U.S. patent application number 12/218504 was filed with the patent office on 2009-12-03 for high-volume on-line spectroscopic composition testing of manufactured pharmaceutical dosage units.
Invention is credited to Linda H. Kidder, E. Neil Lewis, David J. Strachan.
Application Number | 20090294673 12/218504 |
Document ID | / |
Family ID | 30773421 |
Filed Date | 2009-12-03 |
United States Patent
Application |
20090294673 |
Kind Code |
A1 |
Lewis; E. Neil ; et
al. |
December 3, 2009 |
High-volume on-line spectroscopic composition testing of
manufactured pharmaceutical dosage units
Abstract
Disclosed are pharmaceutical dosage unit manufacturing process
control apparatus and methods. These can include acquiring a
plurality of multi-pixel images of a flow of pharmaceutical dosage
units at different wavelengths along an axis that is perpendicular
to a direction of the flow of pharmaceutical dosage units,
processing the images acquired in the step of acquiring, and
providing an indication about the flow of pharmaceutical dosage
units based on the step of processing.
Inventors: |
Lewis; E. Neil; (Brookville,
MD) ; Strachan; David J.; (Baltimore, MD) ;
Kidder; Linda H.; (Wolney, MD) |
Correspondence
Address: |
KRISTOFER E. ELBING
187 PELHAM ISLAND ROAD
WAYLAND
MA
01778
US
|
Family ID: |
30773421 |
Appl. No.: |
12/218504 |
Filed: |
July 15, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10776029 |
Feb 10, 2004 |
7399968 |
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12218504 |
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09507293 |
Feb 18, 2000 |
6690464 |
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10776029 |
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60143801 |
Jul 14, 1999 |
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60120859 |
Feb 19, 1999 |
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Current U.S.
Class: |
250/339.12 |
Current CPC
Class: |
G01N 21/31 20130101;
G01N 21/253 20130101 |
Class at
Publication: |
250/339.12 |
International
Class: |
G01J 5/02 20060101
G01J005/02 |
Claims
1. A pharmaceutical dosage unit manufacturing process control
apparatus, comprising: an image sensor including an array of
detector elements located generally along an axis that is
perpendicular to a direction of a flow of pharmaceutical dosage
units, a spectrally selective element located in an optical path
between a radiation source, the flow of pharmaceutical dosage
units, and the image sensor, and a spectral processor responsive to
an output of the array sensor and having an output port.
2. The apparatus of claim 1 wherein the spectral processor includes
a color mapping module operative to map spectral information into a
color image including differently colored areas that correspond to
different parts of the flow of pharmaceutical dosage units having
differing responses to different wavelengths.
3. The apparatus of claim 2 further including an additional
processor operative to evaluate the differently colored areas, the
additional processor having an input responsive to the mapping
module and an output for providing information about the areas.
4. The apparatus of claim 2 wherein the mapping module is operative
to shift a plurality of the wavelengths in a similar manner.
5. The apparatus of claim 1 wherein the spectral processor includes
a spectral comparison module operative to compare spectral
signatures from a library of known spectral signatures with
spectral information acquired from the image sensor.
6. The apparatus of claim 5 wherein the spectral comparison module
is operative to perform spectral comparisons between the spectral
information acquired from the image sensor and spectral signatures
for known ingredients in a pharmaceutical composition of the dosage
units.
7. The apparatus of claim 5 wherein the processor is operative to
receive, identify, and store newly detected spectral signatures
reported by the spectral comparison module.
8. The apparatus of claim 5 wherein the library of known spectral
signatures includes a plurality of spectral signatures for known
defects.
9. The apparatus of claim 8 wherein the processor is operative to
receive, identify, and store spectral signatures for newly detected
defects reported by the spectral comparison module.
10. The apparatus of claim 1 wherein the spectral processor
includes a spectral comparison module operative to compare spectral
information received by the image sensor from a reference sample
located proximate the flow of pharmaceutical dosage units with
spectral information received by the image sensor from the flow of
pharmaceutical dosage units.
11. The apparatus of claim 1 wherein the image sensor is a
two-dimensional array sensor that further includes detectors
located generally along an axis that is parallel to the direction
of the flow of pharmaceutical dosage units.
12. The apparatus of claim 11 wherein the spectrally selective
element includes a diffraction grating.
13. The apparatus of claim 11 wherein the spectral processor
includes a color mapping module operative to map spectral
information into a color image including differently colored areas
that correspond to different parts of the flow of pharmaceutical
dosage units having differing responses to different
wavelengths.
14. The apparatus of claim 1 further including an image processor
responsive to the output port of the spectral processor and
operative to evaluate information from the spectral processor.
15. The apparatus of claim 1 wherein the image sensor is an
infrared image sensor.
16. The apparatus of claim 1 wherein the image sensor is a near
infrared image sensor.
17. The apparatus of claim 1 further including the radiation source
directed at the flow of pharmaceutical dosage units at a position
to which the array sensor is responsive.
18. The apparatus of claim 17 wherein the radiation source is an
infrared radiation source.
19. The apparatus of claim 1 wherein the flow of pharmaceutical
dosage units includes a series of dosage units located in rows
generally perpendicular to the direction of the flow of
pharmaceutical dosage units and wherein the image sensor includes,
for each of the dosage units in a row, a plurality of detectors
along the axis that is perpendicular to the direction of the flow
of pharmaceutical dosage units.
20. The apparatus of claim 1 wherein the spectral processor is a
real-time processor operative to process the images at a rate that
is at least equal to a rate at which images are acquired by the
image sensor.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This patent application is a continuation of application
Ser. No. 10/776,029 filed on Feb. 10, 2004, now U.S. Pat. No.
7,399,968 issued on Jul. 15, 2008, which is a continuation of
application Ser. No. 09/507,293 filed on Feb. 18, 2000, now U.S.
Pat. No. 6,690,464 issued on Feb. 10, 2004, which claims the
benefit under 35 U.S.C. .sctn. 119 (e) of U.S. provisional
application No. 60/143,801 filed on Jul. 14, 1999 and of U.S.
provisional application No. 60/120,859 filed on Feb. 19, 1999,
which are all herein incorporated by reference.
FIELD OF THE INVENTION
[0002] This invention pertains to quality control systems and
methods that detect process defects in large-scale manufacturing
processes, such as the manufacture of pharmaceutical dosage units,
using continuous spectral imaging techniques.
BACKGROUND OF THE INVENTION
[0003] Defects in pharmaceutical products can be highly dangerous,
or even fatal. And even if such defects are relatively minor, such
as non-uniformly sized capsules, they can result in a significant
loss of goodwill by the manufacturer. It is therefore of the utmost
importance to avoid such defects.
[0004] Several approaches now exist to screen pharmaceutical agents
packaged in predetermined dosage units, such as capsules or
tablets. These include off-line and on-line methods. Off-line
methods include-the testing of samples of reagents and end-products
using various analytical methods. On-line methods attempt to
monitor the process of manufacturing the product to detect defects
as they occur.
[0005] A number of on-line screening approaches currently exist.
One approach includes adding coloring agents to bulk ingredients
and optically checking the shape, integrity, and color of the final
product. Systems employing this approach can take a series of video
images of dosage units and use image processing methods to assess
the shape and color of the dosage units. Other systems employ
groups of discrete optical detectors to detect different colors and
infrared detectors to detect the scattering caused by structural
defects. These systems can be complicated to install and maintain,
and cannot guarantee a defect-free product.
SUMMARY OF THE INVENTION
[0006] Several aspects of the invention are presented in this
application. These relate to improvements to process control
apparatus and methods, including apparatus and methods that detect
process defects in large-scale manufacturing processes, such as the
manufacture of pharmaceutical dosage units, using continuous
spectral imaging techniques.
[0007] Systems according to the invention are advantageous in that
they can continuously test the actual composition of each dosage
unit within its packaging. Such systems can therefore screen for
errors in coloring of ingredients, for contamination or breakdown
that occurs independent of coloring, and for other types of errors
that might not otherwise be detected. And because systems according
to the invention can perform their composition measurements through
the end-user package walls, they can detect contamination or damage
that occurs during packaging.
[0008] Performing composition analysis by comparing spectral
information with libraries of known spectral signatures, allows
small concentrations of potentially dangerous contaminants, such as
potent toxins, to be detected. Without being correlated to a
specific spectral signature, such small concentrations might have
little effect on prior art process monitoring methods, and might
therefore be dismissed as within an error margin.
[0009] Performing composition analysis by comparing spectral
information with libraries of known spectral signatures may also
allow for the detection of unexpected components. Comparing
acquired spectral information with libraries of components may
uncover contaminants not normally associated with the process. This
may allow a manufacturer to avert hazards that arise out of
unforseen circumstances, such as supplier errors or deliberate
tampering.
[0010] Performing composition analysis by comparing spectral
information with libraries of known spectral signatures may further
allow for the detection of subtle shifts in the process. Because
relative quantities of ingredients can be directly measured, a
change in the ratio of these ingredients can be detected. While
such changes may not warrant rejection of the products, they may
allow the process to be optimized and prevent the process from
drifting out of its intending operating range.
[0011] Systems according to the invention may also be advantageous
in that they can allow a process engineer to select optimal process
variables to monitor. By mapping selected spectral information into
an image, which is then processed by an image processor, systems
according to the invention can apply the image processing resources
to the spectral data that correlates best to known and predicted
failure modes. And because the system acquires information about a
large number of wavelengths simultaneously, a system operator can
try a number of different approaches to achieve the best
results.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1 is a diagram of an embodiment of a pharmaceutical
dosage unit manufacturing process control system according to the
invention, including a perspective portion illustrating the
relationship between the image sensor, the spectrally selective
element, and the process stream;
[0013] FIG. 2 is a plan view diagram of an image sensor for use
with the process control system of FIG. 1;
[0014] FIG. 3 is a plan view diagram illustrating output of the
system of FIG. 1;
[0015] FIG. 4 is a flowchart illustrating the operation of the
embodiment of FIG. 1; and
[0016] FIG. 5 is a diagram of a second embodiment of a
pharmaceutical dosage unit manufacturing process control system
according to the invention, including a perspective portion
illustrating the relationship between the image sensor, the
spectrally selective element, and the process stream.
[0017] In the figures, like reference numbers represent like
elements.
DESCRIPTION OF AN ILLUSTRATIVE EMBODIMENT
[0018] Referring to FIG. 1, a pharmaceutical dosage unit
manufacturing process control system according to the invention
features an image sensor 10 and a spectrally selective element 12
facing a web 16 that carries a series of parallel rows of
pharmaceutical dosage units 18, such as capsules, tablets, pellets,
ampoules, or vials, in a process flow direction. For example, the
web can carry a continuous stream of blister-packaged tablets from
the output of a packaging machine. The image sensor is a
multi-element sensor that includes at least a series of adjacent
sensing elements located generally along an axis that is
perpendicular to the flow direction. The spectrally selective
element is a wavelength separating element, and is preferably a
dispersive element, such as a diffraction grating or a prism-based
monochromator.
[0019] Referring to FIGS. 1-2, the image sensor 10 is preferably a
two-dimensional array sensor that includes a two-dimensional array
of detector elements made up of a series of lines of elements
(A1-An, B1-Bn, . . . N1-Nn) that are each located generally along
an axis that is perpendicular to the flow direction. The image
sensor can include an array of integrated semiconductor elements,
such as a Charge-Coupled Device (CCD) array, and is preferably
sensitive to infrared radiation. Uncooled Idium-Galium-Arsenide
(InGaAs) arrays, which are sensitive to near infrared wavelengths,
are suitable image sensors, although sensitivity to longer
wavelengths would be desirable. It is contemplated that the sensors
should preferably have dimensions of at least 64.times.64 or even
256.times.256. Where such sensors are not square, they should-be
oriented with their longer dimension in the direction of the
process flow, as spectral information appears to be typically more
important than spatial information given the nature of
pharmaceutical mass-production equipment.
[0020] The system also includes an image acquisition interface 22
having an input port responsive to an output port of the image
sensor 10. The image acquisition interface receives and/or formats
image signals from the image sensor. It can include an off-the
shelf frame buffer card with a 12-16 bit dynamic range, such as are
available from Matrox Electronic Systems Ltd. of Montreal, Canada,
and Dipix Technologies, of Ottawa, Canada.
[0021] A spectral processor 26 has an input responsive to the image
acquisition interface 22. This spectral processor has a control
output provided to a source control interface 20, which can power
and control an illumination source 14. The illumination source for
near infrared measurements is preferably a Quartz-Tungsten-Halide
lamp.
[0022] The spectral processor 26 is also operatively connected to a
standard input/output (IO) interface 30 and to a local spectral
library 24. The local spectral library includes locally-stored
spectral signatures for known process components. These components
can include ingredients, process products, or results of process
defects or contamination. The IO interface can also operatively
connect the spectral processor to a remote spectral library 28.
[0023] The spectral processor 26 is operatively connected to an
image processor 32 as well. The image processor can be an
off-the-shelf programmable industrial image processor, that
includes special-purpose image processing hardware and image
evaluation routines that are operative to evaluate shapes and
colors of manufactured objects in industrial environments. Such
systems are available from, for example, Cognex, Inc.
[0024] In one embodiment, the system is based on the so-called
IBM-PC architecture. The image acquisition interface 22, IO
interface 30, and image processor 32 each occupy expansion slots on
the system bus. The spectral processor is implemented using
special-purpose spectral processing routines loaded on the host
processor, and the local spectral library is stored in local mass
storage, such as disk storage. Of course, other structures can be
used to implement systems according to the invention, including
various combinations of dedicated hardware and special-purpose
software running on general-purpose hardware. In addition, the
various elements and steps described can be reorganized, divided,
and combined in different ways without departing from the scope and
spirit of the invention. For example, many of the separate
operations described above can be performed simultaneously
according to well-known pipelining and parallel processing
principles.
[0025] In operation, referring to FIGS. 1-4, the spectrally
selective element 12 is sensitive to the radiation reflected off of
a line across the process web 16, and collimated by a first-stage
optic, such as a lens (not shown). The spectrally selective element
separates the spectral components of the reflected radiation along
the axis of the process flow. As a result, the successive lines
A1-An, B1-Bn, . . . N1-Nn of the image sensor are exposed to
spectral components of the radiation that are of successively
higher or lower wavelengths, depending on the relative orientation
of the spectrally selective element and the image sensor. In one
embodiment, a portion of the line image extends beyond the web to
overlap with a stationary reference sample 19 located adjacent the
web. This implementation can allow for the removal of transfer of
calibration requirements between systems that collect pure
component spectra for spectral comparison.
[0026] At a predetermined repetition rate, the image acquisition
interface 22 acquires a data set representative of the radiation
incident on the image sensor (i.e., a spectral line image--step
40). This data set includes image values for each of the pixels
along the imaged line on the process web at a number of different
wavelengths. In the case of a 256.times.256 array, intensity values
at 256 different wavelengths will be stored for each of 256 points
on the imaged line. Once it has been acquired, the image
acquisition interface transfers this data set to the spectral
processor 26.
[0027] The spectral processor 26 then evaluates the acquired
spectral line image (step 42). This evaluation can include a
variety of univariate and multivariate spectral manipulations.
These can include comparing received spectral information with
spectral signatures stored in the library, comparing received
spectral information attributable to manufactured dosage units with
information attributable to the reference sample, or evaluating
simplified test functions, such as looking for the absence of a
particular wavelength or combination of wavelengths. Multivariate
spectral manipulations are discussed in more detail in
"Multivariate Image Analysis," by Paul Geladi and Hans, Grahn,
available from John Wiley, ISBN No. 0-471-93001-6, which is herein
incorporated by reference.
[0028] As a result of its evaluation, the spectral processor 26 may
detect known components (step 44) and/or unknown components (step
46). If an unknown component is detected, the system records a
spectral signature entry for the new component type in the local
spectral library 24 (step 48). The system can also attempt to
identify the newly detected component in an extended or remote
library 28, such as by accessing it through a telephone line or
computer network (step 50). The system then flags the detection of
the new component to the system operator, and reports any retrieved
candidate identities (step 52).
[0029] Once component identification is complete, the system maps
the different detected components into a color (such as grayscale)
line image (step 54). As the system processes further spectral line
images, it accumulates a two-dimensional colored image frame. When
complete, this image can be transferred to the image processor
(step 58), which evaluates the shape and color of the dosage units
(step 60), issues rejection signals for rejected dosage units, and
compiles operation logs.
[0030] As shown in FIG. 3, the color image will resemble the
process web, although it may be stretched or squeezed in the
direction of the process flow, depending on the acquisition rate.
The image can include a color that represents the composition of
the web 16. It will can also include colors that represent known
good components 18A, colors that represent known defect components
18B, and colors that represent unknown components 18C. The mapping
can also take the form of a spectral shift, in which some or all of
the acquired spectral components are shifted in a similar manner,
preserving the relationship between wavelengths. Note that because
the image maps components to colors, it provides information about
spatial distribution of the pharmaceutical composition in addition
to identifying its components.
[0031] While the system can operate in real-time to detect
defective products, its results can also be analyzed further
off-line. For example, some or all of the spectral data sets, or
running averages derived from these data sets can be stored and
periodically compared with extensive off-line databases of spectral
signatures to detect possible new contaminants. Relative spectral
intensities arising from relative amounts of reagents or
ingredients can also be computed to determine if the process is
optimally adjusted.
[0032] Note that the system presented above is self-scanning.
Although it can be synchronized with the process by a sensor, such
synchronization is not required. The system can therefore be easily
retrofit to existing installations and does not require any moving
parts.
[0033] The acquisition method employed by the process control
system can also be computationally efficient. Since data is
acquired and spectrally processed on a line-by-line basis, the
spectral processor does not have to store large amounts of
intermediate results. Once a line has been mapped to a colored line
image, all of the acquired data and intermediate results can be
discarded, and a new line processed. This can allow the system to
operate in real time with relatively simple computer components,
keeping the overall system cost low.
[0034] Referring to FIG. 5, a second embodiment of a pharmaceutical
dosage unit manufacturing process control system according to the
invention includes a variable-bandpass filter 12a between the
two-dimensional array sensor and the process stream. This filter
has a narrow pass-band with a center wavelength that varies along
the process direction. The leading edge A of the filter passes
shorter wavelengths, and as the distance from the leading edge
along the process flow direction increases, the filter passes
successively longer wavelengths. At the trailing edge N of the
filter, the filter passes a narrow range of the longest
wavelengths. The orientation of the filter can also be reversed, so
that the pass-band center wavelength decreases along the process
flow direction. Although the filter has been illustrated as a
series of strips located perpendicular to the process flow
direction, it can be manufactured in practice by continuously
varying the dielectric thickness in an interference filter.
Preferably, the filter should have a range of pass-bands that
matches the range of the camera. Suitable filters are available,
for example, from Optical Coatings Laboratory, Inc. of Santa Rosa,
Calif.
[0035] In operation of this embodiment, acquisition interface 22
acquires data representing a series of variably-filtered,
two-dimensional images. These two-dimensional images each include
image values for the pixels in a series of adjacent lines
perpendicular to the process web. Because of the action of the
variable-bandpass filter, the detected line images that make up
each two-dimensional image will have a spectral content that varies
along the process direction.
[0036] The variably filtered images are combined as they are
acquired in order to obtain full-range spectral images. As each
imaged line progresses along the web, each successive line (N1 . .
. A1) of elements in the array sensor 10 will sense radiation that
has been filtered through a corresponding line (N . . . A) of the
filter. These individual line images can be assembled to create a
full-spectrum line image. The assembly can take place by itself, or
in combination with other operations, such as digital filtering
operations. This embodiment is particularly advantageous because
the variable-bandpass filter is relatively inexpensive and
robust.
[0037] Another approach involves the use of an optical system that
simultaneously projects a number of spectrally-discrete versions of
the same two-dimensional image onto the array sensor 10. Such
systems are described in PCT application No. PCT/US98/14218
published under No. WO09902950, which are herein incorporated by
reference. The use of these systems is advantageous in that they
allow high data throughputs for a given web speed, without adding
moving parts. Systems of this type are available from Optical
Insights, Inc of Tucson, Ariz.
[0038] A further embodiment employs multi-source arrays to provide
successive illumination at different wavelengths and thereby obtain
spectral information from the process. Such arrays are described in
a copending provisional application entitled "Multi-Source Arrays,"
filed on the same day as this application, and herein incorporated
by reference.
[0039] The present invention has now been described in connection
with a number of specific embodiments thereof. However, numerous
modifications which are contemplated as falling within the scope of
the present invention should now be apparent to those skilled in
the art. For example, aspects of the invention may also be
applicable to other types of manufacturing processes, such in
detecting the presence of undesirable by-products in the
manufacture of plastic articles. In addition, while a
two-dimensional image sensor with a dispersive or graded spectrally
selective element is at present contemplated to be the best
approach to acquiring line image data, a one-dimensional image
sensor coupled with a high-speed filtering system might allow a
suitable amount of data to be acquired in some circumstances.
Therefore, it is intended that the scope of the present invention
be limited only by the scope of the claims appended hereto. In
addition, the order of presentation of the claims should not be
construed to limit the scope of any particular term in the
claims.
* * * * *