WO2023039313A1 - Systems and methods for contactless detection of chemicals in a container - Google Patents

Abstract

This disclosure provides systems and methods for the qualitative and/or quantitative touchless measurement of chemicals contained within a container. The container and touchless detection system may be incorporated into an on-demand continuous-flow synthesis apparatus for production of chemicals, and particularly for the on-demand production of pharmaceutical products.

Description

SYSTEMS AND METHODS FOR CONTACTLESS DETECTION OF CHEMICALS IN A CONTAINER

GOVERNMENTAL RIGHTS

[0001] This invention was made with government support under grant no. HR0011-16-2- 0029 awarded by The Department of Defense. The government has certain rights in the invention.

CROSS REFERENCE TO RELATED APPLICATION

[0002] This application claims priority from U.S. Provisional Patent Application number 63/241,306, filed September 7, 2021, the entire content of which is hereby incorporated by reference in its entirety.

FIELD

[0003] This disclosure provides systems and methods for the qualitative and/or quantitative touchless measurement of chemicals contained within a container. The container and touchless detection system may be incorporated into an on-demand continuous-flow synthesis or batch formulation apparatus for production of chemicals, and particularly for the on-demand production of pharmaceutical products.

BACKGROUND

[0004] Product-on-demand systems and methods for the continuous-flow production of small molecules, biologies, fine chemicals, intermediates, as well as active pharmaceutical ingredients (API), and finished drug product in dosage forms, are in development to provide important advantages over traditional chemical manufacturing systems and methods. Most active pharmaceutical ingredients are prepared in large-scale discrete batch or semi-batch processes. The multi-step chemical synthesis, purification, formulation, and final packaging typically require large-scale facilities and expensive operations. The manufacturing typically uses batch processing at multiple locations. This approach generally requires long timescales to proceed from synthesizing of intermediates and chemical products and ingredients to the release of a finished pharmaceutical product. As a result, production of a finished chemical, product, or dosage form can require up to a total of 12 months, with large inventories of intermediates at several stages. Additionally, the facilities used to manufacture chemical products are typically designed for the manufacturing of a particular chemical or product and require extensive disassembly, cleaning, and reassembly in order to manufacture alternative chemical products.

[0005] The ability to synthesize small molecules, fine chemicals, intermediates, as well as API in a continuous manner can allow for a significant reduction in footprints of required facilities. In addition, the use of continuous-flow synthesis in a compact, reconfigurable manufacturing system can allow for high-throughput, on-demand production of chemical products including API and intermediates at a greatly reduced cost.

[0006] Methods for detecting and quantifying specific chemical targets are fundamental tools for the evaluation and testing of industrial quality control. In the context of continuous- flow on-demand production of chemical products, the systems and methods provided herein allow for improved automation, safety, and quality control for the preparation of on-demand chemical and/or pharmaceutical products.

SUMMARY

[0007] In one aspect, the disclosure provides systems and methods for the touchless detection, quantification, monitoring and/or analysis of a fluid sample in a container, comprising (i) a container comprised of one or more translucent or transparent materials and comprising an internal volume suitable for receiving, retaining and/or transferring the fluid sample, and (ii) one or more touchless measurement apparatuses adapted to measure one or more of volume, weight, analyte identity and/or concentration, flow rate, temperature, pressure, turbidity, color, reagent use, reagent verification, and product verification.

[0008] In some embodiments, the system for touchless detection is part of an on-demand continuous-flow apparatus for the production of chemicals.

[0009] In some embodiments, the system for touchless detection is part of an on-demand batch type formulation of chemicals.

[0010] In another aspect, the disclosure provides systems and methods for the on-demand synthesis of chemical compounds, comprising one or more of:

(i) one or more reagent holding/dispensing containers,

(ii) one or more continuous-flow chemical synthesis modules,

(iii) one or more of filtration, wash, crystallization, and/or separation modules; (iv) a touchless measurement system for the quantification, monitonng and/or analysis of a fluid sample in a container, comprising

(a) one or more containers comprised of one or more translucent or transparent materials and comprising an internal volume suitable for receiving, retaining and/or transferring the fluid sample;

(b) one or more touchless measurement apparatus adapted to measure one or more of volume, weight, solute concentration, flow rate, temperature, turbidity, color, reagent verification, and product verification of the fluid sample in the container; and

(iv) one or more processors and/or controller units in communication with one or more of the touchless measurement apparatus, and to one or more reagent holding/dispensing modules, one or more continuous-flow chemical synthesis modules, and one or more of formulation, filtration, wash, crystallization, and separation modules.

[0011] In embodiments of the systems and methods provided by the disclosure, the fluid sample comprises one or more analyte. The analyte may be a small molecule, pharmaceutical precursor, a crude active pharmaceutical ingredient (API), a purified API, a finished API formulation, an impurity, a small molecule, an amino acid, a peptide, a protein, a glycoprotein, and a biologic.

[0012] In embodiments of the systems and methods provided by the disclosure, the touchless measurement apparatus is adapted for spectroscopic analysis, ultrasonic detection and/or optical detection. The spectroscopic analysis may be one or more of UV/Vis spectroscopy, NIRF spectroscopy, Fourier-transform infrared spectroscopy (FTIR) spectroscopy and Raman spectroscopy.

BRIEF DESCRIPTION OF THE FIGURES

[0013] Figure 1 shows one embodiment of the system of the present invention comprising a transmissive flexible container, in this example, an IV bag holder used in the spectroscopic analysis of IV bag samples having light transmissive contents.

[0014] Figure 2 shows the reflective interrogation of the inventive system, wherein the system comprises a container, in this example, an IV bag having contents that are opaque to light transmission. [0015] Figure 3 shows the results of approaches for the transmission measurements of the systems of the present invention. Figure 3A shows the results of an embodiment of the system using a wide gap such that the exemplary IV bag freely floats within the space (3cm). Figure 3B shows the results of an embodiment when the system comprises a tight gap, which firmly clasped each side of the bag (1 cm), was used in the transmissive measurement.

[0016] Figure 4 shows a plot from an embodiment of the system comprising HDX-XR and FlameNIR spectrometers to show the total fluid activities from 200 nm to 1600 nm for the exemplary IV bag containers containing cisatracurium (Cis) and cis-placebo. The inset plot of the UV region highlights the unique activity of Cis-placebo versus water and Cis-drug versus placebo showing the 270-300 nm band which is unique to Cis drug product in an embodiment of this system and shows how it is used to perform concentration analysis.

[0017] Figure 5 summarizes the results of an embodiment of the system comprising a UV- Vis spectrometer where the UV-Vis scans with the 90° trends (Fig. 5A) and 45° trends (Fig. 5B).

[0018] Figure 6 shows the results of an embodiment of the system comprising a Raman spectrometer, wherein the 785 nm Raman scan through the walls of the containers. Results are summarized in Figure 6, with an inset plot for the dark condition, sample holder, and empty IV bag container to show those activities versus the more primary analytes, such as, for example, propofol, lecithin, soybean oil, and benzyl alcohol.

[0019] Figure 7 shows an embodiment of the system comprising volume detection and monitoring using a rigid container (Nalgene bottle). Figure 7A shows the original frame of the bottle. In Figure 7B, the system of the present invention is using the region of interest from open-source software, Open-Source Computer Vision Library (OpenCV), after applying a Canny edge detection module. Figure 7C shows the application of a Probabilistic Hough Transform in the system of the present invention to obtain vertical and horizontal lines. A filter is applied to only keep the liquid-level line. Figure 7D: shows the system where the image is overlaying the cropped region of interest frame.

[0020] Figure 8 shows an embodiment of the system for detection and monitoring of the liquid level in a rigid container using a QR-code obstructing the cropped image view.

DETAILED DESCRIPTION [0021] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of exemplary embodiments or other examples described herein. However, it will be understood that these examples may be practiced without the specific details. In other instances, well-known methods, procedures, and components have not been described in detail, so as to not obscure the following descriptions. Furthermore, the examples disclosed herein are for exemplary purposes only and other examples may be employed in lieu of, or in combination with, the examples disclosed.

[0022] The ability to manufacture chemical products (e.g., small molecules, pharmaceutical precursors, crude active pharmaceutical ingredients (API), purified API, finished API formulations, impurities, amino acids, peptides, proteins, glycoproteins and/or biologies) in a self-contained, and/or readily reconfigurable continuous-flow chemical process has the potential to offer significant advantages over large-scale batch processing. The present disclosure provides systems and methods for touchless monitoring, analysis and/or detection of chemicals in a container in general, and particularly in connection with on-demand continuous-flow chemical production.

[0023] For continuous-flow systems, each functioning module (e.g., reactor, separator, crystallizer, filter, formulator, etc.) within the process may be operated in a continuous fashion, such that the products of each module may be substantially continuously transported from one module to the other until a chemical product is produced. In some embodiments, the chemical product is an active pharmaceutical ingredient, or a formulated finished drug product.

[0024] “On-demand” manufacturing allows a product to be prepared as needed, in volumes that match the demand, and at a location proximate to its site of use, in contrast to the traditional warehousing and distribution schemes.

[0025] The terms “touchless” or “contactless,” in the context of this disclosure, refers to a measurement technique that does not come into direct contact with the substance being measured. For example, such touchless measurement techniques are applied through the wall of the container, without making direct contact with the contents of the container. A measurement technique may be “on-line” or “in-line.” On-line measurement involves diverting a portion of a stream containing the analyte(s) to be measured from the manufacturing process or container for measurement, which sample may be returned to the process stream. For in-line measurement, the sample is not removed or diverted from the process stream or container.

[0026] The disclosure provides systems and methods for the touchless detection, quantification, monitoring and/or analysis of chemicals in a container as part of an on- demand batch method apparatus, or on-demand continuous-flow apparatus for the production of chemicals, and particularly of pharmaceutical products. As part of a continuous-flow process, the raw material(s) and solvents are continuously charged into the system and the product is continuously discharged from the system during the duration of the process.

[0027] Continuous-flow manufacturing systems benefit from integrated touchless realtime monitoring of parameters of the chemical reagents and products, including the identity, quantity, processing conditions and control. Touchless measurement of these parameters translates to increased safety due to reduced manual handling of materials, reduced risk of spills, and reduced risk of intermediate or product contamination. Continuous manufacturing systems further benefit from integrated processing and control based on these measurements to further improve safety, ease of operation, reduce processing times and improve product quality.

[0028] The continuous-flow on-demand system, comprising one or more reagent holding/dispensing containers, continuous-flow chemical synthesis modules and/or one or more formulation, filtration, wash, crystallization, separation modules, may additionally comprise automated systems and methods for detection of chemicals contained within a container or reaction vessel which may be automated such that it has the following functionalities:

The system can keep track of the type and amount of material inside each container;

Volume detections methods are contactless;

Material analysis methods are contactless;

QR code for tracking of containers and material and/or RFID for tracking of containers, material, and usage;

Potential for tampering detection;

Reduced operator error in using the wrong material for a process;

Quality control of the formulated drug product; and Both qualitative and quantitative detection.

[0029] The process monitoring and control systems, including the touchless measurement system and the processor(s) and/or controller unit(s), may monitor the status of a reaction or transformation and actively manipulate parameters to maintain a desired state. For the continuous-flow systems, the touchless measurements may provide process data that may be correlated to the underlying process steps or transformations. Such data may relate to the progress of a chemical reaction, for example by chemically identifying and/or measuring the concentration of process starting materials, intermediates, products or by-products. These data may be useful for process monitoring, control of process parameters, end point determination, and the like, particularly when they relate to product and process quality. The monitoring provides real-time indication that the process steps or transformations are within predetermined process parameters. The touchless measurement of input materials and parameters, processing parameters, and output or endpoint parameters promotes consistent quality of the output materials from any processing step and the final product. Particularly when used as part of an automated control system, the touchless measurement of these parameters allows real time or near real time monitoring of process attributes for adjusting process parameters to optimize reaction conditions. Accordingly, the automated maintenance of the parameters, ensured through continuous assessment during manufacture, provides a real time quality assurance to validate the process and reflect product quality.

[0030] For example, the touchless detection systems of the present invention can be used to set the quality control parameters for API such as cisatracurium besylate. In an embodiment, the tests, methods, and acceptance criteria which are specified in USP43-NF38 for cisatracurium besylate for injection and in ICH guidelines are included in Table 1. Tests and acceptance criteria for information only tests for cisatracurium injection are included in Table 2.

[0031] Table 1 : Test Methods and Acceptance Criteria for Cisatracurium Besylate Inj ection

Chromatography; NMT=Not More Than; USP=United States Pharmacopeia; NLT=No

Less Than

JOf the label claim

*Do not report or include in total degradation products, because this is controlled in the drug substance.

** Due to counterion and not to be reported or included in total degradation products.

§ “The requirements for dosage uniformity are met if the acceptance value of the first 10 dosage units is less than or equal to Ll%” - USP <905> AV=M~XA+ks

AV = acceptance value

M = 98.5 % ifXA< 98.5%

XA= average of individual contents (expressed as %) k = 2.4 (for n=10) s = standard deviation of individual contents

LI = 15

[0032] The touchless detection systems of the present invention allow for continuous monitoring of reagents, intermediates and/or reaction products without contamination of the materials by being in contact with sensors or probes as part of an on-demand continuous -flow synthesis apparatus for production of chemicals. The chemicals detected can be pharmaceutical precursors, crude API, purified API, finished API formulations, impurities, small molecules and amino acids, peptides, proteins, glycoproteins, and biologies. This allows rapid throughput and minimizes cycling times due to the lack of the need to clean the sensors.

[0033] Another aspect provided by this disclosure includes the rapid detection of pharmaceutical products in the field, as well as their quantification to ensure proper dosages are being provided. The pharmaceutical product may be within a container, i.e., closed packaging such as a bottle or an IV bag, and the pharmaceutical product is measured while inside the unopened container using a touchless measurement technique. The measurement of the product in a container may be applied as part of the on-demand system to assess the final product quality. Alternatively, the measurement of the product in a container may be applied through the transparent container using a hand-held instrument without sampling of the material. Raman spectroscopy is the most common technique due to its high specificity and ease of sample presentation, although NIR and MIR instruments are also available and appropriate for certain applications (e.g., drug product excipients). The sample spectrum may be compared to a standard spectrum or library for conformance of identity assessment. These instruments are also in widespread use for pharmaceutical counterfeit detection.

[0034] The containers used in the systems of the present invention may be any chamber, vessel, bottle, conduit, tubing, and the like, that comprises an internal volume suitable for receiving, retaining and/or transferring the sample. The container may be comprised of a rigid or flexible material. Containers may be comprised of translucent or transparent materials and are chemically resistant or non-reactive materials. Container materials may include one or more of glass, polyethylene, high-density polyethylene (HDPE), low density polyethylene (LDPE), polycarbonate, polymethyl methacrylate (PMMA), polyethylene terephthalate (PET), polyvinyl chloride (PVC), polypropylene (PP), liquid silicone rubber (LSR), fluorinated ethylene propylene (FEP), perfluoroalkoxy alkanes (PFA), and the like.

[0035] When the basis of the measurement in the inventive systems relies on the use of electromagnetic radiation, the container will be at least partially constructed of a material that allows electromagnetic radiation to penetrate the container for detection, monitoring and/or analysis of the substance(s) within the container. In other embodiments, the container may comprise a non-transmissive material, such as metal, carbon fiber or other composite, or non- transmissive plastic, and further comprise a window of transmissive material through which the measurement is made.

[0036] The containers used in the systems of the present invention comprise a chamber defining an internal volume suitable for receiving, retaining and/or transferring a fluid sample. The container may additionally comprise one or more ports for the introduction, transfer or removal of the fluid contents, or other chemical components. The container may be, for example, in the form of bottles and IV bags. In other embodiments, the container is a continuous reaction vessel or a fluidic path connecting various unit operations. The continuous reaction vessel may be, for example, a tube reactor, a plug flow reactor (PFR), or a continuous-stirred tank reactor (CSTR).

[0037] The touchless measurement system(s) of the present invention may comprise instruments adapted to measure, for example, quantity (i. e. , volume, weight, etc.), analyte identity and/or concentration, flow rate, temperature, pressure, turbidity, color, reagent use, reagent verification, and product verification.

[0038] The touchless measurement used in the systems of the present invention may be performed using spectroscopic analysis, ultrasonic detection, or optical detection.

[0039] Reagent verification, product verification, analyte identity and concentration analysis within the container used in the systems of the present invention may be performed using electromagnetic radiation spectroscopy, such as UV/Vis, NIRF, FTIR, and Raman.

[0040] Spatially offset Raman spectroscopy (SORS) is a variant of Raman spectroscopy that allows chemical analysis of the contents of a container used in the systems of the present invention, even beneath an obscuring surface. A SORS measurement makes two or more Raman measurements; one at the source and one at an offset position of typically a few millimeters away. The two spectra may be subtracted using a scaled subtraction to produce two spectra representing the subsurface and surface spectra.

[0041] The touchless measurement system(s) of the present invention may be adapted to track fluid volume and/or flow rate within the container using ultrasound or camera and machine vision. Ultrasonic fluid level measurement may be performed, for example using GL Sciences Liquid Level Sensor Reservoir Accessories. Non-limiting examples of suitable ultrasonic flow rate sensors include SonoFlow® CO.55 | Ultrasonic Clamp-On. Liquid volume and flow rate tracking may also be monitored using computer vision and pre-trained instance segmentation using a convolution neural network (CNN) algorithim or related software method. Using this method, the current volume in a transparent container used in the systems of the present invention may be monitored by computer vision based on the pixel area of liquid to vessel. Computer vision may be used to track the fill line of the liquid contents of a transparent container.

[0042] The container used in the systems of the present invention may include one or more surfaces configured to display one or a plurality of optical marks. The optical marks may be placed on an exterior surface of the container and/or on an interior surface of a transparent container. The optical marks can include two-dimensional optically encoded marks, QR codes, barcodes, and the like. In conjunction with a camera, or other optical sensor used in the systems of the present invention, the marks may dynamically convey data such as the volume, change in volume and flow rate.

[0043] For example, in the system of the present invention, to measure the fluid-level in a container, a QR code may be positioned on a surface of the container such that the level of the internal fluid bisects the mark as observed by a scanning system comprising an imaging sensor, such as a camera. The QR codes may have positioning information within the structure of the mark. For example, the large square features of the QR code may provide reference positions within the mark itself. In some embodiments, one purpose of showing the code was to make sure that if the liquid surface is partially blocked, the volume can still be determined.

[0044] Additionally, the container may have a QR code, or other optical mark, to provide a unique exterior identification for the container and its contents. The QR code provides a means of tracking containers and materials and reduce the opportunity for operator error in using the wrong material for a process.

[0045] As an alternative, RFID may be used for tracking of containers, material, and usage in the systems of the present invention. Use of an RFID tag on the container makes it possible to store information of the container, including but not limited to its serial number, size, material, stored material and amount, usage time, used amount, user accessed, location used, and chemical composition. This information can be updated each time that the container is placed and used in a system. [0046] In some embodiments, the systems of the present invention comprise a scanning system. A scanning system uses a light source, such as a laser, which is directed to the optical marks, optionally by a lens or other optical components. The scanner may function by repetitively scanning the light beam in a path or series of paths across the optical marks. Scanning systems may also include a sensor or photodetector which detects light reflected from the optical marks. A portion of the reflected light is detected and converted into an electrical signal, and electronic circuitry or software decodes the electrical signal into a digital representation.

[0047] In some embodiments, in the systems of the present invention, the temperature of the container may be monitored using a touchless temperature sensor. Non-limiting examples of suitable touchless temperature sensors include infrared temperature sensors. Exemplary commercially available temperature sensors include Melexis Technologies NV part number MLX90614KSF-ACC-000-TU-ND.

[0048] In some embodiments, the systems of the present invention can measure turbidity. Turbidity is an optical measurement that indicates the presence of suspended particles in the container contents. Turbidity may be measured by shining light through the container contents, and using a photo detector to measure light scatter. Suitable devices may include Endress Turbimax CUS50D, CUS51D, CUS52D.

[0049] In some embodiments, the sensor(s) of the touchless detection system(s) of the present invention may be electronically coupled to one or more processors and controller units as part of the continuous-flow synthesis apparatus, either as a stand-alone unit or part of a distributed network of apparatuses.

[0050] To ensure acceptable and reproducible outcomes for the chemical product, consideration is given to the quality attributes of reagent materials and solvents for each process step. The identity of raw materials may be confirmed upon receipt and/or prior to their use in the manufacturing process using the touchless measurement provided herein. Reagent containers may be marked with QR codes, barcodes, or other optically encoded marks, for ready identification by an optical scanner. The process of reagent verification is preferably automated and confirms that the proper reagents are loaded into the module(s) before initiation of the chemical reaction sequence. Reagent identification may additionally or alternatively be assessed or verified by the touchless spectroscopic methods provided herein and comparison to a standard for the reagent.

[0051] Following verification, the continuous-flow process is initiated. In continuous reactions, raw materials, and solvents (if used) are continuously charged into the reactor, and the intermediate or product is continuously discharged from the reactor throughout the duration of the process. The reactor may be, for example, a tube reactor, a plug flow reactor (PFR), or a continuous-stirred tank reactor (CSTR). As part of the touchless monitoring system, the touchless measurements may be applied to the reactor to provide real-time monitoring of process parameters to ensure that the chemical reaction progresses within specified limits, thus contributing to process efficiency, selectivity, yield and safety. Process variables, such as temperature, pressure, concentration, and rate of reagent or solvent addition can be adjusted in an adaptive response to the real time, or near real time, touchless measurements. Temperature and pressure may be monitored using thermocouples, infrared sensors, and optical pressure sensors, respectively. Spectroscopic measurements including near-infrared, mid-infrared, Raman, and UV-vis spectroscopy, may be used to monitor for the presence or disappearance of functional groups during the synthesis. By monitoring the specific functional groups, qualitative trending or quantitative assessment of the reaction component levels is achieved. Additionally, by integrating automated, real-time process control, real-time data can be acquired for process monitoring and applied to process control for ensuring product quality. This approach provides improved real-time control of the reaction progress ensuring the reaction parameters remain within specifications. For example, identification of functional groups of certain molecules can be performed with IR and monitoring the characteristic band for carbonyl groups, etc.

[0052] Following the reaction, in-line purification can separate impurities from the reaction product stream or remove excess reagents or solvents that may be incompatible with the subsequent reaction step(s). The separation may involve methods including distillation, nanofiltration and extraction, which may be applied to the removal of impurities, separation of volatile components/solvents, isolation, and recycling of catalysts. Touchless spectroscopic tools (e.g., near-infrared, mid-infrared, Raman, UV-vis, and NMR spectroscopy) may be used to monitor for and quantify the presence or disappearance of unwanted impurities, regents, or solvents. [0053] Crystallization may be used for the purification and/or isolation of the chemical product. Upon addition of a counter-solvent/ anti-solvent, the formation of solid product may be monitored by measuring the turbidity of the resulting suspension, during formulation of an API, as excipients get mixed.

[0054] The following examples have been included to provide guidance to one of ordinary skill in the art for practicing representative embodiments of the presently disclosed subject matter. In light of the present disclosure and the general level of skill in the art, those of skill can appreciate that the following examples are intended to be exemplary only and that numerous changes, modifications, and alterations can be employed without departing from the scope of the presently disclosed subject matter. The synthetic descriptions and specific examples that follow are only intended for the purposes of illustration, and are not to be construed as limiting in any manner to make compounds of the disclosure by other methods.

EXAMPLES

Example 1

[0055] Experimental Setup

[0056] Spectrometers:

• HDX-XR (UV-VIS-NIR)

• FlameNIR (NIR)

• HDX-Raman (785nm)

[0057] Light Source:

• DH-2000-BAL (UV-VIS-NIR)

• HL-2000 (VIS-NIR)

• LASER-785-LAB-ADJ-SMA (785nm laser)

[0058] Fiber and Sampling Accessories:

• 74-ACH (adjustable collimating lens holder)

• QR600-7-SR (UV-VIS probe)

• QR400-7-VIS-NIR (VIS-NIR probe)

• RIP-RPB-785 (Raman probe)

• QP600-025-XSR (UV-VIS patch fiber)

• QP600-025-VIS-NIR (VIS-NIR patch fiber)

• RPH-1 (90745° reflection probe holder) • WS-1 (white reflection standard)

[0059] Samples in IV bags:

• DI Water

• Propofol Drug Product

• Propofol Placebo

• Cisatracurium Drug Product

• Cisatracurium Placebo

[0060] Broadband spectroscopy was used to interrogate all samples in the appropriate mode, whether transmissive or reflective. The samples of water, cisatracurium, and the respective placebo were all able to be measured by transmission through the IV bag and fluid as shown in Fig. 1.

[0061] The method depicted in Fig. 1 used a 74-ACH adjustable collimating lens holder to route the light through a consistent pathlength for the IV bags to sit within. Scans were performed with the HDX-XR spectrometer for UV-VIS measurements and the FlameNIR for the NIR region.

[0062] The propofol drug product and respective placebo were each too optically opaque to allow for transmission measurements. Due to the opacity of the fluid contents, the propofol IV bags simply looked like ‘dark’ reference scans when measured in transmission mode. These samples were interrogated in reflective mode with the RPH-1 90745° reflection probe holder held against the IV bag as shown in Fig. 2. A white reflection standard was used to create the reference condition for these samples. The appropriate reflection probes were used for two optical ranges (UV-vis and NIR) and used the HDX-XR and FlameNIR spectrometers, respectively. The RPH-1 reflection probe holder was used to run a brief distance and angle study with the probe held at 90° and 45° at several distances from the sample.

[0063] Raman scans were all performed using the 785nm Raman probe held at 90° flush- against the sample bags, as is standard for this type of Raman sampling and specific probe.

[0064] Transmission of Cisatracurium Fluids

[0065] Transmissive Pathlength. Two approaches were evaluated for the transmission measurements, including a wide gap, such that the bag could freely float within the space (3 cm), and also a tight gap, which firmly clasped each side of the bag (1 cm). The free-floating scenario (Fig. 3A) had more variation, while the clasping scenario (Fig. 3B) showed strong repeatability.

[0066] In some embodiments a clasping handheld tool (such as a pair of ‘optical pliers’) can provide for quick, repeatable measurements of the transmissive fluids in IV bag style containers.

[0067] Broadband Cisatracurium Activity. Fig. 4 shows a spliced plot from both the HDX-XR and FlameNIR spectrometers to show the total fluid activities from 200 nm to 1600 nm. All trends use air as the light reference. The zoomed-in plot of the UV region highlights the unique activity of the CIS-placebo versus water, and also the CIS-drug versus placebo. The 270-300 nm band shows activity unique to the CIS-drug, and there is enough bandwidth there to allow the performance of concentration analysis.

[0068] With 2 AU of usable absorbance delta, and assuming the provided drug product was at 100% strength, the system should resolve to 0.5% of the total concentration range.

[0069] Due to the opacity of the propofol samples, the NIR range showed no usable differentiation between samples, and the propofol samples essentially blocked all light and registered as a dark scan.

[0070] Reflection of Propofol Fluids. The propofol samples were very white and optically opaque in nature, thus needing a reflective mode to interrogate. As mentioned, a white reflection standard was used as the light reference in all scenarios, and these tests were performed at 90° and 45° at several distances.

[0071] The plots shown in Fig. 5 summarize the results of the UV-VIS scans with the 90° trends (Fig. 5A) and 45° trends (Fig. 5B). In the 90° scenario, the 0 mm ‘flush’ distance provided the best signal, and this direct angle also gave a clearer view of the lowest wavelengths. However, the 45° scenario lost a bit of the clarity of the lower wavelengths but provides a larger and sharper absorbance difference between drug-free and drug-containing solutions. Distancing at 45° did not have much of an observable effect. The data show that there is clear usable activity in the UV region for the propofol drug product, which would provide the capability for concentrarion regression.

[0072] As with cisatracurium, the propofol results showed no significant differences in the NIR wavelength region. [0073] 785 nm Raman Testing. The final technique investigated was 785 nm Raman spectroscopy through the wall of the IV bags. Results are summarized in the plots shown in Fig. 6, with an inlaid plot of Fig. 6A for the dark condition, sample holder, and empty IV bag, to show those activities versus the more primary analytes.

[0074] The majority of the peaks observed from the cisatracurium and propofol samples are unique from one another, but largely persist between the placebo and active drug product. This suggests we are detecting the other inert buffer components in the bulk fluid. This is useful for general spectroscopic ‘fingerprint identification’ of unknown fluids in the field (i.e., two IV bags with ‘clear’ liquid but different drugs/purposes).

[0075] While the propofol scans did not show much optical coherence nor differentiation between the placebo and active drug product, there were a few cisatracurium activities that are indicative of that drug product, indicated by the circled portions in the plots of Fig. 6A and 6B. These peaks can be used as identifiers to confirm the desired drug product is present, though could not provide concentration values as the UV/VIS scans could.

[0076] For both drug products, the most successful detection and quantification approach came from UV absorbance activities in the 250-300 nm region. Transmissive fluids such as the cisatracurium samples are best interrogated in transmissive mode using a fixed pathlength that holds the bag firmly and repeatably. Opaque fluids such as the propofol samples are best interrogated in reflective mode using a reflection probe at 45°. Preliminary calculations estimate there is potential to resolve down to 0.5% of the total concentration using these approaches.

[0077] The Raman spectroscopy provided unique peaks for the bulk fluid used, which may be useful in differentiating between the total IV bag components for different drug products.

Example 2

[0078] Volume Detection

[0079] Provides real time fluid volume with ~15mL granularity. Provides real time flow rate measurements as an extra step to validate pump output.

[0080] Using a 4th generation raspberry pi with 4GB of RAM and a Pi NoIR V2 camera with open-source computer vision modules, OpenCV, generated algorithms using python programming language are called from the terminal. Users are prompt with adjusting the region of interest prior to computation. In real-time, meniscus of fluids are determined and updated in a CSV file at a frequency defined by the user. Flow is calculated by taking the absolute value of the difference in volume at time x and x+1 and dividing by total time inbetween. When the module is closed, the updated CSV file is saved to the users’ directory.

[0081] Water was used as a test case in a translucent HDPE container to test this system. Tubing was connected to the container through the lid and liquid was pumped out for use in the DIHA synthesis platform. The remaining amount of liquid and its rate of transfer was measured and compared with values recorded from other instruments to show the accuracy of this system.

[0082] This method of volume measurement is based on computer vision and it can work with liquids, solids, as well as homogeneous and non-homogeneous mixtures of the two.

Example 3

[0083] Determining API sequence based on reactant QR Codes

[0084] Within the product-on-demand systems, QR codes are detected using either a 4^th generation raspberry pi with 4GB of RAM and a Pi NoIR V2 camera coincided with open- source computer vision modules, OpenCV. QR codes are generated using open-source packages such as PyZBar. Final formulated containers or starting materials containers contain generated QR codes with chemical names embedded as strings. QR codes are read and further applications/sequences are determined based on the information read.

[0085] Labeling the containers using QR code, bar code, RFID, or similar technologies allows automated tracking of raw material, intermediates, and processes in a PoD system. It also reduces operator error by providing a means for the product-on-demand system to match the material with the selected process.

Example 4

[0086] A product-on-demand system comprises multiple containers for starting materials, optionally containers for intermediates, and one or more containers for products. Several unit operations exist in between that can be in the shape of containers, including reactors, such as tube reactors, CSTRs or FWDs, and tubing (PFR), vessels for separation, crystallization and/or filtration. Each of the units are connected is sequence using a fluidic path. Studying the process of the product-on-demand system determines Critical Quality Attributes (CQA) of the system, which are monitored for ensuring the quality of the product. The system described herein can be set on any vessel or fluidic path to monitor the CQA of the system for making a quality product. This may be at any step of the synthesis, purification, or formulation to monitor and control the starting material, intermediates, or final products.

[0087] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0088] The use of the terms “a” and “an” and “the” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0089] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

We Claim:

1. A system for the touchless detection, quantification, monitoring and/or analysis of a sample in a container, comprising a container comprised of one or more translucent or transparent materials and comprising an internal volume suitable for receiving and retaining the sample; and a touchless measurement apparatus adapted to measure one or more of volume, weight, analyte identity and/or concentration, flow rate, temperature, pressure, turbidity, color, reagent use, reagent verification, and product verification of the sample; wherein the system for touchless detection is part of an on-demand continuous-flow apparatus for production of chemicals.

2. The system of claim 1, wherein the sample is a solid sample.

3. The system of claim 1, wherein the sample is a fluid sample.

4. The system of claim 2, wherein the solid sample comprises one or more analytes.

5. The system of claim 3, wherein the fluid sample comprises one or more analytes.

6. The system according to claims 4 or 5, wherein the analyte is a pharmaceutical precursor, a crude active pharmaceutical ingredient (API), a purified API, a finished API formulation, an impurity, a small molecule, an amino acids, a peptide, a protein, a glycoprotein and a biologic.

7. The system according to claims 4 or 5, wherein the analyte is an active pharmaceutical ingredient (API).

8. The system according to claims 4 or 5, wherein the analyte is a finished API formulation.

9. The system according to any one of claims 1 to 8, wherein the touchless measurement apparatus is adapted for spectroscopic analysis, ultrasonic detection or optical detection.

10. The system of claim 9, wherein the spectroscopic analysis is one or more of UV/Vis spectroscopy, NIRF spectroscopy, FTIR spectroscopy and Raman spectroscopy.

22 A system for the on-demand synthesis of chemical compounds, comprising: one or more reagent holding/dispensing containers, one or more continuous-flow chemical synthesis modules, one or more of filtration, wash, crystallization, and separation modules, a touchless measurement system for the quantification, monitoring and/or analysis of a fluid sample in a container, comprising one or more containers comprised of one or more translucent or transparent materials and comprising an internal volume suitable for receiving, retaining and/or transferring the fluid sample, one or more touchless measurement apparatus adapted to measure one or more of volume, weight, analyte identity and/or concentration, flow rate, temperature, pressure, turbidity, color, reagent use, reagent verification, and product verification of the fluid sample in the container; and one or more processors and/or controller units electronically coupled to one or more of the touchless measurement apparatus, and to one or more reagent holding/dispensing modules, one or more continuous-flow chemical synthesis modules, and one or more of filtration, wash, crystallization, and separation modules. The system of claim 11, wherein the one or more containers are selected from one or more of continuous reaction vessels and fluidic path connecting unit operations. The system of claim 12, wherein the continuous reaction vessel is a tube reactor, a plug flow reactor (PFR) or a continuous-stirred tank reactor (CSTR). The system according to claims 11 or 13, wherein the fluid sample comprises one or more analytes. The system of claim 14, wherein the analyte is a pharmaceutical precursor, a crude active pharmaceutical ingredient (API), a purified API, a finished API formulation, an impurity, a small molecule, an amino acids, a peptide, a protein, a glycoprotein and a biologic. The system of claim 15, wherein the analyte is an active pharmaceutical ingredient (API). The system of claim 15, wherein the analyte is a finished API formulation. The system according to any one of claims 11 to 17, wherein the touchless measurement apparatus is adapted for spectroscopic analysis, ultrasonic detection or optical detection. The system of claim 18 wherein the spectroscopic analysis is one or more of UV/Vis spectroscopy, NIRF spectroscopy, FTIR spectroscopy and Raman spectroscopy.