Biological Therapeutic Manufacturing Facilities and Processes

Abstract

The concepts described herein relate to the implementation of manufacturing facilities capable of producing molecules used to treat biological conditions, such as biotherapeutics. Biotherapeutics include a variety of molecules, including proteins, enzymes, and antibodies. The manufacturing facility may include multiple modular cleanrooms configured with specific equipment performing one or more aspects of the processes used to manufacture the biotherapeutics. The modular cleanrooms are arranged so that materials produced by equipment in one modular cleanroom can be transferred to other modular cleanrooms for further processing. Additionally, systems and processes are described that use machine learning techniques to generate models that can be used to predict productivity and / or efficiency metrics for biotherapeutics. Furthermore, models can be generated for controlling the operation of equipment included in the manufacturing line.

Description

Background Art

[0001] The production of molecules that can be used for treating various biological conditions is often carried out on a relatively large scale. For example, proteins can be produced in a facility using bioreactors with volumes ranging from 5000 L to 25,000 L. In many cases, the production lines developed for the production of these molecules include equipment arranged according to a specific footprint that is not easily changed within the production facility. If the type and arrangement of the equipment used for the production of a specific molecule or group of molecules are not flexible, the applicability of a particular production line to other molecules can be limited. That is, by improving the existing production line or constructing a new production line for the production of different molecules, the costs associated with providing the molecule to the public can increase. On the other hand, manufacturers of biological therapeutics often determine limitations on the number of molecules to be produced due to the amount of resources required for the development of facilities for producing one molecule or group of molecules. As a result, the manufacturing costs of biological therapeutics for treating biological conditions may be such that the number of biological conditions that can be treated with biological therapeutics is limited, and the number of biological therapeutics available for the treatment of a specific biological condition can also be limited.

Summary of the Invention

[0002] Furthermore, the control of a system for producing molecules that can be used for treating biological conditions can be complex, and many variables can be considered to optimize the production of the molecules. However, the techniques used for modifying the production process are often ad hoc or accidental, not based on empirical data, and it can be difficult to identify the modifications that can be made to a particular production process that will result in more efficient production of the molecules. Additionally, control systems are typically limited to controlling the production process in a single facility and are not used for controlling the production of one or more molecules in different facilities. Therefore, data collected regarding the production of molecules in a particular production facility may not be used to improve the production of the same or different molecules in other production facilities.

Brief Description of the Drawings

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DETAILED DESCRIPTION OF THE INVENTION

[0013] The concepts described herein relate to the implementation of manufacturing facilities capable of manufacturing molecules such as biotherapeutic agents that can be used for the treatment of biological conditions. As used herein, "biotherapeutic agent" refers to a molecule that produces a product capable of treating a biological condition using living cells derived from a living organism such as a human, animal, plant, fungus, or bacterium. Examples of biotherapeutic agents include various molecules such as proteins, enzymes, and antibodies. Further, as used herein, "biological condition" can refer to an abnormality in the function and / or structure in an individual that causes or may cause detectable features of the abnormality. A biological condition can be characterized by external and / or internal features, signs and / or symptoms indicating a deviation from biological criteria in one or more populations. Examples of biological conditions include at least one of one or more diseases, one or more disorders, one or more injuries, one or more syndromes, one or more impairments, one or more infections, one or more isolated symptoms, or other atypical variations in the biological structure and / or function of an individual.

[0014] Examples of the manufacturing facilities described in this specification include a number of separate modular clean rooms equipped with specific devices that perform one or more aspects of the processes used in the manufacture of biotherapeutics. The modular clean rooms are arranged such that materials produced by the devices of one modular clean room can be transferred to other modular clean rooms for further processing. The modular clean rooms can provide a sterile clean room environment with less than 0.5 micrometers (μm) of particles per 100 ft 3 to 1,000,000 ft per 0.5 μm of particles. Further, the transfer of materials between modular clean rooms can be done without contaminating the materials being transferred. 3

[0015] The separate modular clean rooms can be equipped with devices for performing operations related to solution preparation, inoculum preparation, cell culture, purification, and filling and finishing of the final product. In one example, the modular clean rooms can utilize various cart pumps, bioreactors, chromatography systems, perfusion systems, mixing vessels, filtration devices, temperature control devices, test devices, and material storage containers. Materials can be supplied to the modular clean rooms via an airlock connected to the storage container. The storage container can be placed in the staging area of the manufacturing facility. In various embodiments, the storage container can contain buffer solutions, intermediate products, final products, feedstocks, materials removed in relation to evacuation operations, materials used for supplying cells used in the manufacturing process, such as glucose, or combinations thereof. Also, the modular clean rooms may include an airlock for material transfer and a dressing room for personnel wearing work clothes compliant with the standards of the modular clean rooms.

[0016] The equipment included in individual modular clean rooms can be modified based on the products to be manufactured. For example, a modular clean room configured for the manufacture of a first biotherapeutic using a perfusion system can be modified for the manufacture of a second biotherapeutic using a batch process. In other examples, a modular clean room performing a purification operation using an ion exchange chromatography column for manufacturing a first biotherapeutic can be modified to utilize an affinity chromatography technique for manufacturing a second biotherapeutic. Thus, for manufacturing a new biotherapeutic, the devices arranged within one or more modular clean rooms can be modified to correspond to the footprint required for the manufacture of the new biotherapeutic. In this way, the manufacturing facilities described herein provide devices that can be flexibly utilized in the manufacturing facilities, i.e., a single manufacturing facility can be used for the manufacture of multiple biotherapeutics without incurring significant capital expenditures for modifying the manufacturing facilities. Further, if additional capacity is required, additional modular clean rooms can be added to the manufacturing facility to enhance the manufacture of biotherapeutics. In certain embodiments, single-use materials and corresponding devices can be used for the manufacture of biotherapeutics. In some devices, using single-use materials can minimize system contamination and, since the number of cleaning and repair times required for operating single-use devices is reduced, manufacturing costs can also be minimized.

[0017] Also described herein are systems and techniques for controlling and optimizing the manufacture of biological therapeutics. Data obtained from the manufacturing line can be analyzed using machine learning techniques to identify process variables that are statistically significant with respect to productivity metrics. Productivity metrics include viable cell density, yield, and purity. Further, data obtained from the manufacturing line can be analyzed using machine learning techniques to determine control variables that can be modified to affect one or more process variables. Process variables can be made dependent on control variables. That is, changes to one or more control variables may change one or more process variables. In an exemplary embodiment, changing the flow rate through a chromatography system can affect the carbon dioxide level at one or more points along the manufacturing line for a biological therapeutic. In another exemplary embodiment, modifying the temperature of the bioreactor effluent can affect the dissolved oxygen level of the effluent. In a further example, the agitation rate in a bioreactor can affect the viable cell density of the final product of the manufacturing line.

[0018] In conventional biological therapeutic manufacturing lines, due to the unpredictable nature of biochemical processes, process variables that affect the productivity metrics of the manufacturing line are typically determined based on unsubstantiated evidence, and process variables that affect productivity metrics are often overlooked. Further, in conventional systems, it is difficult to identify control variables that can be modified to affect process variables, and they are typically identified through trial and error and / or after the course of manufacturing. The techniques and systems described herein target a proactive approach of identifying when process variables can be outside of a threshold range of values and determining control variables that can be modified to keep the process variables within their operating ranges.

[0019] Furthermore, conventional production lines for biologic therapeutics are often built in an individualized manner to produce a single biologic therapeutic (e.g., a 5000 L or 10,000 L bioreactor) relatively large-scale over several years. Thus, data on process variables and control variables for additional production lines for a particular biologic therapeutic are typically not available. Thus, the data used to determine the settings of control variables is limited to the data collected from a single production line. The limited amount of information available for the identification of process variables that affect the productivity of the production line and each of those control variables results in some important process variables and / or control variables not being identified or not being able to be identified until the production of the biologic therapeutic is complete.

[0020] The systems and techniques described herein can obtain data from multiple production lines built using modular cleanrooms. The similarity of the equipment and process flow of production lines built using modular cleanrooms can increase the amount of data available for analysis regarding the productivity of the production lines. In this way, process variables and control variables for individual production lines can be identified more easily than for conventional production lines for biologic therapeutics. Furthermore, by analyzing a greater amount of data than is available from conventional systems, process variables and their respective control variables can be identified more accurately and in less time than with conventional systems.

[0021] FIG. 1 is a diagram of some embodiments of an architecture 100 for manufacturing one or more biological therapeutics using an apparatus housed in a number of modular clean rooms. The architecture 100 may include a manufacturing facility 102 for manufacturing biological therapeutics. Additionally, the architecture 100 may include a control system 104 for determining information available for controlling the operation of equipment included in the manufacturing facility 102. The control system 104 may obtain data from sensors that monitor the state of a manufacturing line housed in the manufacturing facility 102. The control system 104 may also obtain data from testing and / or analysis of materials extracted from the manufacturing line. For example, the control system 104 may obtain the results of analytical tests performed on materials extracted from various points on the manufacturing line.

[0022] The control system 104 can analyze the data obtained from the manufacturing facility 102 using one or more machine learning techniques. In certain embodiments, the control system 104 can perform partial least squares analysis to develop one or more models for predicting one or more productivity metrics of the manufacturing line. For example, the control system 104 can develop a model for predicting the viable cell density of the manufacturing line. The model may include a number of process variables of the manufacturing line that affect the viable cell density of the manufacturing line. The control system 104 can also analyze the data obtained from the manufacturing facility 102 to determine one or more control variables that can affect the process variables. The control system 104 can send control instructions to various devices included in the manufacturing facility 102 to change the values of one or more process variables. By way of illustration, the control system 104 can determine that the viable cell density is outside a threshold range and determine to increase the pH of a substance stored in a storage container to return the viable cell density to the threshold range. After this example, the control system 104 can send an instruction to a pump within the manufacturing facility 102 to add an amount of acid or base to the storage container that can change the pH of the substance stored in the storage container to a level corresponding to the viable cell density within the threshold range.

[0023] In various embodiments, the control system 104 can obtain data from a number of manufacturing facilities, including the manufacturing facility 102, and determine a model for predicting productivity metrics at the manufacturing facilities. In some cases, the control system 104 can develop a single model that can be used to predict productivity measurements at multiple manufacturing facilities for one or more biologic therapeutics. For example, the control system 104 can determine a model for predicting the viable cell density of a manufacturing line for a biologic therapeutic at multiple manufacturing facilities. In further cases, the control system 104 can use data obtained from a number of manufacturing facilities to determine individual models for predicting productivity metrics at the number of manufacturing facilities. By way of example, the control system 104 can determine a model for predicting the viable cell density at the manufacturing facility 102 based on data obtained from the manufacturing facility 102 and additional data obtained from additional manufacturing facilities.

[0024] The manufacturing facility 102 can include a number of modular cleanrooms that include equipment that is part of a manufacturing line for manufacturing a biologic therapeutic. Individual modular cleanrooms can include a subset of the equipment utilized in the manufacture of the biologic therapeutic. Materials produced by equipment from one of the modular cleanrooms can be transferred to other modular cleanrooms for further processing until the final biologic therapeutic is produced. In certain embodiments, the packaging or storage of the final biologic therapeutic can be performed in at least one of the modular cleanrooms.

[0025] In the exemplary embodiment of FIG. 1, the manufacturing facility 102 may include a first modular cleanroom 106, a second modular cleanroom 108, a third modular cleanroom 110, a fourth modular cleanroom 112, a fifth modular cleanroom 114, and a sixth modular cleanroom 116. Each of the individual modular cleanrooms 106, 108, 110, 112, 114, 116 can comply with one or more international standards regarding airborne particulate levels within the respective modular cleanrooms 106, 108, 110, 112, 114, 116. For example, the modular cleanrooms 106, 108, 110, 112, 114, 116 can comply with cleanroom grades defined by the International Organization for Standardization (ISO). In the ISO classification of cleanrooms, the number of particles of a threshold size that can be present within the cleanroom is defined. In a specific example, the cleanroom can be classified as an ISO 5 cleanroom with a maximum of 100,000 particles / m of particles sized 0.1 μm or less 3 , a maximum of 23,700 particles / mm of particles sized 0.2 μm 3 , a maximum of 10,200 particles / mm of particles sized 0.3 μm or less 3 , a maximum of 3520 particles / mm of particles sized 0.5 μm or less 3 , and a maximum of 832 particles / m of particles sized 1 μm or less 3 and can be classified as an ISO 5 cleanroom. The modular cleanrooms 106, 108, 110, 112, 114, 116 can also comply with other cleanroom standards such as the EU (European Union)'s GMP classification for cleanrooms. In various embodiments, each of the individual modular cleanrooms 106, 108, 110, 112, 114, 116 of the modular cleanrooms 106, 108, 110, 112, 114, 116 can meet the requirements of an ISO 5 class cleanroom, an ISO 6 class cleanroom, an ISO 7 class cleanroom, an ISO 8 class cleanroom, or an ISO 9 class cleanroom.

[0026] In an exemplary example, the area of the manufacturing facility 102 is from about 10,000 ft 2 to about 75,000 ft 2 , about 15,000 ft 2~ about 50,000 ft 2 or about 20,000 ft 2 ~ about 30,000 ft 2 It can be. Further, the areas of the individual modular clean rooms 106, 108, 110, 112, 114, 116 are about 400 ft 2 ~ about 2000 ft 2 about 600 ft 2 ~ about 1,500 ft 2 or about 700 ft 2 ~ about 1,000 ft 2 It can be. The manufacturing facility 102 may also include a staging area 118 that includes a container 120 for storing materials that can be supplied to the devices included in one or more of the modular clean rooms 106, 108, 110, 112, 114, 116. The staging area may include at least a part of the manufacturing facility 102 not occupied by the modular clean rooms 106, 108, 110, 112, 114, 116. In the exemplary example of FIG. 1, the staging area may include containers 120(1) to 120(12) disposed within an internal portion of the manufacturing facility 102. In other embodiments, one or more of the containers 120(1) to 120(12) can be disposed in other parts of the manufacturing facility 102. For example, one or more of the containers 120(1) to 120(12) can be disposed along the periphery of the manufacturing facility 102, or can be disposed between adjacent modular clean rooms such as between the modular clean room 106 and the modular clean room 108. Further, although there are 12 containers 120 in the manufacturing facility 102 shown in the exemplary embodiment of FIG. 1, in other embodiments, the manufacturing facility 102 may include more or fewer containers. In addition to the staging area 118 and the modular clean room 120, the manufacturing facility 102 may include other areas not shown in FIG. 1 such as a lobby, a conference room, a utility space, a warehouse storage, a quality control facility, an administrative office, and combinations thereof.

[0027] The materials stored in container 120 can be supplied to individual modular clean rooms 106, 108, 110, 112, 114, 116 through various inlet ports included in the modular clean rooms 106, 108, 110, 112, 114, 116. For example, the materials from container 120(1) can be supplied to modular clean room 106 through inlet port 122, and the materials from container 120(2) can be supplied to clean room 106 through inlet port 124. Also, modular clean room 106 may include additional ports 126 used to transfer materials in and out of modular clean room 106. For example, materials manufactured by one or more devices within modular clean room 106 can be transferred through additional port 126 to a storage container (not shown in FIG. 1) or to another modular clean room. Further, each of modular clean rooms 108 may include inlet ports 128 and 130 through which materials can pass from containers 120(3) and 120(4) to modular clean room 108. Also, modular clean room 108 may include an additional port 132 for transferring materials in and out of modular clean room 108. Further, modular clean room 110 can include inlet ports 134, 136 and an additional port 138, and modular clean room 112 can include inlet ports 140, 142 and an additional port 144. Also, modular clean room 114 can include inlet ports 146, 148 and an additional port 150, while modular clean room 116 can include inlet ports 152, 154 and an additional port 156. The inlet ports 134, 136 of modular clean room 110 can each be connected to containers 120(5) and 120(6), and the inlet ports 140, 142 of modular clean room 112 can each be connected to containers 120(7) and 120(8). The additional ports 138, 144 can be used to transfer materials in and out of modular clean rooms 110, 112.In addition, the inlet ports 146, 148 of the modular clean room 114 can be connected to the containers 120(9) and 120(10), and the inlet ports 152, 154 of the modular clean room 116 can be connected to the containers 120(11) and 120(12), while the additional ports 150, 156 can be used to transfer materials in and out of the modular clean rooms 114, 116. In the exemplary embodiment of FIG. 1, the modular clean rooms 106, 108, 110, 112, 114, 116 have two inlet ports and one additional port, but in other embodiments, the modular clean rooms 106, 108, 110, 112, 114, 116 may have inlet ports and / or multiple additional ports or both.

[0028] Modular clean rooms 106, 108, 110, 112, 114, 116 may include various arrangements of equipment included in a manufacturing line for biological therapeutics. In the exemplary embodiment of FIG. 1, modular clean rooms 106, 108, 110, 112, 114, 116 may include different equipment sections that perform different operations in the manufacture of biological therapeutics. For example, modular clean room 106 may include equipment 158, 160, 162, and modular clean room 108 may include equipment 164, 166, 168. Further, modular clean room 110 may include equipment 170, 172, 174, 176, and modular clean room 112 may include equipment 178, 180, 182, 184. Further, modular clean room 114 may include equipment 186, 188, 190, and modular clean room 116 may include equipment 192, 194, 196, 198. The exemplary example of FIG. 1 shows a specific number of equipment within modular clean rooms 106, 108, 110, 112, 114, 116, but in other scenarios, modular clean rooms 106, 108, 110, 112, 114, 116 may include more or fewer numbers of equipment. Additionally, modular clean rooms 106, 108, 110, 112, 114, 116 may include other features other than equipment such as material exchange airlocks, exchange areas, integrity test devices, office furniture, laboratory equipment, computing devices, combinations thereof, etc.

[0029] In an exemplary embodiment, the modular cleanroom 106 may be a solution preparation area, and the apparatuses 158, 160, 162 can be used for the preparation of solutions used in the manufacture of biological therapeutics. For example, the apparatuses 158, 160, 162 may include one or more storage containers, one or more ventilation hoods, combinations thereof, and the like. Further, the modular cleanroom 108 may be an inoculation material preparation area, and the apparatuses 164, 166, 168 can be used for the preparation of inoculation materials that are subsequently used in the manufacture of biological therapeutics. In some cases, the cell lines used in the manufacture of biological therapeutics can be produced using the apparatuses 164, 166, 168. In various examples, the apparatuses 164, 166, 168 may include one or more reactors, one or more incubators, one or more refrigerators, test apparatuses, combinations thereof, and the like.

[0030] The modular cleanroom 110 may also be a cell culture area for manufacturing a medium containing biological therapeutics. The apparatuses 170, 172, 174, 176 may include one or more bioreactors, one or more perfusion systems, one or more chromatography systems, one or more filtration systems, one or more storage containers, one or more temperature control devices, one or more pump systems, combinations thereof, and the like. In certain embodiments, the virus inactivation process can be performed using the apparatuses included in the modular cleanroom 110. Further, the modular cleanroom 112 may be a purification area capable of purifying the product manufactured in the bioreactor of the modular cleanroom 110. The purification of the product manufactured in the modular cleanroom 108 can be performed by separating different molecules contained in the effluent of the bioreactor of the modular cleanroom 108. In particular embodiments, one or more chromatography processes can be used to purify the bioreactor product. The apparatuses 178, 180, 182, 184 included in the modular cleanroom 112 may include one or more chromatography systems, one or more filters, one or more storage containers, one or more pump systems, one or more temperature control devices, combinations thereof, and the like.

[0031] The modular clean room 114 may be a second purification area for further purifying the effluent from the bioreactor of the modular clean room 108. In certain embodiments, the devices 186, 188, 190 may include one or more filtration systems, one or more pumping systems, one or more storage containers, one or more temperature control devices, combinations thereof, and the like. In certain non-limiting embodiments, the purification operation may be performed by the devices of the modular clean room 114 in some cases. Further, the modular clean room 116 may include a biological therapeutic agent area where the biological therapeutic agent produced in the modular clean room 108 is pretreated before being provided to a facility where it can be transported, delivered to a patient, and / or the dosage form of the biological therapeutic agent can be modified for delivery to a patient. In various embodiments, the biological therapeutic agent may include a sterile filtered solution and a diluent. In non-limiting examples, the biological therapeutic agent may include a suspension, a vaccine, or may not include a biological therapeutic agent. In certain embodiments, the biological therapeutic agent can be placed in vials and / or syringes. The devices 192, 194, 196 may include one or more pump devices, one or more storage containers, or one or more filling systems. Using one or more filling systems, a certain amount of the biological therapeutic agent can be dispensed into a container such as a vial or syringe.

[0032] As an illustrative example of FIG. 1, six modular clean rooms are mentioned, but the manufacturing facility 102 may include more or fewer modular clean rooms. In certain embodiments, the manufacturing facility 102 may include additional modular clean rooms including a cell culture area. Also, the manufacturing facility 102 may include additional modular clean rooms including devices for performing purification operations and / or filtration operations.

[0033] FIG. 2 is a schematic diagram of an embodiment of an environment 200 that includes a modular clean room 202 capable of generating a virus inactivation pool. In various embodiments, the environment 200 may be included in a manufacturing facility, such as the manufacturing facility 102 of FIG. 1. The modular clean room 202 may include equipment that can be used to perform cell culture operations. The cell culture operations can be used to produce a biological therapeutic agent using a culture medium containing a cell line that can support the production of the biological therapeutic agent.

[0034] The modular clean room 202 can be connected to a number of storage containers 204. The storage containers 204 can store materials that are supplied to one or more devices included in the modular clean room 202 and / or materials that are transferred from one or more devices housed in the modular clean room 202. In certain embodiments, the storage containers 204 can be located in the staging area of the manufacturing facility. The volume of the storage containers 204 can vary. For example, the volume of an individual storage container can be from about 50 L to about 2000 L, or from about 100 L to about 1000 L. In an exemplary embodiment, the volume of one or more first containers 204 can be about 100 L, the volume of one or more second containers 204 can be about 200 L, and the volume of one or more third containers 204 can be about 1000 L.

[0035] The materials can be transferred via port 206 between the devices arranged within the modular cleanroom 202 and the storage containers 204. In the exemplary example of FIG. 2, the environment 200 may include a storage container 204(1) connected to port 206(1), storage containers 204(2) and 204(3) connected to port 206(2), and a storage container 204(4) connected to port 206(3). Ports 206(1), 206(2), and 206(3) can be connected to the bioreactor 208. In an exemplary embodiment, storage containers 204(1) and 204(4) can provide cell culture medium to the bioreactor 208. Further, storage container 204(2) can supply sodium bicarbonate to the bioreactor 208, and storage container 204(3) can supply cell growth materials such as glucose to the bioreactor 208. In other embodiments, storage container 204(3) can store materials removed from the bioreactor 208 as part of a cell extraction operation.

[0036] The bioreactor 208 may include a container having a volume of about 250 L to about 2000 L or about 500 L to about 1000 L. The bioreactor 208 may include a pumping mechanism, a stirring mechanism, a sparger, combinations thereof, etc. The conditions within the bioreactor 208 are suitable for causing a biological reaction to produce a specific biotherapeutic agent using the cell culture medium supplied to the bioreactor 208 from one or more of the storage containers 204. The bioreactor 208 can operate continuously without stopping for a certain period. For example, the bioreactor 208 can operate for about 5 days to about 40 days, about 10 days to about 30 days, or about 15 days to about 25 days. In the exemplary example of FIG. 2, a single bioreactor 208 housed within the modular cleanroom 202 is shown, but in further embodiments, the modular cleanroom 202 can house two or more bioreactors.

[0037] In an exemplary example, for a single vessel volume, bioreactor 208 can produce from about 0.5 g of a biotherapeutic per liter of cell culture medium per day to about 10 g of a biotherapeutic per liter of cell culture medium per day, from about 1 g of a biotherapeutic per liter of cell culture medium per day to about 6 g of a biotherapeutic per liter of cell culture medium per day, or from about 2 g of a biotherapeutic per liter of cell culture medium per day to about 4 g of a biotherapeutic per liter of cell culture medium per day. In other examples, for two vessel volumes, bioreactor 208 can produce from about 0.25 g of a biotherapeutic per liter of cell culture medium per day to about 7 g of a biotherapeutic per liter of cell culture medium per day, from about 0.5 g of a biotherapeutic per liter of cell culture medium per day to about 5 g of a biotherapeutic per day, or from about 1 g of a biotherapeutic per liter of cell culture medium per day to about 2 g of a biotherapeutic per liter of cell culture medium per day. Although not shown in the exemplary embodiment of FIG. 2, bioreactor 208 may be connected to or include a temperature control system and / or a human machine interface device.

[0038] The bioreactor 208 can be connected to a perfusion system 210 that can utilize one or more pump devices for the addition of feed materials to the bioreactor 208 and the removal of effluent from the bioreactor 208. The perfusion system 210 can supply the effluent to a storage container 212. The effluent stored in the storage container 212 can be obtained by a continuous chromatography system 216. In some cases, the effluent stored in the storage container 212 may pass through a temperature control system 214 that can change the temperature of the effluent before the effluent is supplied to the continuous chromatography system 216. In an exemplary embodiment, the temperature control system 214 may include a heat exchanger that can heat or cool the effluent stored in the storage container 212 when transferring it to the continuous chromatography system 216. The continuous chromatography system 216 may include a group of chromatography columns 218. In various embodiments, the group of chromatography columns 218 may include from 2 to 16 chromatography columns or from 3 to 9 chromatography columns. Further, in certain embodiments, the continuous chromatography system 216 may have disposable flow paths such that the continuous chromatography system 216 is a single-use continuous chromatography system.

[0039] The continuous chromatography system 216 can utilize various chromatography processes. For example, the continuous chromatography system 216 can utilize one or more of a Protein A affinity chromatography process, an ion exchange chromatography process, a mixed mode chromatography process, a hydrophobic interaction chromatography process, or a size exclusion chromatography process. In various embodiments, the diameter of the column 218 of the continuous chromatography system 216 can be from about 40 cm to about 100 cm, from about 50 cm to about 80 cm, or from about 60 cm to about 70 cm. Further, in certain embodiments, the height of the column 218 of the continuous chromatography system 216 can be from about 10 cm to about 40 cm, from about 15 cm to about 30 cm, or from about 20 cm to about 25 cm. In certain embodiments, the amount of product produced by each column 218 of the continuous chromatography system 216 can be from about 80 g / L of resin to about 140 g / L of resin, from about 90 g / L of resin to about 130 g / L of resin, or from about 100 g / L of resin to about 120 g / L of resin. Further, the effluent from the bioreactor 208 can be processed according to a number of cycles of the continuous chromatography system 216, such as 4 to 15 cycles, 6 to 12 cycles, or 8 to 10 cycles. In an exemplary embodiment, the duration of an individual cycle of the continuous chromatography system 216 can be from about 3 hours to about 12 hours, from about 4 hours to about 10 hours, or from about 6 hours to about 8 hours.

[0040] The buffer solution can be supplied to the continuous chromatography system 216 from one or more containers 204(5), 204(6), 204(7), 204(8), 204(9), 204(10), or 204(11) via ports 206(4), 206(5), and / or 206(6). In the exemplary example of FIG. 2, containers 204(5), 204(6), and 204(7) can be connected to port 206(4), container 204(8) can be connected to port 206(5), and containers 204(9), 204(10), and 204(11) can be connected to port 206(6). Other embodiments may include different arrangements of containers connected to one or more of ports 206(4), 206(5), and / or 206(6). Further, although not shown in FIG. 2, a portion of the effluent from the continuous chromatography system 216 can be transferred to one or more of containers 204(5), 204(6), 204(7), 204(8), 204(9), 204(10), or 204(11).

[0041] The effluent from the continuous chromatography system 216 can be supplied to a series of devices including container 220, container 222, pumping device 224, and further container 226. In particular, the effluent from the continuous chromatography system 216 can be supplied to either container 220 or container 222. For example, the delivery of the effluent from the continuous chromatography system 216 can be alternated between container 220 and container 222. Illustratively, the effluent from the continuous chromatography system 216 can be supplied to container 220 for a certain period or until the volume of the effluent stored in container 220 reaches a threshold level. After a certain period of time has elapsed, or after the volume of the effluent in container 220 has reached at least the threshold level, the effluent from the continuous chromatography system 216 can be supplied to container 222. Subsequently, after the effluent from the continuous chromatography system 216 has been supplied to container 222 for a certain period or after the volume of the effluent in container 222 has reached the threshold volume, it can be switched to supply the effluent from the continuous chromatography system 216 to container 220. The operation of filling one of containers 220 and 222 with the effluent from the continuous chromatography system 216 and switching to the other of containers 220 and 222 can continue until the bioreactor 208 no longer produces the product. At least one of container 220 or container 222 can collect the product from the continuous chromatography system 216 for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, or at least 8 days. In an exemplary example, at least one of container 220 or container 222 can collect the product from the continuous chromatography system 216 for 0.5 days to 25 days, 1 day to 20 days, 2 days to 15 days, 3 days to 10 days, 4 days to 8 days, 5 days to 12 days, or 6 days to 15 days. In a particularly illustrative example, the volume of container 220 or container 222 is about 100 liters and the product can be collected from the continuous chromatography system 216 for about 5 days.

[0042] The modular clean room 202 may also include a pump device 224. Using the pump device 224, an acid can be added to the effluent from the continuous chromatography system 216. The addition of acid to the effluent from the continuous chromatography system 216 can be used as a virus inactivation process. In some embodiments, the effluent from the continuous chromatography system 216 can be supplied from the container 220 or the container 222 to the container 226 before the addition of acid to the effluent. In a further embodiment, the pump device 224 can add acid to the effluent from the continuous chromatography system 216, while the effluent is stored in the container 220 or the container 222. In these cases, since the effluent from the continuous chromatography system 216 is supplied to one of the containers 220, 222, the pump device 224 can add acid to the other of the containers 220, 222 to inactivate the virus in the effluent from the continuous chromatography system 216 stored therein. The effluent from the continuous chromatography system 216 can be treated with the acid provided by the pump device 224 for a certain period of time to achieve virus inactivation of the effluent of the continuous chromatography system 216. For example, the effluent of the continuous chromatography system 216 can be treated with the acid provided by the pump device 224 for at least 5 hours, at least 10 hours, at least 15 hours, at least 20 hours, at least 30 hours, at least 40 hours, at least 4 days, or at least 5 days. In an exemplary scenario, the effluent of the continuous chromatography system 216 can be treated with the acid provided by the pump device 224 for 4 hours to 6 days, 12 hours to 5 days, 1 day to 4 days, 18 hours to 3 days, or 2 days to 5 days. In a further embodiment, instead of treating the effluent from the continuous chromatography system 216 with an acid, the effluent from the continuous chromatography system 216 can be treated with a surfactant to produce a virus inactivation pool.

[0043] The virus inactivation pool can be pumped out of the modular cleanroom 202 using a pump 228 that sends the virus inactivation pool through a depth filter 230 and a filter cart 232. The filter cart 232 may include a filter device having an average aperture size of 1 micron or less, 0.8 micron or less, 0.6 micron or less, 0.4 micron or less, 0.2 micron or less, 0.1 micron or less, or 0.05 micron or less. In an exemplary example, the filter device of the filter cart may have an average size of the openings of 0.05 micron to 1 micron, 0.1 micron to 0.6 micron, or 0.2 micron to 0.4 micron. After being pumped out of the modular cleanroom 202, the virus inactivation pool can be stored in a container (not shown) before being supplied to a further modular cleanroom included in the manufacturing facility.

[0044] Figure 3 is a schematic view of an embodiment of an environment 300 including a modular cleanroom 302 capable of manufacturing a virus-filtered biotherapeutic. In various embodiments, the environment 300 may be included in a manufacturing facility such as the manufacturing facility 102 of FIG. 1. The modular cleanroom 302 may include devices that operate in the manufacture of a virus-filtered biotherapeutic using the virus inactivation pool produced by the modular cleanroom 202. For example, the modular cleanroom 302 may include devices that perform purification operations on the virus inactivation pool produced by the modular cleanroom 202.

[0045] The modular clean room 302 may include a number of ports 304 that can be connected to containers that supply various solutions to the equipment included in the modular clean room. In the exemplary embodiment of FIG. 3, the modular clean room 302 may include a first port 304(1) connected to a first storage container 306 and a second port 304(2) connected to a second storage container 308. The first storage container 306 can store a certain amount of the virus-inactivated elution pool produced by the modular clean room 202. Further, the second container 308 can store an amount of buffer solution that can be utilized by one or more devices of the modular clean room 302. The volume of the first storage container 306 may be 1000 L to 3000 L, 1500 L to 2500 L, or 1750 L to 2250 L. Further, the volume of the second storage container 308 may be 500L to 2000L, 750L to 1500L, or 800L to 1200L.

[0046] The modular clean room 302 may also include a third port 304(3), a fourth port 304(4), and a fifth port 304(5). The ports 304(3), 304(4), 304(5) can be connected to additional buffer solution storage containers 310, 312(1), 312(2), 312(3), 312(4), 312(5), and 312(6). The volume of the buffer solution storage container 312 may be different from the volume of the buffer solution storage container 310. By way of example, the volume of the buffer solution storage container 310 may be 50L to 250L or 100L to 200L. Further, the volume of the storage container 312 may be 500 L to 2000 L, 750 L to 1500 L, or 800 L to 1200 L.

[0047] Furthermore, the modular clean room 302 may include a sixth port 304(6) connected to a third storage container 314 and a fourth storage container 316. The third storage container 314 can store an amount of virus inactivation pool produced by the modular clean room 202, and the fourth storage container 316 may contain a buffer solution. The volume of the third storage container 314 may be 1000L to 3000L, 1500L to 2500L, or 1750L to 2250L, and the volume of the fourth storage container 316 may be 500L to 2000L, 750L to 1500L, or 800L to 1200L. In an exemplary example, the storage containers 308, 310, 312, 316 for storing buffer solutions can store sodium bicarbonate buffer solutions. Also, the storage containers 306, 308, 310, 312, 314, 316 can be arranged in the staging area of the manufacturing facility. In a specific embodiment, at least a part of the storage containers 306, 308, 310, 312, 314, 316 can be stored in the staging area together with at least a part of the storage container 204 in FIG. 2.

[0048] The virus inactivation pool from the containers 306, 314 and / or the buffer solution from the containers 308, 316 can be supplied to the temperature control unit 318. The temperature control unit 318 may include a heat exchanger in some embodiments. Furthermore, the temperature control unit 318 may be portable. In a particular embodiment, the temperature control unit 318 may, in some cases, depend on the temperature of the virus inactivation pool and the temperature of the buffer solution.

[0049] A virus-inactivating pool and a buffer solution can be supplied to a first chromatography system 320 including a number of chromatography columns 322 at an appropriate temperature. In various embodiments, the number of chromatography columns 322 used in a given process can be 2 to 16 or 3 to 8. In some embodiments, the first chromatography system 320 may have disposable flow paths such that the first chromatography system 320 is a single-use chromatography system. The first chromatography system 320 can utilize various chromatography processes. For example, the first chromatography system 320 can utilize one or more of a protein A affinity chromatography process, an ion exchange chromatography process, a mixed-mode chromatography process, a hydrophobic interaction chromatography process, a size exclusion chromatography process, or an ion exchange chromatography process. In various embodiments, the diameter of the columns 322 of the first chromatography system 320 can be about 40 cm to about 100 cm, about 50 cm to about 80 cm, or about 60 cm to about 70 cm. Further, the height of the columns 322 of the first chromatography system 320 can be about 10 cm to about 40 cm, about 15 cm to about 30 cm, or about 20 cm to about 25 cm. In certain embodiments, the amount of product produced by each column 322 of the first chromatography system 320 can be about 80 g / L of resin to about 140 g / L of resin, about 90 g / L of resin to about 130 g / L of resin, or about 100 g / L of resin to about 120 g / L of resin. Further, the virus-inactivating pool can be processed according to a number of cycles of the first chromatography system 320, such as 4 to 15 cycles, 6 to 12 cycles, or 8 to 10 cycles. In an exemplary embodiment, the duration of an individual cycle of the first chromatography system 320 can be about 3 hours to about 12 hours, about 4 hours to about 10 hours, about 6 hours to about 8 hours, or about 3 hours to about 6 hours.

[0050] The purified product from the first chromatography system 320 can be stored in the storage container 324. The volume of the storage container 324 may be 100 L to 1500 L, 250 L to 1250 L, 500 L to 1000 L, or 600 L to 700 L. The purified product from the first chromatography system 320 stored in the storage container 324 can be supplied to a further chromatography system 326 having a number of columns 328. The buffer solution may also be supplied from the containers 310, 312 to the further chromatography system 326. The further chromatography system 326 may, in some embodiments, have a configuration similar to that of the first chromatography system 320. Depending on the purity of the product produced by the first chromatography system 320, in some cases, a second chromatography system 326 may be performed.

[0051] In certain embodiments, the number of chromatography columns 328 used in a given process may be from 2 to 16 or from 3 to 8. In some embodiments, the additional chromatography system 326 may have disposable flow paths such that the additional chromatography system 326 is a single-use chromatography system. The additional chromatography system 326 can utilize various chromatography processes. For example, the additional chromatography system 326 can utilize one or more of a Protein A affinity chromatography process, an ion exchange chromatography process, a mixed mode chromatography process, a hydrophobic interaction chromatography process, a size exclusion chromatography process, or an ion exchange chromatography process. In various embodiments, the diameter of the columns 328 of the additional chromatography system 326 may be from about 40 cm to about 100 cm, from about 50 cm to about 80 cm, or from about 60 cm to about 70 cm. Additionally, the height of the columns 328 of the additional chromatography system 326 may be from about 10 cm to about 40 cm, from about 15 cm to about 30 cm, or from about 20 cm to about 25 cm. In certain embodiments, the amount of product produced by each column 328 of the additional chromatography system 326 can be from about 80 g / L of resin to about 140 g / L of resin, from about 90 g / L of resin to about 130 g / L of resin, or from about 100 g / L of resin to about 120 g / L of resin. Further, the purified product produced by the first chromatography system 320 can be processed according to some cycles of the additional chromatography system 326, such as 4 to 15 cycles, 6 to 12 cycles, or 8 to 10 cycles. In an exemplary embodiment, the duration of an individual cycle of the additional chromatography system 326 can be from about 3 hours to about 12 hours, from about 4 hours to about 10 hours, from about 6 hours to about 8 hours, or from about 3 hours to about 6 hours.

[0052] In particular, the product purified by the further chromatography system 326 can be stored in a further storage container 330. The volume of the further storage container 330 can be 100 L to 1500 L, 250 L to 1250 L, 500 L to 1000 L, or 600 L to 700 L. The further storage container 330 can be connected to a pumping device 332 that is connected to a smaller storage container 334. The smaller storage container 334 may contain a further solution, such as a buffer solution, that can be pumped by the pumping device 332. The volume of the smaller storage container 334 can be 25 L to 250 L, 35 L to 150 L, or 40 L to 75 L.

[0053] The pumping device 332 can supply the product purified by the further chromatography system 326 stored in the further storage container 330 and / or the solution stored by the smaller storage container 334 to a virus filtration device 336. The virus filtration device has a filtration area of 1 m 2 ~10 m 2 、a filtration area of 2 m 2 ~8 m 2 、or a filtration area of 3 m 2 ~6 m 2 and may be. The filtration time of the product purified by the first chromatography system 320 and, optionally, by the second chromatography system 326 can be 5 hours to 15 hours, 7 hours to 12 hours, or 8 hours to 10 hours. The virus-filtered biotherapeutic agent from the virus filtration device 336 can be supplied to a filtration cart 338 for transporting the virus-filtered biotherapeutic agent from the modular cleanroom 302.

[0054] FIG. 4 is a schematic diagram of an embodiment of an environment 400 that includes a modular clean room 402 capable of manufacturing a purified biologic therapeutic. In various embodiments, the environment 400 may be included in a manufacturing facility such as the manufacturing facility 102 of FIG. 1. The modular clean room 402 may include equipment that operates in the manufacture of a purified biologic therapeutic using a virus-filtered biologic therapeutic manufactured in the modular clean room 302. For example, the modular clean room 402 may include equipment that performs further purification operations on the virus-filtered biologic therapeutic manufactured by the modular clean room 302.

[0055] The modular clean room 402 may include a number of ports 404 that can be connected to containers that supply various solutions to the equipment included in the modular clean room 402. In the exemplary example of FIG. 4, the modular clean room 402 may include a first port 404(1) that supplies a virus-filtered biotherapeutic produced by the modular clean room 302 to an apparatus disposed within the modular clean room 402 for further purification of the virus-filtered biotherapeutic. In some embodiments, the virus-filtered biotherapeutic can be stored in a storage container connected to the port 404(1). Further, the modular clean room 402 may include a second port 404(2) connected to the storage containers 406(1) and 406(2) and a third port 404(3) connected to the storage containers 406(3) and 406(4). The container 408 can store an amount of buffer solution that can be utilized by one or more apparatuses of the modular clean room 402. The volume of the storage container 406 may be 500L to 2000L, 750L to 1500L, or 800L to 1200L. Further, the modular clean room 402 may include a fourth port 404(4) connected to a storage container 408 that can also store the buffer solution supplied to the apparatuses within the modular clean room 402. The volume of the storage container 408 may be 50L to 250L, or 100L to 200L. In some embodiments, the storage containers 406, 408 can be disposed in a staging area of a manufacturing facility such as the manufacturing facility 102 of FIG. 1.

[0056] The modular cleanroom 402 may include two regions 410 and 412. At least a portion of the two regions 410 and 412 can be separated by a physical barrier. In certain embodiments, the regions 410 and 412 can be separated by a curtain. In other embodiments, the regions 410 and 412 can be separated by at least a partial wall that is accessible between the two regions 410 and 412. The first region 410 may be a filtration region, and the second region 412 may also be a filling / finishing region. In some embodiments, at least a portion of the second region 412 can be disposed under a hood that can have laminar flow within the second region 412. In various embodiments, the particle concentration in the second region 412 may be lower than the particle concentration in the first region 410. In such a situation, the cleanroom classification of the second area 412 may be different from the cleanroom classification of the first area 410.

[0057] The first region 410 of the modular cleanroom 402 may include a first storage container 414 that can store a certain amount of virus-filtered biotherapeutic from the modular cleanroom 302, and a further storage container 416 that can store a certain amount of buffer solution. The volume of the first holding container 414 may be 200 L to 2000 L, 400 L to 1500 L, or 600 L to 1000 L. Additionally, the volume of the further storage container 416 may be 25 L to 200 L, 40 L to 150 L, or 50 L to 100 L. The virus-filtered product stored in the first holding container 414, together with the buffer solution, can be supplied to the filtration device 418 from a further storage container 416 if any. The filtration device 418 can perform ultrafiltration and / or diafiltration operations. In certain embodiments, the filtration device 418 may include a tangential flow filtration device. The filtration device 418 may include a number of membranes that separate molecules based on the size of the pores of the membrane. Diafiltration may be performed by the filtration device 418. The buffer solution obtained from one or more of the containers 406 can be supplied to the filtration device 416 used in the ultrafiltration / diafiltration process. In certain embodiments, the filtration device 416 can be connected to a temperature control unit.

[0058] In an exemplary embodiment, the filtration device 416 may include a filtration area of 2 m 2 to 20 m 2 , 4 m 2 to 15 m 2 , or 8 m 2 to 12 m 2 . In addition, the filtration device 416 can be operated over a number of cycles. For example, the filtration device 416 can operate for 2 to 12 cycles, 4 to 10 cycles, or 6 to 8 cycles to produce a purified biological therapeutic agent. Further, the duration of each cycle of the filtration device 416 may be 2 to 20 hours, 4 to 15 hours, or 6 to 10 hours. In various embodiments, the total processing time on the filtration device 416 can be 4 to 120 hours, 10 to 100 hours, 25 to 75 hours, or 40 to 50 hours.

[0059] The filtered product from the filtration device 416 can be stored in a further storage container 420. The volume of the further storage container 420 may be 50 L to 1200 L, 100 L to 750 L, or 200 L to 400 L. In addition, the further storage container 420 can be connected to a first pumping device 422 that can add a buffer solution from the storage container 408 to the further storage container 420. Further, the first pumping device 422 can provide the purified biological therapeutic agent stored in the further storage container 420 to a second pumping device 424 disposed in the second region 412. The second pumping device 424 can be connected to a third storage container 426 disposed within the second region 412. The second pumping device 424 can be used to provide a buffer solution to the purified biological therapeutic agent stored in the further holding container 420. The volume of the third holding container may be 50 L to 1200 L, 100 L to 750 L, or 200 L to 400 L.

[0060] The purified biological therapeutic agent can undergo one or more filling and / or finishing operations in the second region 412. The filling operation can be performed in an automated process where a number of vials are filled at a specific rate per minute. For example, the filling operation can be performed at a rate of 5 to 100 vials per minute, 10 to 75 vials per minute, or 20 to 60 vials per minute. In an exemplary example, the volume of the vial can be 2 mL to 40 mL, 5 mL to 30 mL, and 10 mL to 20 mL.

[0061] The exemplary examples of FIGS. 2-4 are directed to a perfusion system for manufacturing a biological therapeutic agent, and a modular clean room can also be utilized for manufacturing a biological therapeutic agent using a batch process. In these embodiments, the modular clean room can include one or more bioreactors, and the product produced by one or more bioreactors can be stored in various storage containers. Subsequently, the product stored in the storage container can be supplied to a first chromatography system. In various embodiments, the product stored in the storage container can be supplied to a further storage container connected to the first chromatography system. The first chromatography system can be arranged in the same modular clean room as one or more bioreactors or in another modular clean room in some embodiments. The product stored in the further storage container can be supplied to the first chromatography system. After purification in the first chromatography system, the purified product can be subjected to a virus inactivation process. Subsequently, the virus inactivation pool can be transferred to one or more further modular clean rooms such as the modular clean room 300 of FIG. 3 and the modular clean room 400 of FIG. 4.

[0062] In an exemplary embodiment, the components of the devices included in the modular clean rooms 200, 300, 400 may include a production line for manufacturing biological therapeutics. In some embodiments, the biological therapeutics may include therapeutic proteins. The term "therapeutic protein" refers to a pharmacologically active protein that can be applied to the prevention, treatment, or therapy of human diseases or conditions. Examples of therapeutic proteins include, but are not limited to, monoclonal antibodies, recombinant forms of natural proteins (e.g., receptors, ligands, hormones, enzymes, or cytokines), fusion proteins, peptibodies, and / or monomer domain-binding proteins (e.g., based on domains selected from LDL receptor A-domain, thrombospondin domain, thyroglobulin domain, trefoil / PD domain, VEGF-binding domain, EGF domain, anatoxin domain, Notch / LNR domain, DSL domain, integrin beta domain, and Ca-EGF domain). The terms "polypeptide" and "protein" are used interchangeably herein and include a molecular chain of two or more amino acids covalently linked via peptide bonds. The term does not refer to a specific length of the product.

[0063] The term "recombinant" refers to a substance (e.g., nucleic acid or polypeptide) that has been artificially, artificially or synthetically (i.e., non-naturally) modified. Such modification can be performed on the substance within its natural environment or state. As used herein, the term "recombinant protein" or "recombinant polypeptide" refers to a protein molecule, such as a therapeutic protein of interest, expressed using a recombinant DNA molecule. A "recombinant host cell" is a cell that contains and / or expresses a recombinant nucleic acid.

[0064] The term "polynucleotide" or "nucleic acid" encompasses both single-stranded and double-stranded nucleotide polymers containing two or more nucleotide residues. The nucleotide residues that make up a polynucleotide can be ribonucleotides or deoxyribonucleotides, or modified forms of either type of nucleotide. As used interchangeably herein, a "polynucleotide sequence" or "nucleotide sequence" or "nucleic acid sequence" is the primary sequence of nucleotide residues in a polynucleotide, including a string of nucleotides that represents the primary sequence of oligonucleotides, DNA, and RNA, nucleic acids, or nucleotide residues. Given any particular polynucleotide sequence, either the given nucleic acid or its complementary polynucleotide sequence can be determined. It includes DNA or RNA of genomic or synthetic origin, which may be single-stranded or double-stranded and may represent the sense or antisense strand. Unless otherwise specified, the left end of any single-stranded polynucleotide sequence described herein is the 5' end, and the left end of a double-stranded polynucleotide sequence is in the 5' direction.

[0065] An expression cassette is a common feature of recombinant expression technology. An expression cassette contains a gene encoding a protein of interest, for example, a gene encoding an antibody sequence, such as an immunoglobulin light chain and / or heavy chain sequence. A eukaryotic "expression cassette" refers to the part of an expression vector that produces a protein in a eukaryotic cell such as a mammalian cell. It includes a promoter for mRNA transcription that can function in eukaryotic cells, one or more genes encoding the protein of interest, and mRNA termination and processing signals. Recombinant expression technology typically involves the use of a recombinant expression vector containing an expression cassette, and a mammalian host cell containing the expression cassette or at least the recombinant expression vector comprising the expression cassette, which can be integrated into, for example, the host cell genome.

[0066] The term "vector" refers to any molecule or entity (e.g., nucleic acid, plasmid, bacteriophage, or virus) used to transfer information encoding a protein to a host cell.

[0067] As used herein, the term "expression vector" or "expression construct" refers to a recombinant DNA molecule that contains a desired coding sequence necessary for the expression of a coding sequence linked so as to be functional in a specific host cell and appropriate nucleic acid control sequences.

[0068] The terms "cell", "cell line", and "cell culture" are often used interchangeably, and in this specification, all of these terms include cell progeny.

[0069] The biological therapeutics produced herein can be produced by culturing protein-secreting mammalian cells in one or more single-use perfusion bioreactors containing a liquid medium under conditions such that the cells can secrete recombinant therapeutic proteins into the medium during a production culture period of at least 20 days.

[0070] "Cell culture" refers to an extracellular culture medium (fresh or conditioned) and mammalian cells cultured therein. As used interchangeably herein, "cell culture medium" or "culture medium" refers to a sterile aqueous medium suitable for the growth of cells, preferably animal cells, more preferably mammalian cells (e.g., CHO cells) in in vitro cell culture. "Feed medium" refers to fresh cell culture medium added to the cell culture after inoculating the cells into the cell culture medium and initiating cell growth.

[0071] The term "production culture period" refers to the period during which mammalian cells secreting recombinant therapeutic proteins are maintained under incubation conditions in a bioreactor such that the desired therapeutic protein can be physiologically and continuously produced. In various embodiments, the production culture period can be at least 10 days or more, or at least 20 days or more, for example, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days or more, or 10-20 days or more, or 20-30 days or more, or 30-45 days or more, or 45-60 days or more.

[0072] During the manufacturing culture period, fresh sterile liquid medium is automatically added to one or more perfusion bioreactors and simultaneously mixed from a plurality of different concentrated medium component solutions and aqueous diluents. The term "simultaneously mixed" means that for the preparation of the fresh medium, the concentrated medium components and the diluent are mixed together, and are mixed within seconds or minutes (within 2 minutes) only if necessary to exchange the amount of medium removed from each of the perfusion bioreactors as the permeate volume or cell bleed volume. The bioreactor has a characteristic mixing time and stirring speed based on the bioreactor and impeller design.

[0073] In various embodiments, the fresh sterile liquid medium is added to one or more perfusion bioreactors by injecting a plurality of different concentrated component solutions into each other in a certain ratio, while the aqueous diluent (suitable buffer solution or water) is also added to the plurality of different concentrated medium component solutions in various ratios to maintain a constant culture volume in each perfusion bioreactor. Further, by injecting a plurality of different concentrated component solutions and an aqueous diluent (suitable buffer solution or water) into each other in a certain ratio, the fresh sterile liquid medium is added to one or more perfusion bioreactors to maintain a constant culture volume in each perfusion bioreactor. In still other embodiments, the fresh sterile liquid medium is added to one or more perfusion bioreactors by injecting a plurality of different concentrated component solutions and an aqueous diluent (suitable buffer solution or water) into a mixing chamber in a certain ratio, where the fresh sterile liquid medium is injected into the mixing chamber and then simultaneously mixed therein (in a sterile mixing container fluidly connected to the bioreactor), and then added to each perfusion bioreactor to maintain a constant culture volume.

[0074] The specific ratio at which the medium components and the diluent are properly mixed varies depending on the medium formulation used and the concentration of the concentrated medium components used, and the appropriate ratio can be conveniently calculated by those skilled in the art.

[0075] Sub-surface addition of different concentrated media components solutions and aqueous diluents is preferably avoided. Supplying all media component solutions and aqueous diluents through separate ports, as necessary, can be achieved manually or using a ratio-controlled pump skid and automation to maintain the culture volume in a perfusion bioreactor.

[0076] The term "buffer" or "buffer solution" refers to a solution that resists changes in pH by the action of its conjugate acid-base range. Examples of useful buffer solutions include acetate, MES, citrate, Tris, Bistris, histidine, arginine, succinate, citrate, glutamate, and lactate, or combinations of two or more of these, or other mineral acid or organic acid buffer solutions. Phosphates are another example of useful buffer solutions. Salts containing cations of sodium, ammonium, and potassium are often used in the manufacture of buffer solutions.

[0077] The term "antibody" or "Ab" is used interchangeably and in the broadest sense and includes fully assembled antibodies capable of binding to an antigen, monoclonal antibodies (including human, humanized or chimeric antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments capable of binding to an antigen (e.g., Fab, Fab’, F(ab’)2, Fv, single-chain antibodies, diabodies). Antibodies of any isotype class or subclass, including IgG, IgM, IgD, IgA, and IgE, IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2, or any allotype are contemplated. The term "monoclonal antibody" as used herein refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies comprising the population are identical except for natural-occurring mutations that may be present in trace amounts.

[0078] The term "immunoglobulin" includes two dimerized heavy chains (HC) each covalently bound to a light chain (LC); a single non-dimerized immunoglobulin heavy chain and a covalently bound light chain (HC+LC), or a chimeric immunoglobulin (light chain + heavy chain)-Fc heterotrimer (so-called "half-body"), or a fusion protein (e.g., peptibody) containing a dimerized or non-dimerized Fc domain. An "immunoglobulin" is a protein, but it does not necessarily have to be an antigen-binding protein (e.g., a carrier antibody covalently bound to a clinically relevant target-binding moiety).

[0079] In an "antibody", each tetramer is composed of two identical pairs of polypeptide chains, each having one "light" chain of about 220 amino acids (about 25 kDa) and one "heavy" chain of about 440 amino acids (about 50 - 70 kDa). The amino-terminal portion of each chain contains a "variable" ("V") region of about 100 - 110 or more amino acids that is mainly involved in antigen recognition. At the carboxy-terminal portion of each chain, there is a constant region mainly responsible for effector functions. The variable regions differ among antibodies. The constant regions are the same among different antibodies. Within the variable region of each heavy or light chain, there are three hypervariable subregions, which, in the case of an antibody that is an antigen-binding protein, serve to determine the specificity of the antibody for an antigen. The variable domain residues between the hypervariable regions are called framework residues and generally have a certain degree of homology among different antibodies. Immunoglobulins are classified into different classes according to the amino acid sequence of the constant domain of their heavy chains. Human light chains are classified into κ (kappa) light chains and λ (lambda) light chains. The variable and constant regions within the light and heavy chains are linked by a "J" region of about 12 or more amino acids, and the heavy chain also contains a "D" region of about 10 or more amino acids. Generally, see Fundamental Immunology, Chapter 7 (Paul, W., ed., 2nd ed., Raven Press, N.Y. (1989)). An "antibody" also includes recombinantly produced antibodies, and glycosylated or non-glycosylated antibodies.

[0080] The term "light chain" or "immunoglobulin light chain" includes full-length light chains and fragments thereof that have a variable region sequence sufficient to confer binding specificity. A full-length light chain consists of the variable region domain V L and the constant region domain C L . The variable region domain of the light chain is at the amino terminus of the polypeptide. There are kappa and lambda chains for the light chain.

[0081] The term "heavy chain" or "immunoglobulin heavy chain" includes full-length heavy chains and fragments thereof that have a variable region sequence sufficient to confer binding specificity. A full-length heavy chain consists of the variable region domain, V H , and three constant region domains, C H1 , C H2 , and C H3 . The V H domain is at the amino terminus of the polypeptide, the C H domain is at the carboxyl terminus, and C H3 is closest to the carboxyl terminus of the polypeptide. Heavy chains are classified as mu (μ), delta (δ), gamma (γ), alpha (α), epsilon (ε), and the antibody isotypes are defined as IgM, IgD, IgG, IgA, IgE, respectively. The heavy chain can be of any isotype, including IgG (including IgG1, IgG2, IgG3, and IgG4 subtypes), IgA (including IgA1 and IgA2 subtypes), IgM, and IgE. Some of these can be further classified into subclasses or isotypes, such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0082] The term "antigen-binding protein" (ABP) includes antibodies or antibody fragments that specifically bind to a target ligand or antigen of interest. An antigen-binding protein, such as a therapeutic protein of interest like an immunoglobulin protein, or an antibody or antibody fragment, "specifically binds" when, under similar binding assay conditions, its binding affinity for the target ligand or antigen of interest is significantly higher compared to its affinity for other unrelated proteins, and as a result, it can distinguish that target ligand or antigen. Typically, an antigen-binding protein "specifically binds" to its target antigen when the dissociation constant (KD) is -8 M or less. An antigen-binding protein has "high affinity" when the KD is -9 M or less, and specifically binds with "very high affinity" when the KD is -10 M or less. The "antigen-binding region" or "antigen-binding site" refers to the part of a protein that specifically binds to a particular target ligand or antigen.

[0083] A "chromatography system" is an arrangement of at least one closed chromatography matrix, and includes a closed conduit hardware (e.g., pipes or tubes) for the outflow and efflux of fluid from the at least one closed chromatography matrix. The chromatography system includes one or more pumps and / or valves to automatically or manually control the flow rate and pressure of the fluid. The chromatography system of the processes and facilities of the present invention can incorporate various chromatography matrices selected in an order suitable for the therapeutic protein of interest and known to those skilled in the art. The term "matrix" includes resins, beads, nanoparticles, nanofibers, hydrogels, membranes (e.g., membrane adsorbers), monoliths, or other physical matrices having associated covalently bonded chromatography ligands (e.g., Protein A, Protein G, or other affinity chromatography ligands such as a target ligand, charged moieties, or hydrophobic moieties, etc.).

[0084] The term "elution buffer solution" or "eluate" means a buffer solution used for eluting the protein of interest reversibly bound to the matrix. As used herein, the term "solution" means either a buffered or unbuffered solution containing water. The term "eluate pool" or "eluate pool" means the substance eluted from the matrix containing the recombinant protein of interest.

[0085] The term "single-use" or "single-use component" refers to a specific sterile manufacturing line component that is used interchangeably, i.e., sterile parts used in the automated facility of the present invention or in performing the method of the present invention are constructed or configured to be used in a single manufacturing process (however, they can be reused if quality and aseptic hygiene can be guaranteed for multiple processes). Thereafter, the single-use component does not require cleaning and disinfection of the component in the manufacturing process and can be discarded and replaced by the same component or other single-use components of the modified component for subsequent manufacturing processes. Examples of single-use components that can be used in the present invention include, but are not limited to, perfusion bioreactors, first chromatography systems, second chromatography systems, third chromatography systems, low pH or surfactant virus inactivation systems, neutralization systems, virus filtration systems, or ultrafiltration / diafiltration systems. Such single-use components can be commercially constructed or acquired.

[0086] The term "filter bank" or "filter assembly system" refers to an apparatus comprising a plurality of filter assemblies, each filter assembly including at least one filter, which are used interchangeably. The filters included in the filter assembly may be single-use filters and may be replaced after a certain period of time and / or after use. The filter bank may be a component of a portable device. For example, the filter bank may be disposed on a filtration cart that can be moved to various locations within an automated facility. The filters included in the filter bank may include depth filters, 0.2 micrometer filters, membrane filters, 20 nanometer (nm) filters, virus filtration devices, ultrafiltration devices, diafiltration devices, or a filtration system including combinations thereof. The filter bank can be configured such that while material flows through at least one filter of the filter bank, the other filters of the filter bank remain unused. In various embodiments, the filter bank may be coupled to a diverter valve or other flow control device to control the flow of material to the filters included in the filter bank. The diverter valve or flow control device can be pneumatically controlled.

[0087] The production of the biological therapeutics described herein involves culturing recombinant therapeutic protein-secreting mammalian cells. Such recombinant mammalian host cells are produced by transient or stable transfection. The biological therapeutics can be obtained by culturing the transfected or transformed host cells under physiological conditions in which the cells can express the recombinant protein. Most conveniently, the expressed recombinant protein is secreted directly into the extracellular medium (using an appropriate secretion-directed signal peptide) and recovered therefrom; otherwise, an additional step of isolating the expressed antibody from the cell extract is required.

[0088] Transfected or transformed host cells are usually cultured by any conventional culture such as batch, fed-batch, enhanced fed-batch, or continuous. Host cells used for the production of the biological therapeutics or POIs (e.g., non-glycosylated or glycosylated proteins) described herein can be cultured in various media.

[0089] Predetermined culture conditions such as temperature (which is usually about 37 ± 1 °C for mammalian cells, but not necessarily so), pH (which is usually maintained within the range of about 6.5 to 7.5 for cell culture media, but not necessarily so), oxygenation, etc. will be apparent to those skilled in the art. "Culturing under predetermined culture conditions" or "maintaining under predetermined culture conditions" means that a process control system maintains each parameter at a predetermined set point within a narrow range (i.e., "narrow dead band") optimal for the cell line and biological therapeutic in question, i.e., set to a specific value for that condition, i.e., the intended volume, target temperature, pH, oxygenation level, etc.

[0090] Typically, the viable cell density is from about 1.0×10 6 to about 2×10 8 cells / mL, e.g., in the range of 1.0×10 6 to 2.0×10 7 cells / mL, or in the range of about 4×10 7 cells / mL to about 5×10 7 cells / mL, or in the range of about 1×10 8 cells / mL to about 2×10 8 cells / mL can be used. It is known that increasing the cell concentration relative to the upper limit of the preferred range improves volumetric productivity. Nevertheless, a range of cell densities including any of the above point values is envisioned as the lower or upper limit of the range. The desired scale of recombinant expression and cell culture depends on the type of expression system and the amount of the desired biological therapeutic.

[0091] When a transfected or transformed host cell is cultured, the recombinant polypeptide or protein is directly secreted into the culture medium. Recovery of the recombinant protein involves separation from particulate matter that may include host cells, cell aggregates, and / or lysed cell fragments into a cell-free fraction that does not contain host cells and cell debris, i.e., a cell-free “permeate”. Such cells and cell fragments are removed from the conditioned medium, for example, by centrifugation or microfiltration. For example, for the production of the permeate, hollow fiber membranes (pore size 0.2 μm) or a series of filtration steps, such as depth filtration, can be used, which can be configured on mobile, exchangeable and / or single-use and “filter carts”.

[0092] Purification of the recombinant protein is typically performed by any series of chromatography steps such as anion exchange chromatography, cation exchange chromatography, affinity chromatography (using Protein A or Protein G or Protein L as the affinity ligand or other different affinity ligands), hydrophobic interaction chromatography (HIC), hydroxyapatite chromatography, reverse phase HPLC, and size exclusion chromatography. In particular, in embodiments for producing the biotherapeutic formulations described herein, the recombinant therapeutic protein in the cell-free permeate is captured by one or more chromatographic capture steps of a first chromatographic system that can partially purify and / or concentrate the protein, including but not limited to Protein A or Protein G or Protein L affinity chromatography, or affinity chromatography using a different affinity ligand covalently bound to a solid matrix.

[0093] The first, second, and / or any third chromatography system is preferably configured using one, two, three or more different chromatography matrices (e.g., chromatography columns) that are fluidly connected, optionally and preferably continuously, for the desired therapeutic protein, and may in some cases be placed in a mobile, replaceable, or disposable, single-use unit, skid, or "cart". In various embodiments, the second chromatography system comprises a single-use membrane adsorber (MA), e.g., a surface-functionalized membrane. Such membrane adsorbents may contain anion exchange groups for monoclonal antibody polishing operations in negative mode that remove trace impurities without binding to the protein of interest (so-called "flow-through chromatography").

[0094] In particular embodiments, the method of manufacturing a biotherapeutic agent herein may include switching a protein isolation fraction obtained or collected from a first chromatography system to a low pH or surfactant virus inactivation system and a neutralization system (i.e., if neutralization is required after virus inactivation by low pH) to obtain a virus-inactivated pool containing a recombinant therapeutic protein.

[0095] Thereafter, the obtained virus-inactivated pool is introduced into a second chromatography system (in some embodiments, after storage for at least 10 days, at least 20 days, or at least 30 days) and placed in a temperature-controlled or cooled holding vessel (HV1) to obtain a purified product pool containing the recombinant therapeutic protein. The second chromatography system is configured as needed to further purify the desired therapeutic protein, preferably by continuously and fluidly connecting one, two, three or more different chromatography matrices (e.g., chromatography columns), and may optionally be placed in a mobile, replaceable, or disposable, single-use unit, skid, or "cart".

[0096] The introduction of the virus-inactivated product pool into the second chromatography system is controlled according to an adjusted schedule regarding the culture and virus inactivation steps. The schedule adjustment is calculated to maximize the efficient routing of the virus-inactivated product pool to the second chromatography system. To load the virus-inactivated product pool into the second chromatography system according to the adjusted schedule, either automated (continuous format) or manual control on a batch-by-batch basis (semi-continuous format) is used. (See also Garcia, FA and Vandiver, MW, Throughput Optimization of Continuous Biopharmaceutical Manufacturing Facilities, PDA J Pharm Sci Technol 71(3):189-205(2017)).

[0097] From the second chromatography system, the obtained purified product pool containing the recombinant therapeutic protein is fluidly switched to any third chromatography system and / or virus filtration system to obtain a virus-free permeate containing the recombinant therapeutic protein. Any switching of the purified product pool to a chromatography system and / or virus filtration system is performed under automated or manual control. Optionally, the third chromatography system is preferably continuously and fluidly connected using one, two, three or more different chromatography matrices (e.g., chromatography columns) as required to further purify the therapeutic protein of interest, and in some cases, can be arranged in a mobile, replaceable, or disposable, single-use unit, skid, or "cart". Useful virus systems are commercially available and include single-use virus filtration systems.

[0098] Thereafter, the obtained virus-free permeate containing the purified therapeutic protein of interest is fluidly switched to an ultrafiltration / diafiltration system to obtain a purified therapeutic protein pharmaceutical substance containing the purified recombinant therapeutic protein pharmaceutical substance. If a third chromatography system is not employed in the process (or facility) of the present invention, the purification pool is switched and flows directly and fluidly to a virus filtration system. The switching of the virus-free permeate to the ultrafiltration / diafiltration system is performed by automatic or manual control.

[0099] In scenarios where multiple single-use bioreactors are utilized in a manufacturing facility for a purified therapeutic protein pharmaceutical substance, multiple operations performed on each bioreactor can be carried out simultaneously. For example, while an ultrafiltration / diafiltration operation is being performed on the virus-free permeate produced from a first perfusion bioreactor, a chromatography operation can be carried out on the virus-inactivated product pool produced by a virus inactivation system (and, optionally, a neutralization system). The virus inactivation system can produce this virus-inactivated pool by treating the protein isolation fraction received after treatment of the cell-free permeate cultured in a second single-use perfusion bioreactor by a first chromatography system. In another example, the ultrafiltration / diafiltration operation is performed on the virus-free filtrate ultimately produced by the method of the present invention from the culture in a first single-use perfusion bioreactor, while the virus filtration operation can be performed on the virus-inactivated pool ultimately produced by the method herein from the culture in a second perfusion bioreactor. Further, at least one chromatography process and / or virus filtration process performed on the virus-free permeate produced from a first perfusion bioreactor can be carried out during a continuous chromatography capture or virus inactivation process performed on the amount of cell-free permeate produced by a second single-use bioreactor by the process of the present invention.

[0100] FIG. 5 is a diagram of an architecture 500 that analyzes data obtained from multiple manufacturing facilities and determines operating parameters for controlling components of a device used in a manufacturing line for a purified biologic therapeutic. Architecture 500 may include a global control system 502 that collects and / or analyzes data from a number of manufacturing facilities including a first manufacturing facility 504 and a second manufacturing facility 506. The global control system 502 may analyze data obtained from the first manufacturing facility 504 and the second manufacturing facility 506 to determine control settings for portions of the equipment included in the first manufacturing facility 504 and the second manufacturing facility 506. Data collected by the global control system 502 may correspond to data from sensors associated with various devices used in the manufacturing lines of manufacturing facilities 502, 504. The sensor data may include, or may indicate, temperature values, pH values, dissolved oxygen values, carbon dioxide values, capacitance values, pressure values, the concentration of one or more substances, the amount of one or more types of cells, flow rates, or combinations thereof.

[0101] The first manufacturing facility 504 may include, or alternatively communicate with, a first local control system 508, and the second manufacturing facility 506 may include, or alternatively communicate with, a second local control system 510. The first local control system 508, also referred to herein as the first manufacturing facility control system, and the second local control system 510, also referred to herein as the second manufacturing facility control system. The first local control system 508 can analyze data obtained from components of the devices included in the first manufacturing facility 504. The first local control system 508 can also provide signals for controlling the operation of the components of the devices included in the first manufacturing facility 504. The first manufacturing facility 504 may include a number of modular cleanrooms, such as a first modular cleanroom 512, a second modular cleanroom 514, and a third modular cleanroom 516. The exemplary example of FIG. 5 shows three modular cleanrooms within the first manufacturing facility 504, but the first manufacturing facility 504 may include more or fewer modular cleanrooms. In various examples, the first manufacturing facility 504 may include at least one of the modular cleanroom 200 of FIG. 2, the modular cleanroom 300 of FIG. 3, or the modular cleanroom 400 of FIG. 4.

[0102] In the exemplary embodiment of FIG. 5, the first modular cleanroom 512 may include a first portion of device 518, a second portion of device 520, and a third portion of device 522. Further, the second modular cleanroom 514 may include a fourth component of device 524, a fifth component of device 526, and a sixth component of device 528. Further, the third modular cleanroom 516 may include a seventh component of device 530 and an eighth component of device 532. The exemplary example of FIG. 5 shows that the modular cleanrooms 512, 514, 516 include a specific number of devices, but the modular cleanrooms 512, 514, 516 may include more or fewer devices than the number shown in FIG. 3.

[0103] The components of apparatuses 518, 520, 522, 524, 526, 528, 530, 532 may include various components used in the manufacture of purified biological therapeutics. For example, at least one of the components of apparatuses 518, 520, 522, 524, 526, 528, 530, 532 may include a chromatography system. In other examples, at least one of the components of apparatuses 518, 520, 522, 524, 526, 528, 530, 532 may include a bioreactor. In further embodiments, at least one of the apparatuses may include a perfusion system. Additionally, at least one of the components of apparatuses 518, 520, 522, 524, 526, 528, 530, 532 may include a filter device. In various embodiments, at least one of the components of apparatuses 518, 520, 522, 524, 526, 528, 530, 532 may include a pump device, a temperature control device, a storage container, or a combination thereof.

[0104] The first manufacturing facility 504 may also include a number of containers 534(1), 534(2), and 534(3). In certain embodiments, the containers 534 may be located in the staging area of the first manufacturing facility 504. The containers 534 can store solutions or other materials that can be supplied to one or more of apparatuses 518, 520, 522, 524, 526, 528, 530, 532. In one example, one or more of the containers 534 can store a buffer solution. In further embodiments, one or more of the containers 534 may include materials produced by the modular cleanrooms 512, 514, 516. By way of example, one or more of the containers 534 can store a virus inactivation pool produced by one of the modular cleanrooms 512, 514, 516 that can be supplied to one of the modular cleanrooms 512, 514, 516. The exemplary embodiment of FIG. 5 shows three containers 534 located within the first manufacturing facility 504, but the first manufacturing facility 504 may include fewer or more containers.

[0105] Furthermore, the second local control system 510 can collect and analyze data obtained from components of the devices included in the second manufacturing facility 506. Also, the second local control system 510 can provide signals to control the operation of components of the devices included in the second manufacturing facility 504. The second manufacturing facility 506 can manufacture purified biological therapeutics without placing the devices in a modular cleanroom. The second manufacturing facility 506 can include a fourth container 536 coupled to a ninth component of the device 538, where the ninth component of the device 540 is coupled to a tenth component of the device 540 and to an eleventh component of the device 542. The fourth container 536 and the components of the devices 538, 540, 542 can operate as at least a part of a production line in the manufacture of the purified biological therapeutics. In the exemplary embodiment of FIG. 5, the second manufacturing facility 506 can also include a fifth container 544 and a sixth container 546 coupled to a twelfth component of the device 548. The twelfth component of the device 548 can also be coupled to a thirteenth component of the device 550 that is coupled to a fourteenth component of the device 552. The fourteenth component of the device 552 can also be coupled to a seventh container 554.

[0106] The containers 536, 544, 546 can store various substances supplied to the components of the devices 536 and 548. In an exemplary embodiment, at least one of the containers 536, 544, 546 can store one or more buffer solutions. In a further exemplary embodiment, at least one of the containers 536, 544, 546 can store cell culture media. In a particularly exemplary embodiment, the container 544 can store the effluent from the components of the device 542. Further, the container 554 can store the effluent from the components of the device 552. The exemplary embodiment of FIG. 5 shows a specific number of devices and containers arranged in a specific configuration, but the second manufacturing facility 506 can have a fewer number of devices and containers arranged in various configurations. The components of the devices and the configuration of the components of the devices can be based on the purified biological therapeutics being manufactured at the second manufacturing facility 506.

[0107] The components of devices 538, 540, 542, 548, 550, 552 may include various components used in the manufacture of purified biotherapeutics. For example, at least one of the components of devices 538, 540, 542, 548, 550, 552 may include a chromatography system. In other examples, at least one of the components of devices 538, 540, 542, 548, 550, 552 may include a bioreactor. In further examples, at least one of the components of devices 538, 540, 542, 548, 550, 552 may include a perfusion system. Additionally, at least one of the components of devices 538, 540, 542, 548, 550, 552 may include a filter device. In various embodiments, at least one of the components of devices 538, 540, 542, 548, 550, 552 may include a pump device, a temperature control device, a storage container, or a combination thereof.

[0108] The architecture 500 may include multiple layers of network security to protect the global control system 502, the first local control system 508, and the second local control system 510 from intruders attempting to obtain and / or manipulate data collected and / or stored by the global control system 502, the first local control system 508, and the second local control system 510. The layers of network security may include one or more first firewalls 556, one or more second firewalls 558, and one or more third firewalls 560. The firewalls 556, 558, 560 may include hardware, software, firmware, or combinations thereof that monitor and control communications entering and leaving the global control system 502, the first local control system 508, and the second local control system 510. The firewalls 556, 558, 560 may execute several security rules to permit or block communications directed to the global control system 502, the first local control system 508, and the second local control system 510. In various examples, at least one of the one or more second firewalls 558 or the one or more third firewalls 560 may be combined with the one or more first firewalls 556.

[0109] Conventional manufacturing facility control systems are typically designed to control the preset configuration of equipment. In these scenarios, the logical and hardware couplings between devices do not change. Accordingly, the executable identifiers and control operations for each device are static. Embodiments of manufacturing facility control systems, such as the first local control system 508 and the second local control system 510 described herein, support variable configurations of devices within a manufacturing line. In this case, the components of the devices may have different functions, perform different operations, and / or be controlled using different sets of control commands and / or variables based on the location of the components of the devices within the manufacturing line. Accordingly, the manufacturing lines and control systems described herein include software configurations and physical hardware different from conventional systems.

[0110] The embodiments described herein can be carried out by one or more systems that can automatically control the flow of materials passing through each stage of the process in the manufacture of a purified biotherapeutic formulation. Alternatively, at least some of the control functions can be performed by operator intervention, and there may be situations where operator intervention is required (particularly, process interruptions). The control functions can be performed using process data obtained from sensors coupled to various devices used in the manufacture of a purified biotherapeutic. The sensors can include temperature sensors, pH sensors, flow sensors, weight sensors (e.g., load cells), volume sensors (e.g., guided wave radar sensors), pressure sensors, timers, capacitance sensors, optical density sensors, or combinations thereof. The data produced by the sensors can be locally collected by components of the device. In certain embodiments, the components of the device can transfer sensor data to a manufacturing facility control system. The manufacturing facility control system can collect data from sensors of a number of devices used in the manufacture of a purified biotherapeutic. The manufacturing facility control system can include one or more computing devices and / or one or more data storage devices that communicate electronically with each other. At least some of the one or more computing devices and / or one or more data storage devices can be located in the same location in some scenarios. Further, at least some of the one or more computing devices and / or one or more data storage devices can be located remotely from the devices included in the manufacturing facility. In this case, at least some of the operations performed by the manufacturing facility control system can be executed in a cloud computing architecture.

[0111] Data collected from the sensors can be stored in an electronic data storage device, which may be referred to herein as a "data historian." In various embodiments, a first data historian can collect and store data for at least a subset of the devices operating in a first manufacturing facility 504, and a second data historian can collect and store data for at least a subset of the devices operating in a second manufacturing facility 506. The first data historian and the second data historian can store data for a period of time and then transfer the data to a third data historian, which is a repository of data collected regarding the operation of components of the devices coupled to the first local control system 508 and the second local control system 510. In particular, in embodiments, the third data historian can be coupled to or otherwise communicable with the global control system 502. In certain cases, the first data historian and the second data historian can be reset and can begin collecting and storing additional data from the first manufacturing facility 504 and the second manufacturing facility 506 over an additional period of time. The first local control system 508 and the second local control system 510 may also include one or more batch historians that collect and store data related to the operation of the devices included in the first manufacturing facility 504 and / or the second manufacturing facility 506 for the manufacture of a particular batch of a purified biological therapeutic. The data historian can be accessed and analyzed by the global control system 502, the first local control system 508, and / or the second local control system 510 to determine parameters for the operation of components of the equipment included under the control of the control systems 502, 508, 510.

[0112] The control systems 502, 508, 510 can analyze data obtained from sensors related to the equipment components included in the first manufacturing facility 504 and the second manufacturing facility 506, and determine the operating conditions of one or more equipment components. In some cases, set points and acceptable operating parameters, and / or run recipes for operation of the components of the device, can be input into the control systems 502, 508, 510 by an operator. In other cases, the set points and acceptable operating parameters, and / or the run recipes for operation of the components of the device can be automatically sent to one or more devices used in the manufacturing line via at least one of the control systems 502, 508, 510. Alert and alarm notifications can also be generated by at least one of the control systems 502, 508, 510 based on sensor data obtained from the components of the equipment located in the first manufacturing facility 504 and the second manufacturing facility 506. For example, if the sensor data indicates that the operating conditions of a component of a device within the manufacturing line are outside the threshold range, at least one of the control systems 502, 508, 510 can trigger an alarm and send a notification to the operator.

[0113] Components of various devices used in the manufacture of a purified biological therapeutic agent may include one or more communication interfaces that enable communication between components of the device and / or with one or more of control systems 502, 508, 510. The communication interface may include a hardware device, a firmware device, and / or a software implementation system that enables data communication between components of the devices used in the manufacturing line and / or with at least one of control systems 502, 508, 510. The communication interface enables data communication via a number of networks such as a local area wired network, a local area wireless network, a wide area wireless network, and / or a wide area wired network. In a particular example, the communication interface may include an Ethernet network communication interface, an Internet protocol network communication interface, an Institute of Electrical and Electronics Engineers 802.11 wireless network communication interface, a Bluetooth communication interface, or a combination thereof.

[0114] The components of the apparatus used in the production of a purified biological therapeutic agent may include one or more processors and one or more memory devices. The one or more processors may be a central processing unit such as a standard programmable processor that executes arithmetic and logical operations necessary for the operation of the computing system. The one or more memory devices may include volatile and non-volatile memory and / or removable and non-removable media implemented in any kind of technology for storing information such as computer-readable instructions, data structures, program modules, or other data. Such computer-readable storage media includes, but is not limited to, RAM, ROM, EEPROM, flash memory or other memory technologies, CD-ROM, digital versatile disks or other optical storage devices, magnetic cassettes, magnetic tapes, solid state storage devices, magnetic disk storage devices, RAID storage systems, storage arrays, network-connected storage devices, storage area networks, cloud storage devices, removable storage media, or any other media that can be used for storing desired information and can be accessed by the control systems 502, 508, 510 or the individual devices included in the production line.

[0115] The control systems 502, 508, 510 may store one or more control modules that can execute to control the operation of the components of the equipment included in the manufacturing facilities 504, 506. The control modules may include computer-readable instructions that can execute to cause the components of the devices included in the manufacturing facilities 504, 506 to perform one or more operations. The control modules may be part of a framework in which the components of the devices included in the manufacturing facilities 504, 506 can continuously or semi-continuously produce a purified biological therapeutic agent. The operations performed by the various devices included in the manufacturing facilities 504, 506 may be associated with the start-up process, the holding process, the shutdown process, the supply process, or the end of the manufacturing process.

[0116] The various components of the device can be controlled by different sets of control modules. For example, the perfusion system can be controlled by one or more first control modules, the bioreactor can be controlled by one or more second control modules, and the chromatography system can be controlled by one or more third control modules. Further, in certain embodiments, the components of the same device can be controlled by different control modules depending on the function of the components of the device within the manufacturing line. By way of illustration, a storage container operating as a supply tank can be controlled by one set of control modules, while the same storage container operating as a collection tank can be controlled by another set of control modules.

[0117] In particular, the control systems described herein can be used for controlling a manufacturing line having a flexible configuration. That is, the control systems 502, 508, 510 can accommodate multiple configurations that utilize portable devices that can be coupled to other components of the manufacturing line. In various embodiments, the manufacturing line may include one or more skids that include original manufacturer equipment such as a single-use bioreactor system, a perfusion system, or a continuous chromatography system. The skid can also include a flow control device such as a pump. Further, the skid may include one or more communication interfaces, also referred to herein as "drops", whereby the components of the portable device can be physically coupled to the skid. The physical coupling of the portable components of the device to the skid can be achieved using an electrical cable. The electrical cable wiring can be configured to enable Ethernet communication. In a particular example, the electrical cable wiring may be recommended standard 232 (RS-232) cable wiring.

[0118] The portable components of the device may include, or alternatively be coupled to, a network gateway hardware device that enables communication between each portable component and the manufacturing equipment control system. The network gateway hardware device for each portable device can be coupled to the communication interface of each skid. Further, at least a portion of the skid can be logically configured to be connected to various portable devices. In this way, based on the configuration of a particular manufacturing line, the components of the portable device can be physically connected to a particular skid, and the skid can be configured to operate in different configurations based on the different components coupled to the skid.

[0119] Furthermore, the components of the portable device can be coupled to at least one information communication and / or storage device, such as a dongle. The information communication and / or storage device can store information provided to each device to which it is coupled, and it can control each component of each device via the manufacturing facility control system. The information communication and / or storage device can store information including one or more identifiers of each device, one or more functions of each device, one or more control signals corresponding to each device, one or more status flags associated with each device, or combinations thereof. In some examples, the data stored by the information communication and / or storage device can be based at least in part on the function or type of each device. When the components of the portable device are arranged at different positions along the manufacturing line and / or have different functions, the information communication and / or storage device of the components of the portable device can be switched to a further information communication and / or storage device indicating different functions and different identifiers of the components of the portable device.

[0120] Furthermore, the control systems 502, 508, 510 may include additional logical layers that can be used on conventional control software and systems. In a specific embodiment, the control systems 502, 508, 510 may include other abstraction layers that can assign portable components of the device to various identifiers, tags, operating conditions, and flags corresponding to a specific set of functions of specific devices at specific locations along the manufacturing line. In this way, the components of the device are not logically represented in the control system until the location and function of the device are known. Therefore, the portable components of the device can be connected to the skid in various combinations without changing the basic control software used to control the components of the skid and the portable components of the device.

[0121] In an exemplary embodiment, the manufacturing line included in the first manufacturing facility 504 or the second manufacturing facility 506 may include a first skid including a single-use bioreactor system, a second skid including a perfusion system, and a third skid including a continuous first chromatography system. If the skid is included in the first manufacturing facility 504, one or more skids may be included in each of the modular clean rooms 512, 514, 516. The skid can be configured to connect to a plurality of portable components of portable equipment. For example, the skid may include an interface and physical hardware for connecting to a portable storage container, a filter bank, a split valve system (for switching between alternating dual-flow or multi-flow unit operations that can be automatically switched), and / or other flow control devices.

[0122] In a further example, the control systems 502, 508, 510 can determine to connect a filter bank between the perfusion bioreactor and the first chromatography system based on information obtained from a dongle connected to the filter bank. In this case, the filter bank can operate as a depth filter. The control systems 502, 508, 510 can identify one or more control modules, flags, and / or status identifiers for the depth filter and execute one or more control modules while the filter bank is being used in the manufacturing line. The control systems 502, 508, 510 can monitor the pressure within the filter assembly of the filter bank based on pressure values obtained from a pressure sensor included in the filter assembly. Further, the control systems 502, 508, 510 can determine that the pressure within the first filter assembly through which the material flows has reached at least a threshold level. The threshold level of pressure can indicate that the filter included in the first assembly needs to be replaced because the amount of material that can be processed by the filter has decreased. Thereafter, the control systems 502, 508, 510 can send a signal to control a diverter valve connected to the filter bank to allow the material to flow through the second filter assembly of the filter bank. Thereafter, the filter included in the first filter assembly can be replaced.

[0123] After connecting the components of the portable device to the skid, the components of the portable device can be registered with the control systems 502, 508, 510. The components of the portable device may have a unique address through which the components of the portable device can communicate with the control systems 502, 508, 510. The unique address can indicate a type of portable device and a unit identifier to the control systems 502, 508, 510. A dongle connected to the components of the portable device can store additional identifiers corresponding to the position of the skid to which the components of the portable device are connected and one or more functional roles of the portable device. For example, a mixing tank can be identified as a supply tank or a collection tank based on the position of the components of the portable device and the logical relationship of the droplets to which the components of the portable device are connected. In another example, a filter bank can be identified as a virus filtration device in a first configuration of the manufacturing line and then as a diafiltration device in a second configuration of the manufacturing line. In this case, a first dongle can be connected to the filter bank in the first configuration of the manufacturing line, and a second dongle can be connected to the filter bank in the second configuration of the manufacturing line. Further, the type of filter used in the filter bank can be changed when the filter bank is used in different locations of the manufacturing line.

[0124] In response to obtaining information from the portable device after it is connected to the skid, the control systems 502, 508, 510 can determine the position and function of the portable device and assign a corresponding control template to the portable device. For example, if a storage container functions as a collection tank, the control systems 502, 508, 510 can assign a first set of tags, flags, identifiers, and set points to the storage container, and if the storage container functions as a supply tank, the control systems 502, 508, 510 can assign a second set of tags, flags, identifiers, and set points to the storage container. Thereafter, the control systems 502, 508, 510 can assign a specific set of control modules to the portable device based on the information obtained from the portable device after it is connected to the skid.

[0125] In various embodiments, components of a device that is not considered portable, such as a large storage container (e.g., having a volume exceeding 1000 L), can also be coupled to a skid. In these scenarios, the components of the non-portable device may not include hardware and / or communication and storage devices that enable dynamic configuration of the components of the non-portable device with respect to control systems 502, 508, 510. When the components of the non-portable device are not dynamically configured, an operator of control systems 502, 508, 510 can manually establish templates and / or control modules that are used to control the operation of the components of the non-portable device.

[0126] In addition to controlling the components of the devices included in the manufacturing line, control systems 502, 508, 510 can also track the decay rate of batches during the manufacture of a purified therapeutic protein pharmaceutical substance. The decay rate can be defined as "the period during which the materials used in the manufacture of a sublot can be identified and tracked", and for example, the materials (buffer solution, cell culture solution, etc.) used in a chromatographic eluate pool collection (one of many) obtained can be identified and dynamically tracked. In a continuous batch manufacturing process, control systems 502, 508, 510 can estimate the decay rate for the manufacturing process of a purified therapeutic protein pharmaceutical substance. In various embodiments, control systems 502, 508, 510 can assign a batch identifier to a particular portion of batch manufacture and initiate a decay monitor until the current batch identifier is changed to a new batch identifier and a new decay monitor is executed for the new batch identifier.

[0127] In various embodiments, the global control system 502 can analyze data obtained from the first local control system 508 and the second local control system 510 to generate one or more models for controlling the operation of components of the equipment included in the first manufacturing facility 504 and / or the second manufacturing facility 506. The global control system 502 can also analyze data obtained from the first local control system 508 and the second local control system 510 to generate one or more additional models for predicting the efficiency and / or productivity of components of one or more devices and / or the efficiency and / or productivity of one or more manufacturing lines included in the first manufacturing facility 504 and the second manufacturing facility 506. By using data obtained from multiple manufacturing facilities to predict the operation of manufacturing lines and predict the efficiency and productivity of equipment and parts of manufacturing lines, more accurate models can be generated and the models can be generated more efficiently. The global control system 502 can also analyze data obtained from the first control system 508 and / or the second control system 510 to generate a model for predicting the values of process variables of one or more devices included in the first manufacturing facility 504 and the second manufacturing facility 506.

[0128] In particular, conventional manufacturing equipment is often individualized, and data collected for each conventional manufacturing equipment can only be useful for making decisions about the control of that specific manufacturing equipment. In contrast, the global control system 502 can utilize the similarities between manufacturing equipment to collect a sufficient amount of relevant data more quickly than conventional systems. In this way, the global control system 502 can generate models used for controlling manufacturing lines and models to more quickly and accurately predict the efficiency and / or productivity of manufacturing lines with respect to conventional systems. This is because the amount of data available to the global control system 502 that can be used for generating models increases. Further, by generating one model or a set of models that can be used to control a manufacturing line and predict the efficiency and / or productivity of multiple manufacturing equipment, the global control system 502 can minimize the computational resources used for controlling multiple manufacturing equipment as different models do not have to be executed for different manufacturing equipment. Further, a single control system can execute models for multiple manufacturing equipment.

[0129] In a particular embodiment, the global control system 502 can obtain data from a first local control system 508 that indicates various process conditions for one or more production lines included in the first manufacturing facility 504. The process conditions can correspond to data obtained by sensors associated with components of the devices within the one or more production lines. In some illustrative examples, the process conditions can correspond to a pH value, a temperature value, a capacitance value, a flow rate, a volume, a mass / weight value, a concentration of one or more substances, a cell count, or a combination thereof. The global control system 502 can analyze the data obtained from the first local control system 508 to determine a number of factors that are indicators of the efficiency and / or productivity of the one or more production lines. In various embodiments, the global control system 502 can determine the significance of individual factors based on the data obtained from the first manufacturing facility and identify factors that have significance beyond a threshold level. The global control system 502 can then generate a model having variables corresponding to at least the factors having threshold significance. In this way, the global control system 502 can generate a model executable for predicting efficiency and / or productivity based on factors that have at least a threshold amount of influence on the efficiency and / or productivity of the one or more production lines.

[0130] The global control system 502 can utilize one or more machine learning techniques to determine factors that have at least a threshold amount of impact on the efficiency and / or productivity of one or more production lines of the first manufacturing facility 502. For example, the global control system 502 can utilize inference modeling techniques to determine factors that have at least a threshold amount of impact on the efficiency and / or productivity of one or more production lines of the first manufacturing facility 502. In an exemplary embodiment, the global control system 502 can perform partial least squares techniques to determine factors that have at least a threshold amount of impact on the productivity and / or efficiency of one or more production lines included in the first manufacturing facility 504. In a further exemplary embodiment, the global control system 502 can perform polynomial delay techniques to determine factors that have at least a threshold amount of impact on the productivity and / or efficiency of one or more production lines included in the first manufacturing facility 504. The global control system 502 can also determine coefficients corresponding to each factor included in the model. The coefficients can indicate the amount of impact of each factor on the productivity and / or efficiency of one or more production lines.

[0131] In various embodiments, the global control system 502 can use the partial least squares method to analyze data acquired from the first manufacturing facility 504 over a first period to determine one or more factors that have at least a threshold impact on manufacturing and / or efficiency, include them in the model, and use data acquired over a second period after the first period to validate the model. In a particular embodiment, the global control system 502 can analyze data acquired from the first manufacturing facility 504 for a period at least two days before a set date and / or set time using the partial least squares method and generate a model based on the data acquired during that period. Thereafter, the global control system 502 can use data acquired during a period of at least one day after the set date and / or time to validate the model.

[0132] When the data acquired from the first manufacturing facility 504 changes over time, the global control system 502 can modify the factors included in the model and / or the coefficients associated with the factors. For example, the global control system 502 can change the factors included in the model based on changes in the data acquired from the first manufacturing facility 504. By way of illustration, the global control system 502 can determine that a different set of factors has a threshold amount of impact on the productivity and / or efficiency of the production line than the initial set of factors identified by the global control system 502. In this case, the global control system 502 can modify the factors included in the model used to predict the efficiency and / or productivity of the production line. In a further embodiment, the global control system 502 can determine that the coefficients of the model should be modified based on changes to the data acquired by the global control system 502 from one or more production lines of the first manufacturing facility 504. In some embodiments, the global control system 502 can utilize a rolling window of time to continuously update the model. That is, the global control system 502 can periodically analyze the data acquired from the first manufacturing facility 504 over a predetermined period of time and modify one or more of the factors and / or coefficients included in the model based on changes in the data acquired from the first manufacturing facility 504.

[0133] In various embodiments, the global control system 502 can determine that factors such as the previous day's viable cell density, cell viability, dissolved oxygen measurements, carbon dioxide levels, temperature, and / or pH affect at least a threshold in one or more production lines included in the first manufacturing facility 504. In certain examples, data analyzed by the global control system 502 to determine the factors to include in the model can be obtained from bioreactors included in the first manufacturing facility 504. In further examples, data analyzed by the global control system 502 to determine the factors included in the model can be obtained from one or more chromatography systems. In still other examples, data analyzed by the global control system 502 to determine the factors included in the model can be obtained from one or more filter banks, one or more storage containers, one or more temperature control devices, one or more pumping devices, or combinations thereof.

[0134] In some embodiments, the global control system 502 can determine a model for individual devices included in the production lines of the first manufacturing facility 504. Further, the global control system 502 can determine a model for a single production line that includes multiple pieces of equipment. Further, when the configuration of the production line changes, the global control system 502 can generate different models for different configurations of the production line. The factors included in the model generated by the global control system 502 can also be based at least in part on the bioreactor volume, the purified biotherapeutic produced by the production line, the cell line utilized in the production of the biotherapeutic, a measure of the predicted productivity and / or efficiency, and / or whether the process is a perfusion process or a batch process. Examples of measurements of productivity and / or efficiency for a production line include yield, titer, purity, and viable cell density. In some cases, the global control system 502 can generate a model for a single measure of productivity and / or efficiency, while in other scenarios, the global control system 502 can generate models for multiple measures of productivity and / or efficiency of the production line.

[0135] In a particularly exemplary embodiment, the global control system 502 can obtain data from a 2-liter fed-batch bioreactor and generate a model that predicts the future viable cell density of the 2-liter fed-batch bioreactor, including a factor corresponding to at least one of the viable cell density, cell viability, dissolved oxygen level, carbon dioxide level, temperature, pH, or time since the last viable cell density measurement of the previous day. In other exemplary embodiments, the overall control system 502 can obtain data from a perfusion bioreactor, generate a model for the perfusion bioreactor, and predict the future viable cell density including a factor corresponding to at least one of the perfusion rate, viable cell density of the previous day, and cell viability.

[0136] The global control system 502 can also analyze data obtained from the first local control system 508 to determine factors that affect factors that affect the efficiency and / or productivity of a production line that manufactures a purified biotherapeutic. In the embodiments described herein, a factor that can be an indicator of process efficiency and / or productivity may be referred to as a "process variable," and a factor that can affect a process variable may be referred to as a "control variable." In particular, in an embodiment, a control variable can be associated with a control setting of a device included in the production line. For example, temperature can be affected by changing the temperature setting of a component of a device such as a bioreactor or a heat exchanger. In a further example, the pH can be affected by adding an acidic or basic buffer solution to a device such as a bioreactor, a chromatography system, or a storage container. In various embodiments, at least some of the control variables for a given process variable can be the same as the control variables for another process variable, but in a further scenario, at least some of the control variables for a specified process variable can be different from the control variables for a further process variable. By way of example, at least one of the control variables that affect the dissolved oxygen level can be different from at least one of the control variables that affect the cell viability.

[0137] Control variables that can be changed to affect one or more process variables may not be directly related. In a specific example, a process where the cell density is below a minimum threshold may not result in a higher cell density in response to an increase in the number of cells added to the process. Further, a process where the cell density exceeds a maximum threshold may result in a lower cell density in response to, for example, decreasing the number of cells removed from the process by increasing the bleeding rate. In this case, machine learning techniques can be executed on data obtained by the global control system 502 from the first local control system 508 to determine control variables that can have at least a threshold amount of influence on one or more process variables. In some embodiments, inferential machine learning techniques such as partial least squares can be used to determine one or more control variables corresponding to individual process variables.

[0138] Models generated by the global control system 502 using data obtained from the first local control system 508 can also be utilized with respect to other production lines included in additional manufacturing facilities. For example, a model generated by the global control system 502 using data obtained from the first local control system 508 can be utilized with respect to one or more production lines included in the second manufacturing facility 506. Further, the global control system 502 can generate one or more models for predicting the efficiency and / or productivity of one or more production lines of the first manufacturing facility 504 and the second manufacturing facility 506 using data obtained from both the first local control system 508 and the second local control system 510.

[0139] The global control system 502 can also generate a model that predicts the values of various process variables that can be used in determining control parameters and / or settings for equipment included in the manufacturing line. In particular embodiments, data obtained from the first local control system 508 and / or the second local control system 510 is analyzed to determine factors that are significant in predicting the values of the process variables and that include factors having at least a significant threshold amount in a model that predicts the process value variables. Thereafter, the global control system 502 can compare the predicted values for the process variables to various thresholds for those process variables. The thresholds for the process variables can indicate when to take action with respect to a particular device or process. Thus, when one or more of the process variables are outside of the specified thresholds, the global control system 502 can determine one or more actions that are executable based on the values of the process variables with respect to the thresholds. In various embodiments, the global control system 502 can determine one or more actions that are executable to return the values of the process variables within the thresholds.

[0140] In various embodiments, the global control system 502 can generate a model that determines productivity, efficiency, and / or control of a production line in a facility having a similar configuration of the production line. The configuration of the production line can be similar to other configurations when the equipment included in the production line is of the same or similar type and / or arranged in the same or similar order. Also, the global control system 502 can generate a model for determining the productivity, efficiency, and / or control of individual devices included in a plurality of manufacturing facilities. That is, the global control system 502 can determine a model that predicts the productivity, efficiency, and / or control of bioreactors included in a plurality of manufacturing facilities. In various embodiments, the model can predict the productivity, efficiency, and / or control of bioreactors of the same or similar size and / or manufactured by the same manufacturing company included in a plurality of manufacturing facilities such as the first manufacturing facility 504 and the second manufacturing facility 506. In a further example, the global control system 502 can predict the productivity, efficiency, and / or control of continuous chromatography systems manufactured by the same manufacturing company or of the same or similar size included in a plurality of manufacturing facilities. In certain cases, the global control system 502 can generate a model that describes the number of chromatography columns included in the chromatography system, the length of the columns of the chromatography system, the size and / or molecular weight of the molecules processed by the chromatography system, or a combination thereof.

[0141] In particular, in embodiments, the global control system 502 can generate a model for different growth phases within the bioreactor. For example, the global control system 502 can generate a first model that predicts the productivity, efficiency, and / or control of the growth phase of bioreactors included in one or more manufacturing facilities. In a further example, the global control system 504 can generate a second model that predicts the productivity, efficiency, and / or control of the stationary phase of bioreactors included in one or more manufacturing facilities.

[0142] Furthermore, the global control system 502 can determine a period during which one or more models can be applied with respect to the productivity, efficiency, and / or control of one or more devices included in the production lines of the first manufacturing facility 504 and / or the second manufacturing facility 506. The global control system 502 can also determine a period during which one or more models cannot be applied with respect to the productivity, efficiency, and / or control of one or more devices included in the production lines of the first manufacturing facility 502 and / or the second manufacturing facility 506. By way of example, the global control system 502 can determine parameters corresponding to conditions under which the accuracy of predictions made by a model generated by the global control system 502 exceeds a threshold level of accuracy. In some exemplary examples, the global control system 502 can determine values of temperature, pH value, flow rate, cell culture medium, final product, devices used in the production line, viable cell density value, carbon dioxide level, dissolved oxygen level, or a combination thereof, as applicable to a given model. If the process conditions deviate from those applicable to one or more models, the global control system 502 can determine one or more default operating modes and / or send a notification to the operator indicating that the process conditions deviate from those applicable to one or more models generated by the global control system 502.

[0143] The global control system 502 can also determine data points that may be missing from the data acquired from the first local control system 508 and the second local control system 510. For example, the global control system 502 can periodically obtain data from the first local control system 508 and the second local control system 510. In some cases, at least a portion of the data expected to be received by the global control system 502 may not be received. In these scenarios, the global control system 502 can generate a model and / or perform calculations related to the control of the first manufacturing facility 504 and / or the second manufacturing facility 506 without missing data. In other embodiments, the global control system 502 can estimate missing data. By way of illustration, the global control system 502 can utilize previous data to estimate missing data. In an exemplary embodiment, the global control system 502 can fill in missing data using the average of previous values over a period of time. In other exemplary embodiments, the global control system 502 can fill in missing data by replicating one or more previous values. In a particular exemplary embodiment, the global control system 502 can determine that one or more pH values are missing from a bioreactor included in the first manufacturing facility 504. The global control system 502 can utilize the previous values of the pH of the bioreactor to fill in the missing data, and the global control system 502 can perform one or more models related to the productivity, efficiency, and / or control of the bioreactor using a data set that includes the missing data. In a particular embodiment, the global control system 502 can determine that it is necessary to fill in missing data when a threshold amount of data is missing, for example, when a threshold number of data points are missing over a particular period of time.

[0144] The exemplary example of FIG. 5 includes a first manufacturing facility 504 and a second manufacturing facility 506, but the global control system 502 can generate models that predict the productivity, efficiency, and / or control of more manufacturing facilities. Further, the global control system 502 can generate models applicable to multiple manufacturing facilities including manufacturing lines disposed within a modular clean room. The global control system 502 can also manufacture models applicable to multiple manufacturing facilities including manufacturing lines not located within a modular clean room. In an even further case, the global control system 502 can manufacture models applicable to both a manufacturing facility having a manufacturing line disposed within a modular clean room and a manufacturing facility having a manufacturing line not disposed within a modular clean room. Further, the global control system 502 can generate a model that can be used in relation to the first manufacturing facility 504 and the second manufacturing facility 506, and pass that model to the first local control system 508 and the second local control system 510. In these scenarios, the first local control system 508 and the second local control system 510 can analyze data obtained from components of devices disposed in the first manufacturing facility 504 and the second manufacturing facility 506, and apply that data to the model provided by the global control system 502. In this way, the calculations performed to implement the model with respect to the first manufacturing facility 504 and the second manufacturing facility 506 can be performed by the first local control system 508, the second local control system 510, and / or the global control system 502.

[0145] FIG. 6 is a schematic diagram of a manufacturing facility 600 that includes a number of modular cleanrooms that include components of an apparatus used in the manufacture of one or more biotherapeutic agents. For example, the manufacturing facility 600 may include a first modular cleanroom 602. The first modular cleanroom 602 may include at least one bioreactor capable of performing a biotherapeutic agent such as a recombinant therapeutic protein using a cell culture medium, a cell growth material, and one or more buffer solutions. In one or more examples, the first modular cleanroom 602 may include additional equipment components. In various embodiments, the first modular cleanroom 602 may include a perfusion system. In a further embodiment, the first modular cleanroom 602 may include a continuous chromatography system for treating the effluent produced by the bioreactor. In one or more exemplary embodiments, the first modular cleanroom 602 may include an apparatus for virus inactivating the effluent produced by the bioreactor. By way of example, the first modular cleanroom 602 may include one or more storage containers for storing the effluent produced by the bioreactor such that one or more pump devices can supply an acid or surfactant to the substances stored in one or more storage containers to produce a virus inactivation pool.

[0146] In the exemplary embodiment of FIG. 6, the manufacturing facility 600 may also include a second modular cleanroom 604 and a third modular cleanroom 606. The second modular cleanroom 604 may include a first additional bioreactor, and the third modular cleanroom 606 may include a second additional bioreactor. Using the first additional bioreactor included in the second modular cleanroom 604 and / or the second additional bioreactor included in the third modular cleanroom 606, the same biological therapeutic agent as the bioreactor located in the first modular cleanroom 602 can be manufactured. In various embodiments, the first additional bioreactor included in the second modular cleanroom 604 and / or the second additional bioreactor included in the third modular cleanroom 606 can operate simultaneously to manufacture a biological therapeutic agent. In further embodiments, the first additional bioreactor included in the second modular cleanroom 604 and / or the second additional bioreactor included in the third modular cleanroom 606 can operate in series such that after the bioreactor included in the first modular cleanroom 602 has manufactured a certain amount of the biological therapeutic agent, at least one of the first additional bioreactors included in the second modular cleanroom 604 or at least one of the second additional bioreactors included in the third modular cleanroom 606 can manufacture a further amount of the biological therapeutic agent.

[0147] In a further embodiment, at least one of the first additional bioreactors included in the second modular cleanroom 604 or the second additional bioreactors included in the third modular cleanroom 606 can be used to produce a biotherapeutic different from the biotherapeutic produced by the bioreactor included in the first modular cleanroom 602. In one or more embodiments, the second modular cleanroom 604 and / or the third modular cleanroom 606 may include, in addition to the bioreactor, components of devices such as one or more chromatography systems, one or more storage containers, one or more pumping devices, one or more perfusion systems, one or more filter devices, or one or more combinations thereof. In one or more exemplary embodiments, at least one of the first modular cleanroom 602, the second modular cleanroom 604, or the third modular cleanroom 606 may include an arrangement of components of the device corresponding to the arrangement of the device described with respect to FIG. 2.

[0148] The manufacturing facility 600 may also include a fourth modular cleanroom 608. The fourth modular cleanroom 608 may include devices that can be used for purifying materials manufactured by one or more devices disposed in at least one of the first modular cleanroom 602, the second modular cleanroom 604, or the third modular cleanroom 606. For example, the fourth modular cleanroom 608 may include one or more chromatography systems. In various examples, one or more chromatography systems disposed within the fourth modular cleanroom 608 can purify virus-inactivating substances transmitted from at least one of the first modular cleanroom 602, the second modular cleanroom 604, or the third modular cleanroom 606. In one or more embodiments, the fourth modular cleanroom 608 can include devices for manufacturing virus-inactivating substances, and the virus-inactivating substances are then purified using one or more chromatography systems disposed within the fourth modular cleanroom 608. Further, the fourth modular cleanroom 608 may include one or more virus filtration devices. One or more virus filtration devices can produce virus-free permeate. In one or more exemplary embodiments, the arrangement of the components of the devices included within the fourth modular cleanroom 608 may correspond to the arrangement of the devices described with respect to FIG. 3.

[0149] Furthermore, the manufacturing facility 600 may include a fifth modular cleanroom 610. The fifth modular cleanroom 610 may include one or more additional filtration devices capable of performing one or more filtration operations on the virus-free permeate produced by the devices disposed within the fourth modular cleanroom 608. By way of example, the fifth modular cleanroom 610 may include one or more filtration devices for performing one or more ultrafiltration operations. In one or more embodiments, the fifth modular cleanroom 610 may include one or more filtration devices for performing one or more diafiltration operations. The manufacturing facility 600 may also include a sixth modular cleanroom 612 that may include one or more devices for performing at least one of one or more ultrafiltration operations or one or more diafiltration operations on the virus-free permeate produced by the devices disposed within the fourth modular cleanroom 608. The devices disposed within the fifth modular cleanroom 610 and the devices disposed within the sixth modular cleanroom 612 can operate simultaneously to process the virus-free permeate produced by the devices disposed within the fourth modular cleanroom 608. In further embodiments, the devices disposed within the fifth modular cleanroom 610 and the devices disposed within the sixth modular cleanroom 612 can operate at different times or continuously to process the virus-free permeate produced by the devices disposed within the fourth modular cleanroom 608. In one or more exemplary embodiments, the arrangement of the devices disposed in at least one of the fifth modular cleanroom 610 or the sixth modular cleanroom 612 may correspond to the arrangement of the devices described with respect to FIG. 4.

[0150] Furthermore, the manufacturing facility 600 may include a seventh modular cleanroom 614. The seventh modular cleanroom 614 may include one or more apparatuses for performing one or more cell expansion operations. In various examples, the cells manufactured by the components of the apparatuses included in the seventh modular cleanroom 614 may be used by one or more bioreactors included in the first modular cleanroom 602, the second modular cleanroom 604, and / or the third modular cleanroom 606.

[0151] The individual modular cleanrooms 602, 604, 606, 608, 610, 612, 614 may be of the same or similar dimensions. In further embodiments, one or more of the modular cleanrooms 602, 604, 606, 608, 610, 612, 614 may be of dimensions different from at least one other of the modular cleanrooms 602, 604, 606, 608, 610, 612, 614. In one or more exemplary embodiments, the modular cleanrooms 602, 604, 606, 608, 610, 612, 614 may be from about 15,000 ft 2 to about 50,000 ft 2 in area. Further, the modular cleanrooms 602, 604, 606, 608, 610, 612, 614 can be operated in accordance with one or more cleanroom standards. For example, the environment of at least one of the fifth modular cleanroom 610, the sixth modular cleanroom 612, or the seventh modular cleanroom 614 can be maintained in accordance with ISO 7 cleanroom standards. Additionally, the environment of the fourth modular cleanroom 608 can be maintained in accordance with ISO 8 cleanroom standards. In certain situations, the environment of the fourth modular cleanroom 608 can be maintained in accordance with ISO 8 cleanroom standards. In one or more embodiments, the environment of at least one of the first modular cleanroom 602, the second modular cleanroom 604, or the third modular cleanroom 606 can be maintained in accordance with ISO 8 or ISO 7 cleanroom standards.

[0152] Furthermore, the manufacturing facility 600 shown in the exemplary embodiment of FIG. 6 includes seven modular cleanrooms arranged according to a specific layout. However, in one or more further embodiments, the manufacturing facility 600 may include a different number of modular cleanrooms arranged according to one or more different layouts. Further, the modular cleanrooms 602, 604, 606, 608, 610, 612, 614 can be arranged in positions different from those shown in the exemplary embodiment of FIG. 6.

[0153] The manufacturing facility 600 may also include a staging area 616. The staging area 616 may include storage containers capable of storing materials to be transferred to devices arranged in one or more of the modular cleanrooms 602, 604, 606, 608, 610, 612, 614. Further, the staging area 616 may include one or more storage containers capable of storing materials transferred from one or more of the modular cleanrooms 602, 604, 606, 608, 610, 612, 614. In various embodiments, one or more storage containers arranged within the staging area 616 are connected to at least one port of at least one of the modular cleanrooms 602, 604, 606, 608, 610, 612, or 614 to transfer materials into or out of each of the one or more modular cleanrooms 602, 604, 606, 608, 610, 612, 614.

[0154] The manufacturing facility 600 may also include many additional areas that can support operations performed by devices located in one or more of the modular cleanrooms 602, 604, 606, 608, 610, 612, 614. For example, the manufacturing facility 600 may include a first area 616 that can handle quality control and / or shipping control or labeling control. In various examples, quality control samples can be obtained with respect to one or more devices included in at least one of the modular cleanrooms 602, 604, 606, 608, 610, 612, 614. The quality control samples can then be tested in the quality control area 616.

[0155] In addition, the manufacturing facility 600 may include a second area 618 that can serve as a preparation area. By way of example, at least one of a buffer solution and / or a cell culture medium can be prepared in the second area 618. The manufacturing facility 600 may also include a third area 620 that can handle cleaning and washing areas. Equipment used in the manufacture and / or storage of one or more biotherapeutics can be cleaned and / or sterilized in the third area 620. In one or more embodiments, the manufacturing facility 600 may include a fourth area 622 that can serve as a weighing and / or storage area. For example, the fourth area 622 can be used to weigh materials transferred to one or more of the modular cleanrooms 602, 604, 606, 608, 610, 612, 614. The fourth area 622 can also be used to weigh materials transferred from one or more of the modular cleanrooms 602, 604, 606, 608, 610, 612, 614. In addition, the fourth area 622 may include one or more storage containers for storing materials used by one or more devices included in at least one of the modular cleanrooms 602, 604, 606, 608, 610, 612, 614. Further, the fourth area 622 may include one or more storage containers for storing materials produced by a device included in at least one of the modular cleanrooms 602, 604, 606, 608, 610, 612, 614.

[0156] The exemplary embodiment of FIG. 6 shows that the manufacturing facility 600 may include four additional areas 616, 618, 620, 622 in further embodiments, but the manufacturing facility 600 may include additional areas where one or more operations are performed. For example, the manufacturing facility 600 may include at least one of an office space, one or more shipping areas, one or more receiving areas, one or more waste disposal areas, one or more warehouse areas, and the like. Also, although various operations are described in relation to each of the areas 616, 618, 620, 622, these operations can be performed inside and outside each of the areas 616, 618, 620, 622. Further, the operations described in relation to one of each of the areas 616, 618, 620, 622 can be integrated into other ones of each of the areas 616, 618, 620, 622 in various embodiments. Additionally, although the additional areas 616, 618, 620, 622 are shown as having respective sizes within the manufacturing facility 600, the relative areas associated with each of the areas 616, 618, 620, 622 may be different from those shown in the exemplary embodiment of FIG. 6.

[0157] In one or more examples, at least one of the bioreactor included in the first modular cleanroom 602, the first additional bioreactor included in the second modular cleanroom 604, or the second additional bioreactor included in the third modular cleanroom 606 completes a manufacturing process for a first biologic therapeutic, and at least one of the bioreactor included in the first modular cleanroom 602, the first additional bioreactor included in the second modular cleanroom 604, or the second additional bioreactor included in the third modular cleanroom 606 is used in a manufacturing process to produce a second different biologic therapeutic. In these scenarios, the apparatus can be moved to and / or from one or more of the modular cleanrooms 602, 604, 606, 608, 610, 612, 614. For example, at least one of a pump apparatus, a filter apparatus, a chromatography system, or a storage container can change locations within the manufacturing facility such that the apparatus included in one or more of the modular cleanrooms 602, 604, 606, 608, 610, 612, 614 is appropriately positioned for the manufacture of the second biologic therapeutic. In various examples, a second biologic therapeutic can be manufactured using different bioreactors, while the apparatus included in one or more processes downstream from the bioreactor can be similar or identical to the processes implemented for the manufacture of the first biologic therapeutic. By way of illustration, the first biologic therapeutic can be manufactured by the bioreactor included in the first modular cleanroom 602, and the purification and virus downstream operations can be performed by the apparatus included in the fourth modular cleanroom 608 and the fifth modular cleanroom 610, respectively. Further, the second biologic therapeutic can be manufactured by the first additional bioreactor included in the second modular cleanroom 604, and the purification operation can also be performed by the apparatus included in the fourth modular cleanroom 608.Subsequent post-virus operations can be performed by equipment included in the fifth modular cleanroom 610 or the sixth modular cleanroom 612. In one or more embodiments, before equipment included in at least one of the fourth modular cleanroom 608, the fifth modular cleanroom 610, or the sixth modular cleanroom 612 is reused, at least one of the second biotherapeutic cleanroom 608, the fifth modular cleanroom 610, or the sixth modular cleanroom 612 is reused. For the equipment included in at least one of the second biotherapeutic cleanroom 608, the fifth modular cleanroom 610, or the sixth modular cleanroom 612, before the second biotherapeutic cleanroom 612, for the equipment included in at least one of the second biotherapeutic cleanroom 608, the fifth modular cleanroom 610, or the sixth modular cleanroom 612, a second biotherapeutic cleaning operation can be performed. Further, before the equipment included in at least one of the fourth modular cleanroom 608, the fifth modular cleanroom 610, or the sixth modular cleanroom 612 is reused for performing the second biotherapeutic agent, for the equipment included in at least one of the fourth modular cleanroom 608, the fifth modular cleanroom 610, or the sixth modular cleanroom 612 used for performing the second biotherapeutic agent, single-use components can be replaced with respect to the equipment included in at least one of the fourth modular cleanroom 608, the fifth modular cleanroom 610, or the sixth modular cleanroom 612.

[0158] In various embodiments, the transfer of equipment and / or materials across the manufacturing facility can be tracked using identifiers assigned to each piece of equipment, identifiers assigned to each sample, identifiers assigned to each storage container, or one or more combinations thereof. In an exemplary example, the individual identifiers can be encoded by at least one of an alphanumeric identifier, a barcode, a quick response code (QR), or a radio frequency identification (RFID). In this way, when materials and equipment change locations within the manufacturing facility 600, the respective characteristics of the materials and equipment can be identified at a given point in time.

[0159] FIG. 7 shows some embodiments of a system 700 for controlling a production line for manufacturing a purified biologic therapeutic. System 700 includes a global system 502 that can be implemented by one or more computing devices 702. In certain embodiments, the one or more computing devices 702 can be included in a cloud computing architecture that operates the one or more computing devices 702 in place of an entity that implements the global control system 502. In these scenarios, the cloud computing architecture can instantiate one or more virtual machine instances using the one or more computing devices 702 in place of an entity that implements the global control system 502. The cloud computing architecture can be located at a location remote from the entity that implements the global control system 502. In further embodiments, the one or more computing devices 702 can be under the direct control of an entity that implements the global control system 502. For example, an entity that implements the global control system 502 can maintain the one or more computing devices 702 and perform operations related to the generation of one or more models related to the efficiency, productivity, and / or control of the components of the equipment included in a production line for manufacturing one or more biologic therapeutics. In various embodiments, the one or more computing devices 702 can include one or more server computers.

[0160] The global control system 502 can include one or more processors such as a processor 704. The one or more processors 704 can include at least one hardware processor such as a microprocessor. In some cases, the one or more processors 704 can include a central processing unit, an image processing unit, or both a CPU and a GPU, or other processing devices. Further, the one or more processors 704 can include local memory that can store program modules, program data, and / or one or more operating systems.

[0161] Furthermore, the global control system 502 may include one or more computer-readable storage media, such as a computer-readable storage medium 706. The computer-readable storage medium 706 may include volatile and non-volatile memory implemented in any technology for storing information such as computer-readable instructions, data structures, program modules, or other data, and / or removable and non-removable media. Such computer-readable storage medium 706 may include, but is not limited to, RAM, ROM, EEPROM, flash memory or other memory technology, CD-ROM, digital versatile disk or other optical storage device, magnetic cassette, magnetic tape, solid state storage device, magnetic disk storage device, RAID storage system, storage array, network-connected storage device, storage area network, cloud storage device, removable storage media, or any other media that can be used to store desired information and can be accessed by a computing device. Depending on the configuration of the global control system 502, the computer-readable storage medium 706 may be a type of tangible computer-readable storage medium and may be a non-transitory storage medium.

[0162] The global control system 502 may include one or more communication interfaces 708 for communicating with other computing devices via one or more of the Internet, cable network, satellite network, wide area wireless communication network, wired local area network, wireless local area network, or public switched telephone network.

[0163] The computer-readable storage medium 706 can be used to store any number of functional components executable by one or more processors 704. In many embodiments, these functional components include instructions or programs that are executable by one or more processors 704 and, when executed, implement the operational logic for performing the operations attributed to the global control system 502. The functional components of the global control system 502 executable on one or more processors 704 for performing the various functions and features related to the control and operation of a manufacturing line for manufacturing a biological therapeutic agent described herein include process data collection instructions 710, system control instructions 712, process data analysis instructions 714, and model generation instructions 716.

[0164] Furthermore, the one or more computing devices 702 may include one or more input / output devices (not shown). The one or more input / output devices may include a display device, a keyboard, a remote controller, a mouse, a printer, an audio input / output device, a speaker, a microphone, a camera, and the like.

[0165] The global control system 502 may also include, but is not limited to, a data storage device 718 that may include or be coupled to RAM, ROM, EEPROM, flash memory, one or more hard disks, solid state drives, optical memory (e.g., CD, DVD), or other non-transitory memory technologies. The data storage device 718 can maintain information utilized by the global control system 502 and perform operations related to the control and operation of a manufacturing line that manufactures a biological therapeutic agent. For example, the data storage device 718 can store process data 720 and control modules 722. The process data 720 may include values obtained from sensors coupled to components of devices included in a manufacturing line that manufactures a biological therapeutic agent. The control modules 722 may include instructions for controlling various devices that may be included in a manufacturing line that manufactures a biological therapeutic agent. The control modules 722 may include set points, threshold values, status flags, tags, identifiers, device characteristics, combinations thereof, etc. In some examples, the equipment characteristics may include the type of each piece of equipment, the size of the equipment (e.g., volume).

[0166] The process data collection instruction 710 is executable by one or more processors 704, operates as a component of one or more manufacturing lines, and can obtain data generated by sensors on components of an apparatus for manufacturing a biological therapeutic. Also, the data obtained by the process data collection instruction 710 may include data corresponding to diagnostic or test procedures not based on sensor data. For example, the process data collection instruction 710 can obtain data indicating the concentration of a biological therapeutic at one or more stages of a manufacturing line. In some examples, when the biological therapeutic is an antibody, the measurement of the concentration of the biological therapeutic may include determining the functional concentration or dilution factor of a stock solution of the antibody for a given immunoassay, referred to herein as the "titer". In certain embodiments, the process data collection instruction 710 can send requests to one or more manufacturing facilities to obtain at least a portion of the process data 720. In further embodiments, the global control system 502 can periodically receive components of the process data 720 and store the data as process data 720 in the data storage device 718. Additionally, the data obtained by the process data collection instruction 710 can be requested and / or received by the global control system 502 periodically, at predetermined intervals, at irregular times, or combinations thereof.

[0167] The process data collection instruction 710 can store the data acquired from the manufacturing equipment according to a schema that can efficiently search for the data. In some exemplary embodiments, the data acquired by the process data collection instruction 710 can be stored based on the manufacturing equipment that supplies the data. Further, the data acquired by the process data collection instruction 710 can store the data based on each type of device related to the data, such as a bioreactor, a chromatography system, a filter device, a pump device, a temperature control device, a storage container, etc. Also, the data acquired by the process data collection instruction 710 can be stored based on the type of data to be collected, for example, pH data, temperature data, flow rate data, viable cell density data, capacitance data, volume level data, weight data. Further, the data acquired by the process data collection instruction 710 can be stored based on the configuration of the manufacturing line for manufacturing a biological therapeutic agent, such as the arrangement of various devices within the manufacturing line and / or whether one or more devices included in the manufacturing line are housed in a modular clean room. In various embodiments, the data acquired by the process data collection instruction 710 can be stored based on the manufacturing line, the cell line used in the manufacture of the biological therapeutic agent, and / or the biological therapeutic agent manufactured by the reagent used in the manufacture of the biological therapeutic agent.

[0168] The system control instruction 712 can be executed by the processor 704 and can determine control settings for components of the equipment included in the production line for manufacturing biological therapeutics. Further, the system control instruction 712 can include scheduling instructions for generating control data such as signals or commands, and can be sent to the manufacturing facility for use in controlling components of the equipment included in the production line. In particular embodiments, the control data can indicate the timing for components of the device to perform the specified operations and the modifications or settings for the components of the device. For example, the scheduling instruction 724 can generate control data for the perfusion system indicating the flow rate of the perfusion system. The scheduling instruction 724 can also generate control data indicating the timing for the perfusion system to perform the flow rate. In a further example, the scheduling instruction 724 can generate control data for the bioreactor indicating at least one of the temperature setting of the bioreactor, the pH level of the bioreactor, the supply rate of the bioreactor, or the agitation rate of the bioreactor.

[0169] In a specific embodiment, the system control instruction 712 can analyze the process data 720 with respect to a number of rules for controlling parts of the device included in the production line for manufacturing biological therapeutics. In certain embodiments, the system control instruction 712 can analyze the process data 720 in relation to one or more policies and / or rules and can determine control settings for components of the equipment included in the production line for manufacturing biological therapeutics. The policy and / or rule can indicate various thresholds and / or ranges of values corresponding to the values of each of the process variables and / or control variables. For example, the policy and / or rule can indicate at least one of the pump setting or the flow rate of the buffer solution to the bioreactor in relation to the pH level of the bioreactor. In a further example, the policy and / or rule can indicate the agitation rate of the bioreactor based on the volume of the material in the bioreactor, the growth rate of one or more final products, the temperature associated with the bioreactor, or a combination thereof.

[0170] In some exemplary examples, policies and / or rules can indicate actions corresponding to different volume levels of a storage container. By way of example, a rule corresponding to a storage container connected to a chromatography system can indicate that at a first volume of the substance contained in the storage container, the pump of the chromatography system is stopped, and at a second volume of the substance contained in the storage container that is greater than the first volume, the pump of the chromatography system is set to a low speed setting until a third volume level of the substance in the storage container where the third volume is greater than the second volume is reached. Continuing with this exemplary example, this rule can indicate that at a fourth volume in the storage container, the pump of the chromatography system is set to a high speed setting until the third volume level is reached, and at a fifth volume, if it is greater than the fourth volume, the material being supplied into the storage container can be directed from the storage container into the drain.

[0171] In further exemplary embodiments, a rule can indicate the volume level of a first storage container, which triggers the material being pumped into the first storage container to be diverted to a second storage container. For example, the first storage container and the second storage container can be connected to a chromatography system. The chromatography system can pump the effluent into the first reservoir, and the system control instruction 712 can monitor the volume in the first storage container and send control data to the chromatography system or send a notification to the operator to pump the effluent into the second storage container in response to the volume of the substance contained in the first storage container being at a threshold level. In further exemplary embodiments, the system control instruction 712 can monitor the pressure level of a filter assembly, which is a component of the filter bank. The system control instruction 712 can determine that the pressure level of the filter assembly has reached a threshold level and send control data to the filter assembly in the scheduling instruction 724 or notify the operator to direct the material from the filter assembly to another filter assembly having a pressure below the threshold pressure.

[0172] The system control instructions 720 can also be executable by one or more processors 704 and can determine control modules to be utilized with respect to components of the devices included in the manufacturing line for the manufacture of biological therapeutics. The system control instructions 720 can determine a control module 722 or a set of control modules 722 to effect control of the components of the device based on information received by the global control system 502 for the components of the device. In various embodiments, the system control instructions 712 can obtain information regarding the components of the device including the identifiers of the components of the device and the functions of the components of the device. In this case, the system control instructions 712 can determine a control module 722 or a set of control modules 722 corresponding to the identifiers and functions received by the global control system 502. In an exemplary embodiment, the system control instructions 712 can receive the identifiers and functions of the equipment corresponding to the chromatography system, and the system control instructions 712 can identify one or more of the control modules 722 corresponding to the control of the chromatography system and can execute one or more of the control modules 722 for the control and operation of the chromatography system.

[0173] In a further exemplary embodiment, the system control instruction 712 can determine that the identifier and / or function of a component of the device has changed, identify a different set of control modules 722, and control the operation of the component of the device. By way of example, the system control instruction 712 can identify one or more first control modules 722 and control the operation of the storage container based on a first identifier and a first function received by the global control system 502 with respect to the storage container. Following this example, the storage container can be utilized at different locations within the manufacturing line or with respect to different manufacturing lines, and the system control instruction 712 can obtain information from the manufacturing facility indicating that the storage container is associated with a second identifier and a second function. Next, the system control instruction 712 can determine to utilize one or more second control modules 722 and control the operation of the storage container based on the second identifier and the second function. In a particular exemplary example, the first identifier and the first function can indicate that the storage container operates to collect the effluent from the bioreactor, and the second identifier and the second function can indicate that the storage container operates to collect the effluent from the chromatography system.

[0174] When the manufacturing line is disposed within a number of modular clean rooms, the system control instruction 712 can generate a control signal corresponding to the flow of materials between the modular clean rooms. For example, the system control instruction 712 can determine the flow rate of the materials transferred between the modular clean rooms based on the volume of the materials stored in one or more storage containers and send a signal to the manufacturing facility control system to operate one or more pumping devices to achieve the flow rate. In various embodiments, the signal can be sent to a perfusion system, a chromatography system, and / or a stand-alone pumping device.

[0175] The process data analysis instruction 714 is executable by the processor 704, can analyze the process data 720, and can determine factors that can at least have a threshold impact on the productivity, efficiency, and / or control of a production line for manufacturing a biological therapeutic agent. In an exemplary example, the productivity and / or efficiency of the production line can correspond to the yield of the biological therapeutic agent manufactured by the production line. In other exemplary embodiments, the productivity and / or efficiency of the production line can correspond to the viable cell density associated with the biological therapeutic agent manufactured by the production line. In a further exemplary example, the productivity and / or efficiency of the production line can correspond to the purity of the final product including the biological therapeutic agent manufactured by the production line. In various embodiments, a first portion of the process data 720 can be used to train a model, and a second portion of the process data 720 can be used to validate the model. By way of example, a component of the process data 720 collected over a first period with respect to the production line can be used to train a model regarding the productivity, efficiency, and / or control of the production line, while another component of the process data 720 collected over a second period after the first period with respect to the production line can be used to validate the model.

[0176] The process data analysis instruction 714 can perform a partial least squares technique for identifying factors that at least have a threshold impact on the productivity, efficiency, and / or control of a production line. The process data analysis instruction 714 can generate one or more models that can be used for predicting the productivity and / or efficiency of the production line. The process data analysis instruction 714 can also generate a model for predicting the values of process data used for controlling components of the equipment included in the production line. The model can include a number of variables corresponding to factors that at least have a threshold amount of impact on the productivity and / or efficiency of the production line. The model can also include coefficients associated with each variable. The coefficients can correspond to the amount of impact that each variable has on the productivity, efficiency, and / or control of the production line. In a particular embodiment, the model can include process variables corresponding to the productivity and / or efficiency of the production line, and control variables that can be modified to affect the process variables.

[0177] Model execution instruction 716 is executable by processor 704 and can execute the model generated by process data analysis instruction 714. For example, model execution instruction 716 can obtain parts of process data 720 obtained by process data collection instruction 710 related to the productivity and / or efficiency of the manufacturing line, and apply the parts of process data 720 to a model for predicting the productivity and / or efficiency of the manufacturing line. In certain embodiments, model execution instruction 716 can determine that the productivity and / or efficiency predicted by the model is outside the specified range for productivity and / or efficiency, or less than the threshold productivity and / or efficiency. In this case, model execution instruction 716 can use the model to determine one or more control variables that can be modified to move the productivity and / or efficiency of the manufacturing line within the specified range or above the threshold productivity and / or efficiency. Model execution instruction 716 can also determine settings of control variables that can affect the productivity and / or efficiency of the manufacturing line.

[0178] In an exemplary embodiment, model execution instruction 716 can predict that the viable cell density of the manufacturing line is less than the threshold viable cell density. Model execution instruction 716 can also determine that the pH of the bioreactor is less than the threshold pH level and that the flow rate through the chromatography system is greater than the threshold flow rate. In this case, model execution instruction 716 can use the model to determine that the control variables that can affect the productivity of the manufacturing line are the bleed rate of the bioreactor and the flow rate of the basic buffer solution to the bioreactor. Subsequently, model execution instruction 716 can determine that it is possible to increase the productivity and / or efficiency of the manufacturing line by increasing the draw rate from the bioreactor by a specific amount and increasing the flow of the basic buffer solution to the bioreactor by a specific amount.

[0179] Model execution instruction 716 can also operate in conjunction with scheduling instruction 724 to determine the schedule for the automatic control of one or more production lines. In a specific embodiment, the model execution instruction 716 can execute the model generated by the process data analysis instruction 714 based on the data obtained from the production line to predict the process variables of one or more devices included in the production line. Also, the model execution instruction 716 can execute the model based on the data obtained from the production line to predict the productivity and / or the efficiency measurement criteria of the production line. Further, the model execution instruction 716 can determine the settings of the components of the devices included in the production line such that the process variables and the measured values of productivity and / or efficiency are predicted to be within a specific range. Thereafter, the scheduling instruction 724 can determine the control signals and the timing of the control signals for transmission to each device and operate each device according to the control settings.

[0180] The operations are described with respect to FIG. 6 as being executed by the global control system 502, but at least a portion of the operations can be executed by the local control system. For example, at least a portion of the operations executed by the model execution instruction 716 can be executed by the local control system. By way of example, the global control system 502 can generate models related to productivity, efficiency, and / or control, and the local control system can execute the models. Further, at least a portion of the system control instruction 712 can be executed by the local control system.

[0181] Figures 8 and 9 illustrate an exemplary process for generating and applying models related to the productivity, efficiency, and control of a manufacturing line for manufacturing a biological therapeutic agent, and FIG. 10 illustrates an exemplary process for manufacturing a biological therapeutic agent using a manufacturing facility having a plurality of modular cleanrooms. These processes (and each process described herein) are shown as logical flow graphs, and each operation thereof represents a series of operations that can be implemented, at least in part, in hardware, software, or a combination thereof. In the context of software, an operation represents computer-executable instructions stored on one or more computer-readable storage media that, when executed by one or more processors, perform the recited operations. Generally, computer-executable instructions include routines, programs, objects, components, data structures, etc., that perform a particular function or implement a particular abstract data type. The order in which the operations are described is not intended to be limiting, and any number of the described operations can be combined in any order and / or in parallel to execute the process.

[0182] FIG. 8 is a flowchart of an exemplary process 800 for generating a model used to predict values related to the manufacture and / or efficiency of a manufacturing line. At 802, process 800 includes obtaining first data from a manufacturing line for a biological therapeutic agent over a first period. The data can be obtained by an overall control system that controls the operation of a plurality of facilities manufacturing the biological therapeutic agent. In some embodiments, the equipment of the manufacturing line can be arranged in a number of modular cleanrooms. In further embodiments, the equipment of the manufacturing line can be arranged in a continuous space of a manufacturing facility that does not include modular cleanrooms.

[0183] In 804, process 800 may include determining one or more first variables that are significant in indicating process conditions that affect productivity and / or efficiency metrics of the manufacturing line by analyzing the first data. If the measures of the one or more first variables show statistical significance with respect to the productivity and / or efficiency metrics, the one or more first variables may be significant in indicating process conditions that affect the productivity and / or efficiency metrics. In various embodiments, the one or more first variables can have at least a threshold amount of impact on the productivity and / or efficiency metrics. In an exemplary embodiment, a partial least squares method can be performed to determine the one or more first variables. In some embodiments, the productivity and / or efficiency metrics may correspond to viable cell density, titer, yield, and / or purity of a biologic therapeutic.

[0184] In 806, process 800 may include determining one or more second variables that are significant in controlling at least one aspect of the manufacturing line to modify the value of a manufacturing metric by analyzing the first data. In particular embodiments, the one or more second variables may have a threshold amount of impact on the one or more first variables. In an exemplary embodiment, a partial least squares method can be performed to determine the one or more second variables.

[0185] In 808, process 800 may include generating a model that utilizes at least one or more first variables and one or more second variables. The model may also include one or more coefficients each associated with one or more first variables and / or one or more second variables. In this way, the model can be trained using data obtained during the first period. In 810, process 800 may include obtaining second data from a manufacturing line for a biologic therapeutic agent during a second period after the first period. In 812, process 800 may include performing one or more validation operations on the model based on the second data. In certain embodiments, the one or more validation operations may include comparing a first value of one or more productivity and / or efficiency metrics generated by applying the first data to the model with a second value of one or more productivity and / or efficiency metrics generated by applying the second data to the model.

[0186] In 814, process 800 may include determining whether calibration of the model is necessary. If calibration of the model is not necessary, process 800 may proceed to 816 where the model is executed. With respect to FIG. 9, an example of the model is described. If modification of the model is necessary, process 800 may proceed to 818 where the model is modified. In particular embodiments, the model may be modified if the first value and the second value differ by more than a threshold amount. Further, modification of the model may include modifying at least a first variable or a second variable included in the model. That is, a variable may be removed or added to the model based on the significance of the variable that changes as more data is analyzed. In other embodiments, the model may be modified by changing at least one coefficient included in the model. Modifying at least one coefficient can change the significance of at least one of the first variables and / or at least one of the second variables as more data is analyzed. In some cases, additional data used to modify the model may include the second data obtained during the second period.

[0187] FIG. 9 is a flowchart of an exemplary process 900 for performing a model used to predict values related to the production and / or efficiency of a manufacturing line in the control of a manufacturing line according to some embodiments. At 902, process 900 may include obtaining data from a manufacturing line that manufactures a biologic therapeutic. In some examples, the process data may include information obtained from sensors of components of the equipment included in the manufacturing line. In further examples, the process data may include data obtained by testing materials manufactured by components of the equipment included in the manufacturing line.

[0188] At 904, process 900 may include applying the process data to a model regarding the productivity and / or efficiency of the manufacturing line. In some embodiments, the model can be created using the exemplary process of FIG. 8. Applying the process data to the model can generate one or more productivity and / or efficiency metrics based on the process data.

[0189] At 906, process 900 may include determining that one or more metrics regarding the productivity and / or efficiency of the manufacturing line are outside a threshold range. One or more productivity and / or efficiency metrics outside the threshold range may indicate that various equipment settings need to be changed in order to achieve the desired productivity and / or efficiency metrics.

[0190] At 908, process 900 may include determining one or more process variables to modify for changing one or more metrics. In certain embodiments, the one or more process variables to be changed can be based on the amount of impact that changing a particular process variable has on the productivity and / or efficiency metrics. In various examples, one or more machine learning techniques can be performed to determine one or more process variables to modify.

[0191] At 910, process 900 may include determining one or more control variables to be modified for changes in one or more process variables. For example, increasing the number of cells may not always improve the process. Instead, other variables such as agitation speed, pH, temperature, etc. may affect the number of cells. The control variables corresponding to the process variables can be determined based on the analysis of past data indicating that a change to the control variable has at least a threshold effect on the process variable. In certain embodiments, machine learning techniques can be used to determine one or more control variables that affect each process variable.

[0192] At 912, process 900 may include changing the operation of one or more components of the apparatus to generate control signals to be sent to the components of the one or more apparatuses for modifying one or more metrics for productivity and / or efficiency of the manufacturing line. In various embodiments, the amount of change in the control variable and / or the process variable can be determined, and the control signal can correspond to the amount of change in the operation of various apparatuses that results in a change in the process variable that modifies the productivity and / or efficiency metric.

[0193] FIG. 10 is a flow diagram of an exemplary process 1000 for manufacturing a biotherapeutic agent using a manufacturing facility having a plurality of modular clean rooms. Method 1000 may, at 1002, include transferring into a bioreactor disposed in a first modular clean room at least a cell culture medium, a cell growth material, and a buffer solution. At least one storage container can be disposed outside the first modular clean room. In various examples, the buffer solution can be stored in a first storage container, the cell culture medium can be stored in a second storage container, and the cell growth material can be stored in a third storage container. The first modular clean room may have an area of from about 15,000 ft 2 to about 50,000 ft 2 .

[0194] Furthermore, in 1004, method 1000 may include the production of a cell-free permeate containing a recombinant therapeutic protein in at least one vessel of a bioreactor. The recombinant therapeutic protein can be produced in at least one vessel of the bioreactor. The volume of at least one vessel of the bioreactor may be from about 250 L to about 2000 L. In one or more embodiments, the bioreactor can produce a constant amount of recombinant therapeutic protein at a rate from about 0.5 g of recombinant therapeutic protein per liter of cell culture medium per day to about 10 g of recombinant therapeutic protein per liter of cell culture medium per day.

[0195] In one or more embodiments, the cell-free permeate can be produced by one or more operations performed by the bioreactor. In a further example, the cell-free permeate can be produced by at least one of one or more operations performed by the bioreactor or one or more operations performed by a perfusion system coupled to the bioreactor. In one or more embodiments, the effluent from the bioreactor can be transferred to the perfusion system and the effluent from the perfusion system containing the cell-free permeate can be transferred to a storage container. In various examples, the cell-free permeate can be transferred from the storage container to a temperature control system. The temperature control system may include, in some exemplary examples, a heat exchanger.

[0196] Furthermore, process 1000 may include, at 1006, transferring a certain amount of the cell-free permeate to a chromatography system. The chromatography system may also be disposed within a first modular cleanroom. The cell-free permeate can be transferred from a storage container holding the cell-free permeate to the chromatography system. Further, the cell-free permeate can be transferred from a temperature control system, which can change the temperature of the cell-free permeate, to the chromatography system before transferring the cell-free permeate to the chromatography system. The chromatography system may include a continuous chromatography system that produces a protein separation fraction after 4 to 15 cycles of the continuous chromatography system. Each cycle of the continuous chromatography system may have a duration of from about 3 hours to about 12 hours. The continuous chromatography system can produce a certain amount of the protein isolation fraction from about 80 g / L of resin to about 140 g / L of resin. In one or more embodiments, the chromatography system may include 3 to 9 columns each having a diameter of from about 40 cm to about 100 cm and a height of from about 10 cm to about 40 cm.

[0197] The effluent from the chromatography system can be transferred to one or more storage containers. The one or more storage containers can be disposed within the first modular cleanroom. In one or more exemplary examples, the effluent from the chromatography system can be transferred to two storage containers with alternating movement of the effluent between the two storage containers. For example, the chromatography system can transfer the effluent to a first storage container during a first period. One or more sensors of the first storage container can measure the volume of the effluent from the chromatography system stored in the first storage container. Further, the transfer rate of the effluent from the chromatography system and the time during which the chromatography system transferred the effluent to the first storage container can also be measured.

[0198] In various examples, the volume of the protein isolation fraction stored by the first container can be monitored by a control system. The control system can also monitor the transfer rate of the protein isolation fraction from the chromatography system and the time at which the chromatography system transferred the protein isolation fraction to the first storage container. In one or more embodiments, the control system can determine that one or more threshold criteria are met, stop the transfer of the protein separation strain fraction to the first storage container, and transfer the protein separation strain fraction to a second storage container. In one or more examples, the control system can determine that the volume of the protein separation fraction stored by the first storage container corresponds to a threshold volume. Further, the control system can determine that the amount of time the protein separation fraction was transferred to the first storage container corresponds to a threshold time based on the flow rate of the effluent from the chromatography system to the first storage container. The control system can then send one or more signals to stop the flow of the effluent from the chromatography system to the first storage container and initiate the flow of the effluent from the chromatography system to the second storage container. By way of example, the control system can send one or more signals to a valve that directs the flow of the effluent from the chromatography system to stop the flow of the effluent from the chromatography system to the first storage container and initiate the flow of the effluent from the chromatography system to the second storage container. Further, after threshold conditions are met with respect to the amount of the protein isolation fraction stored by the second storage container, the flow of the effluent from the chromatography system to the second storage container can be stopped, and then the effluent from the chromatography system can be directed to the first storage container.

[0199] Process 1000 may also, at 1008, include the production of a virus-inactivated pool containing a recombinant therapeutic protein by virus inactivation with respect to the effluent of the first chromatography system. The virus-inactivated pool can be produced by adding an acid or a surfactant to the protein isolation fraction produced by the chromatography system. The acid or surfactant can be stored in one or more storage containers located outside the first modular cleanroom. The acid or surfactant can be added to the protein isolation fraction, while the protein isolation fraction is stored in the storage container. In various examples, a pump device located in the first modular cleanroom can be used to treat the protein isolation fraction produced by the chromatography system with an acid or a surfactant to produce a virus-inactivated pool.

[0200] In 1010, process 1000 may include transferring a certain amount of the virus inactivation pool to a second modular cleanroom. The virus inactivation pool can be transferred to the second modular cleanroom by transferring a certain amount of the virus inactivation pool to an additional storage container located outside the first modular cleanroom. In various examples, the additional storage container can be connected to a port of the first modular cleanroom. In one or more embodiments, the virus inactivation pool can be transferred to an additional storage container outside the first modular cleanroom using an additional pump device located within the first modular cleanroom. Further, the virus inactivation pool can pass through one or more filter devices located within the first modular cleanroom before being transferred to an additional storage container located outside the first modular cleanroom. In various examples, the amount of the virus inactivation pool can be transferred to the second modular cleanroom by connecting the additional storage container to a port of the second modular cleanroom. In a further example, the amount of the virus inactivation pool can be transferred to the second modular cleanroom by transferring the contents of the additional storage container to another storage container located outside the second modular cleanroom and connected to a port of the second modular cleanroom. The other storage container located outside the second modular cleanroom may have a volume larger than the volume of the additional storage container that captures the virus inactivation pool from the first modular cleanroom.

[0201] Process 1000 may include, at 1012, performing one or more operations to purify a virus inactivation pool using one or more devices within a second modular cleanroom. The virus inactivation pool can be purified using one or more additional chromatography systems disposed in the second modular cleanroom. In various examples, one or more resins used in one or more chromatography systems disposed within the second modular cleanroom for purifying the virus inactivation pool may be different from one or more resins used in a chromatography system disposed within a first modular cleanroom for producing a protein isolation fraction. Further, one or more chromatography systems included in the second modular cleanroom can perform one or more chromatography techniques different from at least one chromatography technique performed by a chromatography system disposed in the first modular cleanroom. The purification process performed by one or more chromatography systems disposed within the second modular cleanroom can produce a purified product pool. In one or more embodiments, the purified product pool can be transferred to a virus filtration device. The virus filtration device can produce a virus-free permeate. In one or more exemplary embodiments, the virus filtration device can be disposed within the second modular cleanroom.

[0202] In a further example, further purification can be performed. For example, the virus-free permeate can be transferred to a further filtration device capable of performing at least one of one or more ultrafiltration operations or one or more diafiltration operations for the production of a purified protein pharmaceutical substance. In various examples, the further filtration device can be disposed within a third modular cleanroom. The amount of the purified therapeutic protein pharmaceutical substance can be transferred to a number of vials. By way of illustration, one or more filling operations and / or one or more finishing operations can be performed to transfer a fixed amount of the purified protein pharmaceutical substance to 100 vials at a rate of 5 vials per minute. Filling the purified therapeutic protein pharmaceutical substance into vials can be automatically performed using at least one device for filling the purified therapeutic protein pharmaceutical substance into vials. In one or more exemplary embodiments, the volume of each of the vials can be from about 2 mL to about 40 mL.

[0203] Biological therapeutics manufactured using the implementation of Process 1000 can be carried out in a manufacturing facility capable of manufacturing multiple biological therapeutics using different equipment configurations within the modular cleanrooms of the manufacturing facility. For example, after a certain amount of a first biological therapeutic is manufactured using a first arrangement of equipment, a certain amount of a second biological therapeutic can be manufactured using a different arrangement of the equipment. In one or more examples, with respect to the arrangement of the components of the equipment for manufacturing the first biological therapeutic, the components of the equipment within one or more modular cleanrooms can be further removed or relocated to produce a production line used for manufacturing the second biological therapeutic. By way of illustration, for a first arrangement of equipment used to manufacture a first biological therapeutic, one or more filtration devices can be removed or relocated to manufacture a second biological therapeutic. Further, for a first arrangement of equipment used to manufacture a first biological therapeutic, one or more pumping devices and / or one or more storage containers can be added, removed, or relocated to manufacture a second biological therapeutic. In various examples, the chromatography system used to manufacture the first biological therapeutic may not be used to manufacture the second biological therapeutic. Further, in one or more embodiments, a second biological therapeutic can be manufactured using an additional chromatography system that did not manufacture the first biological therapeutic. If the components of the equipment used to manufacture the first biological therapeutic are also used to manufacture the second biological therapeutic, the single-use components of the equipment are removed from the components of the equipment after the manufacture of the first biological therapeutic stops and before the manufacture of the second biological therapeutic starts, and then can be replaced. For example, after a certain amount of a purified therapeutic protein pharmaceutical substance is manufactured, one or more first single-use components can be removed from at least one of a bioreactor, a chromatography system, or an additional chromatography system. Thereafter, one or more first single-use components can be replaced with one or more second single-use components.Thereafter, the bioreactor can obtain additional cell culture medium, additional cell growth material, and additional buffer solution from one or more storage containers, and can produce additional cell-free permeate containing additional recombinant therapeutic proteins different from the first recombinant therapeutic protein produced by the bioreactor.

[0204] Furthermore, process 1000 is implemented in one or more scenarios, where a second bioreactor produces a biotherapeutic, and operations on the effluent from the first bioreactor and the effluent from the second bioreactor can be performed simultaneously. In one or more embodiments, the second bioreactor can be placed within the same modular cleanroom as the first bioreactor. In one or more examples, at least one of one or more ultrafiltration operations or one or more diafiltration operations can be performed in relation to the effluent from the first bioreactor, while an additional amount of virus inactivation pool is purified by one or more chromatography systems, where the additional virus inactivation pool is produced from the effluent of the second bioreactor. In various examples, ultrafiltration and / or diafiltration can be performed within one modular cleanroom, while purification of the virus inactivation pool can be performed within another modular cleanroom. Additionally, at least one of one or more ultrafiltration operations or one or more diafiltration operations can be performed in relation to the effluent produced by the first bioreactor while a virus filtration device processes a certain amount of the additional purified product pool produced from the effluent of the second bioreactor. In these scenarios, ultrafiltration and / or diafiltration can be performed in one modular cleanroom and virus filtration can be performed in another modular cleanroom. Moreover, chromatography operations performed on the effluent from the first bioreactor by one or more chromatography systems placed within one modular cleanroom, on the other hand, additional chromatography operations can be performed on the effluent from the second bioreactor by one or more chromatography systems placed within another modular cleanroom.

[0205] The above subject matter is provided by way of example only and should not be construed as limiting. Further, the claimed subject matter is not limited to embodiments that solve any or all of the deficiencies described in any part of this disclosure. Various modifications and changes can be made to the subject matter described herein without departing from the true spirit and scope of the invention as set forth in the following claims, without following the exemplary configurations and uses illustrated and described. 〔Examples of Implementation〕

[0206] 1. A method comprising: obtaining a first set of data indicative of a first plurality of states of a bioreactor system, the first set being obtained via at least one of a plurality of sensors of the bioreactor system or one or more external assays that measure the state of the bioreactor system at different points in time during operation; analyzing the first set to determine one or more process variables that have at least a threshold impact on a measure of productivity associated with an effluent produced using the bioreactor system, the one or more process variables corresponding to at least one media component utilized in the bioreactor system for the production of the effluent; analyzing the first set to determine one or more control variables that have at least an additional threshold impact on the one or more process variables using the one or more inference modeling techniques; generating a model comprising variables corresponding to the one or more process variables and the one or more control variables, the model predicting the measure of productivity; obtaining a second set of data, the second data set indicative of a second plurality of states of the bioreactor system, obtained via at least one of the plurality of sensors of the bioreactor system or the one or more external assays, obtained after the first data set, analyzing the second data set according to the model to determine a modification to at least one of the one or more control variables and modifying the productivity measurement criterion; and modifying the at least one control variable according to the modification.

[0207] 2. The bioreactor system is included in a first manufacturing facility, and a further bioreactor system is included in a second manufacturing facility. The first data set includes further conditions of the further bioreactor system, and the first data set is also obtained via at least one of a plurality of further sensors of the further bioreactor system or one or more external assays that measure conditions at different times during operation of the further bioreactor system. The method according to 1.

[0208] 3. The bioreactor system is included in a modular cleanroom of a first plurality of modular cleanrooms included in the first manufacturing facility, and the further bioreactor system is included in a further modular cleanroom of a second plurality of modular cleanrooms included in the second manufacturing facility. The method according to 2.

[0209] 4. A first volume of the bioreactor system and a second volume of the further bioreactor system are substantially the same; a first cell culture medium supplied to the bioreactor system and a second cell culture medium of the further bioreactor system include the same cell line; a first biotherapeutic agent produced by the bioreactor system and a second biotherapeutic agent produced by the further bioreactor system are the same. The method according to 2 or 3.

[0210] 5. The method according to any one of 1 to 4, wherein one or more inferential modeling techniques include the partial least squares method.

[0211] 6. A method according to any one of 1 to 5, further comprising the steps of: obtaining third data indicating a third plurality of states of a plurality of devices included in a production line for manufacturing a biological therapeutic agent, the method including the bioreactor system and the chromatography system, the third data set being obtained via at least one of a plurality of sensors of the plurality of devices or one or more external assays that measure the state at different times during operation of the plurality of devices; determining, using one or more inference modeling techniques, one or more additional process variables that at least affect a threshold on additional productivity measurements related to the biological therapeutic agent manufactured using the production line from the third data set; determining, using the one or more inference modeling techniques, one or more additional control variables that at least affect an additional threshold on the one or more additional process variables by analyzing the third data set; and generating an additional model including the one or more additional processes and additional variables corresponding to the one or more additional control variables, wherein the model predicts additional productivity measurement criteria.

[0212] 7. The method according to any one of 1 to 6, wherein the productivity metric includes viable cell density, and the one or more process variables include at least one of a flow rate of a material through a component of the device, a temperature of a material included in a component of the device, or a stirring rate of a material included in a component of the device.

[0213] 8. The method according to any one of 1 to 7, wherein the bioreactor system is connected to a perfusion system.

[0214] 9. The method according to any one of 1 to 7, wherein the bioreactor system is part of a production line that uses batch technology for manufacturing a recombinant therapeutic protein.

[0215] 10. A manufacturing facility for producing a biological therapeutic agent, comprising: a first modular cleanroom equipped with components of a first plurality of devices for producing an effluent containing the biological therapeutic agent, wherein the components of the first plurality of devices include a bioreactor; a second modular cleanroom equipped with components of a second plurality of devices for purifying the final product, wherein the components of the second plurality of devices include at least a filter device; and a staging area equipped with a plurality of storage containers, a first part of the plurality of storage containers for storing a cell culture medium for the bioreactor system, and a second part of the plurality of storage containers for storing a buffer solution for at least one device part included in the components of the first plurality of devices.

[0216] 11. The components of the first plurality of devices include a chromatography system connected to the bioreactor system, the chromatography system purifying the effluent produced in the bioreactor system to produce a purified final product; and the components of the first plurality of devices include a storage container for capturing the purified final product, and the buffer solution is added to a storage container for producing a virus inactivation pool. The manufacturing facility according to 10.

[0217] 12. The bioreactor system is disposed on a first skid, the first skid includes a first plurality of communication interfaces, the chromatography system is disposed on a second skid, and the second skid includes a second plurality of communication interfaces coupled to the communication interfaces of the first plurality of communication interfaces. The manufacturing facility according to 11.

[0218] 13. A dongle is connected to the storage container, and the dongle stores an identifier and a function corresponding to the storage container. The manufacturing facility according to 12.

[0219] 14. The manufacturing facility according to claim 13, further comprising a local control system, wherein the local control system transmits a first signal to at least a part of the components of the first plurality of devices to control the operation of at least a part of the components of the first plurality of devices, and transmits a second signal to at least a part of the components of the second plurality of devices to control the operation of at least a part of the components of the second plurality of devices, and wherein the local control system receives the identifier and the function from the dongle.

[0220] 15. The manufacturing facility according to claim 14 or 15, wherein the local control system identifies one or more control modules executable to control the operation of the storage container according to the function, at least in part, based on the identifier and the function.

[0221] 16. The local control system communicates electronically with a global control system, the global control system analyzes data obtained from the local control system and a further local control system to generate a model for predicting a metric corresponding to the productivity of a production line included in the facility, and the further local control system is disposed in a further facility for manufacturing a further biotherapeutic agent, according to claim 14.

[0222] 17. The manufacturing facility according to any one of claims 10 to 15, further comprising a third modular clean room including at least one further chromatography system, wherein the further chromatography system performs virus filtration of a virus inactivation pool obtained from the first modular clean room.

[0223] 18. The manufacturing facility according to claim 17, wherein the filter system performs an ultrafiltration / diafiltration operation on the effluent obtained from the further chromatography system.

[0224] 19. A system for manufacturing one or more biological therapeutic agents, comprising a first modular clean room equipped with components of a first plurality of devices for manufacturing an effluent containing a biological therapeutic agent, wherein the components of the first plurality of devices include a bioreactor; a second modular clean room equipped with components of a second plurality of devices for purifying the final product, wherein the components of the second plurality of devices include at least a filter device; and a staging area comprising a plurality of storage containers, a first part of the plurality of storage containers for storing a cell culture medium for a bioreactor system, and a second part of the plurality of storage containers for storing a buffer solution for at least one device part included in the components of the first plurality of devices.

[0225] 20. The system of claim 19, wherein the first plurality of devices includes a chromatography system coupled to the bioreactor, the chromatography system purifying a bioreactor effluent produced by the bioreactor to produce a protein isolate fraction, the first plurality of devices including a storage container for capturing the purified bioreactor effluent, and adding a solution containing at least one of an acid or a surfactant to the purified bioreactor effluent to create a virus inactivation pool.

[0226] 21. The system of claim 20, wherein the components of the second plurality of devices include at least one additional chromatography system, the at least one additional chromatography system performing one or more additional purification operations in relation to the virus inactivation pool to create a purified product pool.

[0227] 22. The system according to 21, further comprising a virus filtration device filtration system that performs one or more virus filtration operations on the purified product pool to produce a virus-free permeate. 23. The chromatography system includes a continuous chromatography system having 3 to 9 columns with each column having a diameter of about 40 cm to about 100 cm and a height of about 10 cm to about 40 cm. The chromatography system produces a protein separation fraction in an amount of about 80 g / L to about 140 g / L within 4 to 15 cycles of the chromatography system, where the duration of each cycle is about 3 hours to about 12 hours, as described in 20.

[0228] 24. The area of the modular cleanroom is about 15,000 ft 2 ~ about 50,000 ft 2 ; and the bioreactor includes at least one vessel having a volume of about 250 L to about 2000 L that produces a bioreactor effluent containing a recombinant therapeutic protein, as described in any one of 20 - 23.

[0229] 25. The system according to any one of 20 - 24, further comprising a perfusion system connected to the bioreactor for transferring feed material to the bioreactor and removing effluent from the bioreactor.

[0230] 26. One or more processors; and when executed by the one or more processors, the one or more processors perform the following steps: obtaining a first set of data indicating a first plurality of states of a bioreactor system, wherein the first set is obtained via at least one of a plurality of sensors of the bioreactor system or one or more external assays that measure the state of the bioreactor system at different points in time during operation; analyzing the first set to determine one or more process variables that have at least a threshold effect on a measure of productivity related to an effluent produced using the bioreactor system, wherein the one or more process variables correspond to at least one media component utilized in the bioreactor system for the production of the effluent; analyzing the first set using one or more inference modeling techniques to determine one or more control variables that have at least an additional threshold effect on the one or more process variables; generating a model that includes variables corresponding to the one or more process variables and the one or more control variables, wherein the model predicts the measure of productivity; and obtaining a second set of data, wherein the second data set indicates a second plurality of states of the bioreactor system, is obtained via at least one of the plurality of sensors of the bioreactor system or the one or more external assays, is obtained after the first data set, analyzing the second data set according to the model to determine a modification to at least one of the one or more control variables and modifying the productivity measurement criterion; and causing the at least one control variable to be modified according to the modification. One or more computer-readable storage media storing computer-readable instructions for causing the operations described above, the system according to any one of 19 to 25.

[0231] 27. The manufacturing facility is a first manufacturing facility, the bioreactor is a first bioreactor, the second bioreactor is included in a second manufacturing facility, the first data set includes further multiple conditions of the second bioreactor, and a part of the first data set is obtained via at least one of a plurality of further sensors of the second bioreactor or one or more external assays that measure conditions at different times during operation of the second bioreactor. The system according to 26.

[0232] 28. When executed by the one or more processors, the one or more processors further perform the following steps: obtaining third data indicating a third plurality of states of a plurality of devices included in a production line for manufacturing a biological therapeutic agent, the production line including the bioreactor system and the chromatography system, and the third data set being obtained via at least one of a plurality of sensors of the plurality of devices or one or more external assays that measure states at different times during operation of the plurality of devices; determining, using one or more inference modeling techniques, one or more further process variables that at least affect a threshold value on a further productivity measurement related to the biological therapeutic agent manufactured using the production line from the third data set; determining, using the one or more inference modeling techniques, one or more further control variables that at least affect a further threshold value on the one or more further process variables by analyzing the third data set; and generating a further model including further variables corresponding to the one or more further processes and the one or more further control variables. The system according to 26 or 27, wherein the model predicts a further productivity measurement criterion, the productivity metric includes viable cell density, and the further productivity measurement criterion includes the yield of the purified therapeutic protein pharmaceutical substance.

[0233] 29. The first modular cleanroom includes the following: a perfusion system coupled to a bioreactor; a first storage container for storing a cell-free permeate containing a recombinant therapeutic protein produced in the bioreactor; a first continuous chromatography system coupled to the first storage container, the first continuous chromatography system for generating a protein isolation fraction; a second storage container coupled to the first continuous chromatography system for storing a first amount of the protein isolation fraction; a third storage container coupled to the first continuous chromatography system for storing a second amount of the protein isolation fraction; a first pump device for transferring a virus-inactivated pool to a fourth storage container, the virus-inactivated pool being generated by adding at least one of an acid or a surfactant to the protein isolation fraction; and a second pump device for transferring the virus-inactivated pool to a sixth storage container outside the first modular cleanroom in the staging area via at least one filter device; The second modular cleanroom includes the following: a temperature control device for transferring the virus-inactivated pool from a seventh storage container located outside the second modular cleanroom to a second chromatography system; a temperature control device for transferring a volume of buffer solution from an eighth storage container located outside the second modular container in the staging area to the second chromatography system, the second chromatography system for purifying the virus-inactivated pool; a ninth storage container for storing the effluent from the second chromatography system; a third chromatography system for purifying the effluent from the second chromatography system to generate a purified pool, the third chromatography system being coupled to a tenth storage container for storing a buffer solution, the tenth storage container being disposed outside the second modular cleanroom in the staging area; a third pump device for supplying the purified pool to a virus filtration device disposed in the second modular cleanroom, the virus filtration device for generating a virus-free permeate;And the third modular clean room includes an eleventh storage container for storing virus-free permeate, a filtration device that performs at least one of one or more ultrafiltration operations or one or more diafiltration operations on the virus-free permeate to produce a purified therapeutic protein pharmaceutical substance, and at least one vial filling device for filling the purified therapeutic protein pharmaceutical substance into a plurality of vials, the system according to 19.;

[0234] 30. A method for manufacturing one or more biological therapeutic agents, comprising: obtaining a cell culture medium, a cell growth material, and a buffer solution from at least one storage container by a bioreactor disposed in a first modular clean room; producing a cell-free permeate containing a recombinant therapeutic protein, wherein the recombinant therapeutic protein is produced in at least one container of the bioreactor; transferring the amount of the cell-free permeate to a chromatography system; performing a virus inactivation process on the effluent of the chromatography system to produce a virus-inactivated pool containing the recombinant therapeutic protein; transferring the amount of the virus-inactivated pool to a second modular clean room; and purifying the virus-inactivated pool by performing one or more operations using one or more devices in the second modular clean room.;

[0235] 31. Transferring the effluent from a bioreactor that produces from about 0.5 g to about 10 g of recombinant therapeutic protein per day per liter of cell culture to a perfusion system; transferring the effluent from the perfusion system containing the cell-free permeate to at least one storage container; and transferring the amount of the cell-free permeate to a temperature control system before transferring the amount of the cell-free permeate to the chromatography system, the method according to 30.;

[0236] 32. The method according to 30 or 31, comprising: transferring a first amount of effluent from a chromatography system to a first storage container for a first period; determining to transfer a second amount of effluent from the chromatography system to a second storage container based on the first period corresponding to a threshold period or based on the volume of the first amount of effluent in the first storage container corresponding to a threshold volume; and stopping the inflow of the effluent from the chromatography system into the first storage container and causing the effluent from the chromatography system to flow into the second storage container.

[0237] 33. One or more operations for purifying the virus inactivation pool are performed by a further chromatography system disposed within the second modular cleanroom; a first column of the chromatography system contains a first resin, and a second column of the further chromatography system contains a second resin different from the first resin; one or more operations for purifying the virus inactivation pool produce a purified product pool; and the method according to any one of 30 to 32, comprising transferring the purified product pool to a virus filtration device disposed within the second modular cleanroom to produce a virus-free permeate.

[0238] 34. The step of transferring the amount of the virus inactivation pool to the second modular cleanroom is as follows: transferring the amount of the virus inactivation pool to one or more first storage containers located outside the first modular cleanroom and connected to one or more first ports of the first modular cleanroom; and transferring the amount of the virus inactivation pool from the one or more first storage containers to one or more second storage containers, wherein the one or more second storage containers are located outside the second modular cleanroom and are connected to one or more second ports of the second modular cleanroom, and the one or more second ports are connected to a further chromatography system located within the second modular cleanroom, according to the method of 33.

[0239] 35. The following steps: transferring a certain amount of virus-free permeate to a filter device included in a third modular cleanroom; manufacturing a purified therapeutic protein pharmaceutical substance by performing at least one of one or more ultrafiltration operations or one or more diafiltration operations using the filter device; and transferring the amount of the purified therapeutic protein pharmaceutical substance to the number of vials at a rate of 5 to 100 vials per minute, wherein the volume of each of the number of vials is in a capacity of about 2 mL to about 40 mL, the method according to 33.

[0240] 36. The bioreactor is included in a manufacturing facility having additional bioreactors, and while an additional amount of virus inactivation pool is being processed by the additional chromatography system, at least one of the one or more ultrafiltration operations or the one or more diafiltration operations is performed, and the additional virus inactivation pool is produced from the effluent of the additional bioreactor, the method according to 35.

[0241] 37. The bioreactor is included in a manufacturing facility having additional bioreactors, and while the virus filtration device is processing an additional amount of the purified product pool produced from the effluent of the additional bioreactor, at least one of the one or more ultrafiltration operations or the one or more diafiltration operations is performed, the method according to 35.

[0242] 38. The bioreactor is included in a manufacturing facility that has additional bioreactors, and one or more first operations are performed by one or more first devices located within a first modular cleanroom with respect to a first amount of effluent produced by the additional bioreactors, while one or more second operations are performed by one or more second devices located within a second modular cleanroom with respect to a second amount of effluent produced by the bioreactor, the one or more first operations are performed by a chromatography system, and the one or more second operations are performed by at least one of an additional chromatography system or a virus filtration device, the method according to claim 35.

[0243] 39. The additional bioreactor is disposed within the first modular cleanroom, the method according to any one of claims 35 to 38.

[0244] 40. The following steps: removing one or more first single-use components from at least one of the bioreactor, the chromatography system, or an additional chromatography system after manufacturing an amount of a purified therapeutic protein pharmaceutical substance; exchanging one or more first single-use components with one or more second single-use components; obtaining additional cell culture medium, additional cell growth material, and additional buffer solution from one or more storage containers by the bioreactor; and manufacturing an additional cell-free permeate containing an additional recombinant therapeutic protein different from the recombinant therapeutic protein; the method according to any one of claims 35 to 39.

[0245] 41. A purified therapeutic protein pharmaceutical substance is manufactured by a first production line of a first plurality of devices arranged in a first modular clean room, a second modular clean room, and a third modular clean room, and the method comprises changing a first configuration of parts of the first plurality of devices to produce a second production line with a second configuration of parts of a second plurality of devices arranged in the first modular clean room, the second modular clean room, and the third modular clean room, wherein the second arrangement of parts of the second plurality of devices is produced by: removing a part of a device included in the parts of the first plurality of devices from the first modular clean room, the second modular clean room, or the third modular clean room; adding a first further part of the parts of the first plurality of devices to a plurality of parts of a first device in the first modular clean room within the first modular clean room, the second modular clean room, or the third modular clean room; or changing the position of a second further piece of equipment included in the parts of the first plurality of devices; The method according to any one of items 35 to 39, which is produced by the above.

Claims

1. A system for manufacturing one or more biological therapeutics, comprising the following: A first modular cleanroom comprising a first plurality of devices for manufacturing an effluent containing one biological therapeutic, wherein the first plurality of devices includes a bioreactor for manufacturing the one biological therapeutic; A second modular cleanroom comprising a second plurality of devices for purifying the effluent produced by the first plurality of devices, wherein the second plurality of devices includes at least a filtration system and an effluent containing the one biological therapeutic; A staging area comprising a plurality of storage containers, wherein a first portion of the plurality of storage containers stores a cell culture medium for the bioreactor and a second portion of the plurality of storage containers stores a buffer solution for at least one device included in the first plurality of devices and for at least one device included in the second plurality of devices; One or more processors; and One or more computer-readable storage media that, when executed by the one or more processors, cause the one or more processors to perform the following: Obtaining a first dataset indicative of a first plurality of states of the bioreactor for manufacturing the one biological therapeutic, wherein the first dataset is obtained via at least one sensor of a plurality of sensors of the bioreactor or one or more external assays that measure the state of the bioreactor at different points in time during operation; Analyzing the first dataset using one or more inferential modeling techniques to determine one or more process variables that affect at least a first threshold of a productivity metric for the effluent of the bioreactor; Analyzing the first dataset using one or more inferential modeling techniques to determine one or more control variables that affect a second threshold of at least one or more process variables; Manufacturing a model that includes variables corresponding to the one or more process variables and the one or more control variables, wherein the model predicts a productivity metric; Executing the operations; A system including a manufacturing facility.

2. The first plurality of devices includes a chromatography system coupled to the bioreactor, the chromatography system purifying a bioreactor effluent produced by the bioreactor to produce a protein isolation fraction; and The first plurality of devices includes a storage container for capturing the purified bioreactor effluent and adding a solution containing at least one acid or surfactant to the purified bioreactor effluent to produce a virus inactivation pool; The system according to claim 1.

3. The second plurality of devices includes at least one additional chromatography system, the at least one additional chromatography system performing one or more additional purification operations on the virus inactivation pool to produce a purified product pool, the system according to claim 2.

4. The system according to claim 3, further comprising a virus filtration device filtration system that performs one or more virus filtration operations on the purified product pool to produce a virus-free permeate.

5. The chromatography system includes a continuous chromatography system of 3 to 9 columns, each having a diameter of about 40 cm to about 100 cm and a height of about 10 cm to about 40 cm; and The chromatography system produces a protein isolation fraction of resin of about 80 to about 140 g / L within 4 to 15 cycles of the chromatography system, where the duration of each cycle is about 3 hours to about 12 hours. The system according to claim 2.

6. The area of the modular cleanroom is about 1400 m2 to about 4600 m2; and The bioreactor includes at least one vessel having a volume of about 250 L to about 2000 L for producing a bioreactor effluent containing a recombinant therapeutic protein, the system according to any one of claims 2 to 5.

7. The system according to any one of claims 2 to 5, further comprising a perfusion system coupled to the bioreactor for transferring feed material to the bioreactor and removing the effluent from the bioreactor.

8. The system according to any one of claims 1 to 5, wherein the following: When executed by the one or more processors, the one or more computer-readable storage media cause the one or more processors to perform the following: Obtain a second dataset indicative of a second plurality of states of the bioreactor, the second dataset being obtained via at least one of a plurality of sensors of the bioreactor or one or more external assays and being obtained after the first dataset; Analyze the second dataset according to the model to determine a modification to at least one of one or more control variables to modify the productivity metric; and Modify at least one control variable according to the modification; Further computer-readable instructions are stored for causing the execution of the operations; A system comprising. **Claim 9** The system according to claim 8, wherein The manufacturing facility is a first manufacturing facility and the bioreactor is a first bioreactor; A second bioreactor is included in a second manufacturing facility; and The first dataset includes further conditions of the second bioreactor, and a portion of the first dataset is obtained via at least one of a plurality of further sensors of the second bioreactor or one or more external assays that measure conditions at different times during operation of the second bioreactor. A system. **Claim 10** When executed by the one or more processors, the one or more further computer-readable storage media perform the following: Obtain a third dataset indicative of a third plurality of states of a production line for manufacturing a purified therapeutic protein pharmaceutical substance, the production line including components of the first plurality of devices and components of the second plurality of devices, the third dataset being obtained via at least one of a plurality of further sensors of the production line or one or more external assays that measure states at different times during operation of the production line, obtaining a third dataset indicative of a third plurality of states; Analyze the third dataset using one or more inferential modeling techniques to determine one or more further process variables that affect at least a first further threshold of a further productivity metric for the purified therapeutic protein pharmaceutical substance manufactured using the production line; Analyzing the third data set using one or more inferential modeling techniques to determine one or more additional control variables that affect a second additional threshold on at least one or more additional process variables; and Generating an additional model that includes additional variables corresponding to the one or more additional process variables and the one or more additional control variables, where the model predicts an additional productivity metric, the productivity metric includes viable cell density, and the additional productivity metric includes the yield of the purified therapeutic protein pharmaceutical substance; The system according to any one of claims 8 or 9, comprising one or more additional computer-readable storage media storing computer-readable instructions for causing an additional operation to be performed.

11. A first modular clean room, comprising the following: A perfusion system connected to the bioreactor; A first storage container for storing a cell-free permeate containing a recombinant therapeutic protein produced by the bioreactor; A first continuous chromatography system, connected to the first storage container, for producing a protein isolation fraction; A second storage container, connected to the first continuous chromatography system, for storing a first amount of the protein isolation fraction; A third storage container, connected to the first continuous chromatography system, for storing a second amount of the protein isolation fraction; A first pump device for adding at least one acid or surfactant to the protein isolation fraction and transferring the virus inactivation pool to a fourth storage container; and A second pump device for transferring the virus inactivation pool to a sixth storage container disposed outside the first modular clean room within the staging area via at least one filter device; comprising A second modular clean room, comprising the following: A temperature control unit for transferring the virus inactivation pool from a seventh storage container outside the second modular clean room to a second chromatography system and transferring an amount of buffer solution from an eighth storage container outside the second modular clean room within the staging area to the second chromatography system, where the second chromatography system purifies the virus inactivation pool; A ninth storage container for storing the effluent from the second chromatography system; A third chromatography system that purifies the effluent from the second chromatography system to produce a purified product pool, and is connected to a tenth storage container that stores a buffer solution and is located outside the second modular cleanroom within the staging area; and, A third pumping device that supplies the purified product pool to a virus filtration device installed within the second modular cleanroom to produce a virus-free permeate, comprising, and A third modular cleanroom, comprising the following: An eleventh storage container that stores a virus-free permeate; A filter device that performs one or more ultrafiltration operations or one or more diafiltration operations on the virus-free permeate to produce a purified therapeutic protein pharmaceutical substance; and, At least one vial filling device that fills a plurality of vials with the purified therapeutic protein pharmaceutical substance, The system according to claim 1, comprising.

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