly remove the pharmaceutical product 3000
from the end of the process. In such an alternative embodiment,
control system 900 would preferably control the various independent
drive conveyors 310, and be able to coordinate their movement.
[0110] In the preferred embodiment, dispensing system 400 provides
for the addition of the liquid dose 2000 to each of the carrier
tablets 1000, and provides for real-time monitoring, feedback and
adjustment. To dispense the liquid dose 2000, dispensing system 400
has a gantry 410 that laterally spans above and across drive
conveyor 310, and is longitudinally movable with respect to the
drive conveyor. The movement of gantry 410, including speed and
position, is controlled by control system 900.
[0111] The gantry 410 has a dispensing module 420 movably connected
thereto. The dispensing module 420 is movable along the
longitudinal axis of the gantry 410, which laterally traverses
across the drive conveyor 310. The movement of the dispensing
module 420, including speed and position, is also controlled by the
control system 900.
[0112] Based upon the movement of the gantry 410, and its own
movement with respect to the gantry, the dispensing module 420 is
capable of movement along X and Y axes with respect to the drive
conveyor 310 and the holding trays 210. Additionally, the present
invention contemplates movement of the gantry 410, the dispensing
module 420, and/or both, along a Z-axis with respect to the drive
conveyor 310 and the holding trays 210. The movement of the
dispensing module 420 allows it to accurately dispense the dose
droplet 2100 on each of the carrier tablets 1000 that are in the
array of tablet positions 220 on holding tray 210. Control system
900 can also adjust the movement of the dispensing module 420 and
the gantry 410 to accommodate different sizes and shapes of holding
trays 210, as well as different arrays of tablet positions 220 on
the holding trays.
[0113] The use of the gantry 410 to move the dispensing module 420
along X and Y axes (and the Z axis if desired), provides for smooth
movement and accurate alignment of the dispensing module with each
of the carrier tablets 1000. This is especially significant in the
preferred embodiment of machine 10 where the drive conveyor 310
continues to move the holding tray 210 through the dispensing
system 400 as the dose droplets 2100 are being dispensed. The
continuous movement of each of the carrier tablets 1000 along
machine 10 as the dispensing step is occurring speeds up the
manufacturing process. Additionally, smooth continuous movement of
the holding tray 210 and the carrier tablets 1000 thereon, as
opposed to dispensing onto the carrier tablets via indexing or
discontinuous movement, provides for less wear and tear on the
machine 10 and its components, particularly the drive conveyor 310.
Dispensing module 420 preferably moves in an X-like path to
accurately dispense on each of the carrier tablets 1000. The size
and shape of the X-like path depends upon the dispensing speed and
the spacing of tablet positions 220, as shown in FIGS. 2a and 2b.
It should be further understood by one of ordinary skill in the art
that the dispensing module 420 can be moved along alternative paths
that preferably allow for continuous movement of the carrier
tablets 1000 during dispensing.
[0114] The accuracy of the alignment of the dispensing module 420
with each of the carrier tablets 1000, and the efficiency of the
movement of the module, is facilitated by the use of the
rectangular array of tablet positions 220 along holding tray 210
and the control of the movement of the module and gantry 410 in a
rectangular coordinate system. However, the present invention
contemplates the use of other structures and methods that could
also be used to move the dispensing module 420 with respect to each
of the carrier tablets 1000, as the drive conveyor 310 continues to
move through the dispensing system 400, such as, for example, a
multiple axis robotic arm and/or along different coordinate
systems.
[0115] In the preferred embodiment of machine 10, the dispensing
system 400 has a pair of dispensing modules 420 connected to gantry
410. The use of more than one dispensing module 420 provides for
increased speed and efficiency in dispensing of the liquid dose
2000. Additionally, the use of more than one dispensing module 420
would allow the dispensing system 400 to add different liquid doses
2000 to a carrier tablet 1000 without cleaning or replacing the
module, such as, for example, in layering or on opposing outer
surfaces 1100 and 1200 through re-processing the carrier tablet
back through the dispensing system.
[0116] Dispensing module 420 dispenses a desired amount of active
agent onto the carrier tablet 1000. In the preferred embodiment of
machine 10, the dispensing module 420 has a pump 425, a flow cell
430, and a dispensing head 435. The present invention contemplates
a single dispensing module 420 that has duplicate components, such
as, for example, a pump 425 and a flow cell 430 that are in fluid
communication with a pair of dispensing heads 435, and/or other
combinations or numbers of components for any number of dispensing
modules.
[0117] The pump 425 is connected to a liquid dose source 440. In
the preferred embodiment of the machine 10, the liquid dose source
440 is a movable container 445 that is connected to the pump 425
via removably connectable conduit 447, so that the liquid dose 2000
can be quickly and efficiently replaced.
[0118] The present invention contemplates the use of a liquid dose
source 440 with replaceable cartridges, containers or canisters
(not shown) that can be easily inserted in, or connected to, the
liquid dose source. For lower dosages where only small amounts of
the liquid dose 2000 are being dispensed, the liquid dose source
440 with replaceable cartridges, containers or canisters is
especially useful for facilitating operation of machine 10.
[0119] The pump 425 is preferably a metered, positive displacement
pump (shown in FIGS. 2c through 2f), which causes the dispensing
head 435 to dispense a single dose droplet 2100. The metered,
positive displacement pump 425 is controlled by the control system
900, and facilitates the accuracy and control of dispensing a
single dose droplet 2100 of the desired size so that the proper
dosage of active agent is added to the carrier tablet 1000.
However, the present invention contemplates the use of other types
of pumps, such as, for example, a time-pressure pump or
reciprocating piston pump connected to a dispensing module that can
provide the same degree of accuracy and speed in dosing the carrier
tablet 1000.
[0120] Pump 425 has a motor module 4250 and a piston module 4280,
as shown in FIGS. 2e and 2f. The motor module 4250 has a motor
4255, a connection port 4260 and an adjustment mechanism 4265. The
piston module 4280 has a piston assembly 4285 and a cylinder 4290.
When the piston module 4260 is operably connected to the motor
module 4250 through connection port 4260, the piston on piston
assembly 4285 is driven which imparts both reciprocating and rotary
motion to the piston. The magnitude of the piston stroke is
manually adjustable by the adjustment mechanism 4265. The present
invention contemplates automatic adjustment through use of the real
time monitoring, feedback and control as described herein.
[0121] Pump 425, as controlled by the control system 900, can skip
select tablet positions 220, where the carrier tablets 1000
contained therein have been designated as rejected. Machine 10
provides for inspection of the carrier tablets 1000 before they
undergo the dispensing process described above. In the preferred
embodiment, the tablet inspection is performed by a camera or
video/digital recording device (herein referred to as "camera") 426
and gantry assembly (not shown), which provide images of each of
the carrier tablets 1000 for inspection by control system 900.
[0122] Alternative inspection devices and methods can be used which
determine the condition of the carrier tablet, as well as ensure
that it is properly positioned in tablet position 220. Selective
dispensing by pump 425 improves efficiency by not wasting any
liquid dose 2000 on any carrier tablets 1000 that have already been
deemed to not meet the required tolerances of the pharmaceutical
product 3000 or are not properly positioned for receiving the dose
droplet 2100.
[0123] The pump 425 is connected to the flow cell 430. The flow
cell 430 determines the concentration of the active agent in liquid
contained in container 445 that is going to be dispensed through
the dispensing head 435, which will be used in the real-time
monitoring of the dose droplets 2100. This concentration
information is provided to the control system 900.
[0124] The dispensing head 435 has a dispensing nozzle 450 (shown
in FIG. 2d) through which the pressurized, metered amount of liquid
dose 2000 is dispensed, and forms the dose droplet 2100. The dose
droplet 2100 dispenses onto the outer surface 1100 of the carrier
tablet 1000.
[0125] Nozzle 450 provides for exact amounts of liquid dose 2000
being dispensed. The liquid dose 2000 is preferably dispensed by a
very precise, positive displacement, piston pump 425 that pumps the
liquid through tubing to the nozzle 450. The proper selection of
liquid composition, viscosity, the materials of construction and
orifice size of the nozzle 450 are significant and/or critical
parameters to the reproducibility of droplets formed.
[0126] Nozzle 450 can also be made from a hydrophobic material
and/or have a hydrophobic coating to facilitate formation and
dispensing of dose droplet 2100 by compensating for liquid vehicle
composition/formulation and surface tension.
[0127] In an alternative embodiment shown in FIG. 2g, nozzle 450
has an internal plunger 4510 that is retracted to allow the exact
amount of liquid dose 2000 to enter the dispensing chamber 4520
under pressure of pump 425. Preferably, plunger 4510 is
spring-loaded by a spring 4530, or other biasing device, and can be
retracted by air pressure, such as, for example, by a solenoid
driven pressure source. The liquid dose 2000 is dispensed as a
result of the retraction of the plunger 4510. Under automatic
control, the time that the plunger 4510 is in the open position,
the pressure maintained on the reservoir of liquid dose and the
vehicle composition are significant and/or critical parameters to
the reproducibility of the droplets formed.
[0128] Chamber 4520 is preferably selectively sealed so that the
chamber and liquid dose 2000 contained therein remain under
pressure. A heater 4540 may be utilized to facilitate the ejection
process. Nozzle 450 may have a micro-adjuster 4550 or other
adjustment mechanism, manual or automatic (such as being controlled
by control system 900 with real-time monitoring, feedback and
control), that provides for adjustment of the amount of liquid dose
2000 that is allowed to exit the dispensing chamber 4520. Nozzle
4560 may be a co-axial air exhaust 4560 that further facilitates
dispensing of liquid dose 2000.
[0129] The dispensing system 400 uses a pump and nozzle assembly to
form and dispense the dose droplet 2100. This is advantageous due
to the accuracy of the components as described above and the
ability to perform real-time monitoring of their activities. Also,
the dispensing system 400, through use of nozzle 450, provides a
spherical or substantially spherical dose droplet 2100, which
reduces or prevents splashing and overspray.
[0130] To facilitate formation of a spherical droplet with a
well-defined shape, the liquid dose 2000 can have additives
included, such as, for example, a polymer, such as, for example,
hydroxypropyl cellulose. The present disclosure also contemplates
the use of other additives to be combined with the active agent,
such as, for example, a film former to facilitate formation of film
2200 or a marker ingredient to be used with the imaging techniques
described herein, such as, for example, a surrogate for chemical
imaging.
[0131] The additive or additives, such as, for example, the
polymer, enhances or facilitates the ability of the liquid dose
2000 to lock on to the tablet. The polymer or other such additive
can also provide liquid dose 2000 with the desired surface tension
and/or viscosity so that a single droplet is dispensed by
dispensing system 400, which facilitates control of the amount of
the liquid dose and measurement of the droplet, as will be
described later in greater detail. Examples of such additives
include, but are not limited to, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, carboxymethyl cellulose, polyvinyl
alcohol, polyvinylpyrrolidone, carrageenan (kappa, iota or lambda),
gelatin, polyethylene glycol, polyethylene oxide, pullulan, and/or
acrylic copolymers (e.g., EUDRAGIT.RTM. grades RL, RS, E, L, S,
FS30D), or any combinations thereof.
[0132] The dispensing system 400, and the use of a liquid dose 2000
and dose droplet 2100 that are dispensed onto the carrier tablet
1000 is advantageous over contemporary systems and processes in
that the production facilities or sites where the machine 10 is
located can centrally process, e.g., liquify, the liquid dosage.
This reduces the steps of the production, such as eliminating
off-site production and delivery, which decreases production time
and saves on costs. Where OHC4 compounds are being used, this is
especially advantageous in reducing the handling of the compounds
by the workers.
[0133] Dispensing system 400 can alternatively have a nozzle-plate
assembly 4600 (a portion of which is schematically represented in
FIGS. 2h through 2j) to form and dispense the dose droplet 2100.
The assembly 4600 has a plate 4610 with an aperture or nozzle
opening 4620 therethrough. The plate 4610 is capable of movement
with respect to the supply of liquid dose 2000, as indicated by
arrows 4630. Such movement includes, but is not limited to,
vibration of the plate 4610 in order to actuate the dispensing. The
liquid dose 2000 is dispensed through nozzle opening 4620 when the
plate 4610 is selectively moved towards the supply of the liquid
dose.
[0134] As shown in FIG. 2i, the size of nozzle opening 4620 can be
adjusted or changed to provide for a range of different sizes or
volumes for dose droplet 2100. The ability to accurately size very
small openings in plate 4610 and the dispensing dynamics of the
assembly 4600 allow for dispensing of very small amounts of liquid
dose 2000, preferably as small as one pico litre. As shown in FIG.
2j, a number of nozzle openings 4620 can also be used in the plate
4610 so that array dispensing can be done.
[0135] Nozzle-plate assembly 4600 is advantageous due to its
minimization of components so that there are fewer materials in
contact with the liquid dose 2000. The dispensing operation of the
assembly 4600 is reliable since there are no narrow channels and
the design is insensitive to air entrapment. Dispensing through the
movement of plate 4610 makes the assembly 4600 easy to load and
easy to clean. Dead volume for the supply of liquid dose 2000 is
minimized or eliminated due to the planar or substantially planar
shape of plate 4610.
[0136] The present invention further contemplates the use of other
structures and methods of dispensing the liquid dose 2000 onto the
carrier tablet 1000, such as, for example, by a pad-printing device
where the drug is loaded into the ink cartridge.
[0137] Dispensing system 400 has a dose inspection system 460 that
provides real-time monitoring of each dose droplet 2100 that is to
be added to the carrier tablets 1000. In the preferred embodiment
of the machine 10, dose inspection system 460 uses high-speed
imaging of the dose droplet 2100 to determine the volume of the
droplet. Dose inspection system 460 has a high-speed camera 465,
preferably digital camera, that is connected to gantry 410 and
which is able to take a high-speed image 470 (shown in FIG. 4) of
each dose droplet 2100. In the preferred embodiment of machine 10,
two high-speed, preferably digital, cameras 465 are used, which
correspond to each of the two dispensing modules 420.
[0138] Referring to FIGS. 1 through 4, the image 470 of the dose
droplet 2100 is preferably taken in-flight after the dose droplet
has left the nozzle 450 but before it makes contact with carrier
tablet 1000. The machine 10 uses a laser detector to trigger the
camera 465 to obtain the image 470 due to the high speed of the
dose droplet 2100 (shown generally in FIG. 2d). However, the
present invention contemplates the use of other triggering devices
and methods for triggering camera 465 and obtaining image 470.
[0139] Image 470 is used by the control system 900 to calculate a
volume of each of the dose droplets 2100. The calculated volume of
the dose droplet 2100, along with the concentration obtained from
flow cell 430, is used to determine the dosage of active agent that
is being dispensed onto the carrier tablet 1000. Any dosage that
does not meet tolerances will be marked with an error code by
control system 900 so that the carrier tablet 1000 having that
particular dose droplet 2100 can be rejected.
[0140] Where higher doses of active agent are required in a
pharmaceutical product 3000, dispensing module 420 may dispense a
number of dose droplets 2100 or a stream of liquid dose 2000. Dose
inspection system 460 still has the ability to capture the image
470 of the stream of liquid dose 2000, and the volume and dosage
calculations can be made therefrom.
[0141] Dispensing system 400 has a drying system 475 that performs
drying of the dose droplet 2100 on the carrier tablet 1000. In the
preferred embodiment of the machine 10, drying system 475 has an
oven 480 and drying monitors or oven sensors 482 (not shown in
detail). The oven 480 provides heat and air flow to the dose
droplet 2100 and carrier tablet 1000 so that the film 2200 is
formed on the outer surface 1100 or substantially along the outer
surface of the carrier tablet. The oven sensors 482 monitor the
drying conditions of each of the dose droplets 2100 and carrier
tablets 1000 to ensure that the pharmaceutical product 3000 meets
the required tolerances. The heating or drying of liquid dose 2000
may evaporate excess amounts of liquid, causing the active agent to
become captured in the film 2200. The drying process of drying
system 475, as opposed to allowing the liquid dose 2000 to `air
dry` on the carrier tablet 1000, can be particularly useful where
reduction or elimination of certain excipients from the
pharmaceutical product (via evaporation), such as, for example, a
solvent like methanol, is desired.
[0142] For higher dosages of pharmaceutical product, such as, for
example, above 5 or 10 mg, drying system 475 can dry layers of the
liquid dose 2000 as they are dispensed on top of each other and/or
can dry the liquid dose on opposing sides of the carrier tablet
1000. This allows for a greater volume of liquid dose 2000 to be
carried by carrier tablet 1000.
[0143] Drying conditions, such as, for example, temperature,
air-flow and humidity are monitored by the oven sensors 482, and a
number of such sensors are used to account for any variance in
conditions along the oven 480. The data gathered by the sensors is
provided to control system 900 for evaluation of the quality of the
carrier tablets 1000 and dose droplets 2100 in each of the holding
trays 220.
[0144] In the preferred embodiment, the drying conditions are
monitored for the entire holding tray 220, and error codes can be
assigned to the individual carrier tablets 1000 and dose droplets
2100 contained therein, based upon a holding tray being affected by
an oven condition that does not meet the required tolerances.
Alternatively, portions of trays can be monitored for drying
conditions by placing more sensors 482 in the oven 480 in strategic
positions. Additionally, the present invention contemplates the
monitoring of other conditions or criteria related to the drying
process, such as, for example, conditions that may be more
significant to particular pharmaceutical product 3000.
[0145] The present invention also contemplates oven 480 being an
infrared (IR) oven and/or having a combination of IR, convection,
conduction and/or microwave heating. Drying system 475 can include
dry sensors to detect conditions, such as, for example, the surface
temperature of the carrier tablets 1000, or IR radiation. Drying
system 475 may also include a sensor for turning on the oven, such
as, for example, a photo-cell triggered by holding trays 210
entering the oven 480.
[0146] Dispensing system 400 has a dose confirmation system 500
that provides real-time monitoring, feedback and adjustment for the
liquid dose 2000 that has been added to, and dried on, the carrier
tablet 1000. In particular, the dose confirmation system 500
monitors the positioning of the liquid dose 2000 on the carrier
tablet 1000 and the amount of the liquid dose contained thereon.
Preferably, dose confirmation system 500 can also monitor the
active agent type and distribution of the liquid dose 2000 on the
carrier tablet 1000. Additionally, the dose confirmation system 500
can monitor for other substances, such as, for example, identifying
contaminants present on the carrier tablet 1000, as well as the
amount of such other substances.
[0147] The data obtained by the dose confirmation system 500 is
provided to the control system 900. The control system 900 will
assign error codes to individual carrier tablets 1000 and their
liquid doses 2000 that do not meet the required tolerances of the
pharmaceutical product 3000.
[0148] In the preferred embodiment of the machine 10, dose
confirmation system 500 has a gantry 510 (similar to gantry 410
described above) with a pair of charge coupled device (CCD) cameras
520 that obtain images 525 of each of the carrier tablets 1000. The
images 525 are provided to control system 900 for a determination
of the position of the liquid dose 2000 with respect to the carrier
tablet 1000.
[0149] Dose confirmation system 500 also has a probe 530 (shown in
FIG. 2) that is used for determining the amount, type and/or
distribution of the liquid dose 2000 on the carrier tablet 1000. In
the preferred embodiment of machine 10, the probe 530 uses
near-infrared (NIR) chemical imaging or UV induced fluorescence
chemical imaging to determine the amount of the liquid dose 2000
present on the carrier tablet 1000.
[0150] Probe 530 has components that carry out NIR chemical imaging
on each of the carrier tablets 1000 in holding tray 210, such as,
for example, fiber optics, focal plane array (FPA) detectors,
and/or charge coupled device (CCD) detectors. Additionally, liquid
crystal tunable filters can be used as wavelength selectors for the
NIR chemical imaging. The use of such components, in conjunction
with each other or alternatively, is facilitated by the positioning
of the active agent along or near the surface of the carrier tablet
1000.
[0151] The NIR chemical imaging provides good penetration into the
liquid dose 2000 and upper surface 1100 of the carrier tablet 1000
for an accurate measurement of the quantity of the liquid dose.
This technique is especially useful for the preferred dosing step
where film 2200 is positioned on the upper surface 1100 or
substantially on the upper surface of carrier tablet 1000.
[0152] In the preferred embodiment of machine 10, probe 530 uses a
focal plane array detector to obtain a signal from every point in
the sample area. The sample area preferably includes the entire
holding tray 210 so that all of the carrier tablets 1000 are being
simultaneously measured, which further improves the efficiency of
the process. The focal plane detector is able to obtain
simultaneous spectral information at every frequency for the sample
area. Probe 530 can rapidly and non-destructively measure the
liquid dose 2000 for amount, formulation and/or distribution of
active agent, as well as monitor or detect other substances
contained in or on the carrier tablet 1000.
[0153] The present invention contemplates the use of other methods
and devices for determining the presence, type, distribution and/or
amount of a particular liquid dose or doses 2000 on the carrier
tablet 1000, such as, for example, spectroscopy and/or chemical
imaging utilizing Raman and UV reflectance, and various other types
of imaging, chemical imaging and/or spectroscopy, such as, for
example, UV/visible absorption, fluorescence, laser-induced
fluorescence, luminescence, photoluminescence, terahertz, and
mid-IR. The present invention contemplates the use of various
devices or components that facilitate the use of spectroscopy
and/or chemical imaging for analysis of the pharmaceutical product
3000, such as, for example, lasers (e.g., pulse lasers), beam
splitters, water-vapor free environments (e.g., nitrogen shrouds),
optical delays (e.g., variable optical delays), antennas and/or
semi-conductors. The present invention contemplates the use of room
temperature solid state detectors and/or pulsed time-gated
techniques and components. The present invention contemplates the
use of techniques for analysis of the pharmaceutical product 3000
that are non-ionizing, non-invasive, non-destructive and/or require
low power.
[0154] The present invention contemplates the use of any regions of
the electromagnetic spectrum which allow for analysis of the
carrier tablet 1000 and liquid dose 2000, as well as various
techniques and sources for excitation in using the particular type
of spectroscopy. The present invention also contemplates the use of
other techniques and components for digital imaging to allow for
use of chemical imaging of the tablet 1000 and liquid dose 2000. It
should be further understood that dose confirmation system 500 also
contemplates the use of surrogate detection in any of the spectral
ranges.
[0155] The coating system 600 of machine 10 provides a coating 2300
(shown in FIG. 12) over the liquid dose 2000 in order to prevent
possible abrasion and the resulting loss of any active agent. The
coating 2300 may be a sealant. The coating 2300 provides a uniform
appearance for the pharmaceutical product 3000 by hiding the liquid
dose 2000. The coating can be chosen to closely resemble the color
of the carrier tablet 1000 or be another color, such as, for
example, a contrasting color to provide different commercial
images. Any minor difference in color between the coating 2300 and
carrier tablet 1000 is accounted for by having the perimeter of the
coating align with the edge of the carrier tablet.
[0156] Coating system 600 preferably has a pad-printing device 610,
a coating source 620 and a coating dryer 630. The pad-printing
device transfers the coating to the upper surface 1100 of the
carrier tablet 1000. The pad-printing device 610 is advantageous
because of its efficient transfer of the coating to the carrier
tablet without any waste, e.g., no overspray.
[0157] In the preferred embodiment of machine 10, pad-printing
device 610 is connected to or positions adjacent to the machine 10
to print an array of tablets with each reciprocating stroke.
Pad-printing device 610 can be movably connected to a gantry 615 or
other similar device to facilitate movement of the pad-printing
device with respect to the holding tray 220. The holding tray 220
continues to move as the coating 2300 is being applied by the
pad-printing device 610. However, the present invention
contemplates the use of other devices and methods of positioning
the pad-printing device 610 with respect to each of the tablet
positions 220 so that the coating 2300 is accurately applied.
[0158] The pad-printing device 610 is releasably connected to the
coating source 620. In the preferred embodiment of the machine 10,
the coating source 620 is a movable container 625 that is connected
to the pad-printing device 610 via removably connectable conduit
627, so that the coating can be quickly and efficiently
replaced.
[0159] Alternatively, a spray device or ink jet device (not shown)
can be used to spray the coating upon the carrier tablet 1000. The
spray device could also be movably connected to gantry 615 to pass
over each of the tablet positions 220. The present invention
contemplates the use of other devices and methods for applying a
coating 2300 to the carrier tablet 1000, which covers the liquid
dose 2000, such as, for example, an ultrasonic atomizer. The
coating system 600 can use intermittent, low volume atomized
sprayers to locally apply the coating 2300 over the surface of
tablet 1000 where the dosage has been applied. The sprayer may use
volumetric pumps to intermittently supply coating materials. A two
fluid air-liquid atomization sprayer may also be used to generate a
fine spray.
[0160] As described above with respect to dosing of the carrier
tablet 1000 in layers or on opposing sides, the coating system can
provide the necessary coating depending upon how the liquid dose or
doses 2000 have been added to the carrier tablet, such as, for
example, on both sides or between layers. This can facilitate the
use of higher volumes of dosages for the pharmaceutical product
3000, such as, for example above 5 or 10 mg.
[0161] Coating dryer 630 performs drying of the coating 2300 that
has been applied to the carrier tablet 1000 and over the liquid
dose 2000. The coating dryer 630 preferably has an oven 640 and
oven sensors 650 (not shown in detail). The oven 640 provides heat
and air flow to the coating 2300. The oven sensors 650, similar to
the oven sensors 482 discussed above, monitor the drying conditions
of the coatings 2300 to ensure that the pharmaceutical product 3000
meets the required tolerances.
[0162] The printing system 700 of machine 10 provides an
identification marker on the coating 2300. The printing system
preferably has a pad-printing device 710 that transfers the marker
to the coating 2300 of the carrier tablet 1000 and a pair of
cameras 720 that obtain an image 730 of each of the identification
markers to verify the quality of the image. Unacceptable tablets
will be identified by the control system 900 for subsequent
rejection by system 800.
[0163] In the preferred embodiment of machine 10, pad-printing
device 710 and cameras 720 are movably connected to a gantry 735
(similar to gantries 410, 510 and 615) to facilitate movement of
the pad-printing device with respect to the holding tray 210 that
continues to move as the identification marker is being applied.
However, the present invention contemplates the use of other
devices and/or methods for positioning the pad-printing device 710
or alternative device with respect to each of the tablet positions
220 for accurate application of the identification markers, such
as, for example, lasermarking, inkjet or rotogravure. Each of the
marker images 730 is provided to control system 900 for inspection
and to determine if the printed identification marker meets the
required tolerances of the pharmaceutical product 3000. Also, the
present invention contemplates machine 10 having an ink dryer (not
shown), such as, for example, an oven, that applies heat and/or
air-flow to the identification marker to dry it.
[0164] The acception-rejection system 800 provides a pharmaceutical
product 3000 that has undergone real-time monitoring and adjustment
for quality control to ensure that each product meets the required
tolerances. Based upon the real-time monitoring being continuously
performed at various stages of the process by machine 10, control
system 900 has designated each and every pharmaceutical product
3000 as either acceptable or rejected.
[0165] Acceptable pharmaceutical product 3000 passes through to the
delivery area (not shown in detail), preferably under pressure that
is selectively controlled by the control system 900, while rejected
product drops into a scrap area, preferably under the force of
gravity. However, the present invention contemplates the use of
other structures and methods of separating the pharmaceutical
product 3000 that is designated by control system 900 as acceptable
from the product that has been designated by the control system as
rejected.
[0166] The control system 900 coordinates and synchronizes the
various stages and systems of the machine 10. In the preferred
embodiment, control system 900 is a distributed process control
system that has a number of microprocessors 910 that control the
different systems of machine 10. The microprocessors are preferably
coordinated through a workstation 920. However, the present
invention contemplates other types of system control including
central and regional control, such as, for example, a single
microprocessor 910 controlling all of the systems or similar
systems being controlled by one of several microprocessors 910.
[0167] The microprocessors 910 and workstation 920 are in
communication with each other, preferably through a network 930
using an Ethernet switch 935, which allows for the real-time
monitoring, feedback and adjustment of the process being performed
by the machine 10. The present invention contemplates the use of
other structures and methods for communication, such as, for
example, hardwiring. The control system 900 also has an archive
microprocessor or historian 940, which is used to centrally store
the large amount of data that is compiled for each and every
pharmaceutical product 3000 that is processed by the machine 10.
However, the present invention contemplates other methods of
storage of the process data, such as, for example, microprocessors
910 individually storing the data that they have compiled.
[0168] The control system 900 preferably has a number of monitors
950 that provide displays of the data, portions of the data,
summaries of the data, and/or calculations and conclusions based
upon the data, so that the workers can monitor and/or adjust the
process as it is occurring. More preferably, the monitors 950,
through use of the various microprocessors 910 and/or workstation
920, can selectively display the data, portions of the data,
summaries of the data, calculations based upon the data, and
conclusions based upon the data. Preferably, control system 900
records data for every product 3000, which includes time, initial
tablet status, dose droplet volume, dose droplet concentration,
oven temperature, oven humidity, oven air flow, dosage location on
tablet, dosage quantity and acceptability.
[0169] The operation of the machine 10 is shown in the flow chart
of FIG. 5. The process 5000 is continuous between each stage, and
provides a pharmaceutical product 3000 that is ready for packaging.
In addition to the advantage of cost and time savings, process 5000
minimizes worker contact with the various agents, active and
inactive, of the pharmaceutical product 3000, which reduces
potential contamination, as well as providing safety to the workers
in dealing with potentially harmful active agents or other
substances such as, for example, occupational hazard category 4
(OHC4) compounds.
[0170] The ability of machine 10 to minimize or eliminate worker
contact with the product 3000 (including the addition of a
packaging step as will be described later), provides a great
advantage over contemporary processes and machines. Such
contemporary processes require special safety features, such as,
for example, dust containment devices and special handling by
workers, where OHC4 drugs are being produced. The special safety
features and special handling by workers of the contemporary
machines and processes, increases the cost of production, as well
as the time to produce the product. Machine 10 avoids such costs
and reduces the production time, through its automated, real-time
control, feedback and/or adjustment. The present invention also
contemplates the use of machine 10 in a nitrogen-enriched
environment in order to reduce or eliminate any oxidative
degradation, which is facilitated by the lack of need for worker
intervention in the process 5000.
[0171] FIG. 5 shows process 5000 in combination with processes 6000
and 7000 for the manufacture of the carrier tablet 1000 and the
liquid dose 2000, respectively. Process 5000 requires the use of
carrier tablets 1000 and liquid doses 2000. However, the carrier
tablets 1000 and liquid doses 2000 can be manufactured at other
facilities and delivered to machine 10. Also, other processes can
be used to manufacture the carrier tablets 1000 and the liquid dose
2000 that are different from those shown in FIG. 5.
[0172] Feeding step 5100 provides an array of carrier tablets 1000
that will remain securely positioned as they proceed through
machine 10 to ensure accurate dispensing of the liquid dose 2000,
coating 2300 and identification marker. The feeding step 5100 is
performed by the loading, holding and conveyor systems 100 through
300 as described above, and is subject to real-time monitoring,
feedback and adjustment by the control system 900.
[0173] The feeding step 5100 includes adjustment of the speed of
drive conveyor 310 based on a number of factors, such as, for
example, the drying time required for the liquid dose 2000 or the
amount of time required to dispense the dose droplets 2100. In the
preferred embodiment, the speed of drive conveyor 310 dictates the
speed and positioning of all other movements in machine 10, such
as, for example, synchronization of gantries 410, 510 and 615 based
upon the speed of the drive conveyor. However, the present
invention contemplates synchronization of the systems being based
off of other component's movements or other factors, which provides
accuracy in the various dispensing steps of process 5000.
[0174] The present invention also contemplates the speed of the
conveyor system 300 being adjustable based on the real-time
monitoring of the position of the liquid dose 2000 that has been
dispensed on the carrier tablet 1000. As described above, the dose
confirmation system 500 obtains images 525 of each of the positions
of the liquid dose 2000 on the carrier tablets 1000. Control system
900 could adjust the speed of the drive conveyor 310 with respect
to subsequent holding trays 220 based upon this data, such as, for
example, where the positioning of the liquid dose 2000 is
consistently off center in the same direction. Also, the feeding
step 5100 includes real-time monitoring of the quality of the
carrier tablet 1000, such as, for example, a chipped or broken
tablet, so that the carrier tablet can be designated as rejected,
which prevents the dispensing of the dose droplet 2100 on that
particular carrier tablet.
[0175] Dosing step 5200 is performed by dispensing system 400, and,
in particular, by the pair of dispensing modules 420. Control
system 900 provides a synchronized pulse to metered pump 425 to
actuate the pressurized dispensing of the dose droplet 2100.
However, the present invention contemplates the use of other
signals and techniques to actuate dispensing module 420 for
dosing.
[0176] Calibration of the dosing step 5200 is provided by a weigh
cell 455 (not shown in detail), which monitors the accuracy of the
dispensing modules 420. In operation, gantry 410 is positioned over
the weigh cell 455, and a preset number of dose droplets 2100 are
dispensed onto the weigh cell for weight measurements. This data is
compared to data collected from each of the images 470 of the
dispensed dose droplets 2100. The control system 900 can then
calibrate the dispensing system 400 based upon volume versus weight
comparisons of the preset number of dose droplets 2100.
[0177] Dose inspection step 5250 is performed by the dispensing
system 400 and, in particular, by the dose inspection system 460.
The dose inspection system 460 provides a quantitative measurement
of the dose droplet 2100 prior to it being added to the carrier
tablet 1000, and allows for rejection of those tablets receiving
droplets that do not contain the required amount of active
agent.
[0178] To calibrate the dose inspection step 5250, a vision reticle
(not shown) and calibrated volume (not shown) are provided. The
vision reticle allows for the determination of a position where the
camera 465 can be triggered to capture the image 470 of the dose
droplet 2100. The calibrated volume allows for calibration of the
dose inspection system 460. In operation, gantry 410 is positioned
over the vision reticle. The calibrated volume is released and
detected by the dose inspection system 460, and the control system
900 compares the calculated volume (from image 470) to the known
calibrated volume for calibration of the dose inspection system.
The calibration sequence can be set during the run periodically,
such as, for example, every 15 minutes, or by the number of tablets
having been processed, and/or can be set by some other standard,
which is periodic or otherwise.
[0179] The present invention contemplates real-time adjustment of
the dosing and dose inspection steps 5200 and 5250 based upon the
calibration techniques described above. These calibration steps can
be interposed between holding trays 220, and control system 900 can
adjust dispensing system 400, such as, for example, adjusting the
image volume calculation, based upon discrepancies between the
calibrated values and the measured values. Additionally, the
present invention contemplates real-time adjustment of the dosing
step 5200 based upon the real-time monitoring data obtained by dose
inspection step 5250, such as, for example, adjusting the piston
stroke of the pump 425 to account for dose droplets 2100 having too
large or too small of a volume.
[0180] The high-speed video image method described above for
determining the volume of dose droplets 2100, was compared to a
High Performance Liquid Chromatography method using a weight
analysis as a comparator. As shown in FIGS. 6 through 6e, the
sample of results using images 470 and the algorithms performed on
the images to determine the volume, provided an accurate
determination of the volume of dose droplet 2100 as it is being
dispensed.
[0181] Alternatively, dose inspection system 460 can utilize
optical profilometry for real-time monitoring and feedback control.
The components utilized by dose inspection system 460 to carry out
the optical profilometry are known to one skilled in the art, such
as, for example, a laser and camera. The technique of optical
profilometry is especially useful for larger volumes of liquid dose
2000, such as, for example, greater than 10 microliters, where the
dispensing system 400 is dispensing a stream, as opposed to the
dose droplet 2100.
[0182] For the optical profilometry technique, dose inspection
system 460 performs a first scan of the carrier tablet 1000 prior
to dispensing of the liquid dose 2000 in order to obtain a first
profile of the carrier tablet. A second scan is then performed by
the dose inspection system 460 to obtain a second profile of the
carrier tablet 1000 with the liquid dose 2000 thereon. The
difference in the first and second profiles provides the
measurement of the volume of liquid dose 2000 that has been
dispensed onto the carrier tablet 1000. The present invention
further contemplates the use of optical profilometry of the carrier
tablet 1000 after the liquid dose 2000 has been dried on the
carrier tablet. Also, the first profile may be based upon a
predetermined value for the same carrier tablets 1000 to expedite
the process and eliminate the need for two scans.
[0183] Drying step 5300 and drying air preparation step 5325 are
performed by the drying system 475 and provide for drying of the
dose droplet 2100 on the carrier tablet 1000 as the holding trays
220 move through oven 480. Various drying conditions are monitored
for acceptance or rejection of the holding trays 220. The present
invention contemplates the real-time monitoring of the drying
conditions to be used for real-time adjustment of the drying system
475, such as, for example, temperature, air-flow rate and/or
humidity being adjusted by control system 900 based upon detection
of abnormalities in these conditions.
[0184] Dose confirmation step 5350 is performed by the dose
confirmation system 500 and provides for real-time monitoring of
the position, type, distribution and amount of the liquid dose 2000
that is on the carrier tablet 1000 through use of video (or
digital) images 525 and near-infrared chemical imaging. A sample of
results of the NIR chemical imaging method are shown in FIGS. 7 and
7a.
[0185] A unique spectrum is collected for each pixel on the focal
plane array detector, which results in individual carrier tablet
data consisting of both spatially resolved spectra and wavelength
dependent images. The output can be seen as a series of spatially
resolved spectra (one for each point on the image) or as a series
of wavelength resolved images, as shown alternatively in FIGS. 7
and 7a. The amount of liquid dose 2000 present on each carrier
tablet 1000 can be determined by control system 900 based upon the
relative size of the induced image of the liquid dose and the
intensity at the individual pixels.
[0186] However, as described above, other methods can be
interchanged with the NIR chemical imaging for the analysis of the
amount of active agent. For example, FIG. 7b shows an image derived
from fluorescence where emissions were induced by subjecting the
entire holding tray 210 to UV light excitation. A visible spectrum
CCD camera was used to image the carrier tablets 1000 and each of
their liquid doses 2000. Based upon the area of the liquid doses
2000 and their gray scale intensity at individual pixels, the
amount of each liquid dose can be determined by control system 900.
FIG. 7c shows a luminescence image of a carrier tablet with only
HPC present and no image processing, in contrast to FIG. 7d which
shows a luminescence image of a carrier tablet with an active agent
and HPC present with image processing.
[0187] The present invention also contemplates the use of the
real-time monitoring to provide real-time feedback and adjustment
to the conveyor and dispensing systems 300 and 400, such as, for
example, adjusting the speed for better positioning of the dose
droplet 2100 on the carrier tablet 1000 or adjusting the pump 425
and/or nozzle 450 to increase or decrease the volume of the dose
droplet, which increases or decreases the amount of active agent
that is ultimately dried on the carrier tablet.
[0188] The use of real-time monitoring of the dose droplet 2100
both before and after contact with the carrier tablet 1000, also
would allow for more efficient accounting for any losses occurring
during the process. For example, but not limited to, if the dose
confirmation step 5350 indicated that there is far less dosage
present than was indicated by the dose inspection step 5250, the
dosing and drying steps 5200 and 5300 can be analyzed and adjusted
to account for these losses.
[0189] The coating step 5400 is performed by the coating system 600
and provides a coating 2300 over the liquid dose 2000 through use
of pad-printing device 610 or other dispensing device. FIG. 5 shows
process 5000 in combination with process 8000 for the manufacture
of the coating. Process 5000 uses an over coat for the coating 2300
but the coating can be manufactured at other facilities and
delivered to machine 10. Also, other processes can be used to
manufacture the coating, which are different from the steps shown
in process 8000.
[0190] The coating drying step 5500 and drying air preparation step
5525 are performed by the coating dryer 630 and provide for drying
of the coating 2300 that has been applied over the liquid dose
2000. Similar to the real-time monitoring, feedback and adjustment
described above with respect to the drying system 475 of the
dispensing system 400, the coating drying step 5500 can provide
real-time control of drying of the coating 2300.
[0191] The coating inspection step 5550 is performed based on the
images 730 obtained by cameras 720 of the printing system 700.
Alternatively, a separate image inspection stage, similar to the
components and control used by the printing system 700, can be
included along machine 10 after the holding trays 210 pass through
the coating dryer 630. The coating inspection step 5550 uses
real-time monitoring of the coating 2300 applied over the liquid
dose 2000 for acceptance or rejection of each pharmaceutical
product 3000. The present invention also contemplates the use of
real-time feedback and adjustment of the coating system 600 and, in
particular, the pad-printing device 610 or other dispensing device,
such as, for example, adjustment to speed, positioning, quantity
and/or pressure.
[0192] The printing step 5600 and the dispensing ink step 5625 are
performed by the printing system 700 and provide the identification
marker on the coating 2300 through use of another pad-printing
device or other dispensing device.
[0193] The printing inspection step 5650 is also performed based
upon the images 730 obtained by the cameras 720 of the printing
system 700 and determines the accurate positioning and clarity of
the identification marker. The printing inspection step 5650 uses
real-time monitoring of the identification marker applied over the
coating 2300 for acceptance or rejection of each pharmaceutical
product 3000. The present invention also contemplates the use of
real-time feedback and adjustment of the printing system 700 and,
in particular, the pad-printing device 710 or other dispensing
device, such as, for example, adjustment to speed, positioning,
quantity and/or pressure.
[0194] The delivery step 5700 is performed by the
acception-rejection system 800 and provides a pharmaceutical
product 3000 that is ready for packaging, and which has undergone
real-time monitoring, feedback and adjustment to ensure that each
of the product meets the required tolerances. Each and every
pharmaceutical product 3000 has been designated as either
acceptable or rejected, and control system 900 accepts the
selected/accepted pharmaceutical product accordingly.
[0195] The rejection step 5800 is also performed by the
acception-rejection system 800 and rejects the pharmaceutical
product 3000 that does not meet the required tolerances based upon
the data obtained throughout the process by the real-time
monitoring, feedback and adjustment of the machine 10.
[0196] Referring to FIGS. 8 through 10, another embodiment of a
pharmaceutical manufacturing apparatus or machine of the present
invention is shown and generally referred to by reference numeral
20. The machine 20 has components that are similar to the
components described above with respect to the preferred embodiment
of FIG. 1 and are similarly numbered, such as, conveyor system 300,
drug dispensing system 400 and control system 900. Machine 20 is a
scaled-down version of the preferred embodiment but still provides
real-time monitoring for the process. Each of these systems 300,
400 and 900 are operably connected to each other to efficiently and
ergonomically provide pharmaceutical product 3000 that has each
undergone real-time monitoring, and, preferably, real-time feedback
and adjustment.
[0197] Holding trays 210 are manually placed on drive conveyor 310
where the carrier tablets 1000 begin their descent through machine
20. Each holding tray 210 is identified through use of the bar code
230 on the tray and a scanner 235. The holding trays 210 continue
to move along machine 20 and pass through to the dispensing system
400 where a dispensing module 420, which is mounted to gantry 410,
dispenses dose droplets 2100 on each of the carrier tablets 1000.
Camera 465 takes an image of each dose droplet being dispensed and,
in conjunction with concentration data obtained from flow cell 430,
the real-time monitoring of the amount of active agent being
dispensed occurs.
[0198] After passing through oven 480, where the liquid dose 2000
is dried into a film 2200 on the outer surface 1100 or
substantially along the outer surface of the carrier tablet 1000,
each of the carrier tablets undergoes real-time monitoring of the
position and amount of the liquid dose. Camera 520 (shown in FIG.
9), which is mounted on gantry 510, obtains an image 525 of each of
the carrier tablets 1000 and liquid doses 2000 thereon. The images
525 are processed by control system 900 for the location and
quantity of the dose.
[0199] Under NIR or UV induced fluorescence, camera 520 captures
the image 525 of the deposition spot left after dosing and drying.
Image analysis software uses gray scale to tabulate the number of
pixels and relative intensity of the pixel to develop an image of
the dried spot left behind. High doses will give either a greater
area of coverage or a higher intensity of gray scale. Based on this
information, the dose on the tablet is determined.
[0200] The holding tray 210 is then manually removed from the drive
conveyor 310. Data has been compiled for each pharmaceutical
product 3000 regarding droplet dosage, dose position, quantity of
dose, and drying conditions. This data is used by control system
900 to provide a designation for each of the pharmaceuticals as
either acceptable or rejected. The machine 20 uses separate
scanners 235 at different stages of the machine for identification
of the individual carrier tablets 1000.
[0201] A second alternative embodiment of the pharmaceutical
manufacturing apparatus of the present invention is shown in FIG.
8a and is generally represented by reference numeral 20'. Similar
to the embodiment described above with respect to FIGS. 8 through
10, machine 20' is a scaled down version of the preferred
embodiment of machine 10 shown in FIG. 1. Machine 20' has many
features similar to machines 10 and 20, and such features are
similarly numbered, such as, conveyor system 300, and drug
dispensing system 400. Machine 20' exemplifies the modularity of
the present invention as it includes the features of machine 20 and
additionally has gantry 510, which is readily available for
connection with dose confirmation system 500.
[0202] Referring now to FIGS. 8b through 8o, there is shown a
schematic illustration of an alternative exemplary embodiment for a
spectroscopic detection system or device, which is generally
represented by reference numeral 8020. The spectroscopic detection
system 20 generally comprises at least one radiation transmission
system 8022 and a first control system 8024. Radiation transmission
system 8022 is adapted to provide or transmit incident radiation
(e.g., incident radiation pulse) to at least one pharmaceutical
sample 8010 and detect the emission radiation emitted from the
sample 8010. As illustrated in FIG. 8b, the first control system 24
preferably includes a light source 8026 for providing the desired
wavelength of light or incident radiation to the radiation
transmission system (or light probe) 8022 via excitation line
8023a, an analyzer 8028 for analyzing the emission radiation
detected by the radiation transmission system 8022, which is
communicated to the analyzer 8028 via collection line 23b, and
storage or memory system 8027 for storing emission characteristics
of selected (or desired) actives for subsequent comparison with
detected emission radiation from the sample(s) 8010. Preferably,
the excitation and collection lines 8023a, 8023b are contained
within a single optical line (e.g., fiber optic cable).
[0203] According to this alternative embodiment, the light source
8026 is adapted to generate and provide at least one incident
radiation pulse. More preferably, the light source 8026 is adapted
to generate and provide a plurality of incident radiation pulses.
As discussed in detail below, the spectroscopic detection system
8020 further includes second control (or synchronizing) system 8029
preferably in communication with the first control system 8024
(and, hence, the light source 8026, analyzer 8028 and memory system
8027) and transport system via line 8023d for (i) positioning a
respective sample 8010 proximate the light probe 8022 and (ii)
synchronizing the movement of the samples 8010 on the transport
system 8030 with at least the incident radiation generating system,
more preferably, the incident radiation transmission to and
detection of the emission radiation from the samples 8010 (see FIG.
8c).
[0204] As illustrated in FIG. 8b, the second control system 8029 is
preferably a sub-system or component of the first control system
8024. Alternatively, the second control system 8029 is a separate
component. Radiation transmission system 8022 can be various types
that are employed to effectuate the transmission of light to the
pharmaceutical sample(s) 8010 and receipt of emission radiation
therefrom, such as, for example, a conventional light probe (e.g.,
an n-around-1 fiber light probe). Preferably, the incident
radiation provided by the light probe 8022 comprises light (or
pulse thereof) in the ultraviolet-visible spectral range. The light
thus preferably has a wavelength in the range of approximately
200-800 nm. In one alternative embodiment, the light has a
wavelength in the range of approximately 225-600 nm. In a further
alternative embodiment, the light has a wavelength in the range of
approximately 300-450 nm. The wavelength of the light is preferably
active specific, i.e., based on the spectral or reflectance
characteristics of the selected active agent.
[0205] Although the spectroscopic detection system 8020 illustrated
in FIG. 8b shows one light probe 8022 and associated excitation and
collection lines 8023a, 8023b, it is to be understood that a
plurality of light probes and associated lines can readily be
employed within the scope of this alternative embodiment. As
discussed above, the emission radiation emitted by a pharmaceutical
sample (or each of a plurality of pharmaceutical samples) is
detected by the radiation transmission system or light probe 8022
and at least a first signal indicative of a respective
pharmaceutical sample emission characteristics is communicated to
the analyzer 8028. The emission radiation is then compared to the
stored emission characteristics of selected actives to determine at
least the presence and identity of an active contained in or on a
respective sample or the absence of an active in or on a respective
sample. The concentration of a detected active can also be
determined through known formulations, such as the formulation
disclosed in Massart, et al., Chemomertrics: a Textbook, Data
Handling in Science and Technology, Vol. 2 (1988), which is
incorporated by reference herein.
[0206] Referring now to FIG. 8d, there is shown an alternative
embodiment of a transport system generally designated by reference
numeral 8030 that is usable with the spectroscopic detection system
8020. As illustrated in FIG. 8d, the transport system 8030 includes
a sample table 8032, a position table 8040 and a base 8050.
[0207] Referring now to FIGS. 8e through 8g, the sample table 8032
includes at least one, and more preferably a plurality of, recessed
sample receptacles (or holders) 8034 on the top surface with each
receptacle 8034 being adapted to receive a respective
pharmaceutical sample 8010. Referring to FIGS. 8h and 8i, the
sample table 8032 further includes at least two substantially
parallel "T-shaped" slots 8036 on the bottom surface that are
adapted to slideably receive the position table tracks 8042 (see
FIG. 8d).
[0208] According to this alternative embodiment, the sample table
8032 can comprise various sizes to accommodate the desired number
of receptacles 8034. By way of illustration, in one alternative
embodiment, the sample table 8032 has a length of approximately 16
mm a width of approximately 9 mm and includes 200 receptacles 8034.
The sample table 8032 is preferably constructed of an inert
material, such as Teflon.TM., stainless steel and coated aluminum,
to substantially reduce the possibility of interference with the
transmission of light to and emission of light from the samples
8010 contained in the receptacles 8034. In an alternative
embodiment, the sample table 8032 comprises a two-piece member,
with a light-weight base portion (e.g., aluminum) and a top
receptacle portion (having the receptacles 8034 formed on the top
surface) constructed of an inert material that is secured on the
base portion.
[0209] Referring now to FIGS. 8d and 8j, there is shown the
position table 8040 of the transport system 8030. As illustrated in
FIG. 8j, the position table 8040 includes at least two "T-shaped"
tracks 8042 that preferably extend across the top surface of the
position table 8040. According to this alternative embodiment, the
position table tracks 8042 are configured and positioned for
slideable entry into and through the sample table slots 8036.
[0210] Referring now to FIG. 8k, the position table 8040 similarly
includes two substantially parallel "T-shaped" slots on the bottom
surface that are adapted to slideably receive the base tracks 8052
(see FIGS. 8d, 8l and 8m). The position table 8040 and base 8050
can be constructed out of various light-weight materials, such as
aluminum or ABS. Preferably, the position table 8040 and base 8050
are constructed out of aluminum.
[0211] Referring now to FIGS. 8d and 8n, according to the
invention, slideable engagement of position table tracks 8042 in
sample table slots 8036 effectuates substantially linear movement
of the sample table 8032 in the directions denoted by arrows X and
X' (i.e., sample path "SP.sub.1"). Slideable engagement of base
tracks 8052 in position table slots 8044 effectuates substantially
linear movement of the position table 8040 in the directions
denoted by arrows Y and Y' (i.e., sample path "SP.sub.2"). As will
be appreciated by one having ordinary skill in the art, various
conventional system can be employed within the scope of the
invention to provide the noted movement of the transport system
8030 and, hence, samples 8010. In a preferred alternative
embodiment, a pair of motorized shafts or screws 8060a, 8060b are
provided.
[0212] As illustrated in FIG. 8d, the first shaft 8060a is
preferably in communication with the sample table 8032 and provides
motive forces in the X' and X directions. The second shaft 8060d is
preferably in communication with the position table 8040 and
provides motive forces in the Y' and Y directions. As will further
be appreciated by one having ordinary skill in the art, various
alternative transport systems can be employed within the scope of
the invention. Such systems include a conventional conveyor, which
would provide a single sample path. As indicated above, the
spectroscopic detection system 8020 is further adapted to be in
synchrony with the transport system 8030 of the invention. In a
preferred alternative embodiment, the detection system 8020
includes second control system 8029 that is in communication with
the first control system 8024 and transport system 8030. The second
control system 8029 is designed and adapted to at least perform the
following functions: (i) control the positioning of a sample or
samples 8010 by the transport system 8030, (ii) position a
respective sample 8010 proximate the light probe 8022 (i.e.,
illumination position), and (iii) synchronize the movement of the
sample or samples 8010 by the transport system 8030 with at least
the incident radiation generating system (i.e., light source 8026)
of the invention, more preferably, the illumination of and
detection of emission radiation from each sample 8010 as it
traverses a respective sample path (i.e., SP.sub.1, SP.sub.2). The
noted synchronized sample transport, illumination, detection and
analysis is preferably accomplished at a minimum rate (or speed) in
the range of 1-5 samples/sec., more preferably, approximately 1
sample/sec. Thus, the method and system of the invention provides
high speed, accurate, in-situ analysis of pharmaceutical
formulations, and, in particular, drug candidate samples that is
unparalleled in the art.
[0213] Referring now to FIG. 8o, the spectroscopic system 8020
preferably includes a display system to visually display the sample
I.D., system and test parameters and, most importantly, the results
achieved by virtue of the spectroscopic system and method described
above, e.g., the presence, identity and concentration of the active
present in a sample. As illustrated in FIG. 8o, in one alternative
embodiment, the display system comprises at least one monitor 8065
that is in communication with the second control system 8029 and,
hence, first control system 8024 via line 8023c. In a further
alternative embodiment, the display system includes at least one
computer system or PC 8070 that includes an associated monitor
8072. As will be appreciated by one having ordinary skill in the
art, the computer system 8070 can further be adapted and programmed
to provide direct operator control of the first and/or second
control system 8024, 8029. In yet a further alternative embodiment,
the display system includes at least one monitor 8065 and at least
one computer system 8070.
[0214] The method for in-situ determination of the presence of an
active agent in a pharmaceutical sample in accordance with one
alternative embodiment of the invention thus comprises providing at
least one pharmaceutical sample, moving the pharmaceutical sample
along at least one sample path, generating at least one incident
radiation pulse having a wavelength in the range of approximately
200-800 nm, illuminating the pharmaceutical sample with the
radiation pulse when the sample is moved proximate the probe 8022
(i.e., illumination position), detecting the emission radiation
emitted from the pharmaceutical sample, and comparing the detected
emission radiation with stored emission characteristics of selected
actives to determine at least the presence or absence of an
active.
[0215] In a further alternative embodiment, the method for in-situ
determination of the presence of an active agent in pharmaceutical
samples comprises providing a plurality of pharmaceutical samples,
moving the pharmaceutical samples along at least one sample path,
generating a plurality of incident radiation pulses, each of the
radiation pulses having a wavelength in the range of 200-800 nm,
illuminating each of the pharmaceutical samples when moved to an
illumination position with at least a respective one of the
incident radiation pulses, detecting the emission radiation emitted
from each of the pharmaceutical samples, and comparing the emission
radiation emitted from each of the pharmaceutical samples with
stored emission radiation characteristics of pre-determined actives
to determine the presence or absence of the active. In an
additional alternative embodiment, the noted method includes the
step of synchronizing at least the step of moving the
pharmaceutical samples with the step of generating the incident
radiation pulses.
[0216] Referring to FIGS. 11 and 12, a first embodiment of the
carrier tablet 1000 and the resulting pharmaceutical product 3000,
after being processed by machine 10, are shown. The carrier tablet
1000 preferably has a recess or reservoir 1150 disposed centrally
along outer surface 1100. Reservoir 1150 provides a basin for the
dose droplet 2100 to land after being dispensed to avoid spillage.
The reservoir 1150 has a volume that is sufficient to hold the
liquid dose 2000. Depending on the viscosity of the liquid dose
2000, the volume of the reservoir 1150 may be less than the volume
of the liquid dose (where the viscosity allows the liquid dose to
curve above the open end of the reservoir) or may be equal or
slightly more than the dose volume.
[0217] The reservoir 1150 is preferably smoothly concave to
minimize or avoid splashing. However, the present invention
contemplates the use of other shapes, sizes and positions for
reservoir 1150 to facilitate the dose droplet being added to the
carrier tablet 1000. The present invention also contemplates the
outer surface 1100 not having any reservoir where the liquid dose
2000 has a high viscosity or there is strong surface tension that
prevents the dose from sliding off of the carrier tablet 1000.
[0218] The carrier tablets 1000 preferably have reservoirs 1150
formed in both outer surface 1100 and the opposing outer surface
1200. This avoids having to provide the proper orientation of the
carrier tablet 1000 during the loading stage. Carrier tablets 1000
can also be pre-coated to prevent absorption so that the film 2200
is maintained on outer surface 1100 or substantially along outer
surface 1100. However, for certain liquid doses 2000 and carrier
tablets 1000, this may be unnecessary, where there is no absorption
by the carrier tablet.
[0219] The preferred embodiment of pharmaceutical product 3000
provides the liquid dose on outer surface 1100 or substantially
along the outer surface. This prevents the active agent from
damaging the structure of the carrier tablet 1000. This also
facilitates various methods of real-time monitoring, such as, for
example, NIR chemical imaging that has the ability to analyze
through some depth but not through the entire carrier tablet.
However, the present invention contemplates dispensing the liquid
dose 2000 into the matrix of the carrier tablet 1000, where the
tablet absorbs the dose but is not de-stabilized, such as an orally
disintegrating tablet that is frequently uncoated and has a lesser
hardness than that of a conventionally compressed tablet. For
active agents that will not damage the structure of the carrier
tablet 1000, such as, for example, dissolving of portions of the
tablet, this type of dispensing is sufficient. The present
invention further contemplates a combination of absorption of the
active agent into the matrix of the carrier tablet 1000, while also
forming a film on the outer surface of the carrier tablet.
[0220] Referring to FIGS. 13 and 14, a second embodiment of a
carrier tablet 9000 and the resulting pharmaceutical product 3010,
after being processed by machine 10, are shown. The carrier tablet
9000 preferably has a recess or reservoir 9150 disposed centrally
along outer surface 9100. Reservoir 9150 provides a basin for the
dose droplet 2100 to land after being dispensed to avoid spillage.
Additionally, a second reservoir (not shown) can be used to
surround reservoir 9150, which provides a basin for the coating to
land after being dispensed to avoid spillage and to provide a more
uniform appearance.
[0221] It should be understood that alternative sizes and shapes
for carrier tablets 1000 and 9000 can also be used. For example,
but not limited to, machines 10, 20 and 20' could dispense liquid
dose 2000 into gelatin, Hydroxy Propyl Methyl Cellulose (HPMC) or
injection molded polymer capsule shells, where the shell is used to
hold the dose.
[0222] It should further be understood that some of the components
and/or systems described with respect to machines 10, 20 and 20'
may not need to be utilized for certain pharmaceutical product. For
example, but not limited to, pharmaceutical product that are
vitamins or cosmetics may not require the same rigorous quality
control for all of the criteria as compared to more powerful active
agents. In such instances, control system 900 will not apply any
unnecessary real-time monitoring activities. Additionally, control
system 900 will synchronizes the other systems based upon the lack
of use of certain systems, which will further maximize the
efficiency of the process, such as, for example, where drying of
the carrier tablet 1000 and liquid dose 2000 is minimal or not
required, the other activities can be greatly sped up.
[0223] The present invention contemplates machines 10, 20 and 20',
and the various components and systems therein, being modular. This
will allow machines 10, 20 and 20' to carry out only the necessary
activities for a particular pharmaceutical product 3000 by removing
selected unnecessary components, and will provide time saving, such
as, for example, avoiding passing holding trays 220 through the
coating dryer oven 630 where no coating is being applied.
[0224] The present invention contemplates the interchangeability of
different components to perform the various activities of machines
10, 20 and 20', such as, for example, probe 530 that performs NIR
chemical imaging being interchangeable with other probes that
perform other types of analysis, such as, for example, spectroscopy
and chemical imaging, such as, for example, utilizing Raman, UV
reflectance, fluorescence, and/or terahertz. Machines 10, 20 and
20' can utilize the type of analysis, and hence the components that
perform that analysis, which are most efficient and accurate for a
particular pharmaceutical product 3000. The present invention also
contemplates control system 900 indicating which types of analysis
and their corresponding components are to be used for a particular
pharmaceutical product 3000.
[0225] The present invention further contemplates process 5000
including a packaging step so that the end result is a product 3000
that is ready for shipping, especially where real-time release of
pharmaceutical product 3000 is utilized. The design and modularity
of machines 10, 20 and 20' facilitates the addition of a packaging
step to process 5000.
[0226] Machines 10, 20 and 20' also provide the ability to change
production to a different pharmaceutical product 3000 in a fraction
of the time that it takes to make a similar adjustment to a
contemporary machine. The cleaning of the machines 10, 20 and 20'
for a change of production to a different pharmaceutical product
3000 requires only the cleaning of the dispensing module 420, which
can be quickly disassembled. Dispensing modules 420 are relatively
low-cost which allows for their replacement rather than a
time-consuming repair.
[0227] Machines 10, 20 and 20' and process 5000 improve efficiency
in manufacturing the pharmaceutical product 3000 based upon the
manufacturing steps as well as the quality control steps. The
continuity of process 5000 quickly and efficiently provides the
product 3000 that is directly ready for packaging, without the need
for any quality control testing, e.g., wet chemistry, being
performed on them. Also, machines 10, 20 and 20' provide the
process 5000 that can be run continuously without the need for
stopping as in contemporary devices and techniques.
[0228] The real-time monitoring, feedback and adjustment of the
present invention avoids unnecessary manufacturing steps (e.g.,
dispensing on rejected tablets) and provides quality control based
on the individual properties of each of the pharmaceutical tablets
3000. The present invention is cost effective because it only
discards the defective product 3000 identified by control system
900, rather than discarding all of the product in a batch that has
a significant number of defective tablets, as by contemporary
methods of product sampling.
[0229] Process 5000 is particularly efficient at the production of
low dosage pharmaceuticals, e.g., less than 5 mg of active agent.
Process 5000 provides for the depositing of precise amounts of the
active agent and is thus particularly useful at the lower dosages,
e.g., 1 .mu.g to 1000 .mu.g. Although, machines 10, 20 and 20' and
process 5000 can produce pharmaceuticals with higher amounts of
dosages, e.g., greater than 5 mg, as well as pharmaceutical-like
products, such as, for example, vitamins.
[0230] The dispensing performed by process 5000 results in a dosage
of active agent for the product with a content uniformity for the
batch that is preferably less than 5% relative standard deviation
(RSD), more preferably less than 3% RSD, and most preferably less
than 2% RSD. The accuracy in dispensing of the active agent by
process 5000 is over any range of dosage. The advantage of process
5000, and the resulting accuracy of the dispensing, is especially
evident at lower dosages compared to contemporary manufacturing
processes.
[0231] The present invention contemplates the use of coatings
and/or additives in combination with the liquid dose 2000 for the
purpose of controlling the rate of release of the pharmaceutical
product along the Gastro Intestinal (GI) track. As described above,
where a plurality of active agents are dispensed onto carrier
tablet 1000, such as, for example by layering or on opposing sides
of carrier tablet 1000, the release of the different active agents
can be controlled to occur at desired areas along the GI track
through use of the coatings and/or additives.
[0232] The present invention contemplates the use of individual
systems or combinations of systems of machines 10, 20 and 20' in
combination with other devices, to provide one or more of the steps
described in process 5000. For example, but not limited to,
dispensing module 420 (including pump 425, flow cell 430 and
dispensing head 435) and dose inspection system 460 can be operably
connected to a blister filling machine (not shown).
[0233] The combination of dispensing module 420 and dose inspection
system 460 with the blister filling machine would allow for tablets
that are held in the thermoformed pockets of the blister package to
receive the liquid dose 2000 from the dispensing module. Similar to
the real-time monitoring, feedback and control described above with
respect to machines 10, 20 and 20', the positioning of dispensing
module 420 with respect to the blister package, and, in particular,
each of the tablets, would be adjusted to provide for accurate
dispensing.
[0234] The combination of dispensing module 420, dose inspection
system 460 and the blister filling machine would further provide
for quality control assessment of each and every tablet. If one or
more of the tablets of a blister package were found to not meet the
required tolerances, then the entire blister package would be
rejected. Based upon the accuracy of dispensing module 420, which
will provide a very low rejection rate of tablets, this would still
be a commercially viable process. Alternatively, any tablet that
was rejectable would be removed from the blister package and
replaced by another tablet that was taken from a reservoir of
acceptable tablets.
[0235] It should be further understood by one of ordinary skill in
the art that the degree of real-time monitoring and/or feedback can
be varied depending upon the particular product being manufactured
and/or based upon other factors. For example, but not limited to,
the machine 10, 20 and 20' may only utilize the high-speed imaging
for detection of whether the dose droplet 2100 has accurately been
dispensed upon carrier substrate 1000. Preferably the volume
calculation of dose inspection system 460 is also utilized to
calculate the amount of liquid dose 2000 in the dose droplet 2100.
However, the use of contemporary quality control techniques is also
contemplated, such as batch sampling. Also, the present invention
contemplates the use of contemporary quality control techniques,
such as, for example, batch sampling, in parallel with the
real-time monitoring and/or feedback described herein for machines
10, 20 and 20'.
[0236] It should be further understood by one of ordinary skill in
the art that the various devices, techniques and/or systems
described herein for machines 10, 20 and 20' can be utilized by
themselves or in combination with one or more of the other systems
of machines 10, 20 and 20' or in combination with contemporary
devices for manufacturing pharmaceutical and pharmaceutical-like
product. For example, but not limited to, the high-speed imaging
and volume calculation of dose inspection system 460 may be
followed by a contemporary batch sampling technique for quality
control of the resulting pharmaceutical product 3000.
[0237] The video imaging and volume calculation of dose inspection
system 460 provides versatile real-time monitoring and feedback
control for the pharmaceutical product 3000. This type of quality
control is not dependent on the particular formulation of the
active agent in the liquid dose 2000, as opposed to some forms of
chemical imaging which have such dependency.
[0238] The present invention contemplates the use of other
techniques for real-time monitoring and/or feedback control for
machines 10, 20 and 20' including both contact and non-contact
methods. Alternative non-contact monitoring techniques include
measurement of change in the capacitance before and after
dispensing, measurement of electrical field produced by liquid dose
2000 due to magnetics, and micro-electro-mechanical-systems, such
as, for example, utilizing piezo-resistive pressure sensors. An
alternative contact monitoring technique includes measurement of
the conductance of liquid dose 2000. The present invention
contemplates these alternative contact and non-contact techniques
being used instead of either or both of the dose inspection system
460 and the dose confirmation system 600, as well as in combination
with either or both of the systems, where such alternative
techniques are able to appropriately monitor the pharmaceutical
product being processed, as desired.
[0239] It should also be noted that the terms "first", "second",
"third", "fourth", "upper", "lower", and the like, are used herein
to modify various elements. These modifiers do not imply a spatial,
sequential, or hierarchical order to the modified elements unless
specifically stated.
[0240] While the present invention has been described with
reference to one or more exemplary embodiments, it will be
understood by those skilled in the art that various changes may be
made and equivalents may be substituted for elements thereof
without departing from the scope of the present invention. In
addition, many modifications may be made to adapt a particular
situation or material to the teachings of the disclosure without
departing from the scope thereof. Therefore, it is intended that
the present invention not be limited to the particular
embodiment(s) disclosed as the best mode contemplated, but that the
invention will include all embodiments falling within the scope of
the appended claims.
* * * * *