CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to and the benefit of U.S. Provisional
Application No. 62/246,478, filed October 26, 2015, and U.S. Provisional Application No.
62/299,930, filed February 25, 2016; the contents of both applications are incorporated herein
by reference in their entireties.
BACKGROUND OF THE INVENTION
[0002] Over the past few decades, the biopharmaceutical industry has made a number
of advancements in developing more robust, efficient and cost effective methods for
manufacturing biopharmaceuticals in batch mode. These advancements (e.g., expression
systems, improved tools to develop and model production processes and adoption of singleuse/
disposable systems) can also be applied more acutely to current trends related to
continuous bioprocesses. Continuous processing or production is a flow production method
used to manufacture, produce, or process materials without interruption. Investments in
continuous processing in the biopharmaceutical industry have been influenced by a number
of business drivers, such as accelerated development times for continuously operated steps,
reduced overall costs, maintained stringent quality, regulatory requirements, and increased
flexibility to match changing product demands. Other advantages of continuous over batch
production include consistent product quality, smaller equipment, streamlined process flow,
low process cycle times, steady state operation, and high volumetric productivity.
[0003] In the biopharmaceutical industry, the term "single-use" (also commonly
known as "disposable") refers to a product that is intended for a one-time use. The adoption
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of single-use technologies across all steps of biopharmaceutical manufacturing has
accelerated in recent years. Today, users can choose from a large selection of single-use
products from a range of suppliers. This trend is driven by a number of advantages over
stainless steel systems reduced capital investment and operational costs, improved safety, and
flexibility, etc., with respect to production scheduling. These advantages drive down
contamination rates and enhance the efficiency of a production facility while reducing
manufacturing costs (both operational and maintenance).
[0004] Single-use options exist for most steps of a protein bio-production process.
Such options include process fluid mixing and storage systems, cryopreservation systems,
bioreactors (used for both inoculum expansion and production process steps), bulk material
and product storage, distribution assemblies and manifolds, sensors, and a number of
disposable filtration and chromatography systems. Many of these technologies have already
gained wide industry acceptance and furthermore, have been used to manufacture protein
products that are approved by the regulatory authorities. For cell therapy manufacturing,
plastic dishes and flasks have been used for adherent and non-adherent cell culture and a
large proportion of adherent cell-based therapies are currently manufactured in multi-layered
plastic flasks. The next generation of cell therapies will be manufactured using bioreactors.
For this reason, bioreactor-based cell therapy manufacturing will benefit from utilizing
single-use technologies at various, or even all, steps, including, but not limited to, tissue
acquisition to final drug product formulation.
[0005] In this regard, the strategy is to increase the use of disposable technologies to
produce high quality, safe, and cost effective active pharmaceutical ingredients (APis) and
biopharmaceutical products including, but not limited to, recombinant proteins, monoclonal
antibodies, protein-drug conjugates, viral based therapeutics and cell therapies. With single-
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use technologies, it is possible to maintain and increase quality, reliability of supply,
throughput, and reduce costs of manufacturing processes. Moreover, the market shows an
increase need to develop and implement disposable/single-use technologies for continuous
bio-manufacturing operations or facilities. For example, contract manufacturing organizations
often need to flexibly accommodate large-, mid- and small-volume drugs, preferably within
the same manufacturing facilities.
SUMMARY OF THE INVENTION
[0006] The present invention provides a manufacturing facility for the production of
biopharmaceuticals that offers both batch and continuous manufacturing using at least one
piece of single-use disposable technology.
[0007] The present invention also provides a manufacturing facility for the production
of active pharmaceutical ingredients ("APis") that offers both batch and continuous
manufacturing using at least one piece of single-use disposable technology.
[0008] In one aspect of the invention, the manufacturing facility may include at least
one piece of single-use equipment or device configured to support continuous production of
biopharmaceuticals.
[0009] In another aspect of the invention, the manufacturing facility may include at
least one piece of single-use equipment or device configured to support continuous
production of APis.
[0010] In another aspect of the invention, the manufacturing facility may include at
least one piece of single-use equipment or device configured to support continuous
production cell therapy.
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[0011] In another aspect of the invention, the manufacturing facility may include at
least one piece of single-use equipment or device configured to support continuous
production of bulk recombinant proteins and/or monoclonal antibody products.
[0012] Furthermore, for these contract manufacturing organizations, there are a
number of factors that justify the implementation of single-use technologies. For instance,
there would be greater flexibility in vessel architecture and components used when designing
processes to manufacture proteins and cells, significantly reduced operating costs (e.g., labor,
utility, and maintenance), improved facility throughput as batch turnaround times are
condensed, clean in place and steam in place operations.
[0013] Other objects, advantages and novel features of the present invention will
become apparent from the following detailed description of one or more preferred
embodiments when considered in conjunction with the accompanying drawings. The
disclosure is written for those skilled in the art. Although the disclosure uses terminology
and acronyms that may not be familiar to the layperson, those skilled in the art will be
familiar with the terminology and acronyms used herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] Figure 1 is a schematic representation of batch process options with example
technologies. In Figure 1, "o" represents a connector and"-" represents a tube.
[0015] Figure 2 is a schematic representation of continuous process options with
example technologies. In Figure 2, "o" represents a connector and "-" represents a tube.
[0016] Figure 3 is a schematic representation of hybrid process options with example
technologies. In Figure 3, "o" represents a connector and "-" represents a tube.
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[0017] Figure 4 shows antibody concentration profiles for a Model GS-CHO Cell
Line in laboratory-scale bioreactors with a comparison between the Version 6, Version 7 and
Version 8 platform processes. Figure 4 insert: Top 3 cell lines selected and evaluated from a
single cell line construction.
[0018] Figure 5 is a schematic representation of continuous, batch and hybrid process
options with example technologies.
[0019] Figure 6 shows the implementation of single-use equipment in mammalian
cell-culture manufacturing facilities in accordance with one or more aspects of the invention.
DETAILED DESCRIPTION
[0020] The present invention takes advantage of new and convergmg single-use
technologies and integrates those technologies into a batch-fed, continuous, and/or hybrid
manufacturing facilities and processes. The present invention provides improved methods,
associated apparatus, and systems for manufacturing biopharmaceuticals. Provided herein
are systems, facilities, means, and processes to address batch-fed, continuous, and hybrid
manufacturing in a reasonable time with high yield and product quality. Also provided
herein are systems, facilities, means, and processes to optimize production while reducing the
risk of contamination. The disclosed methods and systems provide optimized configurations,
partly or completely closed, fully disposable, and scalable production systems having
integrated disposables designed for each aspect of cell production, including: input cells (1),
inoculum expansion equipment (2), production stage bioreactor equipment (3), primary
recovery stage equipment ( 4), equipment for the capture step ( 5), ultrafiltration and
diafiltration equipment (6), polishing membranes (7), equipment for polishing using cation
exchange (8), virus reduction filtration equipment (9), ultrafiltration and diafiltration
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equipment (10), and automated bulk fill equipment (11). The disclosed methods and systems
also provide optimized configurations, partly or completely closed, fully disposable, and
scalable production systems having integrated disposables designed for each aspect of cell
production, including: input cells (1), inoculum expansion equipment (2), production stage
perfusion equipment (12), equipment for volume exchange (13), continuous purification
equipment (14), virus reduction filtration equipment (9), ultrafiltration and diafiltration
equipment (10), and automated bulk fill equipment (11). In addition, the disclosed methods
and systems also provide optimized configurations, partly or completely closed, fully
disposable, and scalable production systems having integrated disposables designed for each
aspect of cell production, including: input cells (1), inoculum expansion equipment (2),
production stage bioreactor equipment (3), primary recovery stage equipment ( 4), equipment
for volume exchange (13), continuous purification equipment (14), virus reduction filtration
equipment (9), ultrafiltration and diafiltration equipment (10), and automated bulk fill
equipment (11).
[0021] The present invention provides embodiments that involve a direct connection
between input cells (1) and inoculum expansion equipment (2). This direct connection
mayalso have a sensor that would allow the manufacturing process to be continuous only
regarding this transfer. This would eliminate the need for a processing step involving shake
flask incubation.
[0022] Moreover, the present invention provides for sensors to monitor any process
variable, including, but not limited to, protein concentration, pH, conductivity, viable cell
concentration, capacitance, key metabolites, temperature, titer, metabolites, glucose reuptake,
DO, C02 generation, 0 2 reuptake rate, HPLC, organic acids, saccharides, TCA intermediates,
vitamins, nucleotides, elements, endotoxins, bioburdens, etc. These sensors optionally can be
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in communication with other sensors, and can also optionally adjust the flow rate of fluid into
and/or out of at least one piece of equipment. These sensors can also be in-line sensors or atline
sensors. These sensors or their equivalents are able to communicate with the equipment,
each other, a computer, the internet, or the like. Communication between sensors can be
done in many ways. As just one illustrative example, communication can be accomplished
using the invention as described in U.S. Patent Application No. 15/294,152, filed on October
14, 2016. These sensors have the advantage of reducing human error in manufacturing.
[0023] Also, the present invention can be automated. For example, sensors could be
used to determine seed transfer, harvest initiation, timing for process shifts, feed control, feed
timing, feed flow rates, inline buffer dilution, chromatography peak cutting, VI titration,
UF/DF completion, release tanks/skids, real time modification of chromatography recipes,
and the like.
[0024] The present invention also provides for different pieces of manufacturing
equipment, including hoses and/or connectors, to be surrounded by disposable bags such that
the bags may be used to dispose of any one or more pieces of single-use items. The present
invention additionally provides that one or more pieces of equipment can be in separate
rooms and be connected to equipment in other rooms. Additionally, pieces that are in
separate rooms may not be directly connected to those in another room but still be used as
part of the present invention. Furthermore, not all of the equipment needs to be single-use
equipment.
[0025] The present invention provides a methodology for selecting the optimal
equipment for use in this invention. For example, factors to consider when selecting the
equipment for process recovery includes: pressure, flux, pH, turbidity, acidification, capacity,
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cost, minimum filter area, filtration rate, de-sludge interval, efficiency, percentage of solids,
storage, etc. The present invention also provides criteria for selecting bioreactors, including:
mass transfer of 0 2, cell growth, culture viability, lactate concentration, ammonium
concentration, sodium concentration, potassium concentration, partial pressure of C02,
glutamine concentration, osmolality, antibody concentration, temperature, oligosaccharides,
the presence or absence of baffles, etc. Likewise, the present invention provides criteria for
selecting equipment for continuous chromatography, such as multi-column systems,
including: the interconnection of columns for an optimal use of the resin, ability to be
automated or semi-automated, number of columns the can be used, amount of raw material,
manufacturing time, product quality, time to process, ability to reach steady state, number of
inlets, buffer consumption, higher yields at purification steps, ability to operate in batch and
continuous modes depending on need, etc.
[0026] Figure 5 discloses exemplary equipment that could be used to make and use
the inventions described herein. For example, the equipment for input cells (1) can be any
suitable cell culture equipment including a cell culture flask, such as those commercially
available from Corning Inc., that for inoculum expansion equipment (2) can be any suitable
expansion equipment such as an S20 WAVE unit commercially available from General
Electric Company, the production stage bioreactor equipment (3) could be any suitable
bioreactor such as a BIOSTAT® system commercially available from Sartorious AG, the
primary recovery stage equipment ( 4) could be any suitable filter recovery system such as a
Zeta Plus™ recovery system commercially available from 3M, the equipment for the capture
step (5) could be any suitable chromatography column such as an RTP column commercially
available from General Electric Company, the ultrafiltration and diafiltration equipment (6)
and (10) could be any suitable ultrafiltration and diafiltration unit such as the Hydrosart®
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commercially available from Sartorious AG, the polishing membranes (7) could be any
suitable membranes such as those that are commercially available from Sartorius AG, the
equipment for polishing using cation exchange (8) could be any suitable chromatography
column such as an RTP column commercially available from General Electric Company, the
virus reduction filtration equipment (9) could be any suitable virus reduction system such as
the Planova™ 20N commercially available from Asahi Kasei Medical Co., Ltd., the
automated bulk fill equipment (11) could be any suitable fill equipment sucg as the SciLog®
SciFlex® Filter and Dispense System commercially available from Parker Domnick Hunter,
the production stage perfusion equipment (12) could be any suitable production stage
perfusion reactor equipment such as the Allegro STR bioreactor family commercially
available from Pall Corporation and/or the XCell™ ATF system commercially available from
Repligen Corporation, the equipment for volume exchange (13) could be any suitable volume
exchange equipment such as the ILC system commercially available from Pall Corporation,
and the continuous purification equipment (14) could be any suitable purification equipment
such as the BioSMB system commercially available from Pall Corporation.
[0027] In addition, it is an object of the present invention that these Batch-fed,
continuous, and/or hybrid manufacturing facilities and processes can be done in one or more
facilities. For example, one or more steps could be done in one or more separate facilities
from the others. It is an object of the present invention that these processes can comply with
state, federal, and international regulations regarding Good Manufacturing Processes.
[0028] Batch-fed, continuous, and/or hybrid manufacturing facilities and processes
each have their advantages and disadvantages that depend on numerous factors such as, but
not limited to, cost, cell-type, output volume requirements, and the like. Therefore, it is an
object of the present invention to be able to switch between any of these processes and
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facilities. Such modifications could be quick, timely and/or inexpensive. Such modifications
could be done in such a way as to minimize the risk of contamination by, for example,
inadvertent dripping on the manufacturing floor from any of the tubes, connectors, machines,
or the like. For example, at least one tube between manufacturing components could include
a single use tube. Likewise, at least one connector that connects a tube to a piece of
manufacturing equipment could be a single use connector. As well, more than one of these
connecting tubes and/or connectors could be a single-use item.
[0029] It is another object of the present invention to use at least one piece of singleuse
manufacturing equipment in the manufacturing facilities and processes of the present
invention.
[0030] It is another object of the present invention to use at least one piece of singleuse
connection equipment in the manufacturing facilities and processes of the present
invention.
[0031] The goal is to move towards a continuous process option in which the product
moves directly from one step to the next without any significant intervening product hold (see
e.g., Figures 1, 2, and 3).
[0032] Preferably, the continuous process would operate at a true steady-state, with
the operating conditions (e.g., flow rates and pressures) and product/impurity concentrations
remaining constant throughout the process. With this, fully integrated, continuous single-use
bioprocessing would allow for predictable steady manufacture at smaller scales (therefore
requiring smaller equipment and reducing footprint in existing plants and minimizes the size
of new plants) with the associated cost savings and benefits. This fully integrated system
could also be operated on a larger scale, if such were needed.
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[0033] The devices, facilities and methods described herein are suitable for culturing
any desired cell line including prokaryotic and/or eukaryotic cell lines. Further, in
embodiments, the devices, facilities and methods are suitable for culturing suspension cells or
anchorage-dependent (adherent) cells and are suitable for production operations configured
for production of pharmaceutical and biopharmaceutical products-such as polypeptide
products, nucleic acid products (for example DNA or RNA), or cells and/or viruses such as
those used in cellular and/or viral therapies.
[0034] In embodiments, the cells express or produce a product, such as a recombinant
therapeutic or diagnostic product. As described in more detail below, examples of products
produced by cells include, but are not limited to, antibody molecules (e.g., monoclonal
antibodies, bispecific antibodies), antibody mimetics (polypeptide molecules that bind
specifically to antigens but that are not structurally related to antibodies such as e.g.
DARPins, affibodies, adnectins, or IgNARs), fusion proteins (e.g., Fe fusion proteins,
chimeric cytokines), other recombinant proteins (e.g., glycosylated proteins, enzymes,
hormones), viral therapeutics (e.g., anti-cancer oncolytic viruses, viral vectors for gene
therapy and viral immunotherapy), cell therapeutics (e.g., pluripotent stem cells,
mesenchymal stem cells and adult stem cells), vaccines or lipid-encapsulated particles (e.g.,
exosomes, virus-like particles), RNA (such as e.g. siRNA) or DNA (such as e.g. plasmid
DNA), antibiotics or amino acids. In embodiments, the devices, facilities and methods can be
used for producing biosimilars.
[0035] As mentioned, in embodiments, devices, facilities and methods allow for the
production of eukaryotic cells, e.g., mammalian cells or lower eukaryotic cells such as for
example yeast cells or filamentous fungi cells, or prokaryotic cells such as Gram-positive or
Gram-negative cells and/or products of the eukaryotic or prokaryotic cells, e.g., proteins,
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peptides, antibiotics, amino acids, nucleic acids (such as DNA or RNA), synthesized by the
eukaryotic cells in a large-scale manner. Unless stated otherwise herein, the devices,
facilities, and methods can include any desired volume or production capacity including but
not limited to bench-scale, pilot-scale, and full production scale capacities.
[0036] Moreover and unless stated otherwise herein, the devices, facilities, and
methods can include any suitable reactor(s) including but not limited to stirred tank, airlift,
fiber, microfiber, hollow fiber, ceramic matrix, fluidized bed, fixed bed, single-use and/or
spouted bed bioreactors. As used herein, "reactor" can include a fermentor or fermentation
unit, or any other reaction vessel and the term "reactor" is used interchangeably with
"fermentor." For example, in some aspects, an example bioreactor unit can perform one or
more, or all, of the following: feeding of nutrients and/or carbon sources, injection of suitable
gas (e.g., oxygen), inlet and outlet flow of fermentation or cell culture medium, separation of
gas and liquid phases, maintenance of temperature, maintenance of oxygen and C02 levels,
maintenance of pH level, agitation (e.g., stirring), and/or cleaning/sterilizing. Example reactor
units, such as a fermentation unit, may contain multiple reactors within the unit, for example
the unit can have 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, or 100, or
more bioreactors in each unit and/or a facility may contain multiple units having a single or
multiple reactors within the facility. In various embodiments, the bioreactor can be suitable
for batch, semi fed-batch, fed-batch, perfusion, and/or a continuous fermentation processes.
Any suitable reactor diameter can be used. In embodiments, the bioreactor can have a volume
between about 100 mL and about 50,000 L. Non-limiting examples include a volume of 100
mL, 250 mL, 500 mL, 750 mL, 1 liter, 2 liters, 3 liters, 4 liters, 5 liters, 6 liters, 7 liters, 8
liters, 9 liters, 10 liters, 15 liters, 20 liters, 25 liters, 30 liters, 40 liters, 50 liters, 60 liters, 70
liters, 80 liters, 90 liters, 100 liters, 150 liters, 200 liters, 250 liters, 300 liters, 350 liters, 400
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liters, 450 liters, 500 liters, 550 liters, 600 liters, 650 liters, 700 liters, 750 liters, 800 liters,
850 liters, 900 liters, 950 liters, 1000 liters, 1500 liters, 2000 liters, 2500 liters, 3000 liters,
3500 liters, 4000 liters, 4500 liters, 5000 liters, 6000 liters, 7000 liters, 8000 liters, 9000
liters, 10,000 liters, 15,000 liters, 20,000 liters, and/or 50,000 liters. Additionally, suitable
reactors can be multi-use, single-use, disposable, or non-disposable and can be formed of any
suitable material including metal alloys such as stainless steel (e.g., 316L or any other
suitable stainless steel) and Inconel, plastics, and/or glass.
[0037] In embodiments and unless stated otherwise herein, the devices, facilities, and
methods described herein can also include any suitable unit operation and/or equipment not
otherwise mentioned, such as operations and/or equipment for separation, purification, and
isolation of such products. Any suitable facility and environment can be used, such as
traditional stick-built facilities, modular, mobile and temporary facilities, or any other
suitable construction, facility, and/or layout. For example, in some embodiments modular
clean-rooms can be used. Additionally and unless otherwise stated, the devices, systems, and
methods described herein can be housed and/or performed in a single location or facility or
alternatively be housed and/or performed at separate or multiple locations and/or facilities.
[0038] By way of non-limiting examples and without limitation, U.S. Publication
Nos. 2013/0280797, 2012/0077429, 201110280797, 2009/0305626, and U.S. Patent Nos.
8,298,054, 7,629,167, and 5,656,491, each of which are hereby incorporated by reference in
its entirety, describe example facilities, equipment, and/or systems that may be suitable.
[0039] In embodiments, the cells are eukaryotic cells, e.g., mammalian cells. The
mammalian cells can be for example human or rodent or bovine cell lines or cell strains.
Examples of such cells, cell lines or cell strains are e.g., mouse myeloma (NSO)-cell lines,
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Chinese hamster ovary (CHO)-cell lines, HT1080, H9, HepG2, MCF7, MDBK Jurkat,
NIH3T3, PC12, BHK (baby hamster kidney cell), VERO, SP2/0, YB2/0, YO, C127, L cell,
COS, e.g., COSl and COS7, QC1-3,HEK-293, VERO, PER.C6, HeLA, EBl, EB2, EB3,
oncolytic or hybridoma-celllines. Preferably the mammalian cells are CHO-celllines. In one
embodiment, the cell is a CHO cell. In one embodiment, the cell is a CHO-Kl cell, a CHOKl
SV cell, a DG44 CHO cell, a DUXBll CHO cell, a CHOS, a CHO GS knock-out cell, a
CHO FUT8 GS knock-out cell, a CHOZN, or a CHO-derived cell. The CHO GS knock-out
cell (e.g., GSKO cell) is, for example, a CHO-Kl SV GS knockout cell. The CHO FUT8
knockout cell is, for example, the Potelligent® CHOKl SV (Lonza Biologics, Inc.).
Eukaryotic cells can also be avian cells, cell lines or cell strains, such as for example, EBx®
cells, EB14, EB24, EB26, EB66, or EBvl3.
[0040] In one embodiment, the eukaryotic cells are stem cells. The stem cells can be,
for example, pluripotent stem cells, including embryonic stem cells (ESCs ), adult stem cells,
induced pluripotent stem cells (iPSCs), tissue specific stem cells (e.g., hematopoietic stem
cells) and mesenchymal stem cells (MSCs).
[0041] In one embodiment, the cell is a differentiated form of any of the cells
described herein. In one embodiment, the cell is a cell derived from any primary cell in
culture.
[0042] In embodiments, the cell is a hepatocyte such as a human hepatocyte, animal
hepatocyte, or a non-parenchymal cell. For example, the cell can be a plateable metabolism
qualified human hepatocyte, a plateable induction qualified human hepatocyte, plateable
Qualyst Transporter Certified™ human hepatocyte, suspension qualified human hepatocyte
(including 10-donor and 20-donor pooled hepatocytes), human hepatic kupffer cells, human
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hepatic stellate cells, dog hepatocytes (including single and pooled Beagle hepatocytes),
mouse hepatocytes (including CD-1 and C57BI/6 hepatocytes), rat hepatocytes (including
Sprague-Dawley, Wistar Han, and Wistar hepatocytes), monkey hepatocytes (including
Cynomolgus or Rhesus monkey hepatocytes), cat hepatocytes (including Domestic Shorthair
hepatocytes), and rabbit hepatocytes (including New Zealand White hepatocytes). Example
hepatocytes are commercially available from Triangle Research Labs, LLC, 6 Davis Drive
Research Triangle Park, North Carolina, USA 27709.
[0043] In one embodiment, the eukaryotic cell is a lower eukaryotic cell such as e.g.,
a yeast cell (e.g., Pichia genus (e.g., Pichia pastoris, Pichia methanolica, Pichia kluyveri, and
Pichia angusta), Komagataella genus (e.g., Komagataella pastoris, Komagataella
pseudopastoris or Komagataella phaffii), Saccharomyces genus (e.g., Saccharomyces
cerevisae, cerevisiae, Saccharomyces kluyveri, Saccharomyces uvarum), Kluyveromyces
genus (e.g., Kluyveromyces lactis, Kluyveromyces marxianus), the Candida genus (e.g.,
Candida utilis, Candida cacaoi, Candida boidinii,), the Geotrichum genus (e.g., Geotrichum
fermentans), Hansenula polymorpha, Yarrowia lipolytica, or Schizosaccharomyces pombe.
Preferred is the species Pichia pastoris. Examples for Pichia pastoris strains are X33, GS 115,
KM71, KM71H; and CBS7435.
[0044] In one embodiment, the eukaryotic cell is a fungal cell (e.g., Aspergillus (such
as A. niger, A. fumigatus, A. orzyae, A. nidula), Acremonium (such as A. thermophilum),
Chaetomium (such as C. thermophilum), Chrysosporium (such as C. thermophile), Cordyceps
(such as C. militaris), Corynascus, Ctenomyces, Fusarium (such as F. oxysporum),
Glomerella (such as G. graminicola), Hypocrea (such as H. jecorina), Magnaporthe (such as
M. orzyae), Myceliophthora (such as M. thermophile), Nectria (such as N. heamatococca),
Neurospora (such as N. crassa), Penicillium, Sporotrichum (such as S. thermophile),
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Thielavia (such as T. terrestris, T. heterothallica), Trichoderma (such as T. reesei), or
Verticillium (such as V. dahlia)).
[0045] In one embodiment, the eukaryotic cell is an insect cell (e.g., Sf9, Mimic™
Sf9, Sf21, High Five™ (BT1-TN-5B1-4), or BT1-Ea88 cells), an algae cell (e.g., of the genus
Amphora, Bacillariophyceae, Dunaliella, Chlorella, Chlamydomonas, Cyanophyta
(cyanobacteria), Nannochloropsis, Spirulina, or Ochromonas), or a plant cell (e.g., cells
from monocotyledonous plants (e.g., maize, rice, wheat, or Setaria), or from a dicotyledonous
plants (e.g., cassava, potato, soybean, tomato, tobacco, alfalfa, Physcomitrella patens or
Arabidopsis).
[0046]
[0047]
In one embodiment, the cell is a bacterial or prokaryotic cell.
In embodiments, the prokaryotic cell is a Gram-positive cells such as Bacillus,
Streptomyces Streptococcus, Staphylococcus or Lactobacillus. Bacillus that can be used is,
e.g. the B.subtilis, B.amyloliquefaciens, B.licheniformis, B.natto, or B.megaterium. In
embodiments, the cell is B.subtilis, such as B.subtilis 3NA and B.subtilis 168. Bacillus is
obtainable from, e.g., the Bacillus Genetic Stock Center, Biological Sciences 556, 484 West
12th Avenue, Columbus OH 43210-1214.
[0048] In one embodiment, the prokaryotic cell is a Gram-negative cell, such as
Salmonella spp. or Escherichia coli, such as e.g., TG1, TG2, W3110, DH1, DHB4, DH5a,
HMS 174, HMS174 (DE3), NM533, C600, HB101, JM109, MC4100, XL1-Blue and
Origami, as well as those derived from E.coli B-strains, such as for example BL-21 or BL21
(DE3), all of which are commercially available.
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[0049] Suitable host cells are commercially available, for example, from culture
collections such as the DSMZ (Deutsche Sammlung von Mikroorganismen and Zellkulturen
GmbH, Braunschweig, Germany) or the American Type Culture Collection (ATCC).
[0050] In embodiments, the cultured cells are used to produce proteins e.g.,
antibodies, e.g., monoclonal antibodies, and/or recombinant proteins, for therapeutic use. In
embodiments, the cultured cells produce peptides, amino acids, fatty acids or other useful
biochemical intermediates or metabolites. For example, in embodiments, molecules having a
molecular weight of about 4000 daltons to greater than about 140,000 daltons can be
produced. In embodiments, these molecules can have a range of complexity and can include
posttranslational modifications including glycosylation.
[0051] In embodiments, the protein is, e.g., BOTOX, Myobloc, Neurobloc, Dysport
(or other serotypes of botulinum neurotoxins), alglucosidase alpha, daptomycin, YH-16,
choriogonadotropin alpha, filgrastim, cetrorelix, interleukin-2, aldesleukin, teceleulin,
denileukin diftitox, interferon alpha-n3 (injection), interferon alpha-nl, DL-8234, interferon,
Suntory (gamma-la), interferon gamma, thymosin alpha 1, tasonermin, DigiFab, ViperaTAb,
EchiTAb, CroFab, nesiritide, abatacept, alefacept, Rebif, eptoterminalfa, teriparatide
(osteoporosis), calcitonin injectable (bone disease), calcitonin (nasal, osteoporosis),
etanercept, hemoglobin glutamer 250 (bovine), drotrecogin alpha, collagenase, carperitide,
recombinant human epidermal growth factor (topical gel, wound healing), DWP401,
darbepoetin alpha, epoetin omega, epoetin beta, epoetin alpha, desirudin, lepirudin,
bivalirudin, nonacog alpha, Mononine, eptacog alpha (activated), recombinant Factor
VIII+ VWF, Recombinate, recombinant Factor VIII, Factor VIII (recombinant), Alphnmate,
octocog alpha, Factor VIII, palifermin, Indikinase, tenecteplase, alteplase, pamiteplase,
reteplase, nateplase, monteplase, follitropin alpha, rFSH, hpFSH, micafungin, pegfilgrastim,
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lenograstim, nartograstim, sermorelin, glucagon, exenatide, pramlintide, iniglucerase,
galsulfase, Leucotropin, molgramostirn, triptorelin acetate, histrelin (subcutaneous implant,
Hydron), deslorelin, histrelin, nafarelin, leuprolide sustained release depot (ATRIGEL),
leuprolide implant (DUROS), goserelin, Eutropin, KP-102 program, somatropin, mecasermin
(growth failure), enlfavirtide, Org-33408, insulin glargine, insulin glulisine, insulin (inhaled),
insulin lispro, insulin deternir, insulin (buccal, RapidMist), mecasermin rinfabate, anakinra,
celmoleukin, 99 mTc-apcitide injection, myelopid, Betaseron, glatiramer acetate, Gepon,
sargramostim, oprelvekin, human leukocyte-derived alpha interferons, Bilive, insulin
(recombinant), recombinant human insulin, insulin aspart, mecasenin, Roferon-A, interferonalpha
2, Alfaferone, interferon alfacon-1, interferon alpha, Avonex' recombinant human
luteinizing hormone, dornase alpha, trafermin, ziconotide, taltirelin, diboterminalfa, atosiban,
becaplermin, eptifibatide, Zemaira, CTC-111, Shanvac-B, HPV vaccine (quadrivalent),
octreotide, lanreotide, ancestirn, agalsidase beta, agalsidase alpha, laronidase, prezatide
copper acetate (topical gel), rasburicase, ranibizumab, Actimmune, PEG-Intron, Tricomin,
recombinant house dust mite allergy desensitization injection, recombinant human
parathyroid hormone (PTH) 1-84 (sc, osteoporosis), epoetin delta, transgenic antithrombin
Ill, Granditropin, Vitrase, recombinant insulin, interferon-alpha (oral lozenge), GEM-21S,
vapreotide, idursulfase, omnapatrilat, recombinant serum albumin, certolizumab pegol,
glucarpidase, human recombinant C1 esterase inhibitor (angioedema), lanoteplase,
recombinant human growth hormone, enfuvirtide (needle-free injection, Biojector 2000),
VGV-1, interferon (alpha), lucinactant, aviptadil (inhaled, pulmonary disease), icatibant,
ecallantide, omiganan, Aurograb, pexigananacetate, ADI-PEG-20, LDI-200, degarelix,
cintredelinbesudotox, Favld, MDX-1379, ISAtx-247, liraglutide, teriparatide (osteoporosis),
tifacogin, AA4500, T4N5 liposome lotion, catumaxomab, DWP413, ART-123, Chrysalin,
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desmoteplase, amediplase, corifollitropinalpha, TH-9507, teduglutide, Diamyd, DWP-412,
growth hormone (sustained release injection), recombinant G-CSF, insulin (inhaled, AIR),
insulin (inhaled, Technosphere), insulin (inhaled, AERx), RGN-303, DiaPep277, interferon
beta (hepatitis C viral infection (HCV)), interferon alpha-n3 (oral), belatacept, transdermal
insulin patches, AMG-531, MBP-8298, Xerecept, opebacan, AIDSVAX, GV-1001,
LymphoScan, ranpimase, Lipoxysan, lusupultide, MP52 (beta-tricalciumphosphate carrier,
bone regeneration), melanoma vaccine, sipuleucel-T, CTP-37, Insegia, vitespen, human
thrombin (frozen, surgical bleeding), thrombin, TransMID, alfimeprase, Puricase, terlipressin
(intravenous, hepatorenal syndrome), EUR-1008M, recombinant FGF-1 (injectable, vascular
disease), BDM-E, rotigaptide, ETC-216, P-113, MBI-594AN, duramycin (inhaled, cystic
fibrosis), SCV-07, OPI-45, Endostatin, Angiostatin, ABT-510, Bowman Birk Inhibitor
Concentrate, XMP-629, 99 mTc-Hynic-Annexin V, kahalalide F, CTCE-9908, teverelix
(extended release), ozarelix, romidepsin, BAY-504798, interleukin4, PRX-321, Pepscan,
iboctadekin, rhlactoferrin, TRU-015, IL-21, ATN-161, cilengitide, Albuferon, Biphasix, IRX-
2, omega interferon, PCK-3145, CAP-232, pasireotide, huN901-DMI, ovarian cancer
immunotherapeutic vaccine, SB-249553, Oncovax-CL, OncoVax-P, BLP-25, CerVax-16,
multi-epitope peptide melanoma vaccine (MART-1, gp100, tyrosinase), nemifitide, rAAT
(inhaled), rAAT (dermatological), CORP (inhaled, asthma), pegsunercept, thymosinbeta4,
plitidepsin, GTP-200, ramoplanin, GRASPA, OBI-1, AC-100, salmon calcitonin (oral,
eligen), calcitonin (oral, osteoporosis), examorelin, capromorelin, Cardeva, velafermin, 1311-
TM-601, KK-220, T-10, ularitide, depelestat, hematide, Chrysalin (topical), rNAPc2,
recombinant Factor V111 (PEGylated liposomal), bFGF, PEGylated recombinant
staphylokinase variant, V-10153, SonoLysis Prolyse, NeuroVax, CZEN-002, islet cell
neogenesis therapy, rGLP-1, BIM-51077, LY-548806, exenatide (controlled release,
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Medisorb), AVE-0010, GA-GCB, avorelin, ACM-9604, linaclotid eacetate, CETi-1,
Hemospan, VAL (injectable), fast-acting insulin (injectable, Viadel), intranasal insulin,
insulin (inhaled), insulin (oral, eligen), recombinant methionyl human leptin, pitrakinra
subcutaneous injection, eczema), pitrakinra (inhaled dry powder, asthma), Multikine, RG-
1068, MM-093, NBI-6024, AT-001, PI-0824, Org-39141, Cpn10 (autoimmune
diseases/inflammation), talactoferrin (topical), rEV -131 (ophthalmic), rEV -131 (respiratory
disease), oral recombinant human insulin (diabetes), RPI-78M, oprelvekin (oral), CYT-99007
CTLA4-Ig, DTY-001, valategrast, interferon alpha-n3 (topical), IRX-3, RDP-58, Tauferon,
bile salt stimulated lipase, Merispase, alaline phosphatase, EP-2104R, Melanotan-11,
bremelanotide, ATL-104, recombinant human microplasmin, AX-200, SEMAX, ACV-1,
Xen-2174, CJC-1008, dynorphin A, SI-6603, LAB GHRH, AER-002, BGC-728, malaria
vaccine (virosomes, PeviPRO), ALTU-135, parvovirus B19 vaccine, influenza vaccine
(recombinant neuraminidase), malaria/HBV vaccine, anthrax vaccine, Vacc-5q, Vacc-4x,
HIV vaccine (oral), HPV vaccine, Tat Toxoid, YSPSL, CHS-13340, PTH(1-34) liposomal
cream (Novasome), Ostabolin-C, PTH analog (topical, psoriasis), MBRI-93.02, MTB72F
vaccine (tuberculosis), MVA-Ag85A vaccine (tuberculosis), FARA04, BA-210, recombinant
plague FIV vaccine, AG-702, OxSODrol, rBetV1, Der-pl/Der-p2/Der-p7 allergen-targeting
vaccine (dust mite allergy), PR1 peptide antigen (leukemia), mutant ras vaccine, HPV-16 E7
lipopeptide vaccine, labyrinthin vaccine (adenocarcinoma), CML vaccine, WT1-peptide
vaccine (cancer), IDD-5, CDX-110, Pentrys, Norelin, CytoFab, P-9808, VT-111, icrocaptide,
telbermin (dermatological, diabetic foot ulcer), rupintrivir, reticulose, rGRF, HA, alphagalactosidase
A, ACE-011, ALTU-140, CGX-1160, angiotensin therapeutic vaccine, D-4F,
ETC-642, APP-018, rhMBL, SCV-07 (oral, tuberculosis), DRF-7295, ABT-828, ErbB2-
specific immunotoxin (anticancer), DT3SSIL-3, TST-10088, PR0-1762, Combotox,
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cholecystokinin-B/gastrin-receptor binding pep tides, 111In-hEGF, AE-37, trasnizumabDM1,
Antagonist G, IL-12 (recombinant), PM-02734, IMP-321, rhiGF-BP3, BLX-883,
CUV-1647 (topical), L-19 based radioimmunotherapeutics (cancer), Re-188-P-2045, AMG-
386, DC/1540/KLH vaccine (cancer), VX-001, AVE-9633, AC-9301, NY-ES0-1 vaccine
(peptides), NA17.A2 peptides, melanoma vaccine (pulsed antigen therapeutic), prostate
cancer vaccine, CBP-501, recombinant human lactoferrin (dry eye), FX-06, AP-214, WAP-
8294A (injectable), ACP-HIP, SUN-11031, peptide YY [3-36] (obesity, intranasal), FGLL,
atacicept, BR3-Fc, BN-003, BA-058, human parathyroid hormone 1-34 (nasal, osteoporosis),
F-18-CCR1, AT-1100 (celiac disease/diabetes), JPD-003, PTH(7-34) liposomal cream
(Novasome), duramycin (ophthalmic, dry eye), CAB-2, CTCE-0214, GlycoPEGylated
erythropoietin, EPO-Fc, CNT0-528, AMG-114, JR-013, Factor XIII, aminocandin, PN-951,
716155, SUN-E7001, TH-0318, BAY-73-7977, teverelix (immediate release), EP-51216,
hGH (controlled release, Biosphere), OGP-1, sifuvirtide, TV4710, ALG-889, Org-41259,
rhCC10, F-991, thymopentin (pulmonary diseases), r(m)CRP, hepatoselective insulin,
subalin, L19-IL-2 fusion protein, elafin, NMK-150, ALTU-139, EN-122004, rhTPO,
thrombopoietin receptor agonist (thrombocytopenic disorders), AL-108, AL-208, nerve
growth factor antagonists (pain), SLV-317, CGX-1007, INN0-105, oral teriparatide (eligen),
GEM-OS1, AC-162352, PRX-302, LFn-p24 fusion vaccine (Therapore), EP-1043, S
pneumoniae pediatric vaccine, malaria vaccine, Neisseria meningitidis Group B vaccine,
neonatal group B streptococcal vaccine, anthrax vaccine, HCV vaccine (gpE1 +gpE2+MF-
59), otitis media therapy, HCV vaccine (core antigen+ISCOMATRIX), hPTH(1-34)
(transdermal, ViaDerm), 768974, SYN-101, PGN-0052, aviscumnine, BIM-23190,
tuberculosis vaccine, multi-epitope tyrosinase peptide, cancer vaccine, enkastim, APC-8024,
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GI-5005, ACC-001, TTS-CD3, vascular-targeted TNF (solid tumors), desmopressin (buccal
controlled-release), onercept, and TP-9201.
[0052] In some embodiments, the polypeptide is adalimumab (HUMIRA), infliximab
(REMICADE™), rituximab (RITUXAN™/MAB THERA ™) etanercept (ENBREL™),
bevacizumab (AVASTIN™), trastuzumab (HERCEPTIN™), pegrilgrastim (NEULASTA™),
or any other suitable polypeptide including biosimilars and biobetters.
[0053] Other suitable polypeptides are those listed below and in Table 1 of U.S.
Patent Publication No. 2016/0097074:[0066] In another aspect of the invention, a manufacturing system for
biopharmaceuticals is provided comprising: at least one inputting device connected to at least
one inoculum expansion device through at least one piece of tubing and a connector; said at
least one inoculum expansion device is connected to at least one production stage perfusion
device through at least one piece of tubing and a connector; said at least one production stage
perfusion device is connected to at least one volume exchange device through at least one
piece of tubing and a connector; said at least one volume exchange device is connected to at
least one continuous filtration device through at least one piece of tubing and a connector;
said at least one continuous filtration device is connected to at least one virus reduction
filtration device through at least one piece of tubing and a connector; said at least one virus
reduction filtration device is connected to at least one ultrafiltration and diafiltration device
through at least one piece of tubing and a connector; and said at least one ultrafiltration and
diafiltration device is connected to at least one automated bulk fill device through at least one
piece of tubing and a connector.
[0067] In another aspect of the invention, a method of making biopharmaceuticals is
provided comprising: connecting at least one inputting device to at least one inoculum
expansion device using at least one piece of tubing and a connector such that material can
pass from the inputting device to the inoculum expansion device; connecting said at least one
inoculum expansion device to at least one production stage perfusion device using at least
one piece of tubing and a connector such that material can pass from the inoculum expansion
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device to the production stage perfusion device; connecting said at least one production stage
perfusion device to at least one volume exchange device using at least one piece of tubing
and a connector such that material can pass from the production stage perfusion device to the
volume exchange device; connecting said at least one volume exchange device to at least one
continuous purification device using at least one piece of tubing and a connector such that
material can pass from the volume exchange device to the continuous purification device;
connecting said at least one continuous purification device to at least one virus reduction
filtration device using at least one piece of tubing and a connector such that material can pass
from the continuous purification device to the virus reduction filtration device; connecting
said at least one virus reduction filtration device to at least one ultrafiltration and diafiltration
device using at least one piece of tubing and a connector such that material can pass from the
virus reduction filtration device to the ultrafiltration and diafiltration device; and connecting
said at least one ultrafiltration and diafiltration device to at least one automated bulk fill
device using at least one piece of tubing and a connector such that material can pass from the
ultrafiltration and diafiltration device to the automated bulk fill device.
[0068] In another aspect of the invention, a manufacturing system for
biopharmaceuticals is provided comprising: at least one inputting device connected to at least
one inoculum expansion device through at least one piece of tubing and a connector; said at
least one inoculum expansion device is connected to at least one production stage bioreactor
device through at least one piece of tubing and a connector; said at least one production stage
bioreactor device is connected to at least one primary recovery device through at least one
piece of tubing and a connector; said at least one primary recovery device is connected to at
least one volume exchange device through at least one piece of tubing and a connector; said
at least one volume exchange device is connected to at least one continuous purification
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device through at least one piece of tubing and a connector; said at least one continuous
purification device is connected to at least one virus reduction filtration device through at
least one piece of tubing and a connector; said at least one virus reduction filtration device is
connected to at least one ultrafiltration and diafiltration device through at least one piece of
tubing and a connector; and said at least one ultrafiltration and diafiltration device is
connected to at least one automated bulk fill device through at least one piece of tubing and a
connector.
[0069] In another aspect of the invention, a method of making biopharmaceuticals is
provided comprising: connecting at least one inputting device to at least one inoculum
expansion device using at least one piece of tubing and a connector such that material can
pass from the inputting device to the inoculum expansion device; connecting said at least one
inoculum expansion device to at least one production stage bioreactor device using at least
one piece of tubing and a connector such that material can pass from the inoculum expansion
device to the production stage bioreactor device; connecting said at least one production stage
bioreactor device to at least one primary recovery device using at least one piece of tubing
and a connector such that material can pass from the production stage bioreactor device to the
primary recovery device; connecting said at least one primary recovery device to at least one
volume exchange device using at least one piece of tubing and a connector such that material
can pass from the primary recovery device to the volume exchange device; connecting said at
least one volume exchange device to at least one continuous purification device using at least
one piece of tubing and a connector such that material can pass from the volume exchange
device to the continuous purification device; connecting said at least one continuous
purification device to at least one virus reduction filtration device using at least one piece of
tubing and a connector such that material can pass from the continuous purification device to
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the virus reduction filtration device; connecting said at least one virus reduction filtration
device to at least one ultrafiltration and diafiltration device using at least one piece of tubing
and a connector such that material can pass from the virus reduction filtration device to the
ultrafiltration and diafiltration device; and connecting said at least one ultrafiltration and
diafiltration device to at least one automated bulk fill device using at least one piece of tubing
and a connector such that material can pass from the ultrafiltration and diafiltration device to
the automated bulk fill device.
[0070] In another aspect of the invention, a manufacturing system for
biopharmaceuticals is provided comprising: at least one inputting device connected to at least
one inoculum expansion device through at least one piece of tubing and a connector; said at
least one inoculum expansion device is connected to at least one production stage perfusion
device through at least one piece of tubing and a connector; said at least one production stage
perfusion device is connected to at least one volume exchange device through at least one
piece of tubing and a connector; said at least one volume exchange device is connected to at
least one continuous purification device through at least one piece of tubing and a connector;
said at least one continuous purification device is connected to at least one virus reduction
filtration device through at least one piece of tubing and a connector; said at least one virus
reduction filtration device is connected to at least one ultrafiltration and diafiltration device
through at least one piece of tubing and a connector; and said at least one ultrafiltration and
diafiltration device is connected to at least one automated bulk fill device through at least one
piece of tubing and a connector.
[0071] In another aspect of the invention, a method for manufacturing
biopharmaceuticals is provided comprising: connecting at least one inputting device to at
least one inoculum expansion device using at least one piece of tubing and a connector such
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that material can pass from the inputting device to the inoculum expansiOn device;
connecting said at least one inoculum expansion device to at least one production stage
bioreactor device using at least one piece of tubing and a connector such that material can
pass from the inoculum expansion device to the production stage bioreactor device;
connecting said at least one production stage bioreactor device to at least one primary
recovery device using at least one piece of tubing and a connector such that material can pass
from the production stage bioreactor device to the primary recovery device; connecting said
at least one primary recovery device to at least one volume exchange device using at least one
piece of tubing and a connector such that material can pass from the primary recovery device
to the volume exchange device; connecting said at least one volume exchange device to at
least one continuous purification device using at least one piece of tubing and a connector
such that material can pass from the volume exchange device to the continuous purification
device; connecting said at least one continuous purification device to at least one virus
reduction filtration device using at least one piece of tubing and a connector such that
material can pass from the continuous purification device to the virus reduction filtration
device; connecting said at least one virus reduction filtration device to at least one
ultrafiltration and diafiltration device using at least one piece of tubing and a connector such
that material can pass from the virus reduction filtration device to the ultrafiltration and
diafiltration device; and connecting said at least one ultrafiltration and diafiltration device to
at least one automated bulk fill device using at least one piece of tubing and a connector such
that material can pass from the ultrafiltration and diafiltration device to the automated bulk
fill device.

Claims
1. A manufacturing system for biopharmaceuticals comprising:
at least one inputting device connected to at least one inoculum expansion device
through at least one piece of tubing and a connector;
said at least one inoculum expansion device is connected to at least one production
stage bioreactor device through at least one piece of tubing and a connector;
said at least one production stage bioreactor device is connected to at least one
primary recovery device through at least one piece of tubing and a connector;
said at least one primary recovery device is connected to at least one capturing device
through at least one piece of tubing and a connector;
said at least one capturing device is connected to at least one ultrafiltration and
diafiltration device through at least one piece of tubing and a connector;
said at least one ultrafiltration and diafiltration device is connected to at least one
polishing membranes device through at least one piece of tubing and a connector;
said at least one polishing membranes device is connected to at least one polishing
using cation exchange device through at least one piece of tubing and a connector;
said at least one polishing using cation exchange device is connected to at least one
virus reduction filtration device through at least one piece of tubing and a connector; and
said at least one virus reduction filtration device is connected to at least one
ultrafiltration and diafiltration device through at least one piece of tubing and a connector;
said at least one ultrafiltration and diafiltration device is connected to at least one
automated bulk fill device through at least one piece of tubing and a connector.
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2. The manufacturing system of claim 1, wherein the device can be from at least two
different manufacturers.
3. The manufacturing system of claim 1, wherein at least one device is not made for
single-use.
4. The manufacturing system of claim 1, wherein the system is operated as a closed
system.
5. The manufacturing system of claim 1, further comprising at least one sensor capable
of controlling flow of material between two devices.
6. The manufacturing system of claim 1, wherein the system is automated.
7. The manufacturing system of claim 1, wherein at least one device can be in more than
one room.
8. The manufacturing system of claim 1, further comprising at least one disposable bag
that can be used to dispose of at least one device, tubing or connector.
9. A method of making biopharmaceuticals comprising:
connecting at least one inputting device to at least one inoculum expansion device
using at least one piece of tubing and a connector such that material can pass from the
inputting device to the inoculum expansion device;
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connecting said at least one inoculum expansion device to at least one production
stage bioreactor device using at least one piece of tubing and a connector such that material
can pass from the inoculum expansion device to the production stage bioreactor device;
connecting said at least one production stage bioreactor device to at least one primary
recovery device using at least one piece of tubing and a connector such that material can pass
from the production stage bioreactor device to the primary recovery device;
connecting said at least one primary recovery device to at least one capturing device
using at least one piece of tubing and a connector such that material can pass from the
primary recovery device to the capturing device;
connecting said at least one capturing device to at least one ultrafiltration and
diafiltration device using at least one piece of tubing and a connector such that material can
pass from the capturing device to the ultrafiltration and diafiltration device;
connecting said at least one ultrafiltration and diafiltration device to at least one
polishing membranes device using at least one piece of tubing and a connector such that
material can pass from the ultrafiltration and diafiltration device to the polishing membrane
device;
connecting said at least one polishing membranes device to at least one polishing
using cation exchange device using at least one piece of tubing and a connector such that
material can pass from the polishing membranes device to the polishing using cation
exchange device; and
connecting said at least one polishing using cation exchange device to at least one
virus reduction filtration device using at least one piece of tubing and a connector such that
material can pass from the polishing using cation exchange device to the virus reduction
filtration device.
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10. The method of claim 9, further comprising:
connecting said at least one virus reduction filtration device to at least one
ultrafiltration and diafiltration device such that material can pass from the virus reduction
filtration device to the ultrafiltration and diafiltration device; and
connecting said at least one ultrafiltration and diafiltration device to at least one
automated bulk fill device such that material can pass from the ultrafiltration and diafiltration
device to the automated bulk fill device.
11. The method of claim 9, wherein the method is automated.
12. The method of claim 10, wherein the method is automated.
13. A method of making biopharmaceuticals comprising:
connecting at least one inputting device to at least one inoculum expansion device
using at least one piece of tubing and a connector such that material can pass from the
inputting device to the inoculum expansion device.
14. A manufacturing system for biopharmaceuticals comprising:
at least one inputting device connected to at least one inoculum expansion device
through at least one piece of tubing and a connector;
said at least one inoculum expansion device is connected to at least one production
stage perfusion device through at least one piece of tubing and a connector;
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said at least one production stage perfusion device is connected to at least one volume
exchange device through at least one piece of tubing and a connector;
said at least one volume exchange device is connected to at least one continuous
filtration device through at least one piece of tubing and a connector;
said at least one continuous filtration device is connected to at least one virus
reduction filtration device through at least one piece of tubing and a connector;
said at least one virus reduction filtration device is connected to at least one
ultrafiltration and diafiltration device through at least one piece of tubing and a connector;
and
said at least one ultrafiltration and diafiltration device is connected to at least one
automated bulk fill device through at least one piece of tubing and a connector.
15. The manufacturing system of claim 14, wherein the device can be from at least two
different manufacturers.
16. The manufacturing system of claim 14, wherein at least one device is not made for
single-use.
17. The manufacturing system of claim 14, wherein the system is operated as a closed
system.
18. The manufacturing system of claim 14, further comprising at least one sensor capable
of controlling flow of material between two devices.
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19. The manufacturing system of claim 14, wherein the system is automated.
20. The manufacturing system of claim 14, wherein at least one device can be in more
than one room.
21. The manufacturing system of claim 14, further comprising at least one disposable bag
that can be used to dispose of at least one device, tubing or connector.
22. A method of making biopharmaceuticals comprising:
connecting at least one inputting device to at least one inoculum expansion device
using at least one piece of tubing and a connector such that material can pass from the
inputting device to the inoculum expansion device;
connecting said at least one inoculum expansion device to at least one production
stage perfusion device using at least one piece of tubing and a connector such that material
can pass from the inoculum expansion device to the production stage perfusion device;
connecting said at least one production stage perfusion device to at least one volume
exchange device using at least one piece of tubing and a connector such that material can pass
from the production stage perfusion device to the volume exchange device;
connecting said at least one volume exchange device to at least one continuous
purification device using at least one piece of tubing and a connector such that material can
pass from the volume exchange device to the continuous purification device;
connecting said at least one continuous purification device to at least one virus
reduction filtration device using at least one piece of tubing and a connector such that
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material can pass from the continuous purification device to the virus reduction filtration
device;
connecting said at least one virus reduction filtration device to at least one
ultrafiltration and diafiltration device using at least one piece of tubing and a connector such
that material can pass from the virus reduction filtration device to the ultrafiltration and
diafiltration device; and
connecting said at least one ultrafiltration and diafiltration device to at least one
automated bulk fill device using at least one piece of tubing and a connector such that
material can pass from the ultrafiltration and diafiltration device to the automated bulk fill
device.
23. A manufacturing system for biopharmaceuticals comprising:
at least one inputting device connected to at least one inoculum expansion device
through at least one piece of tubing and a connector;
said at least one inoculum expansion device is connected to at least one production
stage bioreactor device through at least one piece of tubing and a connector;
said at least one production stage bioreactor device is connected to at least one
primary recovery device through at least one piece of tubing and a connector;
said at least one primary recovery device is connected to at least one volume
exchange device through at least one piece of tubing and a connector;
said at least one volume exchange device is connected to at least one continuous
purification device through at least one piece of tubing and a connector;
said at least one continuous purification device is connected to at least one virus
reduction filtration device through at least one piece of tubing and a connector;
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said at least one virus reduction filtration device is connected to at least one
ultrafiltration and diafiltration device through at least one piece of tubing and a connector;
and
said at least one ultrafiltration and diafiltration device is connected to at least one
automated bulk fill device through at least one piece of tubing and a connector.
24. The manufacturing system of claim 23, wherein the device can be from at least two
different manufacturers.
25. The manufacturing system of claim 23, wherein at least one device is not made for
single-use.
26. The manufacturing system of claim 23, wherein the system is operated as a closed
system.
27. The manufacturing system of claim 23, further comprising at least one sensor capable
of controlling flow of material between two devices.
28. The manufacturing system of claim 23, wherein the system is automated.
29. The manufacturing system of claim 23, wherein at least one device can be in more
than one room.
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30. The manufacturing system of claim 23, further comprising at least one disposable bag
that can be used to dispose of at least one of device, tubing or connector.
31. A method of making biopharmaceuticals comprising:
connecting at least one inputting device to at least one inoculum expansion device
using at least one piece of tubing and a connector such that material can pass from the
inputting device to the inoculum expansion device;
connecting said at least one inoculum expansion device to at least one production
stage bioreactor device using at least one piece of tubing and a connector such that material
can pass from the inoculum expansion device to the production stage bioreactor device;
connecting said at least one production stage bioreactor device to at least one primary
recovery device using at least one piece of tubing and a connector such that material can pass
from the production stage bioreactor device to the primary recovery device;
connecting said at least one primary recovery device to at least one volume exchange
device using at least one piece of tubing and a connector such that material can pass from the
primary recovery device to the volume exchange device;
connecting said at least one volume exchange device to at least one continuous
purification device using at least one piece of tubing and a connector such that material can
pass from the volume exchange device to the continuous purification device;
connecting said at least one continuous purification device to at least one virus
reduction filtration device using at least one piece of tubing and a connector such that
material can pass from the continuous purification device to the virus reduction filtration
device;
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connecting said at least one virus reduction filtration device to at least one
ultrafiltration and diafiltration device using at least one piece of tubing and a connector such
that material can pass from the virus reduction filtration device to the ultrafiltration and
diafiltration device; and
connecting said at least one ultrafiltration and diafiltration device to at least one
automated bulk fill device using at least one piece of tubing and a connector such that
material can pass from the ultrafiltration and diafiltration device to the automated bulk fill
device.
32. A manufacturing system for biopharmaceuticals comprising:
at least one inputting device connected to at least one inoculum expansion device
through at least one piece of tubing and a connector;
said at least one inoculum expansion device is connected to at least one production
stage perfusion device through at least one piece of tubing and a connector;
said at least one production stage perfusion device is connected to at least one volume
exchange device through at least one piece of tubing and a connector;
said at least one volume exchange device is connected to at least one continuous
purification device through at least one piece of tubing and a connector;
said at least one continuous purification device is connected to at least one virus
reduction filtration device through at least one piece of tubing and a connector;
said at least one virus reduction filtration device is connected to at least one
ultrafiltration and diafiltration device through at least one piece of tubing and a connector;
and
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said at least one ultrafiltration and diafiltration device is connected to at least one
automated bulk fill device through at least one piece of tubing and a connector.
33. The manufacturing system of claim 32, wherein the device can be from at least two
different manufacturers.
34. The manufacturing system of claim 32, wherein at least one device is not made for
single-use.
35. The manufacturing system of claim 32, wherein there the system operated as a closed
system.
36. The manufacturing system of claim 32, further comprising at least one sensor capable
of controlling flow of material between two devices.
37. The manufacturing system of claim 32, wherein the system is automated.
38. The manufacturing system of claim 32, wherein at least one device can be in more
than one room.
39. The manufacturing system of claim 32, further comprising at least one disposable bag
that can be used to dispose of at least one device, tubing or connector.
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40. A method for manufacturing biopharmaceuticals comprising:
connecting at least one inputting device to at least one inoculum expansion device
using at least one piece of tubing and a connector such that material can pass from the
inputting device to the inoculum expansion device;
connecting said at least one inoculum expansion device to at least one production
stage bioreactor device using at least one piece of tubing and a connector such that material
can pass from the inoculum expansion device to the production stage bioreactor device;
connecting said at least one production stage bioreactor device to at least one primary
recovery device using at least one piece of tubing and a connector such that material can pass
from the production stage bioreactor device to the primary recovery device;
connecting said at least one primary recovery device to at least one volume exchange
device using at least one piece of tubing and a connector such that material can pass from the
primary recovery device to the volume exchange device;
connecting said at least one volume exchange device to at least one continuous
purification device using at least one piece of tubing and a connector such that material can
pass from the volume exchange device to the continuous purification device;
connecting said at least one continuous purification device to at least one virus
reduction filtration device using at least one piece of tubing and a connector such that
material can pass from the continuous purification device to the virus reduction filtration
device;
connecting said at least one virus reduction filtration device to at least one
ultrafiltration and diafiltration device using at least one piece of tubing and a connector such
that material can pass from the virus reduction filtration device to the ultrafiltration and
diafiltration device; and
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connecting said at least one ultrafiltration and diafiltration device to at least one
automated bulk fill device using at least one piece of tubing and a connector such that
material can pass from the ultrafiltration and diafiltration device to the automated bulk fill
device.
41. A manufacturing system for biopharmaceuticals comprising:
at least one inputting device connected to at least one inoculum expansion device
through at least one piece of tubing and a connector.
42. The manufacturing system of claim 41, further comprising a sensor.
43. A method to manufacture a biopharmaceutical product comprising:
inserting a material into an inoculum device for processing;
transferring the material from the inoculum device to an inoculum expansion device
for further processing;
then transferring the material from the inoculum expansion device to a production
stage bioreactor device for further processing;
then transferring the material from the production stage bioreactor device to a primary
recovery device for further processing;
then transferring the material from the primary recovery device to a capturing device
for further processing;
then transferring the material from the capturing device to an ultrafiltration and
diafiltration device for further processing;
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then transferring the material from the ultrafiltration and diafiltration device to a
polishing membrane device for further processing;
then transferring the material from the polishing membrane device to a polishing
using cation exchange device for further processing;
then transferring the material from the polishing using cation exchange device to a
virus reduction filtration device for further processing;
then transferring the material from the virus reduction filtration device to an
ultrafiltration and diafiltration device for further processing; and
then transferring the material from the ultrafiltration and diafiltration device to an
automated bulk fill device to obtain the biopharmaceutical product.
44. A method to manufacture a biopharmaceutical product comprising:
inserting a material into an inoculum device for processing;
transferring the material from the inoculum device to an inoculum expansion device
for further processing;
then transferring the material from the inoculum expansion device to a production
stage perfusion device for further processing;
then transferring the material from the production stage perfusion device to a volume
exchange device for further processing;
then transferring the material from the volume exchange device to a continuous
filtration device for further processing;
then transferring the material from the continuous filtration device to a virus reduction
filtration device for further processing;
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then transferring the material from the virus reduction filtration device to an
ultrafiltration and diafiltration device for further processing; and
then transferring the material from the ultrafiltration and diafiltration device to an
automated bulk fill device to obtain the biopharmaceutical product.
45. A method to manufacture a biopharmaceutical product comprising:
inserting a material into an inoculum device for processing;
transferring the material from the inoculum device to an inoculum expansion device
for further processing;
then transferring the material from the inoculum expansion device to a production
stage bioreactor device for further processing;
then transferring the material from the production stage bioreactor device to a primary
recovery device for further processing;
then transferring the material from the primary recovery device to a volume exchange
device for further processing;
then transferring the material from the volume exchange device to a continuous
purification device for further processing;
then transferring the material from the continuous purification device to a virus
reduction filtration device for further processing;
then transferring the material from the virus reduction filtration device to an
ultrafiltration and diafiltration device for further processing; and
then transferring the material from the ultrafiltration and diafiltration device to an
automated bulk fill device to obtain the biopharmaceutical product.
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46. A method to manufacture a biopharmaceutical product comprising:
inserting a material into an inoculum device for processing;
transferring the material from the inoculum device to an inoculum expansion device
for further processing;
then transferring the material from the inoculum expansion device to a production
stage perfusion device for further processing;
then transferring the material from the production stage perfusion device to a volume
exchange device for further processing;
then transferring the material from the volume exchange device to a continuous
purification device for further processing;
then transferring the material from the continuous purification device to a virus
reduction filtration device for further processing;
then transferring the material from the virus reduction filtration device to an
ultrafiltration and diafiltration device for further processing; and
then transferring the material from the ultrafiltration and diafiltration device to an
automated bulk fill device to obtain the biopharmaceutical product.