Abstract:
Embodiments of the present invention are directed to a customizable bio-manufacturing system which includes a manufacturing space having a first air handling system for providing supply air and a second air handling system for handling exhaust air, the supply air system being optionally provided with at least one of filtration, heating, cooling and or humidity control and a plurality of portable modules provided within the manufacturing space. At least one module having an interior capable of being interconnected with another module interior and each module&#39;s interior includes one or more components to perform at least one specific task of a biological, chemical, and/or pharmaceutical manufacturing process. At least one module includes an on-board environmental control system for controlling an environment within the module and a connection means for interconnecting the module interior with another module interior. The system also includes a central controller operating to at least perform one or more of operation and information collection for the operation of at least one of the system and one or more modules.

Description:
CLAIM TO PRIORITY 
     The present application claims priority to 35 U.S.C. §119(e) of U.S. provisional patent application No. 60/541,572, filed Feb. 3, 2004, the entire disclosure of which is incorporated herein by reference. 
    
    
     FIELD OF THE INVENTION 
     The present invention is directed to manufacturing systems in general, and more specifically, to a flexible manufacturing platform, which includes portable, controlled-environment manufacturing modules having disposable manufacturing components, automation, electronic batch control, record generation, storage and documentation. 
     BACKGROUND OF THE INVENTION 
     An axiom in the business world is that between cost, speed and quality, maximizing any two sacrifices the third. Bio/chemical/pharmaceutical manufacturing is no exception. Moreover, a critical factor in bio-manufacturing is quality: products, when made properly, are life-saving, when made improperly are life-threatening. 
     The speed for producing drugs for clinical trials and speed to market are also important factors, with clinical milestones impacting the value of the drug pipeline, stock values, financing, partnering and licensing opportunities. In addition, the high cost of drug development has been a topic of increasing interest within the industry and appears as part of the public concern about rising health care costs. 
     Much of the expense of biopharmaceutical manufacturing can be attributed to the capital investment required to build manufacturing infrastructure for producing a particular drug. Ideally, having manufacturing capacity immediately available to support every clinical and commercial need would greatly speed development of drugs. However, the capital investment required to build such bio-manufacturing capacity is too great, especially since facilities would sit idle while waiting for the drug in the development pipeline. The dilemma is compounded by the difficulty to accurately predict production capacity requirements, since development timelines, dosages, market size, clinical success and regulatory approval are all uncertainties. Due to the foregoing uncertainties and the high probability that an individual drug will fail during clinical trials, any investment in facilities to manufacture drugs prior to successful clinical trials and/or regulatory approval is a high risk endeavor. 
     To reduce such expenses, an ideal bio-manufacturing facility would be one that is inexpensive to build, can be rapidly expanded and reconfigured to handle new processes and produce drugs quickly. Moreover, it would be advantageous for such a manufacturing facility to be able to maintain and improve upon the high level of quality required for current good manufacturing practice (cGMP) for drug manufacture (e.g., conformance with 21 C.F.R. Part 11). 
     Other manufacturing expenses may be attributable to, for example, the extensive use of non-disposable components. Such components must be cleaned after every use. Moreover, such components are expensive. For example, stainless steel vessels are used extensively in drug manufacturing processes. Such vessels must be connected by stainless steel piping to other unit operations, media and buffer supply, water, and clean-in-place and steam-in-place systems. The fabrication and installation of these vessels, and all the utilities that support them, is expensive and requires considerable lead time to design and manufacture. 
     Even assuming a bio-manufacturing facility can be built, the resulting facility is often difficult to reconfigure for new processes or cannot be built inexpensively enough to manufacture multiple products simultaneously (the manufacturing scheme must be replicated in several parallel clean room suites, separated by airlocks, accessed through clean corridors and served by dedicated HVAC units). An example of such a traditional bio-pharmaceutical manufacturing system is shown in  FIG. 3 . As shown, cell culture processes, purification and post viral clearance formulation/filling processes, are all provided in separate areas, with air-locks provided between each manufacturing space. Moreover, inside such clean rooms, manual operations generate reams of paperwork, providing many opportunities for error and long QA review and batch release cycles. 
     SUMMARY OF THE INVENTION 
     Embodiments of the present invention are directed to manufacturing systems/platforms which are both flexible and efficient for manufacturing bio-pharmaceuticals (for example). The invention allows, for example, for fixed fermentation and processing equipment used in conventional scale manufacturing suites, for example, having separate environmentally controlled clean rooms which may now be replaced with controlled-environment modules for one or more steps of a drug or biological manufacturing process. The module operations allow for segregation from typical sources of process contamination: e.g., personnel, multi-use equipment and ambient air. In some embodiments, environmental control may be defined as controlling one or more of air flow, heat, cold, humidity and pressure. 
     The system according to some embodiments may be designed to handle multi-product, concurrent bio/chem-manufacturing in a common, unclassified (or classified) manufacturing space, using a plurality of connected process modules (module train). The ability to use an unclassified space is due to the integrity and control of the environment inside the module for one or more steps of the manufacturing process. Such concurrent manufacturing activities may include both upstream and downstream bio-processing as well as bulk drug substance and drug product filling operations for one or more products. 
     Modules, according to some embodiments of the invention, may be designed and qualified to provide self-contained manufacturing environments that assure appropriate industry standard environmental quality (e.g., Class 100, Class 10,000). Modules may be connected in any order as dictated by a product&#39;s manufacturing process. Thus, the module system of bio-pharmaceutical manufacturing (according to some embodiments of the invention), as well as associated control and monitoring systems, enable the system to offer additional capabilities over and above those of more traditional plants. Specifically, the system supports the rapid reconfiguration and concurrent operation of multiple manufacturing stages, e.g., from culture inoculation to bulk filling, in a common unclassified manufacturing space. 
     In addition, use of disposable components in some embodiments of the invention allows for a more practical and less expensive platform system by eliminating the need for clean-in-place (CIP) and sterilization-in-place (SIP) operations, thereby minimizing fluid transfer lines (e.g., steam) and corresponding required manipulations. The elimination of these required utilities is significant—modules require only power and/or data connections, and in some cases gasses, to support manufacturing operations. 
     Some embodiments of the invention also utilize centralized and/or remote electronic monitoring, control, automation and data record production and storage for a manufacturing batch process using a central controller (for example). Process automation may be used to reduce the number of manual operations, resulting in a reduction of operator error and an increase in the operability, efficiency and/or the reliability of the system. 
     Equipment for bio-processing is contained inside each module, and is typically physically and electronically integrated therein. For example, valves may be attached to a module&#39;s wall or an internal frame of the module, control panels may be separated and/or removed to the exterior of a module for ease of access. Motors and drive units may be placed outside the module for ease of access while a pump head or similar process component of the motor/pump/drive unit penetrates (preferably, sealably) into the interior of the module. Sensors for monitoring (environmentally or otherwise) may be also integrated into the body of a module and communicating with the central controller to provide continuous online monitoring of many (if not all) parameters of the operation (e.g., non-viable and viable particulates). 
     As noted above, the modules and the equipment inside the modules may be controlled and monitored using a central controller unit (e.g., computer system, associated software and user interface). The central control unit may thus be used for setup of modules/module train (i.e., manufacturing process) and allow for verification of correct installation of disposable process components, monitoring, automation, process control and generation of electronic batch records for one or more individual modules and preferably, an entire module train (e.g., the entire manufacturing process). For example, the status of a particular module can be readily discerned and tracked (e.g., clean, dirty, in process, assigned to a specific process, etc.) and the flow of process intermediates and materials into, between and out of modules and/or areas of a manufacturing facility may also be monitored. Monitoring may be accomplished via one or more sensors. 
     Other aspects of the invention include module portability, which is one factor which attributes to the systems flexibility. Modules may be easily moved from one location to the next for qualification, setup, operation and cleaning. In addition, each module may include connection ports to allow modules to be easily coupled to each other. This enables easy transfer of materials between unit operations, or to containers to enable transfer of materials into and out of modules from the manufacturing space. Access to the interior, to access doors and ports of a module may be accomplished by the inclusion of one or more glove ports, which maintains the environment within the module. 
     Accordingly, in one embodiment of the invention, a customizable manufacturing system includes at least one module having an interior capable of being interconnected with another module interior, where the module interior includes one or more components to perform at least one specific task of a biological, chemical, and/or pharmaceutical manufacturing process. The at least one module includes an on-board environmental control system for controlling an environment within the module, a connection means for interconnecting the module interior with another module interior and a central controller operating to at least perform one or more of operation and information collection for the operation of the system. 
     In another embodiment of the present invention, a method for operating a customizable biopharmaceutical manufacturing system is provided. The system includes at least one module having an interior capable of being interconnected with another module interior, where the module interior includes one or more components to perform at least one specific task of a biological, chemical, and/or pharmaceutical manufacturing process. The at least one module includes an on-board environmental control system for controlling an environment within the module, a connection means for interconnecting the module interior with another module interior and a central controller operating to at least perform one or more of operation and information collection for the operation of the system. The method includes one or more of selecting one or more modules each for conducting one or more procedures for a manufacturing process and connecting the one or more modules to the central controller, where the central controller operates to perform at least one of setup, monitoring and control of the one or more modules. 
     In another embodiment of the invention, a process module for a customizable biopharmaceutical manufacturing system includes an interior capable of interconnection with another module interior, where the module operates to perform at least one specific procedure of a manufacturing process, an environmental control module for controlling an environment within the module, an air inlet, an air outlet, at least one connection port for interconnecting the module with another module and an access for accessing an interior of the module. The process module electronically communicates with a central control unit operational to perform at least one of setup, monitoring, controlling, automating of the operation of the process or module, and managing electronic batch records. 
     In yet another embodiment of the present invention, a customizable manufacturing system includes a manufacturing space having a first air handling system for providing supply air to one or more modules and a second air handling system for handling exhaust air from one or more modules, the supply air system being optionally provided with at least one of filtration, heating, cooling and or humidity control. The system may also include a plurality of portable modules provided within the manufacturing space, where at least one module includes an interior capable of being interconnected with another module interior and each module&#39;s interior includes one or more components to perform at least one specific task of a biological, chemical, and/or pharmaceutical manufacturing process. At least one module of the plurality of modules includes an on-board environmental control system for controlling an environment within the module and a connection means for interconnecting the module interior with another module interior. The system also includes a central controller operating to at least perform one or more of operation and information collection for the operation of at least one of the system and one or more modules. 
     Still other embodiments of the present invention are directed to individual module units as well as computer application programs and media for accomplishing any methods for operating the module system. Accordingly, these and other embodiments, objects and advantages of the present invention will become more clear in the detailed description of the embodiments of the invention and attached  FIGS. 1-11 . A brief description of the figures is set out below. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1A  illustrates a perspective view of a manufacturing space and corresponding module train according to some embodiments of the present invention. 
         FIG. 1B  illustrates a block diagram of a manufacturing space and corresponding modules according to some embodiments of the present invention. 
         FIG. 2  illustrates a block diagram of a manufacturing space and corresponding modules and support areas according to some embodiments of the present invention. 
         FIG. 3  illustrates a block diagram of a traditional manufacturing plant. 
         FIG. 4  illustrates a side view of a manufacturing space illustrating support utilities and module connection to air supply and exhaust headers, according to some embodiment of the present invention. 
         FIG. 5  illustrates a partial side-top view of the air supply and return of a module according to some embodiments of the present invention. 
         FIG. 6A  illustrates a perspective view of a stationary connection port according to some embodiments of the present invention. 
         FIG. 6B  illustrates a perspective view of a flexible connection port according to some embodiments of the present invention. 
         FIG. 6C  illustrates a side view of a manufacturing space illustrating support utilities and module connection to air supply and exhaust headers with two modules being connected together. 
         FIG. 7  illustrates a perspective view of an access means according to some embodiments of the present invention. 
         FIG. 8A  illustrates a top view of a module having a laminar flow zone according to some embodiments of the present invention. 
         FIG. 8B  illustrates a side view of the module having the laminar flow zone illustrated in  FIG. 8A . 
         FIG. 9  illustrates a block diagram of a module train and central controller arrangement according to some embodiments of the present invention. 
         FIG. 10  is a flow chart illustrating a qualification lifecycle for modules according to some embodiments of the present invention. 
         FIG. 11  is an architectural plan illustrating product, process and personnel flow for a manufacturing facility according to the present invention. 
         FIG. 12  is a flow chart illustrating a module life cycle according to some embodiments of the present invention. 
     
    
    
     DETAILED DESCRIPTION OF THE EMBODIMENTS 
     As shown in  FIG. 1A , a flexible manufacturing system  100  which may be used to manufacture biopharmaceuticals, or other clean-room type of manufacturing process. As shown, a module train (modules  102 - 118 ) may be linked together in a single (common) manufacturing process positioned in a manufacturing space  120 , with each preferably having a connection with an air handling system in the manufacturing space.  FIG. 1B  illustrates an overview of the types of processes that may be housed in specific modules interconnected in a single room. Such processes may include culturing of cells ( 122 ), recovery and purification modules ( 124 ) and post viral clearance formulation and filling modules ( 126 ). Each module may access an air-handling (supply/exhaust) system included in the manufacturing space via one or more snorkels. 
     As noted above, the common manufacturing space (see  FIG. 2 ) may generally include a dedicated air handling system providing air quality equivalent to laboratory grade and controlled room temperature to the common manufacturing space. The common manufacturing space may also include a dedicated air handling system for providing supply air to one or more modules and a second air handling system for handling exhaust air from one or more modules The module air handling systems preferably maintains a unidirectional flow from modules for downstream processes to modules for upstream processes to create a flow of air from the cleaner environment to the dirtier environment. The manufacturing space may include easily cleanable surfaces including laboratory grade vinyl flooring, and is preferably maintained with appropriate housekeeping controls. 
     As also shown, each of the modules may include a set of wheels so that each module may be easily moved around the space. Other means for maneuvering a module are also within the scope of the described embodiments (e.g., trolley system). As shown in  FIG. 1A , each module may be designated with the acronym “_OW”—which means, “on wheels” (i.e., the mobility of the modules). Accordingly, the modules may include SOW (seed culture on wheels), BOW (bioreactor on wheels), PROW (primary recovery on wheels), COW (chromatography on wheels), UFOW (ultra-filtration on wheels), BFOW (bulk-fill on wheels) and VOW (vialing on wheels). 
     As shown in  FIG. 2 , the manufacturing space may be directed to a space for manufacturing bio-pharmaceuticals (for example) and may include additional areas, preferably adjacent the manufacturing area. Such additional areas may include a quality assurance (QA) sections, administrative sections, plant utilities (air-handling, electrical and plumbing), quality control areas, laboratory and receiving areas. 
     The manufacturing space is preferably arranged according to a flow, which moves modules/train to and from the manufacturing space. Specifically, modules exit the manufacturing space via an exiting area to be received at a product change-out area (arrow A). After processing in the product change-out area, a module may be placed back into the manufacturing space to be re-connected in its respective spot in the module chain (arrows B). 
     The supply of utilities as well as fresh air and collection of exhaust air from modules may be accomplished through the connections to common air handling equipment and utilities located in the manufacturing space. The HVAC systems supporting modules in the manufacturing space may include two headers extending the length of each process train area, one for supply, and one for exhaust. The supply headers may be sourced from a common supply air handler, with redundant backup. The exhaust may occur through blowers exhausted to the roof through a common header system. 
     As shown in  FIG. 4 , the manufacturing space includes a dedicated air handling system  401   a ,  401   b , for the common manufacturing air space, and preferably a separate module specific air handling system. It is worth noting, however, that embodiments of the present invention are not limited to systems where the common manufacturing space and the modules have two separate and distinct air systems, however, such a system is preferable. 
     The module specific air-handling system generally includes drop-down HVAC snorkels, one  402   a  for supplying fresh air  402  and one  404   a  for collecting exhaust air  404  to modules, may be connected to each module  406  (or modules that only require such). Such snorkels may be fully flexible, so as to enable easier connection to each module so as not to restrict a location of a module in the manufacturing space. As also shown, electrical and/or data connections  408  may be made to each module. The air supplied to the modules may be delivered through an air handler that controls temperature (15-30° C.) and relative humidity (10-60% RH). The air is delivered via the flexible snorkel to a module intake blower, where it may be pre-filtered and even HEPA filtered prior to entry into the module. It is worth noting that the system maintains pressure within two interconnected modules such that the more downstream module preferably has a higher pressure. 
     The on-board air-handling system for a module is shown in  FIG. 5 . As shown, the air handling unit may comprise two separate units: one for supply air  502  and one for exhaust  504 , each of which may include separate fans, controls and duct work. In addition, each may include a designate HEPA filtration system. A damper control on the intake or exhaust may be used to regulate module pressurization for positive pressure within the module during processing. For example, using an intake unit rated at 700 cubic feet per minute, the system may maintain 0.1-0.3 inches water column positive pressure within the module. 
     Modules may be linked to one another via, for example, connection ports as shown in  FIGS. 6A and 6B  (also see  FIG. 6C ). Specifically, the ports generally may include an opening sized large enough to pass material from one module to the next, and thus typically may be sized to be under three (3) feet in diameter, and most preferably, between six (6) inches and one (1) foot, although any diameter may be chosen. The connection port preferably includes a flexible connection tube/tunnel that is sealable between modules. Preferably, the tunnel is made of a flexible material. 
     Preferably, the connection ports include a stationary port  602  and a flexible port  604 . Each port preferably includes a clamping member (or other fixation device) for clamping and sealing with a port or tube of an adjacent module. The system may use clamp and gasket technology to hold the sleeve in place and to make a sealed connection. 
     Containers or components can be transferred between modules through the transfer port connections. The modules preferably remain under positive pressure and will equilibrate when connected. Thus, the environment surrounding the process remains contained and segregated from the ambient environment in the common manufacturing space. Modules may be accessed via, for example, glove ports  702 , which may be provided on any side of a module (see  FIG. 7 ), or other access means (e.g., door, window, preferably sealable). 
       FIGS. 8A and 8B  illustrate a particular embodiment of the present invention for a laminar flow zone for a module  800 , which may be applicable to classify particular embodiments for Class 100 classification. The laminar flow zone resides within the module and is supplied by the module HEPA-filtered air (although supply air may also be separately supplied). The laminar zone may also be additionally HEPA filtered. The laminar flow zone is preferably maintained by physical barriers  802 ,  804  (for example) as shown in the figures. The isolated laminar flow zone may have specific cleaning and operating procedures and may be monitored by the central processor via sensors. Access to the laminar flow zones may be made through glove ports  806  (or specific laminar flow zone specific glove ports). Such specific glove ports may require a sanitization step to sanitize gloves prior use in the laminar zone. 
     The modules may be constructed of easily cleanable materials. For example, stainless steel or aluminum may be used for their frameworks and glass or plastic (e.g., ¼″ Lexan®) may be used for the walls of a module. Modules may also be constructed of frameless plastic (e.g. injection molded). Each module is preferably sealed from the surrounding environment using Room Temperature Vulcanizing (RTV) silicone (for example) for joints, and corrosion-resistant gaskets for doors and ports. Each module may also be outfitted with sealed electrical ports and on-board HVAC system(s). 
     Modules may also be constructed with a bottom sump container sized to hold, for example, a maximum process volume handled in the module. Construction of the sump permits retention of the process fluid within the module in the event of a catastrophic rupture of a process container therein. Once collected, process fluid may be treated in the sump and/or then removed through a low-point drain (for example) which may be opened by a ball valve and directed either to a drain or to an additional collection container for further treatment. Such a sump design prevents catastrophic spills from being leaked to the common manufacturing space. 
     In some embodiments of the invention, the processes taking place within each module are computer controlled and monitored via a computer system and corresponding software (together “central controller”), which also allows automation of the system. Thus, as shown in  FIG. 9 , which illustrates a block diagram of the system arrangement, the equipment located in each module  902  may include data collection sensors and controls which may be in communication with the central controller  904  either via hardwire or wireless connection. Each module may additionally include an electronics control panel, which may also be used to monitor, collect and control the module and processes occurring therein. The central controller may also include data storage  906  to store data as well as application and/or operation software for the central controller and system operation. The software may include a graphical-user-interface (GUI) displayable on a workstation  908 . The GUI may display a number of different screens for setting up, monitoring and controlling the modules and the overall manufacturing process. 
     Accordingly, such software may be used to control a procedure of a module, and may be customized via the central computer and/or an electronic control panel on a module. A procedure is a strategy for carrying out a particular process in a module (i.e., material produced or that has been produced by a single execution of a batch process). A process may be a sequence of chemical, physical or biological activities for the conversion, transport, or storage of material or energy. 
     Other Considerations 
     Qualification testing (IQ/OQ/PQ) of all module mounted HVAC systems may include pressure monitoring, smoke testing, and particulate sampling and testing. Specifically, qualification of module air handling systems may be accomplished in a manner consistent with normal process suite classifications for typical manufacturing systems. For example, a bioreactor fermentation module may be operated as unclassified, while purification modules may be classified as Class 10,000. Seed and bulk drug substance fill module environments may be classified as Class 100 environments. 
     For quality assurance in some system embodiments of the present invention, each module may have a qualification lifecycle. Specifically, as shown in  FIG. 10 , the qualification lifecycle of a module includes: design, construction, commissioning, qualification, operation/use, maintenance, change control and retirement (for example). Such qualification activities may include:
         Installation Qualification (generally applied to modules and process equipment): documentation list, hardware/software specification verification, physical evaluation and verification, and calibrated instrument verification.   HVAC Operational Qualification: pressure control verification, air flow velocity verification, HEPA filter performance certification, and air flow pattern characterization and verification.   Bioreactor Module Operational Qualification: module operations (power, communications, blowers, lights, door function, port connections, sensor verification, etc.), bioreactor operations (temperature control, gas flow control, agitation control, safety features, disposables installation, filling, mixing, sampling and transfer of materials), and ancillary equipment operation (pumps, tube welders, sensors).   Chromatography Module Operational Qualification: Module Operations (Power, Communications, Blowers, Lights, Door Function, RTP Connections, Sensors, etc.), chromatography operations (column packing and HETP qualification, flow path verification, adsorption pressure verification, bubble trap function, safety features, liquid transfer and collection, buffer feed valve control and function, and ancillary equipment operation (pumps, sensors).   Filtration Module Operational Qualification: module operations (power, communications, blowers, lights, door function, port connections, sensor, etc.), filtration system operations (flow control, disposables installation, filling, mixing, sampling and transfer of materials), ancillary equipment operation (pumps, sensors),       

     To work effectively as a multi-product manufacturing environment, embodiments of the present invention may include predetermined material and personnel work flows. An example of such flows are illustrate in  FIG. 11 . Specifically, materials are received at a warehouse portion and stored in an appropriately controlled quarantine area. Materials may then be sampled in a Raw Materials Sampling Room, preferably provided adjacent the receiving area, to conduct quality control inspection. Upon Quality Control (QC) release, the materials are then available for manufacturing use and moved to a segregated and controlled storage area within the warehouse. It is worth noting that the areas on  FIG. 11  designated “FLEXMAX” corresponding to common manufacturing spaces. 
     Materials may be transported into the common manufacturing space with personnel or through a separate entrance for large materials and equipment. Materials transported into or out of the common manufacturing space are preferably transported in sealed containers to maintain environments. Transport of shedding materials into the common manufacturing space is preferably minimized, and surfaces of containers and equipment are preferably wiped down with sanitizing agent in the equipment staging area before entering the manufacturing area. During batch setup activities, components are preferably prepared and loaded into modules. Exposed exterior package may be wiped with sanitizing agent prior to being loaded into the appropriate module. 
     Product may be manufactured by sequential batch operations and transferred from one module to the next. At the end of each batch process operation, modules may be coupled via the connection ports and product transferred (either in closed containers or by pumping through tubing from one module to the next). Intermediate process materials or final bulk substances are sealed in containers before removal from the modules. When transferring from an unclassified module to a class 10,000 module, appropriate measures are used to isolate the different environments. Intermediates, work-in-process, or product may be stored at the appropriate specified environmental conditions in designated storage areas. 
     Liquid process waste may be inactivated chemically by use of appropriate methods know to those of skill in the art, as needed, and then pumped to a pH neutralization system for discharge per applicable codes. Solid process waste may be bagged and disposed using methods appropriate for the waste. 
     Regarding personnel flows, preferably, all personnel flows revolve around the common manufacturing space. Access to this space is restricted to authorized personnel, with separate entry and exit paths to maintain the cleanliness of the common manufacturing space. 
     Basic gowning requirements for entering the common manufacturing space may include such items as non-shedding lab coats, safety goggles, bouffant hair covers, boots, and gloves. Since modules preferably provide environmental control around the process housed therein, movement of the operators (outside the modules) need not be unduly restricted (i.e. appropriately trained operators may work on all in-process modules in the common manufacturing space, for all (or most) unit operations or processes). 
     Baseline data for the common manufacturing space is collected as part of qualification activities and compared with module data. The evaluation of the module cleaning procedures may employ surface sampling for viable microorganisms by both swab and contact plate sampling. Sample sites are selected from appropriate locations on module surfaces, equipment surfaces, glove surfaces, and materials/components added to the module for manufacturing. Evaluation under dynamic conditions may consider multiple activities occurring within a single module, as well as other activities such as concurrent module processing or module cleaning that might be occurring within the common manufacturing space. Aspects such as personnel operations, cleaning procedures and the materials/component sanitization procedures are also be evaluated, as are excursion events such as spills inside and outside the modules. 
     The majority of product contact surfaces generally include disposable, single-use equipment and components, eliminating the requirements for cleaning and sterilization which are typically required for multi-use equipment. Additionally, use of disposable contact surfaces eliminates the possibility of product cross-contamination. Typical disposable components include bioreactor vessels, shake flasks, hollow fiber capsules, filters, tubing, connections, temperature probes, bulk storage bags, and chromatography capsules. Such disposable components may also be subject to qualification. 
     It is recognized that non-disposable products are also used for manufacturing processes. When use of disposable product contact material is not possible, such as in the case of certain sensors and chromatography system component fittings, the methods and systems according to some embodiments of the present invention are used to minimize cross-contamination. Control aspects for small fittings and sensor surfaces may include dedicating equipment to a specific module and employing qualified manual cleaning procedures. 
     Modules are preferably designed to allow GMP operations typically found in bio-therapeutics manufacturing and may be constructed independently of one another and then connected, as needed, via the connection ports in a process-specific sequence. Examples of some various potential process steps and the corresponding module configurations are described below in Table I. 
                             TABLE I               Process Class   Process Description   Typical Equipment                   Bioreactor   Culture initiation   Disposable bioreactors           to production   Incubators, tube           scale cell culture   welders, pumps,           bioreactors   gases, scales,               process vessels (bags)       Filtration   Tangential flow   Filters (capsule,           filtration, dead    hollow fiber),           end filtration,   pumps, tube           diafiltration   welders, scales,               process vessels (bags)       Chromatography   Dedicated column   Chromatography           processing   Columns,           with buffer feeds,   chromatography media,            sensors, and   pumps, scales, process           product collection   vessels (bags)       Chromatography   Combined unit   Typical for post-       Filtration   operations   chromatography               filtration               requirements for               storage or virus/               endotoxin removal       Bulk Drug   Filling bulk drug   Filling head       Filling   substance liquid                into bottles, closing                and sealing           Drug Substance   Aseptic filling of   Filling head, vialing       Filling   sterilized drug    equipment           substance (e.g.               vialing, stoppering)                    
Module Lifecycle
 
     During the Operation/Use Phase, the module generally makes the following activities as illustrated in  FIG. 12 . Table II provided below includes details on the activities performed during various operational stages. 
                               TABLE II                   Module Operational Stages            Module Operational           Stage   Detail of Activities Occurring in Module               Power-up   Electrical, utility and data connections established           and checked       Cleaning   Cleaning procedure executed       Equilibration   Post-cleaning, module sealed           Differential pressure, particle counts, temperature           and humidity reach equilibration conditions       Module Clearance   Module release to scheduled batch           Disposables and supplies loaded           Checklist review of critical operating states           and preparation       Module Allocation   Module is assigned (allocated) electronically to           process a specific batch/lot number for           its unit operation.           No other batch records allowed to process           in the module       Transfer In   Process fluids transferred from source           module to subject module       Processing   Unit operation is executed per batch record       Transfer Out   Process fluids transferred from subject           module to destination module       Module Release   Module is released from assigned batch,           identified as “Dirty” and scheduled           for cleaning                    
Startup Verification
 
     Modules that are taken offline (i.e. disconnected from power and data connections), are processed or modified through offline events such as decontamination, modification, or reconfiguration, may be tested upon being re-connected. Testing verifies that the module is sufficiently powered, operational, and communicating to the SCADA (supervisory control and data acquisition) system. The method of verification involves physical reconnection, power-up (supplying all powered components and verifying operation), and data connection (manipulation of sensors to induce changes on SCADA instrument value, verifying expected response. 
     The Startup Verification applies only to modules removed from the manufacturing floor in response to process-driven events, and IS NOT a substitute for Qualification or Re-Qualification for modules modified through change control procedures, although the Start-Up Verification may be a component of the qualification. 
     Design and Procedural Controls 
     Modules are preferably designed to provide a controlled environment around each unit manufacturing process. Fermentation and primary recovery may be performed in modules operated as unclassified space, while downstream purification may be performed in a Class 10,000 environment. Inoculation and bulk drug substance filling may be performed in Class 100 environments. Exemplary key attributes that contribute to control of the module environment may include:
         closed modules in which manual operations are conducted through glove ports;   individual, segregated air handling systems that provide one pass, HEPA filtered air to the module;   operation of module under positive pressure during manufacturing, operation and cleaning;   control and continual monitoring of temperature, humidity, airflow and particulates;   routine environmental monitoring program that includes automated, continuous, on-line monitoring of modules during manufacturing for total particulates with alarms for out-of-tolerance events;   routine sampling of classified modules for viable particulates in accordance with industry standards for controlled environments;   limited access to the common manufacturing space with separate entry and exit paths;   gowning of personnel entering common manufacturing space including lab coats, boots, bouffant hair covers, gloves and safety goggles;   materials transported into or out of common manufacturing space in sealed containers; surfaces wiped with sanitizing agent before entering manufacturing area;   transfers between coupled modules accomplished by pumping through tubing or transfer of sealed containers via RTP (rapid transfer port) or similar;   removal of final bulk product or intermediate in sealed containers;   liquid process waste inactivation prior to removing from module;   solid waste removed in sealed bag;   modules designed for containment of large spills and inactivation of spill before removal via closed system;   procedures for abnormal events similar to those used in traditional facilities;   validated cleaning procedures executed with verification step in electronic batch record steps;   clean status requires completion of procedure, including appropriate environmental monitoring;   clean status of modules tracked by electronic documentation system; “clean” status required in order for module to be assigned to a batch;   validation of module integrity and air handling system under static and dynamic conditions of normal use and abnormal events such as spills, power failures;   cleaning validations support and substantiate module cleaning procedures and multi-use equipment/process component cleaning procedures;       

     Table III includes information related to controls for ensuring product/process segregation. 
     
       
         
               
               
             
           
               
                 TABLE III 
               
               
                   
               
               
                 Control 
                 Description 
               
               
                   
               
             
             
               
                 Material Staging 
                 Materials requested from warehouse and staged 
               
               
                   
                 in a manufacturing area according to a defined  
               
               
                   
                 production schedule. Materials labeled for client- 
               
               
                   
                 specific allocation or general operational use.  
               
               
                   
                 Labeling may be by use of sticker, barcode,  
               
               
                   
                 combination, or other means of secure and  
               
               
                   
                 accurate identification. 
               
               
                 Material 
                 Materials may be assigned to specific batches in 
               
               
                 allocation 
                 the staging area and, upon a module becoming 
               
               
                 to batch 
                 available, transferred to a specific module for a 
               
               
                 and module 
                 specific batch. The batch record may include a 
               
               
                   
                 bill of materials for each operation in each 
               
               
                   
                 module. A Module (Line) clearance procedure is  
               
               
                   
                 executed as verification of correct preparation. 
               
               
                 Batch allocation  
                 Module clearance permits the assignment of a 
               
               
                 to module 
                 scheduled batch to a specific module. Electronic 
               
               
                   
                 allocation prevents any other batches or 
               
               
                   
                 operations to be executed in the assigned module. 
               
               
                 Processing 
                 During processing, routine and excursion events 
               
               
                   
                 may be predetermined by procedure and 
               
               
                   
                 programmed electronically in the central control 
               
               
                   
                 module and electronic-batch records where 
               
               
                   
                 appropriate. The controls are generally pre- 
               
               
                   
                 determined to control normal processing events 
               
               
                   
                 and to prevent abnormal events from impacting 
               
               
                   
                 other modules. 
               
               
                 Batch release  
                 At the end of a unit operation in a module, 
               
               
                 from module 
                 product is transferred to its next unit operation. 
               
               
                   
                 Upon completion of transfer, the module is  
               
               
                   
                 electronically released from the batch and  
               
               
                   
                 scheduled for cleaning. The cleaning and 
               
               
                   
                 inspection cycle is preferably required to be 
               
               
                   
                 completed prior to allowing the next batch 
               
               
                   
                 to be allocated to the module. 
               
               
                 WIP, Intermediates  
                 Any materials removed from the modules for 
               
               
                 and product storage 
                 storage are to be placed in a sealed and labeled 
               
               
                   
                 container. 
               
               
                 Excursion Event 
                 In the event of an excursion that may have 
               
               
                 Matrix 
                 adverse product quality impact, an excursion 
               
               
                   
                 event/response plan (Table IV) ensures adequate 
               
               
                   
                 and timely assessment of the occurrence and its 
               
               
                   
                 impact. 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
             
           
               
                 TABLE IV 
               
             
             
               
                   
               
               
                 Excursion Event Information 
               
             
          
           
               
                 Event 
                 Response Range 
                 Requirement 
               
               
                   
               
               
                 Air Supply 
                 Turn off exhaust blowers, 
                 Qualify and monitor recovery time needed to 
               
               
                 Header 
                 modules inactive and ambient 
                 reach normal particle count, temp, and DP 
               
               
                 Failure 
                   
                   
               
               
                 Air Exhaust 
                 Maintain positive differential 
                 Qualify and monitor recovery time needed to 
               
               
                 Header 
                 with air supply, modules 
                 reach normal particle count, temp, and DP 
               
               
                 Failure 
                 inactive 
                   
               
               
                 Air Supply 
                 Maintain positive differential 
                 Qualify and monitor recovery time needed to 
               
               
                 Local Failure 
                 with header air supply, 
                 reach normal particle count, temp, and DP 
               
               
                   
                 modules inactive 
                   
               
               
                 Air Exhaust 
                 Maintain positive differential 
                 Qualify and monitor recovery time needed to 
               
               
                 Local Failure 
                 with header air supply, 
                 reach normal particle count, temp, and DP 
               
               
                   
                 modules inactive 
                   
               
               
                 Power Loss 
                 Modules Inactive, Ambient 
                 Qualify and monitor recovery time needed to 
               
               
                   
                 until power restored 
                 reach normal particle count, temp, and DP 
               
               
                 Module 
                 Minor - monitor status of 
                 Evaluate process impact case-by-case, 
               
               
                 Surface 
                 rupture, repair or patch, 
                 Monitor recovery to reach normal particle 
               
               
                 Rupture - 
                 continue as Active 
                 count, temp, and DP 
               
               
                 Minor 
                   
                   
               
               
                 Module 
                 Major - Inactive, Repair 
                 Transfer process fluids out of module, take 
               
               
                 Surface 
                   
                 offline and repair 
               
               
                 Rupture - 
                   
                 Determine process status case by case 
               
               
                 Major 
                   
                   
               
               
                 Module Glove 
                 Minor - monitor status of 
                 Evaluate process impact case-by-case, 
               
               
                 Rupture - 
                 rupture, repair or patch, 
                 Monitor recovery to reach normal particle 
               
               
                 Minor 
                 continue as Active 
                 count, temp, and DP 
               
               
                 Module Glove 
                 Major - Inactive, Repair 
                 Transfer process fluids out of module, take 
               
               
                 Rupture - 
                   
                 offline and repair 
               
               
                 Major 
                   
                 Determine process status case by case 
               
               
                 Minor Process 
                 Minor - monitor status of 
                 Evaluate process impact case-by-case, Clean 
               
               
                 Fluid Spill 
                 rupture, repair or patch, 
                 spill area using glove ports 
               
               
                   
                 continue as Active 
                 Clean vigorously at interbatch cleaning 
               
               
                 Minor 
                 Minor - monitor status of 
                 Evaluate process impact case-by-case 
               
               
                 Chemical 
                 rupture, repair or patch, 
                 Clean spill area using glove ports 
               
               
                 Spill 
                 continue as Active 
                 Clean vigorously at interbatch cleaning 
               
               
                 Major Process 
                 Major - Inactive, Repair 
                 Transfer process fluids out of module 
               
               
                 Fluid Spill 
                   
                 Take offline and repair 
               
               
                   
                   
                 Decontaminate 
               
               
                 Major 
                 Module becomes Inactive, in 
                 Transfer process fluids out of module 
               
               
                 Chemical 
                 need of Repair 
                 Take offline and repair 
               
               
                 Spill 
                   
                 Decontaminate. 
               
               
                 Module Door 
                 Maintain positive differential 
                 Continue processing 
               
               
                 Open 
                 pressure, Module Active 
                 Evaluate and then collect and analyze 
               
               
                   
                   
                 additional process samples 
               
               
                   
                   
                 record event 
               
               
                 Negative 
                 Verify sealed process 
                 Evaluate process impact case-by-case, 
               
               
                 Differential 
                 containers, module inactive, 
                 Qualify and monitor recovery time needed to 
               
               
                 Pressure 
                 ambient after exhaust blowers 
                 reach normal particle count, temp, and DP 
               
               
                   
                 turned off 
               
               
                   
               
             
          
         
       
     
     Some embodiments of the present invention also include on-line quality assurance and cGMP compliance verification, including electronic GMP data management using a controlled and qualified database system with qualified applications and hardware customized to specific practices to enable dock-to-dock tracking of raw materials, equipment, manufacturing components, work-in-process intermediates, and final product. This allows for a paperless system which captures electronic data in a repository allowing for continuous, “real-time” review and decision making, resulting in quality assurance and procedural compliance. Additionally, the system may also include a capability to generate paper versions of the electronic reports. 
     Accordingly, some of the online system components may include electronic materials control, electronic document control, electronic batch records, automated process controls, real time automated monitoring of processing and environment inside the modules, real-time, automated collection of batch and environmental data. 
     Online QA capabilities may be created to meet the requirements of 21 CFR Part 11 requirements and take into consideration the evolving expectations for software development and validation. Real time quality assurance facilitates efficient assessment/evaluation of batch disposition as data are acquired. Process excursions which may have adverse product quality impact on a real time basis may be identified and assessed in a timely manner. 
     Data from the manufacturing process may be collected continuously and used to control process equipment and determine batch sequencing permissions. The types of data that are preferably continuously collected are detailed in Table V. 
                               TABLE V                   Continuously Collected Process Control Data                Typical Data Points               Material Transfer           Lot Details   Lot Status, Quantity, FIFO Status       Location   Warehouse, shelf, rack number       Lot Completion   Reconciliation       Analytical Instruments           and Testing           In-Process Data   pH, Conductivity, bioburden, endotoxin,           surface sampling, TOC,           A 280 , FTIR, UV       Batch Release Data   Bioactivity, potency, impurity profile,           concentration, physicochemical characteristics       Batch Execution/           Processing           Batch Initiation and   Lot number assignment, sequential control       Execution   and status, comments, deviations, parameter           entries, signatures       Bill of Materials   Status verification, usage and disposition       Batch Completion   Compliance assessment/Status                    
Central Control Module
 
     Electronic process controls, batch records, Standard Operating Procedures (SOPs), and data capture may be incorporated into a central control unit. The control unit allows the incorporation of real-time monitoring and control of various parameters of the manufacturing processes. Such monitoring allows operator interaction with minimal intrusion into controlled areas as well as minimize the chance of human error. Examples of such process analytical components are described in Table VI. 
     
       
         
               
             
               
               
             
           
               
                 TABLE VI 
               
             
             
               
                   
               
               
                 Process Analytical Technologies 
               
             
          
           
               
                 Process/Operation 
                 Typical Data Monitored 
               
               
                   
               
               
                 Modules 
                 Module Temperature, Relative Humidity and 
               
               
                   
                 Differential Pressure, Particle Counts, Status, 
               
               
                   
                 Active Batches 
               
               
                 Bioreactors 
                 Reactor Setpoints, Temperature, Agitation, Gas 
               
               
                   
                 Flowrate, pH, Dissolved Oxygen, Weight/Volume/ 
               
               
                   
                 Level, Pressure, Consumables, Subsystem and 
               
               
                   
                 System Status, Metrology, Maintenance and 
               
               
                   
                 Validation Status 
               
               
                 Filtration Systems 
                 Pressure, Volume/Weight/Level, Flowrate, pH, 
               
               
                   
                 Conductivity, Consumables, Subsystem and 
               
               
                   
                 System Status, Metrology, Maintenance 
               
               
                   
                 and Validation Status 
               
               
                 Chromatography 
                 Pressure, Volume/Weight/Level, Flowrate, pH, 
               
               
                 Systems 
                 Conductivity, UV Wavelength, Consumables, 
               
               
                   
                 Subsystem and System Status, Metrology, 
               
               
                   
                 Maintenance and Validation Status 
               
               
                 Filling Systems 
                 Pressure, Volume/Weight/Level, Flowrate, pH, 
               
               
                   
                 Conductivity, Consumables, Subsystem and 
               
               
                   
                 System Status, Metrology, Maintenance and 
               
               
                   
                 Validation Status 
               
               
                   
               
             
          
         
       
     
     Having described the invention with reference to the presently preferred embodiments, it should be understood that numerous changes in creating and operating such systems and methods may be introduced without departing from the true spirit of the invention.