FIELD OF INVENTION

The present invention relates broadly to the inspection of the integrity of blister packaging for pharmaceutical tablets, specifically to the non-destructive inspection of the integrity of blister packaging for pharmaceutical tablets.

BACKGROUND

Any mention and/or discussion of prior art throughout the specification should not be considered, in any way, as an admission that this prior art is well known or forms part of common general knowledge in the field.

To ensure that the produced drugs and medicine in pharmaceutical industries cater to consumer demands in terms of safety, quality and quantity is highly dependent on the efficiency and efficacy of pharmaceutical packing as well as defect identification. Any deviation to maintain stringent quality standards in pharmaceutical products puts the consumers’ life at risk.

In particular, over-the-counter (OTC) drugs and medicines, which are mass-produced and packaged at a very high speed, may suffer from defective packaging. Pharmaceutical industries use blister packaging or PTP (press through packaging), for such products requiring unit-dose confinement like tablets, capsules, lozenges, etc. to maintain the high production assembly line throughput. Blister packs confine the products in a cavity and a lidding material seals the cavity, usually with a paper backing or aluminum or film seal. The main advantages of blister packaging include stable and reliable storage condition of the medicine, unit dose and serial packaging; safe, hygienic, portable and convenient packaging; increased shelf life; and tamper evident to counter forgery. While systems/packaging designs have been proposed to aid in the monitoring of the dispensing of content such as tablets from the blisters by end-users (e.g. US 5,412,372, WO 2018/044313 Al), such systems/packaging designs crucially rely on the initial integrity of the blister package as fabricated on the production assembly line. Poor or tampered sealing of the fabricated blister package increases the risk of exposure to external environmental factors such microbes, gas, light and temperature, which could degrade product quality and prove fatal for the consumers. Recognizing defects in such blister packs without compromising on the throughput is a challenge.

Popular approaches in pharmaceutical industries for blister package integrity testing include vacuum leak test, internal pressure method, trace gas detection method and visual inspection. The existing available test methods for blister packages are destructive and unreliable because small semi-rigid, flexible and multi-cavity blister packages do not have enough air inside the package to identify defects by simple vacuum decay methods. Moreover, immersion of such packages in water is detrimental towards both the product and package to detect small defects. In addition, most test methods require offline analysis, use of expensive equipment, have low throughput and high processing time, and generate large rejects and waste, which affects the production/packaging cost and time.

Embodiments of the present invention seek to address at least one of the above problems.

SUMMARY

In accordance with a first aspect of the present invention, there is provided a method of integrity testing of a blister package, the method comprising the steps of:

providing an electrode structure comprising at least one pair of electrodes;

disposing a blister of the blister package relative to the electrode structure such that the blister is subjectable to an electric field resulting from the application of an AC bias voltage to the electrode structure;

applying the AC bias voltage to the electrode structure;

measuring an electrical property of the blister over a frequency range while the AC bias voltage is varied over the frequency range; and

determining the integrity of the blister package based on the measured electrical property of the blister over the frequency range.

In accordance with a second aspect of the present invention, there is provided a system for integrity testing of a blister package, the system comprising:

an electrode structure comprising at least one pair of electrodes;

a source for application of an AC bias voltage to the electrode structure such that a blister of the blister package disposed relative to the electrode structure is subjectable to an electric field;

a measuring unit configured to measure an electrical property of the blister over a frequency range while the AC bias voltage is varied over the frequency range; and

a processing unit for determining the integrity of the blister package based on the measured electrical property of the blister over the frequency range. BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments of the invention will be better understood and readily apparent to one of ordinary skill in the art from the following written description, by way of example only, and in conjunction with the drawings, in which:

Figure 1A) shows a schematic representation of cross section of a good blister package unit with tablet in cavity.

Figure 1B) shows a schematic representation of cross section of a blister package unit with defective lid with tablet in blister.

Figure 1C) shows a schematic representation of cross section of a blister package unit with defective lid and no product filling.

Figure 1D) shows a schematic representation of cross section of a blister package unit with no lid and no tablet.

Figure 2A) shows a schematic representation of the cross-section of a single unit of a blister pack with the two electrodes for testing, according to an example embodiments.

Figure 2B) shows photographs of circular disk and blister cavity shaped electrode for use in an example embodiment.

Figure 3A) shows plots of impedance (in Ohms) vs frequency (in Hertz)for four experimental cases according to example embodiments: (I) blister unit with tablet, (II) blister unit with tablet and tampered lid,( III) blister unit with tablet and no lid, and (IV) blister unit with no tablet and no lid.

Figure 3B) shows plots of phase (in Degrees) vs frequency (in Hertz) for four experimental cases according to example embodiments: (I) blister unit with tablet, (II) blister unit with tablet and tampered lid,( III) blister unit with tablet and no lid, and (IV) blister unit with no tablet and no lid.

Figure 3C) shows plots of capacitance (in Farads) vs frequency (in Hertz) for four experimental cases according to example embodiments: (I) blister unit with tablet, (II) blister unit with tablet and tampered lid,( III) blister unit with tablet and no lid, and (IV) blister unit with no tablet and no lid.

Figure 4A) shows a schematic diagram illustrating interdigitated ring electrodes for use in example embodiments.

Figure 4B) shows schematic diagrams of different possible textured surfaces (pyramids, saw tooth and pores) of electrodes for use in example embodiments.

Figure 4C) shows a schematic diagram illustrating an array detection set up according to an example embodiment. Figure 4D) shows a schematic diagram illustrating cross-section of non-contact detection scheme for blister-package integrity testing according to an example embodiment.

Figure 5 shows a flowchart illustrating a method of integrity testing of a blister package, according to an example embodiment.

Figure 6 shows a schematic drawings illustrating a system for integrity testing of a blister package, according to an example embodiment.

DETAILED DESCRIPTION

Embodiments of the present invention use a circular disk electrode for the lidding material and a semispherical/cylindrical cavity shaped electrode for the blister to electrically profile and recognize defects in tablet blister packs. The electrode-pair detection setup is connected to a frequency response analyzer in example embodiments, which generates an AC electric field of varying frequencies as the input to the system. The output response is analyzed in the form of an electrical quantity, for example, capacitanceThe presence of a defect, for example, tom seal, leads to air gap/lack of lidding material, which generates a differential capacitance reading when compared to a well-sealed blister unit in a packet

As mentioned in the background section, blister packaging at high speed could suffer from following drawbacks- no sealing or partial/tampered sealing with no/partial contents inside cavity (loss of product during sealing), which result in defects in the form of lack of lidding material and/or exposure of product to environment at the lid-cavity interface. Specifically, Figure 1 shows schematic representations of the cross section of a blister package unit with possible defects: A) good unit with tablet in cavity, B) defective lid (hole) with tablet in cavity, C) defective lid (hole) and no product filling and D) no lid and no tablet. Advantageously, embodiments of the present invention exploring an electrical quantity, which differs with and without a proper sealing. For example, capacitance between a sensing and reference electrode is altered when an external entity perturbs the electric field, or an existing material composition changes. As another example, absence of sealing layer alters the fringing fields between electrodes, which in turn, changes the capacitance.

The frequency response analysis using the proposed electrode-pair system according to example embodiments can advantageously help in identifying the presence or absence of different types of defects in the seal. The detection setup of two copper electrodes according to example embodiments includes one circular shaped disk electrode connected to the lid and the other electrode shaped to conform to the shape of the blister. An AC electric field from a frequency response analyzer system is applied across the electrode pair serving as sensing and reference electrodes, respectively, according to example embodiments. The output can be monitored electrically in the form of, for example, capacitance according to example embodiments. For instance, the absence of sealing material leads to exposed product/pinhole, which results in decreased capacitance. Monitoring the capacitance change according to example embodiments can enable classification of good and defective samples in real-time with high throughput to preferably match the sealing/packaging process throughput. Based on the extent of damage, for example, capacitance fingerprints can be created to quantify the defect. However, a single frequency analysis can give only limited information in terms of change in an electrical parameter, for example, capacitance, for integrity testing of blister packages without divulging details regarding the type of defect. To overcome this a wide frequency analysis is used according to example embodiments, which allows complete electrical characterization of the lid-tablet-cavity unit by converting the complex impedance-frequency spectrum into simple circuit elements comprising of resistance (R), capacitance (C) and inductance (L), akin to a Randles circuit model for an electrochemical cell. Moreover, such a wide range frequency analysis advantageously provides sufficient inputs for machine learning to create electrical templates to classify and quantify defects according to example embodimens. For example, a highly complex mixture (such as capsules with fluid contents like multi-vitamin capsules) may yield a different frequency response, if broken and leaking inside cavity, as opposed to a solid tablet and hence a particular locked frequency may not be able to scan the contents effectively.

Copper was used for the construction of metal electrodes according to example embodiments, by way of example, not limitation. As shown in Figures 2A and B, a circular disk shaped electrode 200 and a hollow cavity electrode 202 conforming to the blister’s 204 shape sandwiching the lid 206-blister 204 interface of an individual blister unit from a blister package formed the testing set up according to an example embodiments. The blister package used for testing (Dazit 5 MG Tablet, SUN pharmaceuticals) has a blister 204 made of an insulating material and a metallic film lid 206. The testing was done over a frequency (f) range from 100 Hz to 1 MHz at an AC bias voltage of 1 V to get impedance (Z), capacitance (C) and Phase (0) using a E4980AL LCR meter as the frequency response analyser 208 connected to the electrode pair 200, 202. In this embodiment, the electrodes 200, 202 are provided with respective plastic supports 2010, 212.

Both the electrodes 200, 202 are in contact with the blister packet while testing according to this example embodiment. As will be appreciated by a person skilled in the art, for lower frequencies, the electrical field strength and penetration depth is lower. As a result, any air gap (lack of material) arising due to defects reduces electrical field lines through the blister package reflected via capacitance instantaneously during integrity testing according to this example embodiment. It is preferred that the electrodes 200, 202 touch the blister package to allow the short-range electric field lines to penetrate the blister package In other words, in this example embodiment the lid 206-blister 204 interface is preferably sandwiched between the electrodes 200, 202. It is noted that at higher RF frequencies, the electrical field strength is stronger with greater penetration depth allowing package scanning from a distance without the need to touch the blister packs, according to different example embodiments. The experiments were done using the electrode pair 200, 202 for the following cases listed below:

I. Blister unit with tablet and lid - to obtain the electrical signature of a well-packed blister unit, curve 300 in Figure 3A, curve 310 in Figure 3B, and curve 320 in Figure 3C.

II. Blister unit with tablet and tampered lid- to identify the effect of minor tampering of seal area on the electrical frequency response, curve 302 in Figure 3A, curve 312 in Figure 3B, and curve 322 in Figure 3C.

III. Blister unit with tablet and no lid- to identify the influence of lidding material on the electrical frequency response, curve 304 in Figure 3A, curve 314 in Figure 3B, and curve 324 in Figure 3C.

IV. Blister unit with no tablet and no lid- to identify the absence of product filling on the electrical frequency response, curve 306 in Figure 3A, curve 316 in Figure 3B, and curve 326 in Figure 3C.

As can be seen in Figure 3A-C, the frequency response scans for impedance (Figure 3A), phase (Figure 3B) and capacitance (Figure 3C) are readily distinguishable between the four cases, advantageously enabling identification of tampered seal, absence of product and absence of lidding seal, clearly illustrating the contributions of each component of the package towards the overall electrical signature of the blister unit. Any deviation from the ideal electrical fingerprint affects the measured electrical quantity.

Modifications of example embodiments

The use of the above mentioned electrode -pair system according to example embodiments allows defect identification on both the lidding and cavity side, but can be limited to a specific blister shape, and operates in contact mode and is configured for high sensitivity measurement when dealing with highly non-conductive packages. To overcome these drawbacks, extended design considerations and possible integration of sensors data with a data analytics tool are provided according to modified example embodiments.

With reference to Figure 4 A, an electrode design comprising of interdigitated ring electrodes 400, 402 can help to encompass different blister unit sizes. With reference to Figure 4B, using a textured electrode surface for one or both of the electrodes of the/each pair of electrodes such as pores- 404, saw tooth- 406 and/or pyramid- 408 textured can help in producing a highly concentrated and strong electric field, which can drastically increase the sensitivity of the detection when there is a defect. Such electrode -pair systems can be operated either as a single sensor, which electrically profiles each blister unit moving on a conveyor system, or as a sensor array 410 as shown in Figure 4C according to an example embodiment that simultaneously records electrical signatures from different locations and identifies the location of defects based on the differential readings. For example, the sensor array 410 detects blister unit 1 to be good as indicated at numeral 412, while blister unit 2 is detected as compromised, here a missing lid portion exposing the tablet as indicated at numeral 414 in Figure 4C. When traversing on the lidding surface, the sensor array 410 (or a single sensor in different embodiments) will cross both well-sealed and defective sites; thus measuring the electrical quantity at each scan point over the whole package to give electrical signatures for the package. Overall, electrode systems according to example embodiments can adventurously identify the type of defects (no seal, seal tom, no product, etc.), defect location and quantify defects (size of pinholes, amount of product, etc.) by comparing against control standards (well-sealed blister packages). Referring again to Figure 4C, the exposed seal portion(s) will give a differential capacitance compared to well-sealed areas and the numbering of the electrodes in the array 410 will reveal the location of defects.

Also, designing the above electrode systems compatible with radio frequency (3 KHz to 300 GHz) operation will create a stronger fringing electric field, which eliminates the need for sandwiching the blister(s) between opposing electrodes. The observed trend shows a more apparent change in the capacitance compared to the phase or impedance. This is attributable to the fact that the impedance and phase change is a cumulative effect of resistance, capacitance and inductive elements, which makes overall change smaller compared to the capacitance readout that directly measures the change in dielectric property of the package due to the presence or absence of material between the electrodes (without including other circuit elements). In addition, lower frequencies (< 100 Hz) are dominated by power line interference (50 Hz noise) while at higher frequencies (> 1 KHz) the separation is lesser. This is attributable to the insulating nature of the blister packaging material making it hard to polarize the sealing area by electrical excitation. In addition, the flexible nature of the blister packaging material contributes to motion induced noises in the low frequency region (few 100 Hz). To overcome this, a high frequency operation in non-contact mode can be employed according to modified example embodiments.

The RF ranges from few kHz to GHz. For frequencies up to few MHz, the electrodes used in the example embodiment described above are compatible with the LCR meter allowing contact mode of operation with the lid-blister interface sandwiched between the electrodes. To achieve non-contact mode of operation according to modified example embodiments, impedance analysis at frequencies greater than 1 MHz is involved, which is possible using high frequency operating systems like impedance analyzer and network analyzer. Such high frequencies (> 1 MHz) produce stronger fringing fields spanning larger distances that can advantageously penetrate the material under test without the need for electrodes to be in contact with the package. However, delivering such high frequency signals to the package under test without transmission loss, signal attenuation and electromagnetic interference can be a challenge. Hence, a RF measurement system (network analyzer and impedance analyzer) compatible electrode design is used in such modified embodiments. Furthermore, using a RF compatible electrode array to obtain impedance signatures across the blister unit according to such modified example embodiments generates a stronger electrical field that can advantageously provide an in-depth blister unit impedance profile to study and classify defects both in contact and in non-contact mode. Embodiments of the present invention can advantageously allow examination of different types of blister packages and their contents (conductive and insulating) for characterizing defective seals, poor inner coatings, lack of product filling, product leak, etc., preferably in a non-contact mode. This can be done either by traversing the package 416 underneath the electrode system 418, which can included one or more pairs 410, 422 of electrodes e.g. 424, 426, to electrically profile the entire package 416 as it is moved, for example underneath, the electrode system by way a conveyor system 428 as illustrated in Figure 4D (or vice versa), or by using an extended electrode array system for a complete blister strip, which will cross validate multiple blister units in a, at least temporally, stationary blister strip relative to the electrode array against control standards and identify the defective unit.

Systems according to example embodiments can generate a massive dataset due to multipoint scanning/multiple electrodes. These electrical fingerprints preferably serve as input patterns for machine learning systems to quantitatively and qualitatively identify and classify defects.

Figure 5 shows a flowchart 500 illustrating a method of integrity testing of a blister package, according to an example embodiment. At step 502, an electrode structure comprising at least one pair of electrodes is provided. At step 504, a blister of the blister package is disposed relative to the electrode structure such that the blister is subjectable to an electric field resulting from the application of an AC bias voltage to the electrode structure. At step 506, the AC bias voltage is applied to the electrode structure. At step 508, an electrical property of the blister is measured over a frequency range while the AC bias voltage is varied over the frequency range. At step 510, the integrity of the blister package is determined based on the measured electrical property of the blister over the frequency range.

The electrical property may comprise one or more of a group consisting of capacitance, resistance, phase and impedance.

The integrity of the blister package may be determined based on identifying a hole in a seal lid of the blister, absence of a content intended for the blister, and/or absence of the seal lid based on the measured electrical property of the seal portion over the frequency range.

Disposing the blister of the blister package relative to the electrode structure may comprise sandwiching the blister between the electrodes of the pair of electrodes. The pair of electrodes may comprise a disk-shaped electrode and a cavity shaped electrode. Sandwiching the blister between the electrodes of the pair of electrodes may comprise receiving the blister within the cavity of the cavity shaped electrode. The disk-shaped electrode and a cavity shaped electrode may be circular. The frequency range may comprise from about 100 Hz to 1 MHz.

The blister may be disposed at the same side of the electrodes of the pair of electrodes. The pair of electrodes may comprise two plate electrodes. The blister of the blister package may be disposed relative to the electrode structure such that the blister is subjectable to an fringing electric field resulting from the application of an AC bias voltage to the two plate electrodes. The frequency range may comprises the radio frequency range, for example from about 3 KHz to 300 GHz.

A surface of at least one of the pair of electrodes may be textured. The surface of the at least one of the electrodes may be pyramid textured, saw tooth textured, or pore textured.

The electrode structure may comprise an array of pairs of electrodes.

Disposing the blister of the blister package relative to the electrode structure may comprise conveying the blister package past the electrode structure or vice versa.

Figure 6 shows a schematic drawings illustrating a system 600 for integrity testing of a blister package, according to an example embodiment. The system 600 comprises an electrode structure 602 comprising at least one pair of electrodes 604, 606, a source 608 for application of an AC bias voltage to the electrode structure 602 such that a blister of the blister package disposed relative to the electrode structure is subjectable to an electric field, a measuring unit 610 configured to measure an electrical property of the blister over a frequency range while the AC bias voltage is varied over the frequency range, and a processing unit 612 for determining the integrity of the blister package based on the measured electrical property of the blister over the frequency range.

The electrical property may comprises one or more of a group consisting of capacitance, resistance, phase and impedance.

The processing unit 612 may be configured to determine the integrity of the blister package based on identifying a hole in a seal lid of the blister, absence of a content intended for the blister, and/or absence of the seal lid based on the measured electrical property of the seal portion over the frequency range.

The electrode structure 602 may be configured for sandwiching the blister between the electrodes of the pair of electrodes 604, 606. The pair of electrodes 604, 606 may comprise a disk-shaped electrode and a cavity shaped electrode. The cavity of the cavity shaped electrode may be configured for receiving the blister. The disk- shaped electrode and the cavity shaped electrode may be circular. The frequency range may comprise from about 100 Hz to 1 MHz.

The electrode structure 602 may be configured for disposing at the same side of the blister. The pair of electrodes 604, 606 may comprise two plate electrodes. The electrode structure 602 may be configured such that the blister is subjectable to an fringing electric field resulting from the application of an AC bias voltage to the two plate electrodes. The frequency range may comprise the radio frequency range, for example from about 3 KHz to 300 GHz.

A surface of at least one of the pair of electrodes 604, 606 may be textured. The surface of the at least one of the electrodes is pyramid textured, saw tooth textured, or pore textured. The electrode structure may comprise an array of pairs of electrodes.

The system may comprising a conveyer unit 614 for conveying the blister package past the electrode structure or vice versa.

One or more of the source 608, the measurement unit 608, and the processing unit 610 may be implemented in a single device 616.

Embodiments of the present invention can have one or more of the following features and associated benefits/advantages:

Industrial applications of example embodiment of the present invention include, but are not limited to the environment of pharmaceutical drug manufacturers filling blister packets and sealing at high speed. During this process, there is a high probability for improper sealing, lack of product filling, tom lid material etc., which leads to poor sample quality. Moreover, existing methods for leak testing for such blister packs are highly dependent on cavity and lidding material, the nature of product, suffer from low throughput and are destructive to both package and product. Furthermore, it generates huge financial loss in terms of package reject and waste disposal.

The electrical screening approach according to example embodiments can solve the above issues:

- The approach can detect tampered/poor seals for different type/quantity of product as well as cavity/seal material. The approach can identify and locate defective seals at a rapid rate in-line, thereby increasing the throughput during packaging and reducing wastage.

The approach can recognize poorly sealed contents non-destructively, thus allowing re-packaging and no product wastage.

The various functions or processes disclosed herein such as the data processing to identify and locate defective seals may be described as data and/or instructions embodied in various computer-readable media, in terms of their behavioral, register transfer, logic component, transistor, layout geometries, and/or other characteristics. Computer-readable media in which such formatted data and/or instructions may be embodied include, but are not limited to, non volatile storage media in various forms (e.g., optical, magnetic or semiconductor storage media) and carrier waves that may be used to transfer such formatted data and/or instructions through wireless, optical, or wired signaling media or any combination thereof. Examples of transfers of such formatted data and/or instructions by carrier waves include, but are not limited to, transfers (uploads, downloads, e-mail, etc.) over the internet and/or other computer networks via one or more data transfer protocols (e.g., HTTP, FTP, SMTP, etc.). When received within a computer system via one or more computer-readable media, such data and/or instruction-based expressions of components and/or processes under the system described may be processed by a processing entity (e.g., one or more processors) within the computer system in conjunction with execution of one or more other computer programs.

Aspects of the systems and methods described herein, such as the source for applying the AC bias to the electrode structure, the measuring unit configured to measure an electrical property of the blister over a frequency range while the AC bias voltage is varied over the frequency range, and/or the processing unit for determining the integrity of the blister package may be implemented as functionality programmed into any of a variety of circuitry, including programmable logic devices (PLDs), such as field programmable gate arrays (FPGAs), programmable array logic (PAF) devices, electrically programmable logic and memory devices and standard cell-based devices, as well as application specific integrated circuits (ASICs). Some other possibilities for implementing aspects of the system include: microcontrollers with memory (such as electronically erasable programmable read only memory (EEPROM)), embedded microprocessors, firmware, software, etc. Furthermore, aspects of the system may be embodied in microprocessors having software -based circuit emulation, discrete logic (sequential and combinatorial), custom devices, fuzzy (neural) logic, quantum devices, and hybrids of any of the above device types. Of course the underlying device technologies may be provided in a variety of component types, e.g., metal-oxide semiconductor field-effect transistor (MOSFET) technologies like complementary metal- oxide semiconductor (CMOS), bipolar technologies like emitter-coupled logic (ECL), polymer technologies (e.g., silicon-conjugated polymer and metal-conjugated polymer- metal structures), mixed analog and digital, etc.

The above description of illustrated embodiments of the systems and methods is not intended to be exhaustive or to limit the systems and methods to the precise forms disclosed. While specific embodiments of, and examples for, the systems components and methods are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the systems, components and methods, as those skilled in the relevant art will recognize. The teachings of the systems and methods provided herein can be applied to other processing systems and methods, not only for the systems and methods described above.

The elements and acts of the various embodiments described above can be combined to provide further embodiments. These and other changes can be made to the systems and methods in light of the above detailed description.

In general, in the following claims, the terms used should not be construed to limit the systems and methods to the specific embodiments disclosed in the specification and the claims, but should be construed to include all processing systems that operate under the claims. Accordingly, the systems and methods are not limited by the disclosure, but instead the scope of the systems and methods is to be determined entirely by the claims.

Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise," "comprising," and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in a sense of "including, but not limited to." Words using the singular or plural number also include the plural or singular number respectively. Additionally, the words "herein," "hereunder," "above," "below," and words of similar import refer to this application as a whole and not to any particular portions of this application. When the word "or" is used in reference to a list of two or more items, that word covers all of the following interpretations of the word: any of the items in the list, all of the items in the list and any combination of the items in the list.