WO2016120589A2

WO2016120589A2 - Apparatus and method for use in a process analytical technology system

Info

Publication number: WO2016120589A2
Application number: PCT/GB2016/050068
Authority: WO
Inventors: Martin GADSBY
Original assignee: Optimal Industrial Automation Limited
Priority date: 2015-01-27
Filing date: 2016-01-12
Publication date: 2016-08-04
Also published as: GB201501326D0; WO2016120589A3

Abstract

A process control apparatus for a Process Analytical Technology system (204) including a knowledge management module for: - defining an external process in terms of at least one quality attribute thereof, measurable by means of a process analytical chemistry tool; - enabling a relationship to be defined between at least one process parameter of said external process and said at least one quality attribute; and - receiving data representative of said at least one quality attribute, monitoring variations in said at least one quality attribute and providing output data representative thereof for use by a control module configured to control one or more process parameters so as to control said at least one quality attribute; the apparatus including a process analytical chemistry selection function, operably communicable with a selection module (200, 202) in which is stored, in respect of one or more specified process analytical chemistry tools, respective data representative of a plurality of respective wavenumber outputs derived therefrom as a result of physically operating the or each respective process analytical chemistry tool in a plurality of respective configurations, said selection function being configured to interface with said selection module so as to enable a specified process analytical chemistry tool in a specified configuration to be selected for association with said external process and thereby cause the data representative of the wavenumber output pattern associated with said selected process analytical chemistry tool in said selected configuration to be retrieved from said selection module and applied to said knowledge management module for use thereby in generating said output data.

Description

APPARATUS AND METHOD FOR USE IN A PROCESS ANALYTICAL

TECHNOLOGY SYSTEM

This invention relates generally to Process Analytical Technology (PAT) and, more particularly, to an apparatus and method for use in a PAT system for designing/analysing and/or controlling processes, such as drug discovery, research and development and manufacturing processes.

Process Analytical Technology (PAT) is a term used for describing an approach to manufacturing which involves defining the Critical Process Parameters (CPPs) of the equipment used to make a product, which affect the Critical Quality Attributes (CQAs) of the product, and then controlling these CPPs within defined limits. This allows manufacturers to produce products with consistent quality and helps to reduce waste and overall costs.

A complete PAT system usually combines three key tools:

* Process Analytical Chemistry (PAC) tools: in-line, at-line and on-line analytical instruments used to measure those parameters that have been defined as CQAs for a specific process. Typically, such tools comprise spectral instruments such as Near Infrared (NIR), Raman spectroscopy, laser diffraction for particle size, ultraviolet-visible (UV-vis) spectroscopy, etc.

* Multivariate data acquisition and data analysis tools: usually advanced software packages which aid in design of experiments, collection of raw data and statistical analysis of that data. A multivariate analysis package is typically employed, that enables the building and real-time execution of multi-dimensional mathematical models, the input being the spectra from the above-mentioned instruments, and the output being the CQA(s) required for a specific process.

* Knowledge management tools: often software packages which accumulate quality control data acquired over time for specific processes with the aim of defining process weaknesses and implementing and monitoring process and control improvement initiatives. There are hundreds of different PAC tool types and technologies, all of which need to be set up in very specific ways, have different input requirements, run at different speeds and, ultimately, communicate their outputs in different formats. Similarly, different multivariate analysis packages communicate in different respective formats, and there is a need to integrate the PAC tools, multivariate analysis package, and any required third part data historians, laboratory information management systems, etc. together in a synchronous system, that is relatively easily assembled and built to form a cohesive, understandable and validatable PAT knowledge management system which provides full data traceability.

PAT knowledge management systems have thus been developed that function to control the flow and movement of data, its transformation into knowledge, any required operator interactions and univariate data exchanges with control systems and third party systems. In general, such PAT knowledge management systems are used, particularly in pharmaceutical manufacturing environments, to monitor existing or 'validated' manufacturing processes in real time, whilst they are running, such that users can develop a mechanistic understanding of each specific process in terms of how changes to CPPs affect CQAs, and then generate an output to a controller configured to modify each process in terms of its CPPs to optimise a selected one or more of its CQAs, such as product quality, yield, manufacturing time, etc.

More recently, as such systems are becoming more widely used within validated production situations, there is an increasing need for new processes to be pre-tested and pre-validated before they are introduced into a live production system, in order that new functions can be tested, bugs fixed, etc. without undue adverse effect on the validated manufacturing process. In many cases, a new process of this type will be a 'clone' of an existing process which is required to be pre-validated before it goes live'. Thus, an integrated PAT system, including one or more specific instruments, a multivariate analysis package and a knowledge management package, of the type described above, may also be used to pre-validate new processes in the same or similar manner to that in which existing processes are validated and optimised. However, although the multivariate analysis package and knowledge management tool used for this purpose will be the same as those being used for the live' processes, in many cases, a different spectral instrument or instruments will have to be used for the pre-validation process, because the instruments that will be used for monitoring the process when it goes live' are being used within the validated production system and cannot be de-commissioned without interfering with the overall production process.

Many such instruments are unique in the sense that it is not unusual to obtain slightly different outputs, in relation to wavenumber, from two apparently identical instruments, placed side-by-side, run with identical settings, in identical configurations and with identical products under them.

There are, typically, 1024 wavenumbers used during each instrument reading. If a single wavenumber is selected, at random, and Identical' instruments 'A' and 'B' are placed in identical first configurations with identical products and run with identical settings, instrument TV may, for example, output the signal for wavenumber 1 ,400 at 1 ,400.016584, whereas instrument 'B' may output the signal for the same wavenumber at 1 ,400.654320. It can be seen, therefore, that whilst these outputs are very similar, they are not the same. In addition, because some of the values are derived inside the instrument with complex maths, the output value will change very slightly depending on the instrument's setting. Thus, if the same two instruments are placed in identical second configurations, instrument ^!A' may now output the signal for wavenumber 1 ,400 at 1 ,399.934562 whereas instrument 'B' might output the signal for the same wavenumber at 1 ,400.145793; and these types of variations apply across all of the required outputs. Thus, if 1024 outputs are potentially required in a specific set-up, then all 1024 wavenumbers will vary from instrument to instrument and setup to set-up.

Thus, as stated above, it is not currently possible to build a precise validation process without having the specific target instrument to connect to as, without it, the unique "fingerprint" of wavenumbers that that instrument will return in a particular configuration is unknown. As a result, it is not possible, using current technologies, to build a pre-validation process, within a test and development system, without the target instrument(s), and these are invariably unavailable as they will be in use within the live production plant.

It is therefore an object of aspects of the present invention to address at least some of these issues and provide an apparatus and method which ameliorates the problems outlined above.

In accordance with a first aspect of the present invention, there is provided a process control apparatus for a Process Analytical Technology system including a knowledge management module for:

- defining an external process in terms of at least one quality attribute thereof, measurable by means of a process analytical chemistry tool;

- enabling a relationship to be defined between at least one process parameter of said external process and said at least one quality attribute; and

- receiving data representative of said at least one quality attribute, monitoring variations in said at least one quality attribute and providing output data representative thereof for use by a control module configured to control one or more process parameters so as to control said at least one quality attribute; the apparatus including a process analytical chemistry selection function, operably communicable with a selection module in which is stored, in respect of one or more specified process analytical chemistry tools, respective data representative of a plurality of respective wavenumber outputs derived therefrom as a result of physically operating the or each respective process analytical chemistry tool in a plurality of respective configurations, said selection function being configured to interface with said selection module so as to enable a specified process analytical chemistry tool in a specified configuration to be selected for association with said external process and thereby cause the data representative of the wavenumber output pattern associated with said selected process analytical chemistry tool in said selected configuration to be retrieved from said selection module and applied to said knowledge management module for use thereby in generating said output data

In one exemplary embodiment of the invention, said selection module may be configured to store, in respect of the or each process analytical chemistry tool, one or more of the following data items:

- a descriptor, predefined or user-defined;

- meta data in respect of each wavenumber output patter, said meta data being associated with a specific configuration of the respective process analytical instrument;

- a tag to enable identification of a respective instrument, and its respective configuration, by said knowledge management module;

- data representative of the respective instrument's calibration/referencing at the time of the wavenumber output pattern being derived,

The selection function may be configured to provide a user interface (such as a GUI) enabling a user to select one or more of said specified process analytical chemistry tools in a specified configuration from said selection module.

In accordance with one exemplary embodiment of the invention, the apparatus may be configured to generate a virtual tag (for example, a virtual OPC tag) in respect of a process analytical chemistry instrument in a specified configuration selected from said selection module.

The selection module may be configured to store a plurality of data sets representative spectra of outputs derived from a specified process analytical chemistry instrument in a specified configuration, as well as the respective unique wavenumber output pattern, as a result of physically employing said process analytical chemistry tool in a plurality of respective configurations to measure an output from a target .

According to another aspect of the present invention, there is provided selection module for apparatus as described above, the selection module comprising a storage device in which is stored, in respect of one or more specified process analytical chemistry tools, respective data representative of a plurality of unique wavenumber output patterns derived therefrom as a result of physically operating the or each respective process analytical chemistry tool in a plurality of respective configurations.

According to another aspect of the present invention, there is provided a method of manufacturing process control apparatus for a Process Analytical Technology system, the method comprising providing a knowledge management module for:

- defining an external process in terms of at least one quality attribute thereof, measurable by means of a process analytical chemistry tool; - enabling a relationship to be defined between at least one process parameter of said external process and said at least one quality attribute; and

- receiving data representative of said at least one quality attribute, monitoring variations in said at least one quality attribute, and providing output data representative thereof for use by a control module configured to control one or more process parameters so as to control said at least one quality attribute

;the method further including providing a process analytical chemistry selection function, operably communicable with a selection module as described above, said selection function being configured to interface with said selection module so as to enable a specified process analytical chemistry tool in a specified configuration to be selected for association with said external process and thereby cause and thereby cause the data representative of the wavenumber output pattern associated with said selected process analytical chemistry tool in said selected configuration to be retrieved from said selection module and applied to said knowledge management module for use thereby in generating said output data

According to yet another aspect of the present invention, there is provided a method of manufacturing a selection module as described above, the method comprising: obtaining, in respect of one or more physical process analytical chemistry tools, data representative of a plurality of unique wavenumber output patterns from respective spectral outputs thereof in response to physical operation of said tool in a plurality of respective configurations, and storing, in a selection module, said data representative of said unique wavenumber output patterns in association with a respective identifier representative of the physical process analytical chemistry tool and the configuration to which it relates;

- configuring a selection function for operable communication with said selection module, so as to enable a physical process analytical chemistry tool in a specified configuration to be selected for association with said external process and thereby cause the wavenumber output pattern data associated with said selected process analytical chemistry tool in said selected configuration to be retrieved from said selection module and applied to a knowledge management module of a Process Analytical Technology system for use thereby in generating output data for use by a control module.

Thus, aspects of the present invention involve obtaining a number of wavenumber fingerprints for any one instrument, and then off-line and without the instrument these can be built into virtual processes, which can then be virtually tested using the dummy spectra as simulated inputs. Subsequently, it is possible to 'switch' these from virtual processes to live processes where they connect to the real target instrument. When the process is run, the instrument is configured, this configuration typically containing the wavenumber range and interval but not the specific wavenumber fingerprint values. The process will be expecting wavenumber responses that line up with the previously obtained wavenumber fingerprint values, and the signal response for every individual wavenumber will then be correctly 'piped' to the software module that expects it.

These and other aspects of the present invention will become apparent from the following specific description in which embodiments of the invention are described, by way of examples only, and with reference to the accompanying drawings, in which:

Figure 1 is a schematic block diagram illustrating the principle of process loop optimisation in PAT;

Figure 2 is a schematic block diagram illustrating principle elements of a

NIR spectroscopic measurement instrument;

Figure 3 is a schematic diagram illustrating the spectral output of a NIR spectroscope for a particular product and configuration;

Figure 3a is a simplistic graphical illustration of spectra obtained from two different PAC tools;

Figure 4 is a schematic block diagram illustrating apparatus according to an exemplary embodiment of the present invention; and

Figure 5 is a schematic block diagram illustrating the data elements stored in an instrument module according to an exemplary embodiment of the present invention, in respect of the physical analytical instruments available for selection.

Thus, as explained above, in recent years, significant effort has been made in various industries, particularly life sciences industries such as pharmaceutical manufacturing, to control process parameters (CPPs) that are critical for assuring critical quality attributes (CQAs) that, in turn, are critical in defining product quality, and such control is now typically performed in real time during the production process in accordance with the principles of Process Analytical Technology (PAT), Referring to Figure 1 of the drawings, these principles are illustrated schematically and it can be seen that a PAT system 10, including the above-mentioned spectral instrument(s), multivariate analysis tool and knowledge management package monitors CQAs arising from a process 12, analyses the results of such monitoring to determine any adjustments to the CPPs that might be necessary to improve or optimise the CQAs, and feeds the results of such analysis to a process control module 14, which operates to adjust/control the CPPs 16 accordingly.

This optimisation process forms a continuous loop with the aim of reaching and maintaining an optimum validated equilibrium, at least within allowable process tolerances or variances. This aim/outcome is illustrated schematically in Figure 1 by a significantly reduced product variability.

In order to describe, in detail, the key novel features of the present invention, the principles and operation of NIR spectroscopy will now be described in the context of an exemplary embodiment of the present invention. However, it is to be clearly understood that the present invention is not in any way intended to be limited in respect of the type of PAC instrument(s) used and, whilst the format of output data may vary from instrument to instrument, the underlying concept of the present invention is the same, irrespective of the instrument or, indeed, the process to which it is applied.

Referring to Figure 2 of the drawings, a NIR spectrometer is generally composed of a light source 100, a monochromator 102, a sample holder 104, a first detector 106a for detecting transmittance, and a second detector 106b for detecting diffuse reflectance. However, a number of different optical configurations are known and can be used to separate the polychromatic NIR spectral region into monochromatic frequencies, as will be well known to a person skilled in the art.

Thus, in basic terms, when light returned from a target is received at the input of a NIR-spectroscopic analysis instrument, and as illustrated by way of example only in Figure 3 of the drawings, a spectrum is generated, which includes the output at the fundamental excitation vibration frequency at a first wavenumber, and a number of overtones and/or combination bands (depending on the instrument) at a plurality of other respective wavenumbers. In respect of two, 'identical' instruments in identical configurations to which identical input excitation signals have been applied, the resultant spectra will be very similar but they will not necessarily be identical as each individual instrument is unique in this regard. More importantly, however, even in the unlikely event that the spectra are identical, they will have resulted from plots in which the y values are plotted from slightly different x values, as shown in Figure 3a of the drawings, and, although the end result might be the same and the above-mentioned output variations are minuscule, they can be quite significant in the PAT applications described herein. It can be seen that the graph in Figure 3a (which is a simplistic representation of the spectra) is the same for both instruments, but it was generated from output values at slightly different wavenumbers. Using the example described above in respect of instruments 'A' and 'B', if the x values are considered to be the wavenumbers, then the y value outputs from the two instruments, for wavenumber 1 ,400 would be plotted at 1 ,400.654320 and 1 ,400.016584 respectively.

Each target will, of course, cause a particular NIR spectroscope to generate a different spectrum and the unique set of spectra resulting from a plurality of input signals in respect of a particular instrument in a particular configuration will be referred to herein as its spectral "fingerprint", whereas the specific wavenumbers from which each such spectra are 'plotted' will be referred to herein as wavenumber "fingerprints". It will be appreciated by a person skilled in the art that the term "configuration" used herein in respect of a PAC instrument is intended to be construed generally in terms of one or a combination of process parameters, such as product, test runs, position in the plant, or any other variable associated with a particular process, instrument or production plant, and it is these factors that affect the spectral fingerprint of a respective instruiment. Variations in wavenumber fingerprints from instrument to instrument, on the other hand, are dependent on, and caused by, the specific internal configurations of the instruments (which are vendor and instrument specific), and the specific, unique instrument itself.

In order to address some of the problems associated with the above- described variations in wavenumber fingerprints associated with individual

PAC instruments, aspects of the present invention propose the use of a module for storing and enabling access to a set of wavenumber "fingerprints" associated with a plurality of different instruments in a plurality of different, respective specified configurations.

When a specific physical instrument is available, for example, before it is dedicated to use on the live production plant or else during a specified downtime, the instrument may be used to generate a 'fingerprint' of wavenumbers. A wavenumber 'fingerprint' can be generated in respect of a particular configuration by actuating a measurement of a known target such that the resultant spectral response signal is received by the input of the instrument and then capturing the output thereof. From this output, which will comprise a spectral response, the wavenumber fingerprint can be extracted. However, this wavenumber fingerprint is specific to the configuration of the instrument when the spectral response is generated. If the instrument is required to be used in different configurations, its wavenumber fingerprint will be slightly different. Thus, in accordance with exemplary embodiments of the present invention, multiple wavenumber fingerprints are obtained and stored in respect of each PAC tool in various respective configurations (e.g. different products, test runs, positions in the production plant, etc.), whereby it will be appreciated that each wavenumber fingerprint for a specific instrument in a specific configuration will be unique. The resultant data is stored in association with data representative of the instrument and the configuration to which it relates. Thus, there will be stored multiple wavenumber fingerprints for each instrument: one for each configuration. In addition, multiple spectral fingerprints can be stored for a single instrument in a specified configuration, but there will be only one wavenumber fingerprint for each instrument in each configuration, and such multiple spectra can be used sequentially in the Virtual' instrument, as required.

Referring to Figure 4 of the drawings, the spectral data and wavenumber 'fingerprints' referred to above may be stored in an instrument module 200. The instrument module 200 is interfaced to a selection function 202, according to an exemplary embodiment of the present invention, which is configured to enable a user to view and select an instrument, in a specified respective configuration, for use within a particular pre-validation PAT process. The selection function 202 provides the user with the option of selecting more than one instrument and configuration (and associated wavenumber fingerprint), if required by the specific process being pre- validated. Furthermore, the user may opt to include instrument "spares", which would only be used within the validated process in the event of failure of the principal instrument(s). Once an instrument and respective configuration, or set of instruments/configurations, has/have been selected, the data representative of the respective wavenumber fingerprint associated therewith can be retrieved from the instrument module 200 and imported to a PAT system 204.

Referring to Figure 5 of the drawings, the type and, to a certain extent, the format of data stored within the instrument module will now be described by way of example only, and it will be understood that the present invention is not necessarily intended to be limited in this regard. In a PAT validation system, there may be provided an instrument store in which is stored data representative of all physical process analytical chemistry tools available for use within that system. Thus, in such an instrument store, the following data may be recorded for each available instrument A, B, C, D, E, F, etc:

- Instrument manufacturer

- Instrument model

- instrument serial number

- Any MAC addresses or similar that can be used to uniquely identify the instrument electronically

- Current calibration/referencing data including data of execution

- Last date of servicing

In an instrument store according to an exemplary embodiment of the present invention, the following additional data is recorded for each available instrument/configuration combination:

- Operator entered descriptor

- Meta data associated with a specific configuration

- (optionally) a unique tag to enable identification by the knowledge management software package

- The spectral data and/or 'fingerprint(s)' of wavenumbers output from the physical instrument: as previously stated, multiple spectral data sets may be stored in respect of an instrument/configuration ,„

13

combination, but there will be only one, unique wavenumber fingerprint

- Information relating to the instrument's calibration/referencing at the time of the fingerprint(s) being gathered In prior art arrangements, if a process is to be pre-validated using process control apparatus within a PAT system, it is physically built, using the factory floor machinery/device(s) to be used, one or more PAC tools (similar but usually not identical to those that will be used in the final process), test system fixtures, etc. and then 'built' within the PAT system, with, for example, OPC tags being used as the interface that enables the required communication between the various data sources.

A system according to an exemplary embodiment of the invention can be incorporated into, or bolted onto, existing process control apparatus (used for ongoing control and optimisation of validated processes).

Thus, the resultant process control apparatus may include a switching function, enabling the user to 'build' a process for pre-validation without the target instrument itself being present. The process itself may be physically built in a known manner, except that the instruments and the associated OPC tags therefor would be omitted, and instead 'virtual' instruments, each in specified configuration (from the instrument store) and the OPC tag(s) required for communication with the instrument store are used to build the process. A selection function, providing the user with a graphical user interface, may provided for this purpose, so as to provide the user with a list of available virtual instrument/configuration combination(s) enabling them to select therefrom. The selection function may apply the appropriate virtual or simulated OPC tag(s) according to the selected virtual instrument(s). It will be appreciated that, in some cases, where the process validation procedure requires the use of multiple PAC tools, some of these may be physically available, and some may not. Thus, apparatus according to an exemplary embodiment of the invention may provide the user with the option of building a process which includes one or more physical instrument/configuration combinations (and their associated OPC tags) and one or more virtual instruments (and their associated virtual OPC tags) as required. Once the process has been built, the PAT system can perform the validation process in a known manner, and output the results in a manner that will be apparent to a person skilled in the art. Spectral data stored in respect of the selected virtual instrument(s) can be fed into the process, as required and, if more than one set of spectral data is available for a specific instrument in a specific configuration, the apparatus may be configured to cycle or 'rotate' this spectral data to provide some dynamism into the testing process, as might occur in reality.

It will be apparent to a person skilled in the art, from the foregoing description, that modifications and variations can be made to the described embodiments without departing from the scope of the invention as claimed.

Claims

1 . A process control apparatus for a Process Analytical Technology system including a knowledge management module for:

2. Apparatus according to claim 1 , wherein said selection module is configured to store, in respect of the or each process analytical chemistry tool, one or more of the following data items:

- a descriptor, predefined or user-defined;

- meta data in respect of each wavenumber output pattern, said meta data being associated with a specific configuration of the respective process analytical instrument;

- data representative of the respective instrument's calibration/referencing at the time of the wavenumber output pattern being derived.

3. Apparatus according to claim 1 or claim 2, wherein the selection function is configured to provide a user interface enabling a user to select one or more of said specified process analytical chemistry tools in a specified respective configuration from said selection module.

4. Apparatus according to any of the preceding claims, configured to generate a virtual tag in respect of a process analytical chemistry instrument in a specified configuration selected from said selection module.

5. Apparatus according to any of the preceding claims, wherein the selection module is configured to store a plurality of data sets representative of spectra of outputs derived from a specified process analytical chemistry instrument in a specified configuration, as well as the respective unique wavenumber output pattern, as a result of physically employing said process analytical chemistry tool in a plurality of respective configurations to measure an output from a target .

6. A selection module for apparatus according to any of the preceding claims, the selection module comprising a storage device in which is stored, in respect of one or more specified process analytical chemistry tools, respective data representative of a plurality of unique wavenumber output patterns derived therefrom as a result of physically operating the or each respective process analytical chemistry tool in a plurality of respective configurations.

7. A method of manufacturing process control apparatus for a Process Analytical Technology system including a knowledge management module for: - defining an external process in terms of at least one quality attribute thereof, measurable by means of a process analytical chemistry tool;

- receiving data representative of said at least one quality attribute, monitoring variations in said at least one quality attribute, and providing output data representative thereof for use by a control module configured to control one or more process parameters so as to control said at least one quality attribute; the method comprising providing a process analytical chemistry selection function, operably communicable with a selection module as described above, said selection function being configured to interface with said selection module so as to enable a specified process analytical chemistry tool in a specified configuration to be selected for association with said external process and thereby cause and thereby cause the data representative of the wavenumber output pattern associated with said selected process analytical chemistry tool in said selected configuration to be retrieved from said selection module and applied to said knowledge management module for use thereby in generating said output data

8. A method of manufacturing a selection module according to claim 6, the method comprising:

obtaining, in respect of one or more physical process analytical chemistry tools, data representative of a plurality of unique wavenumber output patterns from respective spectral outputs thereof in response to physical operation of said tool in a plurality of respective configurations, and storing, in a selection module, said data representative of said unique wavenumber output patterns in association with a respective identifier representative of the physical process analytical chemistry tool and the configuration to which it relates; - configuring a selection function for operable communication with said selection module, so as to enable a physical process analytical chemistry tool in a specified configuration to be selected for association with said external process and thereby cause the wavenumber output pattern data associated with said selected process analytical chemistry tool in said selected configuration to be retrieved from said selection module and applied to a knowledge management module of a Process Analytical Technology system for use thereby in generating output data for use by a control module.

9. A process control apparatus substantially as herein described with reference to the accompanying drawings.