TECHNICAL FIELD

[0001] Embodiments of the present disclosure relate generally to manufacturing therapeutics for the prevention and treatment of infectious diseases and public health threats; and more specifically to processes, a modular manufacturing system, a modular manufacturing unit, and components for manufacturing such therapeutics.

BACKGROUND

[0002] Few threats compare with infectious diseases in terms of potential for catastrophic loss of life. Globalization is increasing the threat of emerging infectious diseases spreading outside the country of origin. Due to increased international travel, particularly by air, an infection can spread around the world in a short period of time.

[0003] With nearly four billion trips taken by air in 2016, an infection can make its way around the world in a day or less. Modeling by Gates Foundation shows that a virulent strain of airborne influenza could spread to all major capitals within 60 days and kill more than 33 million people within 250 days (Protecting Humanity from Future Health Crises Report of the High-level Panel on the Global Response to Health Crises 2016 Advance Unedited Copy; UN). [0004] Pandemics have become a threat to global health security yet nations devote only a fraction of the resources spent on national security to prevent and to prepare for pandemics, and the cost of pandemics in terms of global GDP are estimated to fall within the same range as the impact of climate change (The Neglected Dimension of Global Security A Framework to Counter Infectious Disease Crises: Commission on the Global Health Risk Framework for the Future; Pandemic risk: how large are the expected losses?; Bull World Health Organ 2018; 96:129-134).

[0005] A significant challenge in emerging infectious diseases is that outbreaks can rapidly propagate locally and spread regionally and globally before vaccines or manufactured antibody therapeutics can be deployed. BRIEF SUMMARY

[0006] In an embodiment, a method of treating plasma for pathogen reduction is provided. The method includes receiving a batch of plasma packaged as a plurality of plasma samples containing a raised level of one or more antibodies, introducing riboflavin to the batch of plasma, exposing the batch of plasma containing the riboflavin to ultraviolet radiation to reduce pathogens contained in the batch of plasma to obtain a treated batch of plasma, and employing the treated batch of plasma in a process to concentrate the one or more antibodies to manufacture a hyperimmune composition of antibodies.

[0007] In a further embodiment, a method of preparing pathogen reduced plasma for hyperimmune antibody composition manufacturing is provided. The method includes receiving a plurality of treated plasma samples, the plurality of treated plasma samples containing riboflavin employed in an ultraviolet radiation pathogen reduction process, pooling the plurality of treated plasma samples to generate a pooled treated plasma sample, filtering the pooled treated plasma sample via a depth filter including activated carbon to remove at least a portion of the riboflavin to generate a filtered plasma sample, and employing the filtered plasma sample in a process to concentrate one or more antibodies contained in the filtered plasma sample to manufacture a hyperimmune composition of the one or more antibodies.

[0008] In a further embodiment, a modular system for manufacturing a hyperimmune antibody composition is provided. The modular system includes a transfer system configured to transfer products between stations without exposure to a local environment, an isolation station including at least one chromatography column configured to isolate at least one antibody in a pooled plasma sample to create an isolated antibody composition, a filtering station including a virus filter configured to reduce viral contaminants in the isolated antibody composition obtained from the isolation station via the transfer system to create a filtered antibody composition, a concentration station including a concentration receptacle configured to concentrate and formulate the filtered antibody composition obtained from the filtering station via the transfer system to create a concentrated antibody composition, and a sterilization station including a sterilizing filter configured to sterilize the concentrated antibody composition obtained from the concentration station via the transfer system to create the hyperimmune antibody composition

[0009] In a further embodiment, a method for manufacturing a hyperimmune antibody composition is provided. The method includes receiving pooled plasma containing raised levels of at least one antibody at an isolation station, isolating the at least one antibody in the pooled plasma at the isolation station including a chromatography column to create an isolated antibody composition, transferring the isolated antibody composition from the isolation station to a filtering station without exposure to a local environment, filtering the isolated antibody composition to reduce viral contaminants in the isolated antibody composition to create a filtered antibody composition, transferring the filtered antibody composition from the filtering station to a concentration station without exposure to the local environment, concentrating the filtered antibody composition at the concentration station to create a concentrated antibody composition, transferring the concentrated antibody composition from the concentration station to a sterilization station without exposure to the local environment, and sterilizing the concentrated antibody composition at the sterilization station to create the hyperimmune antibody composition

[0010] In a further embodiment, a thawing drape is provided. The thawing drape includes a panel comprising a water-resistant material, the panel having a top and a bottom, a plurality of pockets disposed on a first side of the panel, the plurality of pockets having openings oriented towards the top of the panel and comprising a permeable material permitting fluid flow, and a trough disposed at the bottom of the panel on the first side, the trough configured to catch and collect liquid exiting the plurality of pockets.

[0011] Other aspects and embodiments of the present disclosure are described in more detail below.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012] The accompanying drawings, which are incorporated herein and form a part of the specification, illustrate the present disclosure and, together with the description, further serve to explain the principles of the disclosure and to enable a person skilled in the pertinent art to make and use the disclosure.

[0013] FIG. 1 shows a schematic of a modular response platform in accordance with embodiments hereof.

[0014] FIG. 2 is a flowchart illustrating hyperimmune antibody composition manufacturing process for a modular response platform in accordance with embodiments hereof.

[0015] FIG. 3 is an illustration of a modular manufacturing unit for manufacturing an infectious disease therapeutic in accordance with embodiments hereof.

[0016] FIG. 4 shows a schematic of a modular manufacturing unit for manufacturing a hyperimmune antibody composition in accordance with embodiments hereof. [0017] FIG. 5 shows a hyperimmune antibody composition manufacturing process for a modular manufacturing unit in accordance with embodiments hereof.

[0018] FIG. 6 shows a thawing apparatus for a modular manufacturing unit in accordance with embodiments hereof.

DETAILED DESCRIPTION

[0019] The present disclosure addresses an unmet need for processes and systems to manufacture rapidly deploy able therapeutic and/or prophylactic products that can confer immediate passive immunity to protect health, infrastructure, and security personnel, and provide a protective barrier against new and emerging pandemic pathogens (e.g., fence in pandemic pathogens in early stages of an outbreak). In particular, the present disclosure provides a modular response platform configured for rapidly manufacturing hyperimmune antibody compositions.

[0020] The present disclosure describes a modular response platform including processes, equipment, and materials configured for rapidly manufacturing hyperimmune antibody compositions. The modular response platform may include processes, materials, and equipment for performing assays to screen potential plasma donors. The modular response platform may further include processes, materials, and equipment for plasma collection (plasmapheresis). The modular response platform may further include processes, materials, and equipment for pathogen reduction in the collected plasma. The modular response platform may further a modular manufacturing unit (also referred to as an MMU) configured for manufacturing hyperimmune antibody compositions. The modular response platform may further include processes, materials, and equipment for distributing a deployable therapeutic.

[0021] Embodiments of the present disclosure provide a process for preparing a sterile polyclonal immunoglobulin composition (hyperimmune antibody composition), a modular response platform including at least a modular manufacturing unit for performing the process, to facilitate the manufacture of an antibody therapeutic or prophylactic product (e.g., derived from convalescent plasma) on-site in areas of emerging infectious disease and during emergency situations. The process for the modular manufacturing unit is configured and adapted (in terms of size, materials, and processing time) for execution in a modular shipping container or enclosure that can be deployed to manufacture therapeutic in areas where there are declared outbreaks. The modular manufacturing unit and modular response platform may also be used in non-outbreak situations. For example, the modular manufacturing unit may be deployed to a country with an area-specific pathogen that does not have a commercially available therapeutic, or with a pathogen that pharmaceutical companies do not manufacture a product for because there is not a large enough global market.

[0022] In embodiments, the modular response platform may be leveraged to quickly address a known or unknown pathogen, generating product directly at the point of need and using a distributed care strategy. In embodiments, the modular response platform may be deployed early in an outbreak situation preventing further spread of the pathogen into the population. Some embodiments provide immediate passive immunity to protect personnel essential to stabilizing health, infrastructure, and security needed during an outbreak. In embodiments, a product (e.g., sterile polyclonal immunoglobulin composition) may be manufactured and deployed locally, reducing transport in and out of epidemic areas.

[0023] Embodiments of the modular response platform described herein facilitate the rapid response on-site nature of the hyperimmune antibody composition manufacturing methods discussed herein. In particular, elements of the modular response platform and processes described herein differ from conventional or traditional antibody manufacturing equipment, methods, and techniques to facilitate the rapid deployment of antibody manufacturing facilities in an on-site manner with non-expert operators. To optimize mobility, rapidity, and ease of use, the modular response platform and modular manufacturing unit employ systems and processes that may have drawbacks in a traditionally sited manufacturing environment, such as lower efficiency, higher cost, and others.

[0024] Immunoglobulins, referred to interchangeably herein as antibodies or immune globulins, are normal constituents of the human body fluid and are used at physiological levels without creating pharmacologic/toxicologic active metabolites. The plasma from convalescent individuals, as a source of neutralizing antibodies for use in passive immunotherapy, has been used for the treatment of many types of viral infections, including, e.g., Ebola virus, Cytomegalovirus, respiratory syncytial virus, smallpox virus, hepatitis A and B viruses, influenza, and rabies virus. Passive antibody therapy prevents many human viral diseases, and there are currently several human polyclonal immunoglobulin products approved for passive immunotherapy against various viral infections including varicella, rabies, vaccinia, hepatitis A and B, cytomegalovirus, and respiratory syncytial virus.

[0025] In embodiments, polyclonal immunoglobulin compositions may be used for the treatment of a known infectious disease, a mutant strain of an infectious disease, or a new infectious disease.

[0026] Hyperimmune products include products manufactured from plasma that have elevated (hyper) or raised levels of antibodies relevant to a pathogen of interest. Development of a hyperimmune product from high titer plasma offers advantages over convalescent plasma, creating an opportunity for a more standardized product that can be administered to a larger number of patients. Purified and concentrated hyperimmune polyclonal antibody compositions offer an improved therapeutic, e.g., each plasma donation goes further as compared to single plasma units, as the use of multiple donors in a plasma pool and subsequent product creates a more heterogeneous product and improved overall product consistency in patient use. The ability to deliver a more concentrated antibody also allows for lower dosing volumes and flexibility in route of administration. Additionally, purification of the hyperimmune antibody compositions may include orthogonal viral reduction steps, improving overall patient safety.

[0027] Standardized and validated hyperimmune manufacturing processes for the manufacture of licensed commercial products such as HEPAGAM B [Hepatitis B Immunoglobulin (Human) Injection], CNJ-016 [Vaccina Immune Globulin Intravenous (Human)], ANTHRASIL [Anthrax Immune Globulin Intravenous (human)], and VARIZIG [Varicella Zoster Immunoglobulin Intravenous (Human)] are available. These manufacturing processes are designed for employment at a dedicated facility remote from the outbreak site of an emerging infectious disease. The manufacturing processes at such facilities may be optimized for factors such as cost and efficiency, rather than rapid deployment by non-expert operators. Accordingly, such traditional manufacturing processes may take too long (e.g., at least about 1 week) to effectively combat emerging infectious diseases and provide additional time to spread far beyond initial outbreak sites.

[0028] Embodiments described herein are directed to improved processes and systems for manufacturing compositions having antibodies that bind to an antigen, which may be used in a region of an emerging infectious disease and/or for rapid production of a sterile polyclonal immunoglobulin composition. In embodiments, such compositions as described herein may be manufactured and ready for use within less than 48 hours, less than 36 hours, less than 30 hours, or less than 24 hours. Additionally, because the manufacturing processes are provided in a mobile on-site unit in settings that lack the infrastructure to support a conventional manufacturing facility, the time to deployment may be greatly reduced.

[0029] In embodiments, the antibodies of the hyperimmune antibody compositions described herein may include polyclonal antibodies. In embodiments, the antibodies of the compositions may include IgG antibodies. In embodiments, IgG antibodies of the compositions may be at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of the total protein content of the compositions. In other embodiments, IgG antibodies of the compositions may be about 50% to 100%, about 60% to 100%, about 70% to 100%, about 80% to 100%, about 90% to 100%, about 95% to 100%, about 50% to about 95%, about 60% to about 95%, about 70% to about 95%, about 80% to about 95%, about 85% to about 95%, about 90% to about 95%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 80% to about 90%, about 85% to about 90% of the total protein content of the compositions, or any range or value therein. The percent IgG content may be measured, for example, by chromatography or gel electrophoresis. The chromatography may be, without limit, size exclusion chromatography. The gel electrophoresis may be SDS-PAGE or agarose gel electrophoresis.

[0030] In embodiments, the antibodies employed in manufacturing compositions in accordance with embodiments hereof may be from pooled plasma, serum samples, or any combination thereof, as discussed herein. The antibodies may be from pooled plasma, serum samples, or any combination thereof derived from a single mammalian donor or a plurality of mammalian donors. The antibodies may be from pooled plasma, serum samples, or combinations thereof from a single human donor or a plurality of human donors. The single donor or the plurality of donors may have elevated or raised levels of antibodies against an infectious agent. The single donor or the plurality of donors may have been infected with an infectious agent prior to pooling plasma and/or serum. The single donor or plurality of donors may have been infected with the infectious agent and recovered from the infection. The single donor or plurality of donors may have been exposed to an infected patient (e.g., a family member, a neighbor, etc.), but did not show signs of disease or the single donor or plurality of donors may have been vaccinated with a vaccine to the infectious agent prior to the pooling of plasma and/or serum.

[0031] In embodiments, the compositions may include antibodies to specific antigens obtained from plasma and/or serum. The compositions may be enriched with antibodies specific to one or more epitopes of a virus, a bacterium, a fungus, or a parasite. In embodiments, the compositions may be prepared from a plasma and/or serum obtained from an individual or plurality of individuals with elevated levels of antibodies specific to the infectious agent. The individual or the plurality of individuals may have elevated levels of antibodies due to previous exposure to an antigen (e.g., an individual or pool of individuals previously infected with an infectious agent). The individual or the plurality of individuals may have elevated levels of antibodies due to intentional stimulation of the immune response (e.g., administration of a vaccine). In embodiments, the antibodies may be immune globulins. [0032] In embodiments, a composition of neutralizing antibodies may be a hyperimmune composition of antibodies.

[0033] In embodiments, the hyperimmune compositions may be derived from an individual or a plurality of individuals who have been positively diagnosed as being infectious agent probable (i. e. , previously having or likely previously having an infection), e.g., using the assays and/or methods described herein or known in the art. The hyperimmune compositions may be derived from an individual or plurality of individuals who have been positively identified to have elevated or raised levels of one or more antibodies against an infectious agent, e.g., using the assays and/or methods described herein or known in the art. In other embodiments, the hyperimmune compositions may be derived from an individual or plurality of individuals that have been hyper-immunized with one or more antigens. The IgG circulating in the exposed or hyperimmunized individual or individuals are specific to the infectious agent may be at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10%.

[0034] In embodiments, compositions including neutralizing antibodies may include blood, a blood product, or a combination thereof.

[0035] In embodiments, hyperimmune compositions may be prepared by a method that includes (a) identifying one or more suitable donors and (b) processing the plasma or serum from the one or more suitable donors according to the methods described herein to produce and/or manufacture the hyperimmune composition. In embodiments, the method may include purifying antibodies from the processed plasma or serum. In embodiments, the purified antibodies may be an IgG antibody.

[0036] In embodiments, a composition may include neutralizing antibodies that have a percent neutralization of at least 0.25%, at least 0.5%, at least 0.75%, or at least 1%.

[0037] Embodiments discussed herein are directed to manufacturing processes for preparing polyclonal immunoglobulin compositions, for example, a hyperimmune composition of antibodies. Manufacturing processes are provided that may be useful in a public health emergency, e.g., in the region of an emerging infectious disease and/or pandemic or in the production of blood products in a specific region where the products do not have a global market to justify a pharmaceutical company manufacturing the products (e.g., snake antivenom). In embodiments, hyperimmune compositions may be prepared from pooled donor plasma samples from a convalescent donor, convalescent donors, an immunized donor, immunized donors, an asymptomatic infection-household contact donor, asymptomatic infection-household contact donors, or a combination thereof according to manufacturing processes described herein.

[0038] Embodiments discussed herein are directed to manufacturing processes for preparing a polyclonal immunoglobulin composition. In embodiments, the manufacturing processes may include receiving a batch of plasma packaged as a plurality of plasma samples, each containing a raised level of one or more antibodies. During such manufacturing processes, the batch of plasma may be pooled and/or separated into individual aliquots as discussed below. Such samples may be obtained from donors exposed to an infectious agent or an antigenic component. The manufacturing processes may further include introducing riboflavin to the batch of plasma. The manufacturing processes may further include exposing the batch of plasma containing the riboflavin to ultraviolet radiation to reduce pathogens contained in the batch of plasma to obtain a treated batch of plasma. The manufacturing processes may further include employing the treated batch of plasma in a process to concentrate the one or more antibodies to manufacture a hyperimmune composition of antibodies.

[0039] Embodiments discussed herein are directed to a process for preparing a polyclonal immunoglobulin composition, e.g., hyperimmune antibody composition. The process may include receiving individual donations of plasma packaged as a plurality of plasma samples, each containing a raised level of one or more antibodies. During the manufacturing process, the batch of plasma may be further separated into individual aliquots as discussed below. Such samples may be obtained from donors exposed to an infectious agent or an antigenic component. The process may further include introducing riboflavin to the individual donations of plasma. The process may further include exposing the batch of plasma containing the riboflavin to ultraviolet radiation to reduce pathogens contained in the individual plasma donations to obtain a treated batch of plasma donations. The process may further include pooling individually treated donations to create a batch and employing the treated batch of plasma in a process to concentrate the one or more antibodies to manufacture a hyperimmune composition of antibodies.

[0040] In embodiments, donor plasma samples may be obtained in a region of an outbreak of an infectious agent or where an infectious agent is emerging. In embodiments, the infectious agent may be viral or bacterial. The infectious agent may be a known or unknown viral or bacterial pathogen. In embodiments, a plurality of donor plasma samples may be obtained. In embodiments, each donor plasma sample may be dispensed in a sample container, e.g., a bag, a tank, or other type of receptacle. In embodiments, donor plasma samples may be frozen in sample containers, e.g., for storage. In embodiments, the sample containers may be a singleuse sample container.

[0041] In embodiments, a plurality of plasma samples to be pooled may be frozen and thawed before use. In embodiments, a frozen plurality of plasma samples may be thawed. In embodiments, thawing may be performed at a thawing station (see FIG. 6). In embodiments, thawing may take less than 30 hours, less than 29 hours, less than 28 hours, less than 27 hours, less than 26 hours, less than 25 hours, less than 24 hours, less than 23 hours, less than 22 hours, less than 21 hours, less than 20 hours, less than 19 hours, less than 18 hours, less than 17 hours, less than 16 hours, less than 15 hours, less than 14 hours, less than 13 hours, or less than 12 hours. In other embodiments, thawing may take between about 12 and about 30 hours, between about 12 to about 25 hours, between about 14 and about 28 hours, or between about 16 and about 25 hours. In embodiments, a thawing station may be part of a pooling station.

[0042] Thawing may proceed via any suitable means. In embodiments, thawing may include placing sample containers containing frozen donor plasma samples into a thawing station. The thawing station may include a thawing drape, an example of which is shown in FIG. 6. In embodiments, the thawing drape may be a single-use thawing drape. Thus, no pre-use or postuse cleaning is required for a single-use thawing drape. An example of a thawing drape consistent with embodiments hereof is discussed in greater detail with respect to FIG. 6.

[0043] In embodiments, processes may include treating the plurality of donor plasma samples (i.e., the batch of plasma) individually before pooling the plasma samples and/or treating the pooled plasma for pathogen reduction before isolating immunoglobulin from the pooled plasma. The pathogen reduction may be performed external to a housing where the process takes place. In embodiments, pathogen reduction may be performed internal to a housing where the process takes place. The pathogen reduced plurality of donor plasma samples may be frozen, e.g., to store until ready for pooling. In embodiments, no further pathogen reduction (or other viral reduction) is performed during the process except for virus filtration and isolation of immunoglobulin. Pathogen reduction steps are discussed in greater detail below with respect to FIGS. 4-6.

[0044] Processes in accordance with embodiments hereof may include pooling a plurality of plasma samples from donors exposed to an infectious agent or an antigenic component thereof to produce a pooled plasma composition. The plurality of plasma samples may be thawed prior to pooling and/or may be pooled without having been frozen. In embodiments, plasma may be pooled after a pathogen reduction step. In further embodiments, plasma may be pooled prior to a pathogen reduction step, aliquoted individually to facilitate the pathogen reduction step, and then pooled again prior to manufacture.

[0045] In embodiments, a volume of pooled plasma may be less than 100 L, less than 90 L, less than 80 L, less than 70 L, less than 50 L, less than 40 L, less than 30 L, or less than 20 L. In other embodiments, a volume of pooled plasma may be about 10 L to about 100 L; about 10 L to about 90 L; about 10 L to about 80 L; about 10 L to about 70 L; about 10 L to about 60 L; about 10 L to about 50 L; about 15 L to about 100 L; about 15 L to about 90 L; about 15 L to about 80 L; about 15 L to about 70 L; about 15 L to about 60 L; about 15 L to about 50 L; about 20 L to about 100 L, or about 30 L to about 50 L.

[0046] In embodiments, pooling may be performed at a pooling station. The pooling station may include a pooling receptacle to receive a plurality of donor plasma samples. One or more plasma samples of a plurality of plasma samples may be pooled into the pooling receptacle. In embodiments, a pooling receptacle may hold up to 100 L, up to 90 L, up to 80 L, up to 70 L, up to 60 L, up to 50 L, up to 40 L, up to 30 L, up to 20 L, or up to 10 L. In other embodiments, a pooling receptacle may hold about 10 L to about 100 L; about 10 L to about 90 L; about 10 L to about 80 L; about 10 L to about 70 L; about 10 L to about 60 L; about 10 L to about 50 L; about 15 L to about 100 L; about 15 L to about 90 L; about 15 L to about 80 L; about 15 L to about 70 L; about 15 L to about 60 L; about 15 L to about 50 L; about 20 L to about 100 L; or about 30 L to about 50 L. In embodiments, a pooling receptacle may be a single-use receptacle. [0047] In embodiments, pooling may take place while sample containers are in the thawing drape. Thus, the donor plasma may be extracted from the sample containers without having to be removed from the thawing drape. The pooling station and/or the thawing drape may include a hose configured to transfer the plasma samples from the plurality of sample containers into a first pooling receptacle of the pooling station for pooling of the plasma samples. The hose may transfer one sample container at a time into the pooling receptacle and then be moved to a next sample container, e.g., until all sample containers are emptied and/or the first pooling receptacle is full. After the plasma samples have been pooled into the first pooling receptacle, the thawing drape and the plurality of sample containers may be disposed of, thus freeing up the footprint of the thawing drape. In further embodiments, pooling may take place after the sample containers have been thawed and removed from the thawing drape.

[0048] In embodiments, pooled plasma may be treated prior to isolating immunoglobulin, e.g., dilution, lipid reduction, or ionic strength adjustment. The pooled plasma composition may be diluted. Diluting may be performed prior to isolating immunoglobulin from the pooled plasma. Diluting may be part of a treatment of the pooled plasma. [0049] In embodiments, pooled plasma may be treated before isolating immunoglobulin from the pooled plasma to reduce lipids. The process may include adding an additive to the plasma. The additive may reduce lipids in the pooled plasma. The additive may comprise dextran sulphate, LRA (lipid removal agent) - advanced minerals, cryoprecipitation with or without ethanol, cold ammonium sulphate precipitation, or any combination thereof. In further embodiments, the additive may comprise dextran sulphate. In embodiments, the additive may be added to about 0.026% w/w to about 0.034% w/w for lipid precipitation. The lipid reduction treatment may be performed prior to isolating immunoglobulin from the pooled plasma. Some embodiments may include clarifying pooled plasma through depth filtration for reduction of lipids.

[0050] In embodiments, lipid reduction may be performed with one or more plasma clarification filters. In further embodiments, plasma clarification filters may be depth filters. Plasma clarification filters may be single-use filters. A filter media for plasma clarification filters may include cellulose. A filter media for plasma clarification filters may include a fine stainless-steel or plastic screen. In a further embodiment, a filter media for plasma clarification filters may be a fine stainless-steel screen. In further embodiments, lipid reduction may be performed prior to isolating immunoglobulin from the pooled plasma.

[0051] In additional embodiments, pooled plasma may be further filtered to remove riboflavin and/or riboflavin degradants via the use of a depth filter during the lipid reduction filtration process. In embodiments, a plasma clarification filter may include activated carbon. In further embodiments, activated carbon may be added to pooled plasma prior to filtration via a plasma clarification filter. These additional steps may be conducted to remove riboflavin added during a pathogen reduction step.

[0052] In embodiments, ionic strength of pooled plasma may be adjusted. For example, the ionic strength adjustment may be performed prior to isolating immunoglobulin from the pooled plasma. In embodiments, ionic strength adjustment may be part of treatment of pooled plasma. In additional embodiments, treated plasma may be collected in a receptacle prior to isolating immunoglobulin.

[0053] In embodiments, one or more treatments of the pooled plasma may be completed at the pooling station. In further embodiments, one or more of treatments of the pooled plasma may be completed at an isolating station. In embodiments, treatment of pooled plasma may be completed at a dedicate treatment station.

[0054] In embodiments, manufacturing processes include isolating (also referred to as purifying herein) immunoglobulin from batches of donor plasma pools containing low titers, medium titers, high titers, or a combination thereof of titers of antibodies. Isolating at least one antibody from the pooled plasma sample may generate an isolated antibody composition. The isolating may be performed at an isolating station. The isolating station may include one or more chromatography columns for isolating immunoglobulin from pooled plasma obtained from the pooling station. In embodiments, one or more chromatography columns may include viral reduction capabilities.

[0055] In embodiments, immunoglobulin may be isolated from pooled plasma compositions (or treated pooled plasma compositions) using at least one chromatography column to produce an isolated antibody composition, i.e., a polyclonal immunoglobulin composition. In further embodiments, immunoglobulin may be isolated from a pooled plasma composition by ion exchange (IEX) or affinity chromatography. In other embodiments, ion exchange (IEX) chromatography may include a weak ion exchange resin or a strong ion exchange resin.

[0056] In embodiments, a single chromatography column or a plurality of chromatography columns may be single-use. In embodiments, isolating stations may include resin capture filters. In embodiments, resin capture filters may be single-use filters. In embodiments, resin capture filters may be disposed in line with chromatography columns. Single-use, i.e., disposable, chromatography columns may facilitate rapid manufacturing and ease of set-up. Preparing chromatography columns, e.g., packing and equilibrating resins, may be time consuming and/or require specific expertise. The modular manufacturing system described herein may employ single use chromatography columns packed with pre-equilibrated resin. An operator, therefore, may receive one or more ready to use chromatography columns and install it into the isolation station to begin manufacturing immediately without the requirement of the time consuming and difficult packing and equilibrating steps. After use, the one or more chromatography columns may be removed and replaced by one or more other ready to use chromatography columns.

[0057] In embodiments, chromatography columns may use pre-equilibrated resin. Preequilibrating the resin minimizes total processing time for the process, allowing for the process to be completed within 48 hours, 36 hours, 30 hours, or 24 hours. The pre-equilibrated resin may be nearly ready to use when received by the operator.

[0058] In embodiments, manufacturing processes may include filtering isolated antibody compositions to remove or reduce viral contaminants by size exclusion to produce virus filtered polyclonal immunoglobulin compositions.

[0059] In embodiments, filtering may be performed at a filtering station. The filtering station may include one or more pre-filters and/or virus filters for removing or reducing viral contaminants by size exclusion from the isolated antibody composition obtained from the isolation station to generate a filtered antibody composition. A virus filter may be a single-use virus filter, consistent with the single-use nature of aspects discussed herein. A virus filter may include Cuprammonium regenerated cellulose or a polyethersulfone membrane. In embodiments, virus filters may include a pore size of about 0.02 pm (about 20 nm). In embodiments, virus filters may include a hollow fiber membrane structure or a sheet membrane structure.

[0060] In embodiments, manufacturing processes may include concentrating a filtered antibody composition to produce a concentrated antibody composition. Concentrating may be performed at a concentration station. A concentration station may include a receptacle for concentrating the filtered antibody composition obtained from the filtering station. Concentration may include ultrafiltration and/or diafiltration with a filter. Diafiltering a concentrated polyclonal immunoglobulin composition may be performed before filter sterilizing. In embodiments, there may be no further pathogen and/or viral reduction performed after filtering of an isolated polyclonal immunoglobulin composition to remove or reduce viral contaminants by size exclusion to produce a virus filtered polyclonal immunoglobulin composition.

[0061] In embodiments, immunoglobulin may be concentrated and/or diafiltered against a formulation buffer. In embodiments, concentrated antibody compositions may be formulated in a solution. Formulation may be performed at the concentration station and/or at a dedicated formulation station.

[0062] In embodiments, formulation solutions may include L-proline, acetate, or a combination thereof. Formulation solutions may include L-proline at a concentration of about 170 mM to about 290 mM. Formulation solutions may further include acetate at a concentration of about 0 to about 25 mM. Formulation solutions may be pH adjusted. In embodiments, the pH of a concentrating polyclonal immunoglobulin composition may be adjusted before filter sterilizing. In embodiments, the pH may be adjusted to between about 4.0 to about 7.0.

[0063] In embodiments, concentrated polyclonal immunoglobulin may be diafiltered directly into a formulation solution, which does not require further pH adjustment. In embodiments, the formulation chosen for the process may include a protein stabilizer to impart stability with respect to protein aggregation. In embodiments, incorporation of acetate as a buffering component may allow for control of pH in a drug substance manufacturing step without requiring addition of acid or base by the operator. This may reduce complexity while providing assurance that the product is maintained within a pH range that is appropriate to maintain stability of a product.

[0064] In embodiments, processes may include filter sterilizing formulated polyclonal immunoglobulin compositions to produce sterile hyperimmune antibody compositions. The filter sterilization may be performed at a sterilization station. The sterilization station may include a filter for sterilizing concentrated immunoglobulin received from a concentration station. A formulated polyclonal immunoglobulin composition may be sterilized using a 0.2 pm filter.

[0065] In embodiments, filter sterilization stations may include a laminar flow hood or directional HEP A filtered air supply. In embodiments, filter sterilizing may be completed within a modular manufacturing unit under a directional HEPA filtered air supply.

[0066] In embodiments, a filter sterilization step may be a final step in the manufacture of a bulk drug substance prior to packaging. In embodiments, a bulk drug substance may be filled into sterile packaging and then stored short-term at about 2°C to about 8°C until use in a distributed care strategy. The bulk drug substance may also be frozen and stored at sub-zero temperatures and/or kept at room temperature, e.g., for distribution.

[0067] In embodiments, manufacturing processes may further include packaging or filling sterile polyclonal immunoglobulin compositions into a plurality of sterile drug product containers, a multi-use drug product container, and/or a bulk packaging container for transport to a separate facility. Packaging or filling may be performed at a packaging station. A packaging station may include a plurality of sterile drug product containers for packaging a concentrated sterile immunoglobulin composition obtained from a sterilization station. Drug product containers may be single-use drug product containers. Single-use sterile drug product containers may be selected from the group consisting of a bag, a vial, a bottle, a syringe, a micro-injector, and any combination thereof.

[0068] A resulting product may include a bulk drug product. A sterile polyclonal immunoglobulin composition may include a hyperimmune composition of antibodies. In embodiments, sterile polyclonal immunoglobulin compositions may be formulated for intramuscular or intravenous administration. In embodiments, sterile polyclonal immunoglobulin compositions may be formulated for intramuscular administration.

[0069] In embodiments, packaged sterile polyclonal immunoglobulin compositions may be finished products (e.g., a sterile drug product). After packaging a plurality of single-use sterile drug product containers each may include a volume sufficient for a single dose of a sterile polyclonal immunoglobulin composition. A dose may be less than 10 mL. In other embodiments, a dose may be greater than 10 mL. In further embodiments, a dose may be about 1 mL to about 10 mL, about 1 mL to about 9 mL, about 1 mL to about 8 mL, about 1 mL to about 7 mL, about 1 mL to about 6 mL, about 1 mL to about 5 mL, about 2 mL to about 10 mL, about 2 mL to about 9 mL, about 2 mL to about 8 mL, about 2 mL to about 7 mL, about 2 mL to about 6 mL, or about 2 mL to about 5 mL.

[0070] In embodiments, one or more of the process steps or procedures may be performed in a station. There may be no structural separation between stations. In embodiments, there may be structural separation between a pooling station and all subsequent stations. In embodiments, there may be structural separation between all stations.

[0071] Embodiments hereof may include a transfer system configured to facilitate closed and continuous movement of product between various stations. A transfer system may be a single use collection of components, including tubes, valves, connectors, locks, and pumping equipment designed and employed to permit closed and continuous movement of product through the modular manufacturing unit.

[0072] As used herein, “product” refers to various states and stages of initial plasma samples as they are used in the manufacture of a hyperimmune composition. For example, product refers to a batch of plasma, pooled plasma samples, an isolated antibody composition, a filtered antibody composition, a concentrated antibody composition, a hyperimmune antibody composition, etc. As used herein, “closed system” refers to a process system with equipment designed and operated such that a product is not exposed to the local environment. Materials may be introduced to a closed system in such a way to avoid exposure of a product to the environment. As used herein, “functionally closed system” refers to a process system that may be routinely opened (e.g., to make a connection), but is returned to a closed state through a sanitization or sterilization step prior to process use.

[0073] In embodiments, a transfer system operates to continuously move product from one station to another station, a feature which enables the closed nature of the system as well as the rapid nature of the manufacturing. A transfer system is closed to the local environment, which permits manufacture of hyperimmune compositions within an environment that may not otherwise achieve the levels of sterility associated with traditional manufacturing sites. This feature may provide a particular advantage in a mobile setting of a modular manufacturing unit discussed herein, as maintaining sterility may be more difficult in on-site deployment in developing areas or areas lacking sufficient infrastructure. Further details of transfer systems in accordance with embodiments hereof are discussed below. [0074] In embodiments, pooling after pathogen reduction, isolating, filtering, concentrating, formulating, and filter sterilizing, as described herein, may be completed in less than 48 hours, less than 36 hours, less than 30 hours, or less than 24 hours. In other embodiments, pooling, isolating, filtering, concentrating, formulating, filter sterilizing, and packaging, as described herein, may be completed in less than 48 hours, less than 36 hours, less than 30 hours, or less than 24 hours.

[0075] In embodiments, manufacturing processes may be performed in a modular manufacturing unit, a hospital, a laboratory, a GMP facility, or the like, as described herein.

[0076] Embodiments hereof include a modular manufacturing unit for preparing a sterile polyclonal immunoglobulin composition. The modular manufacturing unit may include: (a) a pooling station including a pooling receptacle to receive a batch of plasma packaged as a plurality of plasma samples containing raised antibody levels from donors exposed to an infectious agent or an antigenic component thereof; (b) an isolation station including one or more chromatography columns (optionally single-use) for isolating immunoglobulin from the pooled plasma obtained from the pooling station; (c) a filtering station including a virus filter (optionally single-use) for removing or reducing viral contaminants by size exclusion from the isolated immunoglobulin obtained from the isolation station; (d) a concentration station including a concentration receptacle for concentrating the filtered immunoglobulin obtained from the filtering station; and (e) a sterilization station including a filter for sterilizing the concentrated immunoglobulin obtained from the concentration station. In a further embodiment, the modular manufacturing unit may include (I) a packaging station comprising a plurality of single-use drug product containers for packaging the concentrated sterile immunoglobulin composition obtained from the sterilization station. In further embodiments, a modular manufacturing unit may also include a transfer system configured to facilitate closed transfer between stations, i.e., transfer without exposure to a local environment.

[0077] In embodiments, some or all of the process, as described herein, may be completed within a modular manufacturing unit. In embodiments, some or all of the process, as described herein, may be completed within a closed system. In embodiments, for example, pooling, isolating, filtering, concentrating, formulating, and filter sterilizing may be completed within modular manufacturing unit, which may be a closed modular system. In further embodiments, some aspects may take place in a functionally closed environment. In embodiments, packaging may also be completed within modular manufacturing unit, which may be a closed modular system. [0078] FIG. 1 illustrates a modular response platform 1 consistent with embodiments hereof. The modular response platform 1, provides a complete, end-to-end solution providing a rapidly deployable therapeutic or prophylactic product. In embodiments, the modular response platform 1 may include, e.g., a (e.g., field-deployable) donor screening assay 5, a modular plasmapheresis or plasma collection unit 153, a pathogen reduction system 151, a modular manufacturing unit 100 to manufacture the hyperimmune antibody composition, and deployment of a deployable therapeutic 52, such as a hyperimmune antibody composition.

[0079] Field-deploy able donor screening assay 5 may identify appropriate donors suitable for plasma collection. In embodiments, appropriate donors are determined by titer of antibodies to the disease target to identify plasma samples having a raised level of antibodies. One or more of the donors may be a convalescent donor, an immunized donor, or an asymptomatic infection-household contact donor.

[0080] The plasma collection unit 153 may be employed for plasma collection purposes. The plasma collection unit 153 includes all of the equipment, materials, and supplies necessary for obtaining plasma from donors. The plasma collection unit 153 may include medical supplies as well as transport vehicles and equipment for maintaining the quality of the plasma (refrigeration/freezing equipment) after collection.

[0081] After collecting the plasma from the appropriate donors, for e.g., using a modular plasmapheresis or plasma collection unit 153, the collected plasma may undergo an operation in a pathogen reduction system 151. The pathogen reduction system 151, described in greater detail below, includes equipment, materials, and supplies required to reduce a pathogen level in the collected plasma prior to manufacturing antibody compositions. The pathogen reduction system 151 may further include thawing, refrigeration, and freezing equipment as necessary.

[0082] The deployable therapeutic 52, such as a hyperimmune antibody composition, may then be manufactured in a modular manufacturing unit 100. A resulting deploy able therapeutic 52, such as a hyperimmune antibody composition, may be ready for deployment in single-use drug product containers 60. In embodiments, a resulting deployable therapeutic 52, such as a hyperimmune antibody composition, may be stored in a large drug product container and frozen for future packaging and deployment.

[0083] A significant challenge in emerging infectious diseases is that outbreaks can rapidly propagate locally and spread regionally and globally before vaccines or manufactured antibody therapeutics can be deployed. Thus, it is important to have an effective strategy to identify and screen potential plasma donors. In embodiments, a modular response platform 1 may include a screening assay 5 to assess potential donors on site for levels of antibodies to the target pathogen. The screening assay 5 may include an immunoglobulin screening assay. The screening assay 5 may include an ELISA, flow through assay, lateral flow assay or other assays known in the art for immunoglobulin screening. The screening assay 5 may be configured to establish the titer of pathogen specific antibody in human convalescent plasma to identify those samples with raised levels of antibodies. The screening assay 5 may facilitate identifying the survivors for ongoing plasma donation including asymptomatic infection-household contacts. [0084] In embodiments, plasma collection or plasmapheresis may take place separate from the modular manufacturing unit, e.g., in a hospital, a clinic, other permanent structure, a mobile unit such as a dedicated van, truck or other vehicle, or any combination thereof. In embodiments, a plasma collection or plasmapheresis unit 153 may be a modular unit capable of plasma collection or plasmapheresis and being deployed and implemented in-line with the modular manufacturing unit 100. In embodiments, a modular plasma collection unit or facility for plasmapheresis or plasma collection may be a self-contained unit. The modular plasma collection unit or facility may allow for collection of donor convalescent plasma for further manufacture into a hyperimmune antibody composition in the modular manufacturing unit 100. In embodiments, an output of a plasmapheresis or plasma collection unit may be frozen convalescent plasma.

[0085] Human plasma may contain viruses and other infectious disease agents that could be harmful to process operators and to individuals receiving a final product produced by a modular manufacturing unit 100. One or more clearance methods may be employed to remove viruses. A pathogen reduction system 151 may be implemented to treat plasma prior to pooling for further manufacturing in the modular manufacturing unit 100.

[0086] A pathogen reduction system 151 may work to reduce a broad panel of pathogen types, which are not comprehensively included in standard plasma testing. The pathogen types may be a virus, a bacterium, a fungus, a parasite, or any combination thereof. The pathogen reduction system 151 may be implemented following a plasmapheresis or plasma collection operation performed at the plasma collection unit or facility 153 and on individual plasma donations, prior to plasma pooling and antibody purification steps. Utilizing a pathogen reduction system 151 at this stage may provide assurance that the plasma has been effectively pathogen-reduced prior to operator contact.

[0087] A pathogen reduction system 151 may utilize ultraviolet (UV) light illumination of plasma to which a non-toxic, non-mutagenic photosensitizing agent has been added or introduced. In embodiments, the non-mutagenic photosensitizing agent may be vitamin B2, i.e., riboflavin. This process creates nucleic acid modifications, which effectively inactivates a variety of pathogens. Viruses, bacteria, parasites, and white blood cells are prevented from replicating, and transmission of pathogens and white blood cells is reduced. In embodiments, a pathogen reduction system 151 may involve a system that comprises disposable kits and a standalone table-top illuminator unit, enabling flexibility in treatment of the collected product to occur pre- or post-storage. In further embodiments, a pathogen reduction system 151 may utilize the MIRASOL Pathogen Reduction Technology System developed by TERUMOBCT. In other embodiments, a pathogen reduction system 151 may utilize other systems or technologies configured to provide UV radiation to a riboflavin containing substance.

[0088] In embodiments, plasma following pathogen reduction (pathogen reduced plasma or treated plasma) may be used in a process for preparing a polyclonal immunoglobulin composition, which is described above.

[0089] FIG. 2 illustrates a process 200 for manufacturing a hyperimmune antibody composition. As described above, the modular manufacturing unit 100 may be configured to facilitate and/or carry out the process 200 to purify or isolate immunoglobulin from donor plasma pools containing high titers of antibodies to manufacture a hyperimmune antibody composition. The process 200 is implemented to target public health threats (e.g., emerging infectious diseases and/or pandemics) in a region and to provide countries with methods of producing a product to region specific diseases that pharmaceutical companies will not make due to a lack of global market. The process 200 further provides a local ability to produce hyperimmune antibody compositions, without the transportation and time barriers associated with transporting plasma out of a region, manufacturing, and transporting the manufactured product back in. As described above, in embodiments, a pathogen reduction process virally inactivates the plasma at the front end of the process 200, prior to plasma purification.

[0090] Further details of a process 200 for preparing a sterile polyclonal immunoglobulin composition (the hyperimmune antibody composition, i.e., therapeutic drug product) are shown, for example, in FIGS. 3-6 according to some embodiments. In embodiments, a process 200 may vary from the operations shown. For example, in embodiments, additional operations may be included as part of a process 200. In embodiments, operations may be omitted from a process 200. In embodiments, an order of operations may vary from the order shown in FIG. 2. The following discussion of a process 200 makes reference to various aspects of FIGS. 3-6. [0091] FIG. 3 illustrates a schematic of a modular manufacturing unit 100 in accordance with an embodiment hereof. A manufacturing process performed in the modular manufacturing unit 100 is simple and robust so that local non-expert individuals can perform the process with minimal training. Thus, the modular manufacturing unit 100 reduces touch points and areas for error. For example, in embodiments, materials provided for or with the modular manufacturing unit 100 are packaged in such a way that they are easily identified, without the impact of a language barrier between a developer and an end-user or operator. The modular manufacturing unit 100 may include one or more training guides to provide an overview of the equipment, operations, key steps, and troubleshooting.

[0092] In embodiments, one or more of the process and/or systems described herein may be performed in a modular manufacturing unit 100 which can be transported to an area of about 100 to about 1000 square feet, about 100 to about 800 square feet, about 100 to about 600 square feet, about 100 to about 500 square feet, or about 100 to about 400 square feet. In other embodiments, one or more of the process and/or systems described herein may be performed in a unit which can be transported to an area of less than 1000 square feet, less than 900 square feet, less than 800 square feet, less than 700 square feet, less than 600 square feet, less than 500 square feet, less than 400 square feet, less than 300 square feet, or less than 200 square feet. In embodiments, a modular manufacturing unit 100 may be manufactured with the same size and shape as a standard shipping container to facilitate transport.

[0093] In embodiments, the modular manufacturing unit 100 may be a self-contained system. The modular manufacturing unit 100 may be a self-contained clean room. The modular manufacturing unit 100 may provide a climate-controlled space for plasma pooling and throughout the manufacture of a final product in ready-to-use packaging. The modular manufacturing unit 100 may be self-sustaining and configured to not rely on local resources such as water or power. The modular manufacturing unit 100 may be temperature controlled. The modular manufacturing unit 100 may have a low footprint for both operation and waste. The modular manufacturing unit 100 may be configured to withstand shipping conditions including changes in temperature and handling.

[0094] In embodiments, a modular manufacturing unit 100 may be enclosed in a housing, e.g., a shipping container or enclosure, a temporary structure, or a vehicle (e.g., a trailer truck). In embodiments, a modular manufacturing unit 100 may move on its own. In embodiments, a modular manufacturing unit 100 may be moved by a separate mode of transportation (e.g., a truck, an automobile, a plane, a helicopter, a boat, a train, or a trailer). In embodiments, a modular manufacturing unit 100 may be in motion while in operation, In embodiments, a modular manufacturing unit 100 may be stationary while in operation. In embodiments, a modular manufacturing unit 100 may be moved and used in multiple locations. In embodiments, a modular manufacturing unit 100 may be moved to a desired location and thereafter remains stationary. In other embodiments, a modular manufacturing unit 100 may be in a truck or vehicle, and/or could be readily movable in a tent or temporary structure. In embodiments, a modular manufacturing unit 100 may be moved or transported with little or no damage to the modular manufacturing unit 100 upon delivery or arrival at the desired location. [0095] As shown in FIG. 3, a modular manufacturing unit 100 may include a plurality of stations 101. Each station 101 may be configured for one or more operations of the manufacturing process 200. FIG. 4 illustrates additional features of the modular manufacturing unit 100. The modular manufacturing unit 100 may include a pooling station 110, an isolation station 120, a filtering station 130, a concentration station 140, a sterilization station 150, and a packaging station 160. The modular manufacturing unit 100 further includes a transfer system 111 to transfer product between the stations 101 in a closed and/or continuous fashion, as described further below. In embodiments, fewer or more stations 101 may be included in a modular manufacturing unit 100. In embodiments, additional stations may be a part of a modular manufacturing unit 100. For example, in embodiments, a pooling station 110 may include a thawing station 108, as shown in FIG. 4. In embodiments, two stations may be combined into one station. For example, in embodiments, a sterilization station 150 and a packaging station 160 may be combined into one station.

[0096] In embodiments, a modular manufacturing unit 100 consistent with embodiments hereof may further include a pathogen reduction station, providing all of the equipment and functionality discussed herein with respect to pathogen reduction processes, such as pathogen reduction system 151 and the pathogen reduction operation 204.

[0097] As discussed herein, the described various stations 101 include hardware, software, and other components necessary to carry out the functionality described herein. Such components may further include equipment, devices, containers, receptacles, tubing, hoses, valves, connectors, and other features or components necessary to receive a plasma product, carry out the described processes and techniques on the product, and transfer the product to the next station. Where necessary, specific components of each station are described in detail.

[0098] In embodiments, a modular manufacturing unit 100 may include a housing 105 that contains all stations 101 of the modular manufacturing unit 100 (e.g., a pooling station 110, an isolation station 120, a filtering station 130, a concentration station 140, a sterilization station 150, and a packaging station 160). In embodiments, a housing 105 may be a shipping container or enclosure. In embodiments, a modular manufacturing unit 100 may be part of a vehicle, a truck, a trailer, or a shipping container.

[0099] Referring again to FIG. 3, the modular manufacturing unit 100 may include an entry way 103 for gowning. In embodiments, modular manufacturing unit 100 may include a main space 107 for in which plasma pooling, treatment, and chromatography are performed, as well as virus filtration, ultrafiltration/diafiltration, and formulation are performed. In embodiments, a pathogen inactivation process may be performed in a main space 107 of a modular manufacturing unit 100. In embodiments, a main space 107 may be divided into a primary area or a first unit 102 and a secondary area or second unit 104. In embodiments, a pooling station 110, an isolation station 120, a filtering station 130, and a concentration station 140 may be in a primary area or first unit 102. In embodiments, a sterilization station 150 and a packaging station 160 may be conducted in a secondary area or second unit 104 within a modular manufacturing unit 100.

[0100] In embodiments, a modular manufacturing unit 100 may include a HEP A filtered air supply 106. In embodiments, a HEPA filtered air supply 106 may be directional. In embodiments, a second unit 104 may further include a laminar flow hood equipped with an additional directional HEPA filtered air supply 106. In other embodiments, a second unit 104 may include a directional HEPA filtered air supply 106.

[0101] In embodiments, cross contamination of a virally filtered (downstream) manufactured product with an upstream product may be managed, reduced, or mitigated using a unidirectional enclosed product flow path consisting entirely of single-use or disposable components. Thus, a process 200 may be carried out in a modular manufacturing unit 100 with purpose-built, enclosed, sterile, single-use product flow paths and procedures to prevent potential contamination of a product by the environment. By maintaining as much of the process in a closed-system as possible, the risk of environmental contamination to the process and product is mitigated. Additional details of a modular manufacturing unit 100 in accordance with an embodiment hereof are discussed below in connection with a process 200.

[0102] Returning now to FIG. 2, with reference to FIG. 5, the process 200 may include a plasma collection operation 202. The plasma collection operation 202 may include plasmapheresis or plasma collection. The plasma collection operation 202 may include obtaining plasma samples 10 having raised antibody levels from donors exposed to an infectious agent or antigenic component thereof. The plasma collection operation 202 may take place in a region of an outbreak of the infectious agent or where the infectious agent is emerging. In embodiments, an infectious agent may be viral or bacterial, for example, an infectious agent may be a known or unknown viral or bacterial pathogen. A plurality of plasma samples 10 may be obtained, as represented in FIG. 5. In embodiments, each plasma sample 10 may be disposed in a sample container 11. Sample container 11 may be a bag, a vial, or other type of sample container. In embodiments, a sample container 11 may be a single-use sample container.

[0103] The process 200 may include a pathogen reduction operation 204. The pathogen reduction operation 204 includes treating a batch of plasma samples 10 for pathogen reduction. The batch of plasma samples 10 may be received in individual packages or sample containers 11. The batch of plasma samples may be treated individually and/or may be pooled and divided into individual aliquots prior to treatment.

[0104] As used herein, “pathogen reduction” refers to decreasing the relative number of infectious pathogens (e.g., viruses, bacteria, parasites) in a sample, either by physical removal (e.g., nanofiltration) or by an inactivation technology (e.g., MIRASOL Pathogen Reduction Technology (PRT) System developed by Terumo BCT (combination of riboflavin (vitamin B2) and UV light to inactivate viruses) or INTERCEPT Blood System developed by Cerus Corporation (nucleic acid targeting mechanism of action to inactive viruses).

[0105] A pathogen reduction operation 204 may utilize ultraviolet (UV) light illumination of the pooled plasma 12 to which a non-toxic, non-mutagenic photosensitizing agent 205 has been added or introduced. In embodiments, a non-mutagenic photosensitizing agent 205 may be vitamin B2, i.e., riboflavin. The pathogen reduction operation 204 creates nucleic acid modifications, which effectively inactivates a variety of pathogens. Viruses, bacteria, parasites, and white blood cells are prevented from replicating, and transmission of pathogens and white blood cells is reduced. In embodiments, a pathogen reduction operation 204 may involve a system that comprises disposable kits and a standalone table-top illuminator unit 207, enabling flexibility in treatment of the collected product to occur pre- or post-storage. In further embodiments, a pathogen reduction operation 204 may utilize the MIRASOL Pathogen Reduction Technology System developed by TERUMOBCT. In other embodiments, a pathogen reduction operation 204 may utilize other systems or technologies configured to provide UV radiation to a riboflavin containing substance.

[0106] The pathogen reduction operation 204 is performed on treated plasma (i.e., treated with the non-mutagenic photosensitizing agent 205) to generate pathogen reduced plasma 25. The received batch of plasma samples 10 may be pooled and homogenized before being individually packaged and treated with the non-mutagenic photosensitizing agent 205. In other embodiments, a batch of plasma samples 10 is treated with a non-mutagenic photosensitizing agent 205 without pooling first.

[0107] The pathogen reduction operation 204 may be performed external to the housing 105 of the modular manufacturing unit 100. In embodiments, a pathogen reduction operation 204 is performed internal to a housing 105 of a modular manufacturing unit 100. In embodiments, no further pathogen reduction (or other viral reduction) is completed after a viral filtering operation 218.

[0108] A process 200 may include a freezing operation 206. The freezing operation 206 includes the freezing of a plurality of pathogen reduced plasma samples 25. The process 200 may include a thawing operation 208. The thawing operation 208 includes the thawing of frozen pathogen reduced plasma samples 25. The thawing operation 208 may be performed at a thawing station 108, which may include a thawing drape 70 having pockets 72, as discussed in greater detail below with respect to FIG. 6. In embodiments, a thawing operation 208 takes less than 25 hours. In other embodiments, a thawing operation 208 takes between about 16 and about 25 hours. In embodiments, a thawing station 108 may be part of a pooling station 110 as shown in FIG. 4.

[0109] A process 200 may include a pooling operation 210. In embodiments, a pooling operation 210 includes pooling a received plasma sample (e.g., a plurality of pathogen reduced plasma samples 25) to generate a pooled plasma sample 23. In embodiments, a received plasma sample may include a plurality of pathogen reduced plasma samples having raised antibody levels from donors exposed to an infectious agent or an antigenic component thereof to produce pooled plasma. The pathogen reduced plasma samples 25 may also be referred to as treated plasma samples. In embodiments, a volume of pooled plasma sample 23 may be less than 100 L, less than 90 L, less than 80 L, less than 70 L, less than 60 L, less than 50 L, less than 40 L, less than 30 L, less than 20 L, or less than 10 L. In embodiments, the volume of pooled plasma sample 23 may be about 10 L to about 100 L; about 10 L to about 90 L; about 10 L to about 80 L; about 10 L to about 70 L; about 10 L to about 60 L; about 10 L to about 50 L; about 15 L to about 100 L; about 15 L to about 90 L; 15 L to about 80 L; about 15 L to about 70 L; about 15 L to about 60 L; about 15 L to about 50 L; about 20 L to about 100 L, or about 30 L to about 50 L.

[0110] In embodiments, a pooling operation 210 is performed at a pooling station 110. In embodiments, a pooling station may include a pooling receptacle 13 (see FIG. 5) to receive a plurality of pathogen reduced or treated plasma samples 25. The pathogen reduced plasm samples 25 may include plasma samples from donors exposed to an infectious agent or an antigenic component thereof that have been treated to reduce pathogens contained therein. In embodiments, plasma samples 10 are pooled into a pooling receptacle 13 as pathogen reduced pooled plasma 23. In embodiments, a pooling receptacle 13 may be configured to hold up to 100 L, up to 90 L, up to 80 L, up to 70 L, up to 60 L, up to 50 L, up to 40 L, up to 30 L, or up to 20 L. In other embodiments, a pooling receptacle 13 may be configured to hold about 10 L to about 100 L, about 10 L to about 90 L, about 10 L to about 80 L, about 10 L to about 70 L, about 10 L to about 60 L, about 10 L to about 50 L, about 15 L to 100 L, about 15 L to about 90 L, about 15 L to about 80 L, about 15 L to about 70 L, about 15 L to about 60 L, about 15 L to about 50 L, about 20 L to about 100 L, or about 30 L to about 50 L. In further embodiments, a pooling receptacle 13 may be configured to hold up to 30 L of pooled plasma. In embodiments, a pooling receptacle 13 may be a single-use receptacle.

[0111] In embodiments, a pooling operation 210 may take place while sample containers are in a thawing drape 70. Thus, donor plasma may be extracted from the sample containers without having to be removed from the thawing drape 70. The pooling station and/or the thawing drape may include a hose, tube, or other liquid transfer device configured to transfer the plasma samples from the plurality of sample containers into the pooling receptacle 13 of the pooling station for pooling of the plasma samples. The hose may transfer the contents of one sample container at a time into the pooling receptacle 13 and/or may be configured to transfer the contents of multiple sample containers.

[0112] A pooling operation 210 may further include steps of diluting the pathogen reduced pooled plasma 23 and/or adding additives. For example, the pooling operation 210 may include adding an additive 80 to the plasma to facilitate lipid reduction. In embodiments, an additive may include any suitable lipid reduction agent.

[0113] A process 200 may include a filtering operation 212. The filtering operation 212 includes filtering the pathogen reduced pooled plasma 23, through depth filtration. Performing the filtering operation 212 to filter the pathogen reduced plasma sample results in production of a filtered plasma sample. Filtering the pathogen reduced plasma may serve to clarify the product through reduction of lipids. The filtering may be completed with one or more plasma clarification filters 217. A plasma clarification filters 217 may be depth filters. A plasma clarification filters 217 may be single-use filters. A filter media for plasma clarification filters 217 may include cellulose, a fine stainless-steel screen, or a fine plastic screen.

[0114] A filtering operation 212 may further include filtering to remove excess Vitamin B2 (riboflavin) in the pathogen reduced pooled plasma 23. In such embodiments, a plasma clarification filter 217 may further include activated carbon. In additional embodiments, activated carbon may be added to the pathogen reduced plasma prior to depth filtration. The use of activated carbon in depth filtration may serve to reduce a level of riboflavin and/or riboflavin degradants ( lumichrome, 2-Ketoflavin and formylmethylflavin) resulting from UV irradiation. The level of riboflavin may be reduced by up to 95%, 96%, 97%, 98%, and/or 99%.

[0115] Riboflavin reduction may be particularly important in the context of the modular manufacturing unit 100 discussed herein. A riboflavin enabled UV irradiation process for pathogen reduction discussed above is not typically employed in the manufacture of antibody compositions. It may be less efficient for large plasma quantities, face regulatory hurdles, and require further changes to the manufacturing process in conventional large scale manufacturing facilities. In the context of a modular manufacturing unit 100 in accordance with embodiments hereof, a riboflavin enabled UV irradiation process provides additional value because it can be employed to reduce pathogens efficiently in smaller batches and individually packaged plasma samples.

[0116] Use of a riboflavin enabled UV irradiation process leads to the presence of riboflavin in the pathogen reduced plasma sample. The presence of riboflavin in the pathogen reduced plasma sample may result in increased IgG dimer content (as measured by size exclusion) present in any bulk hyperimmune antibody composition at the completion of manufacturing. The potential for increased IgG dimer content however may be reduced during a depth filtration process employing activated carbon.

[0117] A process 200 may further include an ionic adjusting operation 214. An ionic adjusting operation 214 includes adjusting the ionic strength of the pooled plasma (before or after depth filtration). In embodiments, an isolating operation 216 may be performed prior to isolating immunoglobulin from the pooled plasma 12. In embodiments, an isolating operation 216 may be part of treatment of the pooled plasma 12. In embodiments, treated plasma may be collected in a receptacle prior to isolating immunoglobulin.

[0118] In embodiments, the operations 210, 212, and 214 may be referred to as treatment of the received pooled plasma and may be completed at the pooling station 110. In further embodiments, treatment of the pooled plasma may be completed at the isolating station 120. In embodiments, treatment of the pooled plasma may occur at a separate treatment station. In embodiments, treating the pooled plasma 12 may reduce the presence of lipids and/or riboflavin and may be performed prior to isolating immunoglobulin from the pooled plasma.

[0119] The process 200 may further include one or more transfer operations 215. The transfer operations 215 include transferring product (e.g., a plasma composition at any stage of manufacture) between the various stations via a transfer system 111 in a closed and/or continuous manner. Transfer operations 215 may occur between the operations 214 and 216, between the operations 216 and 218, between the operations 218 and 220, between the operations 220 and 222, and between operations 222 and 224. For example, transfer operations 215 may include, but are not limited to transferring the pathogen reduced pooled plasma 23 from the pooling station 110 to the isolation station 120, transferring the isolated antibody composition 22 from the isolation station 120 to a filtering station 130; transferring the filtered antibody composition 32 from the filtering station 130 to a concentration station 140; transferring the concentrated antibody composition 42 from the concentration station 140 to a sterilization station 150 and transferring the sterile antibody composition 52 from the sterilization station 150 to a packaging station 160.

[0120] A transfer system 111 in accordance with embodiments hereof may effect these transfers in a closed fashion. Once the pathogen reduced pooled plasma enters the transfer system, the transfer system 111 may be configured to facilitate movement of the product through each subsequent station and operation while preventing the product from contacting the local environment. Transfer from station to station without local environment contact permits manufacture to occur in an environment that is not completely sterile and/or with operators that may not be trained in proper sterile procedure. Each of these features is advantageous in the context of the modular manufacturing unit.

[0121] The closed nature of the system may further be facilitated through the use of single-use products in the transfer system 111. In embodiments, any process or system component which comes into direct contact with the plasma samples or any of the immunoglobulin compositions may be a single-use component (e.g., a container, a receptacle, a filter, a column, a hose, a tube, etc.). This permits the transfer system to be reused quickly for new production runs without the requirement to clean and or sterilize the components in between.

[0122] In further embodiments, a transfer system 111 provides continuous flow between all or some of the stations and components of a modular manufacturing unit 100. Continuous flow facilitates the closed nature of the system, as requirements to perform transfers, e.g., pouring and dumping, of large amounts of fluids in batches is reduced. A continuous flow also facilitates the rapidity of the manufacturing process, as various stations may operate in parallel. For example, in certain situations it may not be necessary for all of the product to pass through the plasma clarification filter 217 before beginning chromatography. Further, in certain situations it may not be necessary for all of the product to pass through chromatography columns 20 before beginning viral reduction filtration.

[0123] A transfer system 111 includes a collection of components, including tubing, valves, connectors, manifolds, surge bags, and pumps configured to facilitate the closed and continuous transport of product between a pooling station 110, an isolation station 120, a filtering station 130, a concentration station 140, a sterilization station 150, and a packaging station 160. Further details of the transfer system are illustrated in FIG. 5.

[0124] In embodiments, a transfer system 111 includes a plurality of pumps 531 and a control unit 532. The pumps 531 may be, for example, peristaltic pumps or other continuous flow pumps permitting a single use flow pathway. The control unit 532 is configured to control the flow rates and pressures generated by the pumps 531. To maintain the continuous flow of the transfer system, the control unit 532 is configured to coordinate the flow rates of the individual pumps 531 so as to prevent discontinuities in flow and/or pressure build-ups. For example, a first pump 531 may be operated to provide product flow to the isolation station 120, i.e., from the pooling station 110 and/or the plasma clarification filter 217. A second pump 531 may be operated to provide product flow through the filtering station 130 after exit from the isolation station 120. A third pump 531 is provided at the concentration station 140 to maintain product flow through the filter 40 during ultrafiltration/diafiltration. The third pump 531 may be located at the inlet or outlet of the filter 40 to properly meter flow through the filter 40. The third pump 531 may be operated by the control unit 532 in conjunction with the first pump 531 and the second pump 532. If the first pump 531 operates at a higher flow rate than the second pump 531 , it may cause a volume or pressure build-up in the transfer system 111. Accordingly, the control unit 532 operates the plurality of pumps 531 to maintain continuous flow between the stations, as described above. Although two pumps 531 are illustrated in FIG. 5, any number of pumps may be controlled by the control unit 532.

[0125] A process 200 may include isolating operation 216. The isolating operation 216 includes performing chromatography at the isolation station 120 to isolate antibodies in the pooled plasma. In embodiments, the isolating operation 216 includes isolating immunoglobulin from the received plasma. The received plasma may be received from the pooling station 110 and/or from a treatment station (if employed). The received plasma has undergone at least pathogen reduction and filtration to reduce lipids and/or riboflavin. The received plasma is employed in the antibody isolation process using at least one chromatography column 20 of the isolation station 120 to produce an isolated antibody composition 22, which may be transferred to a surge bag after passing through the chromatography column 20.

[0126] In embodiments, isolating immunoglobulin may include two or more chromatography columns, as shown, for example, in FIG. 5. In embodiments, the immunoglobulin may be isolated from pooled plasma 12 by ion exchange (IEX), or affinity chromatography. In embodiments, the chromatography column 20 may be a single-use column. [0127] In embodiments, chromatography column 20 may use pre-equilibrated resin. In embodiments, pre-equilibrating resin minimizes total processing time for the process 200, allowing for the process 200 to be completed within 48 hours, within 36 hours, within 30 hours, or within 24 hours. In embodiments, resin may be nearly ready to use when received by the end user or operator. In embodiments, pre-equilibrated resin may be stored for up to 12 weeks. In embodiments, pre-equilibrated resin may be stored for longer than 12 weeks. In embodiments, pre-equilibrated resin may be stored at room temperature. In embodiments, preequilibrated resin may be stored at about 4°C, about 20°C, or about 60°C. In embodiments, pre-equilibrated resin may be stored in a chromatography column 20.

[0128] In embodiments, resin may be pre-equilibrated with an equilibration buffer to achieve a target pH and conductivity, for example a target pH between about 7.0 and about 8.0 at 25°C. In embodiments, target conductivity may be between about 4.0 mS/cm and about 4.8 mS/cm at 25°C.

[0129] The isolating operation 216 may be performed at the isolation station 120. The isolating station 120 includes one or more chromatography columns 20 for isolating immunoglobulin from the pathogen reduced pooled plasma 23 obtained from the pooling station 110. In embodiments, an isolating station 120 may further include an optional resin capture filter. The resin capture filter may be a single-use filter. The resin capture filter may be disposed in line within the transfer system between a chromatography column 20 and the filtering station 130. In additional embodiments, a chromatography column 20 may include viral reduction capabilities.

[0130] The process 200 further includes a viral filtering operation 218. The viral filtering operation 218 includes viral filtering the isolated antibody composition 22 to remove or reduce viral contaminants by size exclusion to produce a filtered antibody composition 32. In embodiments, a viral filtering operation 218 may be performed at a filtering station 130. The transfer system 111 may be employed in an operation 215 to facilitate the transfer of the isolated antibody composition 22 from the isolation station 120 to the filtering station 130. In embodiments, a filtering station 130 includes one or more virus filters 30 and/or pre-filters for removing or reducing viral contaminants by size exclusion from the isolated antibody composition 22 obtained from an isolation station 120. In embodiments, a virus filter 30 may be a single-use virus filter. In embodiments, a virus filter 30 may include a Cuprammonium regenerated cellulose or polyethersulfone membrane. In embodiments, a virus filter 30 may include a pore size of about 0.02 pm (about 20 nm). In embodiments, a virus filter 30 may include a hollow fiber membrane structure. In embodiments, a virus filter 30 may be a flat membrane structure. In embodiments, a filtering station 130 may further comprise a pre-filter 29. In embodiments, a minimum viral reduction (or average minimum viral reduction) is a 90% reduction, a 99% reduction, a 99.9% reduction, a 99.99% reduction, a 99.999% reduction, or a 99.9999% reduction.

[0131] In embodiments, a membrane exchange process may be included after viral filtering operation 218 to further purify the filtered antibody composition 22.

[0132] The process 200 may include a concentrating operation 220. In embodiments, a concentrating operation 220 includes concentrating a filtered antibody composition 32 to produce a concentrated antibody composition 42. The concentrating operation 220 is performed at the concentration station 140. The transfer system 111 may be employed in a transfer operation 215 to facilitate the transfer of the filtered antibody composition 32 from the filtering station 130 to the concentration station 140. The concentration station 140 includes a concentration receptacle 41 that receives and collects the filtered antibody composition 32 from the filtering station. The concentrating operation 220 includes ultrafiltration and/or diafiltration with the filter 40. Diafiltering the filtered antibody composition 32 is performed to remove excess solvent to concentrate the antibodies and produce the concentrated antibody composition 42.

[0133] The concentrating operation 220 begins when reception of the filtered antibody composition 32 begins. As the filtered antibody composition 32 reaches the concentration station 140, the concentrating operation 220 begins and continues as more filtered antibody composition 32 continues to be received. After completion of the concentrating operation 220 to concentrate the antibody composition, the upstream components of the transfer system 111 are closed off from the concentration station 140. Thus, all of the product is permitted to collect at the concentration station 140 before the process 200 continues. After completion of concentration at concentrating operation 220, further operations may take place at the concentration station 140.

[0134] The process 200 may include an adjusting operation 222. The adjusting operation 222 may include adjusting the pH of concentrated antibody composition 42. In embodiments, adjusting the pH of the concentrated antibody composition 42 may be performed prior to sterile filtering (in a sterile filtering operation 226, discussed below).

[0135] The process 200 may include a formulating operation 224. The formulating operation 224, which may be performed at the concentration station 140, includes formulating the concentrated antibody composition 42 with a solution 46 comprising an excipient 47 to produce a formulated antibody composition 48. In embodiments, an excipient 47 includes L-proline, acetate, or a combination thereof. In embodiments, a concentrated antibody composition 42 may be diafiltered directly into a solution 46, which does not require further pH adjustment. Thus, in embodiments, adjusting operation 222 may be omitted.

[0136] In embodiments, an excipient 47 is provided in a liquid solution 46. Conventional manufacturing facilities typically employ excipient in a powdered form due to an increased efficiency. Powdered excipient, however, is difficult to deliver to a closed system such as that employed in the modular manufacturing unit 100. Liquid excipient may be delivered without exposing the product to the local environment. Accordingly, despite a lower efficiency, a liquid excipient may be employed in the manufacturing process of the modular manufacturing unit 100 so as to facilitate the maintenance of the closed system.

[0137] In embodiments, a bioburden reduction operation may be performed after formulation and prior to sterilization. Bioburden reduction may be performed to reduce a number of microorganisms (e.g., bacteria) present in the formulated antibody composition prior to sterilization. Bioburden reduction may be performed via any suitable means, e.g., via a prefilter.

[0138] The process 200 may further include a sterile filtering operation 226. The sterile filtering operation 226 includes filter sterilizing the formulated antibody composition 48 to produce a sterile antibody composition 52. The sterile filtering operation 226 is performed at the sterilization station 150. The transfer system 111 may be employed in a transfer operation 215 to facilitate the transfer of the formulated antibody composition 48 from the concentration station 140 to the sterilization station 150. In embodiments, a formulated antibody composition 48 may be sterilized using a 0.2 pm filter 50. In embodiments, a sterile filtering operation 226 may be performed at a sterilization station 150. The sterilization station 150 may include a filter (e.g., 0.2 pm filter 50) for sterilizing the concentrated antibody composition 42 from the concentration station 140. In embodiments, sterilization station 150 may further comprise one or more pre-filters.

[0139] In embodiments, a resulting product (sterile antibody composition 52) may be a sterile polyclonal immunoglobulin composition or hyperimmune antibody composition to be employed as a bulk drug product. The sterile antibody composition 52 may be formulated for intramuscular administration or intravenous administration.

[0140] The process 200 may further include a packaging operation 228. In embodiments, the packaging operation 228 includes packaging or filling the sterile antibody composition 52 into a plurality of sterile drug product containers 60. Packaging operation 260 may be performed at the packaging station 160. The transfer system 111 may be employed in a transfer operation 215 to facilitate the transfer of the sterile antibody composition 52 from the sterilization station 150 to the packaging station 160. The packaging station 160 may include a plurality of sterile drug product containers 60 for packaging the concentrated sterile antibody composition 52 obtained from the sterilization station 150 via the transfer system 111. Drug product containers 60 may be single-use drug product containers. Single-use sterile drug product containers 60 may be selected from the group consisting of a bag, a vial, a bottle, a tank, a syringe, a microinjector, and any combination thereof.

[0141] The process 200 may further include an inspecting operation 230. The inspecting operation 230 may include visually inspecting the single-use sterile drug product containers 60 packaged with the sterile antibody composition 52 . In embodiments, an inspecting operation 230 includes checking for particulates in a sterile antibody composition 52 and/or checking for issues with drug product containers 60.

[0142] Further embodiments may include labeling drug product containers 60 and/or packaging the drug product containers 60 (e.g., within a box for delivery).

[0143] In embodiments, a packaged sterile antibody composition 52 (hyperimmune antibody composition) may be a finished product (e.g., a deployable therapeutic). In embodiments, after packaging a plurality of single-use sterile drug product containers 60 each may include a volume sufficient for a single dose or a plurality of doses of a sterile antibody composition 52. [0144] In embodiments, a pooling operation 210, an isolating operation 216, a viral filtering operation 218, a concentrating operation 220, a formulating operation 224, and a sterile filtering operation 226 may be completed in less than 48 hours, less than 30 hours, or less than 24 hours.

[0145] In embodiments, a pooling operation 210, an isolating operation 216, a viral filtering operation 218, a concentrating operation 220, a formulating operation 224, a sterile filtering operation 226, and a packaging operation 228 may be completed in less than 48 hours, less than 36 hours, or less than 24 hours.

[0146] FIG. 6 illustrates a thawing drape consistent with embodiments hereof. The thawing drape 70 includes a panel 71. The panel 71 may be a rectangular shape and may be made of a non-permeable material, e.g., a woven polyester, nylon, or any other suitable material. The panel 71 has a first side 77 and a second side 81, a top 75 and a bottom 79. The thawing drape 70 includes a plurality of pockets 72 disposed on the first side 77. The pockets 72 are configured to receive a sample container containing a donor plasma sample. The plurality of pockets 72 may be arranged in a two-dimensional array, such as an 8x3 array including 8 rows of 3 pockets 72 each. In other embodiments, the thawing drape 70 may include 8 pockets 72, 10 pockets 72, 12 pockets 72, 15 pockets 72, 20 pockets 72, 22 pockets 72, 24 pockets 72, or more pockets 72. The plurality of pockets 72 may be formed of a non-insulating material to increase thermal transfer for frozen plasma samples contained in the pockets 72. In embodiments, a plurality of pockets 72 may include a mesh material, such as a mesh netting, for example to promote air flow to enhance the thawing process. The material of the plurality of pockets 72 may allow for heat transfer and may be moisture permeable. For example, a mesh netting increases air flow around receptacles, which may lead to faster thawing times.

[0147] In embodiments, a thawing drape 70 may include fasteners 74 such as grommets configured for hanging the thawing drape 70. The fasteners 74 may be configured to hang from a protrusion and may be disposed at a top 75 of the panel 71. In embodiments, the protrusions may be selected from pegs, nails, screws, or the like, and any combination thereof. In embodiments, a thawing drape 70 may further comprise a pocket, trough, or collection device 76 at a base or bottom 79 of the panel 71 of the thawing drape 70 to collect any moisture created by the plurality of thawing plasma samples. The collection device 76 may include a drain line 78 configured to drain liquid away from the trough and into a sink or drainpipe.

[0148] The thawing drape 70 may reduce the footprint required to thaw plasma samples. The thawing drape 70 is configured to hang vertically and may hold several dozen frozen plasma samples for thawing. The thawing drape 70 may be arranged against a wall of the modular manufacturing unit 100, thereby providing the plurality of plasma samples with ample room to thaw while taking up only a small amount of floor space in the modular manufacturing unit 100.

[0149] As used in this application, except as otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout the application.

[0150] As used herein, “and/or” is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and/or” as used in a phrase such as “A and/or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Likewise, the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0151] As used herein, the term “about” is understood as within a range of normal tolerance in the art and not more than ±10% of a stated value. By way of example only, about 50 means from 45 to 55 including all values in between. As used herein, the phrase “about” a specific value also includes the specific value, for example, about 50 includes 50. [0152] The terms “antibody,” “antibodies,” “immunoglobulin,” and “immunoglobulins” are used interchangeably herein and refer to a molecule with an antigen binding site that specifically binds an antigen. The terms as used herein include whole antibodies and any antigen binding fragments (i.e., “antigen-binding fragments”) or single chains thereof. An “antibody” refers, in one embodiment, to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, or an antigen-binding fragment thereof. In another embodiment, an “antibody” refers to a single chain antibody comprising a single variable domain, e.g., VHH domain. Each heavy chain includes a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. In certain naturally-occurring antibodies, the heavy chain constant region includes three domains, CHI, CH2 and CH3. In certain naturally-occurring antibodies, each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL.

[0153] As used herein, the term “polyclonal antibodies” refers to a mixture of immunoglobulins secreted by different B cell lineages that react against an antigen (e.g., an infectious agent or an antigenic component thereof). In embodiments, the polyclonal antibodies identify different epitopes on an antigen or bind to different antigens.

[0154] As used herein, the terms “neutralizing antibody” or “neutralizing antibodies” refer to antibodies that bind a target (e.g., an infectious agent) where such binding results in neutralizing the biological effect of the target.

[0155] As used herein, the terms “antigen” and “immunogen” refer to any substance that is capable of inducing an immune response. An antigen may be whole cell (e.g., bacterial cell), virus, fungus, or an antigenic portion or component thereof.

[0156] As used herein, the term “epitope” designates a particular molecular surface feature of an antigen, for example a fragment of an antigen, which is capable of being bound by at least one antibody. Antigens usually present several surface features that can act as points of interaction for specific antibodies. Any such distinct molecular feature constitutes an epitope. On a molecular level, an epitope therefore corresponds to a particular molecular surface feature of an antigen (for example a fragment of an antigen) which is recognized and bound by a specific antibody.

[0157] As used herein, the term “infectious disease” refers to disorders caused by organisms such as a virus, a bacterium, a fungus, or a parasite.

[0158] As used herein, the term “infectious agent” refers to agents that cause disease, e.g., a virus, a bacterium, a fungus, a parasite, or an infectious component thereof. [0159] As used herein, the term “viral infection” refers to a diseased state in which a virus invades a cell and uses the cell's machinery to multiply or replicate, ultimately resulting in the release of new viral particles. This release results in the infection of other cells by the newly produced particles. Latent infection by certain viruses is also a possible result of viral infection. [0160] As used herein, the term “viral load” refers to the quantity of virus in a given volume. In embodiments, this term refers to a measurement of the amount of a virus in an organism, typically in the bloodstream, usually stated in virus particles per milliliter.

[0161] As used herein, the terms “treat,” “treating,” and “treatment” refer to administering therapy in an amount, manner, or mode effective to improve a condition, symptom, or parameter associated with a disease or disorder. Thus, “treating” a virus infection means inhibiting or preventing the replication of the virus, inhibiting, or preventing viral transmission, and/or ameliorating, alleviating, or otherwise improving the symptoms of a disease or condition caused by or associated with the virus. In embodiments, the treatment can be considered therapeutic if there is a reduction in viral load, and/or a decrease in mortality and/or morbidity. [0162] As used herein, the term “reducing the risk of an infection” refers to decreasing the likelihood or probability of developing a disease, disorder, or symptom associated with an infection in a subject, wherein the subject is, for example a subject who is at risk for developing such a disease, disorder, or symptom.

[0163] As used herein, the terms “preventing” and “prevention” as used with the methods of the disclosure described herein refer to activities designed to protect patients or other members (e.g., individuals) of the public from actual or potential health threats and their harmful consequences.

[0164] As used herein, the term “pre-equilibrating” refers to preliminary treatment of the resin within the chromatography column to reduce the overall time needed to equilibrate the resin prior to purification.

[0165] As used herein, the term “effective amount” refers to an amount of therapeutic agent or a composition comprising therapeutic agent (e.g., a hyperimmune composition), alone or in combination with another therapeutic agent, effective to treat or reduce symptoms, or reduce the risk, potential, possibility or occurrence of a disease or disorder (e.g., an infectious disease) in a subject. An effective amount may include an amount of therapeutic agent or a composition comprising therapeutic agent (e.g., a hyperimmune composition), alone or in combination with another therapeutic agent, which provides some improvement or benefit to a subject having or at risk of having an infection. [0166] As used herein, “sterile” refers to substantially free of living germs and/or microorganisms and as further recognized and described by governmental standards pertaining to compositions and processes described and claimed herein.

[0167] As used herein, “administering” refers to the physical introduction of therapeutic agent or a composition comprising therapeutic agent (e.g., a hyperimmune composition) to a subject, using any of the various methods and delivery systems known to those skilled in the art. The different routes of administration for antibodies described herein include intravenous, intraperitoneal, intramuscular, subcutaneous, intrauterinal, spinal or other parenteral routes of administration, for example, by injection or infusion. As used herein, the term “parenteral administration” means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intraperitoneal, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, transtracheal, intratracheal, pulmonary, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraventricle, intravitreal, epidural, and intrastemal injection, and infusion, as well as in vivo electroporation. Alternatively, an antibody described herein can be administered via a non-parenteral route, such as a topical, epidermal, or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually, or topically. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.

[0168] As used herein, the term “vaccine” refers to a prophylactic or therapeutic material providing at least one antigen, preferably an immunogen. The antigen or immunogen may be derived from any material that is suitable for vaccination. For example, the antigen or immunogen may be derived from a pathogen, such as from bacteria or virus particles etc., or from a tumor or cancerous tissue. The vaccine antigen or immunogen stimulates the body's adaptive immune system to provide an adaptive immune response.

[0169] As used herein, the term “immunized” refers to being sufficiently vaccinated to achieve a protective immune response.

[0170] As used herein, the term “hyperimmune” refers to a state of having an elevated level of antibodies to a target, e.g., against an infectious disease, compared to a reference level (e.g., level of infectious disease antibodies in normal source donor comprising non-specific antibodies). In embodiments, the elevated level of antibodies to a target is generated from exposure to the target infectious disease. In another embodiment, the elevated level of antibodies is generated from donor stimulation (e.g., administration of a vaccine to the target). In another embodiment, the elevated level of antibodies is generated by purifying an immunoglobulin source. In embodiments, the antibodies described herein are immune globulins.

[0171] As used herein, the term “hyperimmune composition” refers to a composition comprising an elevated level of antibodies, e.g., polyclonal antibodies, to one or more specific antigens, which is obtained from plasma and/or serum. In embodiments, the hyperimmune composition is enriched with antibodies specific to one or more particular epitopes of an infectious disease. In embodiments, the hyperimmune compositions described herein are prepared from plasma and/or serum obtained from an individual (e.g., human, animal, or convalescent donor) or pool of individuals (e.g., donors) with elevated levels of infectious disease antibodies. In embodiments, the individual or pool of individuals described herein have elevated levels of infectious disease antibodies due to previous exposure to infectious disease antigen (e.g., an individual or pool of individuals previously infected with a virus). In embodiments, the individual or pool of individuals described herein have elevated levels of infectious disease antibodies due to intentional stimulation of the immune response (e.g., administration of a vaccine). In embodiments, the hyperimmune composition contains purified immunoglobulins derived from such individuals or pools of individuals. In embodiments, the antibodies described herein are immune globulins. In embodiments, the hyperimmune composition comprises IgG antibodies.

[0172] As used herein, the term “hyperimmunization” or “hyperimmunized” refer to a state of immunity that is greater than normal (e.g. , non-infected subj ects or healthy subj ects) and results in a higher titer than normal number of antibodies to an antigen. In embodiments, hyperimmunization can be the result of a previous infection with the infectious disease, such that the individual or pool of individuals have higher titer of certain antibodies against the infectious disease, compared to an individual or pool of individuals who have never been infected with the infectious disease. In embodiments, hyperimmunization can involve the repeated administration of a single antigen or multiple antigens of a given infectious disease to one or more subjects to generate an enhanced immune response (e.g., higher titer of antibodies against the infectious disease compared to a subject not exposed to the antigen).

[0173] As used herein, the term “passive immunization” refers to conferral of immunity by the administration, by any route, of exogenously produced immune molecules (e.g., antibodies) into a subject. Passive immunization differs from “active” immunization, where immunity is obtained by introduction of an immunogen into an individual to elicit an immune response.

[0174] As used herein, the terms “pooled plasma,” “pooled plasma samples,” and “pooled plasma composition” refer to a mixture of two or more plasma samples from one or more donors and/or a composition prepared from the same (e.g., an immunoglobulin composition). In embodiments, the plasma samples are obtained from a single donor. In embodiments, the plasma samples are obtained from a plurality of donors. Elevated titer of a particular antibody or set of antibodies in pooled plasma reflects the elevated titers of the antibody samples that make up the pooled plasma. For example, plasma samples can be obtained from donors or subjects that have been vaccinated (e.g., with a vaccine) or donors or subjects that have high titers of antibodies to an infectious disease antigen (e.g., after infection) as compared to the antibody level(s) found in a population of subjects never infected with the infectious agent or the population as a whole. Upon pooling of the plasma samples, a pooled plasma composition is produced (e.g., that has an elevated titer of antibodies specific to a particular antigen). Pooled plasma compositions can be used to prepare immunoglobulin (e.g., that is subsequently administered to a subject) via methods known in the art (e.g., fractionation, purification, isolation, etc.). The present disclosure provides that pooled plasma compositions, pooled serum compositions, and immunoglobulin compositions prepared from same can be administered to a subject to provide prophylactic and/or therapeutic benefits to the subject or an embryo, fetus or infant carried by a subject. Accordingly, the term pooled plasma composition or pooled serum composition can refer to immunoglobulin prepared from pooled plasma or pooled serum samples, respectively.

[0175] As used herein, the terms “subject” or “individual,” used interchangeably herein, refer to any subject, particularly a mammalian subject, particularly humans. Other subjects may include non-human primates, cattle, dogs, cats, guinea pigs, rabbits, rats, mice, horses, goats, sheep, and so on. In embodiments, the terms “subject” or “individual” can refer to a single subject or individual. In other embodiments, the terms “subject” or “individual” can refer to a plurality of subjects or individuals.

[0176] As used herein, the term “donor” refers to a subject who is a source of a biological material. In embodiments, the biological material may include blood, a blood product, a combination thereof. In embodiments, the donor is a mammal. In further embodiments, the mammal may include, without limit, a human, a non-human primate, or a horse. In embodiments, the donor is a plasma and/or serum donor. In embodiments, the term “donor” can refer to a single donor. In other embodiments, the term “donor” can refer to a plurality of donors.

[0177] As used herein, the terms “at risk for infection” and “at risk for disease” refer to a subject that is predisposed to experiencing a particular infection or disease. This predisposition may be genetic (e.g., a particular genetic tendency to experience the disease, such as heritable disorders), or due to other factors (e.g., immunosuppression, compromised immune system, immunodeficiency, environmental conditions, geography, exposures to detrimental compounds present in the environment, etc.). Thus, it is not intended that the present disclosure be limited to any particular risk (e.g., a subject may be “at risk for disease” simply by being exposed to and interacting with other people).

[0178] As used herein, the term “sterile” refers to the absence of or within acceptable amounts according to FDA or USP standards of detectable microorganism contamination such as bacteria, fungi, and pathologic viruses.

[0179] As used herein “log reduction” refers to the relative number of infectious pathogens eliminated (e.g., from a sample or surface). For example, a “5-log reduction” means lowering the number of pathogen by 100,000-fold, e.g., if a sample has 100,000 pathogenic microbes in it, a 5-log reduction would reduce the number of pathogenic microbes to one. The highest percentage pathogen reduction that is generally used is 99.9999%. This percentage can be written as, e.g., greater than 6-log reduction or a 6-log kill rate. The average log reduction may vary depending on the pathogen. For example, in studies with viral pathogens, the Pathogen Reduction Technology (PRT) system provides average log reduction of 4.46 +/- 0.39 for intracellular HIV, 5.93 +/- 0.20 for cells associated HIV, and 5.19 +/- 0.50 for West Nile virus. For the non-enveloped porcine parvovirus, a reduction factor greater than 5.0 log was observed. Staphylococcus epidermidis and Escherichia coli bacteria were also tested with observed reduction factors to the limits of detection of 4.0 log or greater.

[0180] As used herein, “chromatography” refers to a method of separating the substances of a solution based on one or more of its chemical properties. More specifically, separating a desired substance from a solution.

[0181] As used herein, “depth filtration” refers to the use of the thickness of a cellulose based filter media to trap suspended particles and separate them from their carrying fluid. Optionally, filter aid (e.g., diatomaceous earth) may be employed in combination with the filter media to increase the capacity to trap suspended particles.

[0182] As used herein, “excipient” refers to a substance formulated alongside the of a medication included for the purpose of long-term stabilization, bulking up solid formulations that contain potent active ingredients in small amounts, or to confer therapeutic enhancement on the active ingredient in the final dosage form. The selection of appropriate excipients also depends upon the route of administration and the dosage form, as well as the active ingredient and other factors. [0183] As used herein, “filter sterilization” refers to the use of membranes to trap contaminants larger than the pore size on the surface of the membrane.

[0184] As used herein, the term “housing” or “covering” refers to a barrier between the internal and external environment. In embodiments, the housing is a shipping container or enclosure, a temporary walled structure, or a vehicle (e.g., a trailer truck).

[0185] As used herein, the term “modular system” refers to an enclosure comprising isolated, self-contained functional elements designed to carry out the processes described herein.

[0186] As used herein, a “viral filter” refers to a virus clearance technology. It may include retrovirus or retrovirus and parvovirus removal depending on the size of filter. Examples of commercially available virus filtration products include PLANOVA (Asahi Kasei), VIRESOLVE (Millipore Sigma), PEGASUS Prime (Pall Life Sciences), PEGASUS SV4 (Pall Life Sciences), and VIROSART (Sartorius).

[0187] As used herein, the term “single-use” refers to a property of a component or material which renders it useful for an intended purpose for a limited period of time. Specifically, a single-use component or material is designated to function without cleaning or maintenance during use.

[0188] In embodiments, the container is "a sample container” or "a plurality of sample containers" (e.g., a first sample container, a second sample container, etc.) used to hold a plasma sample (e.g., a donor plasma sample) before or during the process. In embodiments, the sample container is a bag, a vial, a bottle, a tank (e.g., a collection tank), a syringe, a microinjector, or any combination thereof. In embodiments, the sample container is a bag. In embodiments, the sample container is for a single use.

[0189] In embodiments, the container is “a receptacle” (e.g., a pooling receptacle, a second receptacle, etc.) used to hold a component or a material (e.g., pooled plasma, a composition (e.g., polyclonal immunoglobulin composition), a solution, a buffer, or a formulation), before or during the process. In embodiments, the receptacle is a bag, a vial, a bottle, a tank (e.g., a buffer tank or a collection tank), a syringe, a micro-injector, or any combination thereof. In embodiments, the receptacle is for a single use.

[0190] In embodiments, the container is “a drug product container” or “a plurality of drug product containers” used to hold a final drug product (e.g., a sterile polyclonal immunoglobulin composition). In embodiments, the drug product container is a bag, a vial, a bottle, a tank (e.g., a collection tank), a syringe, a micro-injector, or any combination thereof. In embodiments, the drug product container is for a single use. [0191] Various embodiments described herein provide a process for preparing a sterile polyclonal immunoglobulin composition, and a modular response platform and modular manufacturing unit for performing the process, to facilitate the manufacture of an antibody therapeutic or prophylactic product (derived from convalescent plasma) on-site in areas of emerging infectious disease and during emergency situations. The process for the modular manufacturing unit is feasible (in terms of size, materials, and processing time) to be executed in a modular shipping container or enclosure (i.e., the modular system) that can be deployed to manufacture therapeutic in areas where there are declared outbreaks in a relatively short amount of time (e.g., about 1 day). In embodiments, processes described herein may also be carried out in a dedicated clean room environment. Further variations of the embodiments described above may also be provided.

[0192] The aforementioned description of the specific embodiments fully reveal the general nature of the disclosure that others can, by applying knowledge within the skill of the art, readily modify and/or adapt for various applications such specific embodiments, without undue experimentation, without departing from the general concept of the present disclosure. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology herein is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance.

[0193] The breadth and scope of the present disclosure should not be limited by any of the above-described exemplary embodiments but should be defined only in accordance with the following claims and their equivalents. Similarly, the following examples are merely illustrative and should not be construed as limiting the scope of this disclosure in any way as many variations and equivalents will become apparent to those skilled in the art upon reading the present disclosure.

[0194] Further embodiments consistent with the disclosure include at least the following.

[0195] An embodiment includes a process for preparing a sterile polyclonal immunoglobulin composition. The process includes (a) pooling a plurality of plasma samples from donors exposed to an infectious agent or an antigenic component thereof to produce a pooled plasma composition; (b) isolating immunoglobulin from the pooled plasma composition using a chromatography column to produce an isolated polyclonal immunoglobulin composition; (c) filtering the isolated polyclonal immunoglobulin composition to remove or reduce viral contaminants by size exclusion to produce a virus filtered polyclonal immunoglobulin composition; (d) concentrating the virus filtered polyclonal immunoglobulin composition to produce a concentrated polyclonal immunoglobulin composition; (e) formulating the concentrated polyclonal immunoglobulin composition with a solution comprising an excipient to produce a formulated polyclonal immunoglobulin composition; and (f) filter sterilizing the formulated polyclonal immunoglobulin composition to produce a sterile polyclonal immunoglobulin composition.

[0196] A further embodiment includes the features of previous embodiments and further includes treating the plurality of plasma samples or the pooled plasma composition for pathogen reduction before (a) or (b), respectively.

[0197] A further embodiment includes the features of previous embodiments and further includes no further pathogen and/or viral reduction is performed after (c).

[0198] A further embodiment includes the features of previous embodiments and further includes diluting the pooled plasma composition before (b).

[0199] A further embodiment includes the features of previous embodiments and further includes treating the pooled plasma composition before (b) to reduce lipids.

[0200] A further embodiment includes the features of previous embodiments and further includes depth filtration.

[0201] A further embodiment includes the features of previous embodiments and further includes isolating the from the pooled plasma composition by ion exchange (IEX) chromatography.

[0202] A further embodiment includes the features of previous embodiments and further includes diafiltering the concentrated polyclonal immunoglobulin composition before (f).

[0203] A further embodiment includes the features of previous embodiments and further includes adjusting the pH of the concentrated polyclonal immunoglobulin composition before (f).

[0204] A further embodiment includes the features of previous embodiments and further includes diafiltering the concentrated polyclonal immunoglobulin directly into the solution of (e) which does not require further pH adjustment.

[0205] A further embodiment includes the features of previous embodiments, wherein the excipient comprises L-proline, acetate, or a combination thereof.

[0206] A further embodiment includes the features of previous embodiments, wherein the formulated polyclonal immunoglobulin composition is sterilized using a 0.2 pm filter.

[0207] The process of any one of the preceding embodiments, wherein (a)-(f) are completed within a modular system. [0208] A further embodiment includes the features of previous embodiments, wherein (f) is completed within the modular system under a directional HEPA filtered air supply.

[0209] A further embodiment includes the features of previous embodiments, wherein (a)-(e), (b)-(e), (b)-(f), or (a)-(f) are completed within a closed modular system.

[0210] A further embodiment includes the features of previous embodiments, wherein any process component which comes into direct contact with the plasma samples or any of the immunoglobulin compositions of (a)-(f) is a single-use component.

[0211] A further embodiment includes the features of previous embodiments, wherein the modular system or closed modular system is located in the region of an outbreak of the infectious agent or where the infectious agent is emerging.

[0212] A further embodiment includes the features of previous embodiments, wherein the infectious agent is a known or unknown viral or bacterial pathogen.

[0213] A further embodiment includes the features of previous embodiments, wherein the infectious agent is viral or bacterial.

[0214] A further embodiment includes the features of previous embodiments, wherein the sterile polyclonal immunoglobulin composition is a hyperimmune composition.

[0215] A further embodiment includes the features of previous embodiments, wherein one or more of the donors is a convalescent donor, an immunized donor, or an asymptomatic infection-household contact.

[0216] A further embodiment includes the features of previous embodiments, wherein the volume of the pooled plasma is less than 100 L, less than 90 L, less than 80 L, less than 70 L, less than 60 L, less than 50 L, less than 40 L, less than 30 L, less than 20 L, or less than 10 L. [0217] A further embodiment includes the features of previous embodiments, wherein the volume of pooled plasma is about 10 L to about 100 L; about 10 L to about 90 L; about 10 L to about 80 L; about 10 L to about 70 L; about 10 L to about 60 L; about 10 L to about 50 L; about 15 L to about 100 L; about 15 L to about 90 L; about 15 L to about 80 L; about 15 L to about 70 L; about 15 L to about 60 L; about 15 L to about 50 L; about 20 L to about 100 L, or about 30 L to about 50 L.

[0218] A further embodiment includes the features of previous embodiments, wherein the sterile polyclonal immunoglobulin composition is formulated for intramuscular administration. [0219] A further embodiment includes the features of previous embodiments, wherein the chromatography column comprises a single-use chromatography column. [0220] A further embodiment includes the features of previous embodiments, further comprising packaging the sterile polyclonal immunoglobulin composition into a single-use drug product container or a plurality of single-use drug product containers.

[0221] A further embodiment includes the features of previous embodiments, wherein the single-use drug product container or the plurality of single-use drug product containers are selected from the group consisting of a bag, a vial, a bottle, a syringe, a micro-injector, and combinations thereof.

[0222] A further embodiment includes the features of previous embodiments, wherein after packaging the single-use drug product container or the plurality of single-use drug product containers each comprises a volume sufficient for a single dose of the sterile polyclonal immunoglobulin composition.

[0223] A further embodiment includes the features of previous embodiments, wherein the dose is less than 10 mL.

[0224] A further embodiment includes the features of previous embodiments, wherein the dose is about 1 mL to about 10 mL, about 1 mL to about 9 mL, about 1 mL to about 8 mL, about 1 mL to about 7 mL, about 1 mL to about 6 mL, about 1 mL to about 5 mL, about 2 mL to about 10 mL, about 2 mL to about 9 mL, about 2 mL to about 8 mL, about 2 mL to about 7 mL, about 2 mL to about 6 mL, or about 2 mL to about 5 mL.

[0225] A further embodiment includes the features of previous embodiments, wherein (a)-(f) are completed in less than 48 hours, less than 36 hours, less than 30 hours, or less than 24 hours. [0226] A further embodiment includes a modular system for preparing a sterile polyclonal immunoglobulin composition comprising: (a) a pooling station comprising a pooling receptacle to receive a plurality of plasma samples from donors exposed to an infectious agent or an antigenic component thereof; (b) an isolation station comprising a chromatography column for isolating immunoglobulin from the pooled plasma obtained from the pooling station; (c) a filtering station comprising a virus filter for removing or reducing viral contaminants by size exclusion from the isolated immunoglobulin obtained from the isolation station; (d) a concentration station comprising a second receptacle for concentrating the filtered immunoglobulin obtained from the filtering station; and (e) a sterilization station comprising a filter for sterilizing the concentrated immunoglobulin obtained from the concentration station. [0227] A further embodiment includes the features of previous embodiments, wherein the stations of (a)-(e) are within a housing.

[0228] A further embodiment includes the features of previous embodiments, wherein the plurality of plasma samples undergo a pathogen reduction treatment before (a). [0229] A further embodiment includes the features of previous embodiments, wherein said pathogen reduction treatment is external to the housing.

[0230] A further embodiment includes the features of previous embodiments, wherein said pathogen reduction treatment is internal to the housing.

[0231] A further embodiment includes the features of previous embodiments, wherein stations (a)-(d) are in a first unit of the modular system.

[0232] A further embodiment includes the features of previous embodiments, wherein station (e) is in a second unit of the modular system under a directional HEPA filtered air supply.

[0233] A further embodiment includes the features of previous embodiments, wherein each component which comes into direct contact with the plasma samples or any of the immunoglobulin compositions is a single-use component.

[0234] A further embodiment includes the features of previous embodiments, wherein the modular system is a closed system.

[0235] A further embodiment includes the features of previous embodiments, wherein the modular system is a self-contained system.

[0236] A further embodiment includes the features of previous embodiments, wherein the pooling station comprises a thawing station.

[0237] A further embodiment includes the features of previous embodiments, wherein the thawing station comprises a thawing drape having a plurality of pockets.

[0238] A further embodiment includes the features of previous embodiments, wherein the thawing drape comprises a single-use thawing drape.

[0239] A further embodiment includes the features of previous embodiments, wherein each pocket is configured to receive one of a plurality of sample containers comprising the plasma samples.

[0240] A further embodiment includes the features of previous embodiments, wherein the pooling station further comprises a hose configured to transfer the plasma samples from the plurality of sample containers into the pooling receptacle of the pooling station for pooling of the plasma samples.

[0241] A further embodiment includes the features of previous embodiments, wherein the plurality of pockets is arranged in a two-dimensional array.

[0242] A further embodiment includes the features of previous embodiments, wherein the plurality of pockets comprises a non-insulating material.

[0243] A further embodiment includes the features of previous embodiments, wherein the thawing drape comprises grommets configured for hanging the thawing drape. [0244] A further embodiment includes the features of previous embodiments, wherein the pooled plasma is diluted before transfer to the isolation station of (b).

[0245] A further embodiment includes the features of previous embodiments, wherein the pooled plasma is treated to reduce lipids before transfer to the isolation station of (b).

[0246] A further embodiment includes the features of previous embodiments, wherein the treatment comprises depth filtration.

[0247] A further embodiment includes the features of previous embodiments, wherein the immunoglobulin is isolated from the pooled plasma composition by ion exchange (IEX) chromatography in the isolation station of (b).

[0248] A further embodiment includes the features of previous embodiments, wherein the filtered polyclonal immunoglobulin composition is diafiltered before transfer to the concentration station of (d).

[0249] A further embodiment includes the features of previous embodiments, wherein the pH of the concentrated polyclonal immunoglobulin composition is adjusted before transfer to the sterilization station of (f).

[0250] A further embodiment includes the features of previous embodiments, wherein the concentrated polyclonal immunoglobulin is diafiltered directly into a solution which does not require further pH adjustment.

[0251] A further embodiment includes the features of previous embodiments, wherein the solution comprises L-proline, acetate, or a combination thereof.

[0252] A further embodiment includes the features of previous embodiments, wherein the filter for sterilizing the concentrated immunoglobulin is a 0.2 pm filter.

[0253] A further embodiment includes the features of previous embodiments, wherein the modular system is located in the region of an outbreak of the infectious agent or where the infectious agent is emerging.

[0254] A further embodiment includes the features of previous embodiments, wherein the infectious agent is a known or unknown viral or bacterial pathogen.

[0255] A further embodiment includes the features of previous embodiments, wherein the infectious agent is a virus or a bacterium.

[0256] A further embodiment includes the features of previous embodiments, wherein the sterile polyclonal immunoglobulin composition is a hyperimmune composition.

[0257] A further embodiment includes the features of previous embodiments, wherein one or more of the donors is a convalescent donor, an immunized donor, or an asymptomatic infection-household contact. [0258] A further embodiment includes the features of previous embodiments, wherein the volume of the pooled plasma is less than 100 L, less than 90 L, less than 80 L, less than 70 L, less than 60 L, less than 50 L, less than 40 L, less than 30 L, less than 20 L, or less than 10 L.

[0259] A further embodiment includes the features of previous embodiments, wherein the volume of pooled plasma is about 10 L to about 100 L; about 10 L to about 90 L; about 10 L to about 80 L; about 10 L to about 70 L; about 10 L to about 60 L; about 10 L to about 50 L; about 15 L to about 100 L; about 15 L to about 90 L; about 15 L to about 80 L; about 15 L to about 70 L; about 15 L to about 60 L; about 15 L to about 50 L; about 20 L to about 100 L, or about 30 L to about 50 L.

[0260] A further embodiment includes the features of previous embodiments, wherein the sample container, the pooling receptacle, and/or the second receptacle is selected from the group consisting of a bag, a vial, a bottle, a tank, a syringe, a micro-injector, and any combination thereof.

[0261] A further embodiment includes the features of previous embodiments, further comprising a packaging station comprising a plurality of drug product containers for packaging the concentrated sterile immunoglobulin composition obtained from the sterilization station.

[0262] A further embodiment includes the features of previous embodiments, wherein the plurality of drug product containers are selected from the group consisting of a bag, a vial, a bottle, a syringe, a micro-injector, and any combination thereof.

[0263] A further embodiment includes the features of previous embodiments, wherein the plurality of drug product containers are single-use drug product containers.

[0264] A further embodiment includes the features of previous embodiments, wherein the packaging station is in a second unit of the modular system under a directional HEPA filtered air supply.

[0265] A further embodiment includes the features of previous embodiments, wherein after packaging the plurality of drug product containers each comprises a volume sufficient for a single dose of sterile polyclonal immunoglobulin composition.

[0266] A further embodiment includes the features of previous embodiments, wherein the dose is less than 10 mL.

[0267] A further embodiment includes the features of previous embodiments, wherein the dose is about 1 mL to about 10 mL, about 1 mL to about 9 mL, about 1 mL to about 8 mL, about 1 mL to about 7 mL, about 1 mL to about 6 mL, about 1 mL to about 5 mL, about 2 mL to about 10 mL, about 2 mL to about 9 mL, about 2 mL to about 8 mL, about 2 mL to about 7 mL, about 2 mL to about 6 mL, or about 2 mL to about 5 mL. [0268] A further embodiment includes the features of previous embodiments, wherein the sterile polyclonal immunoglobulin composition is formulated for intramuscular administration. [0269] A further embodiment includes the features of previous embodiments, wherein the sterile polyclonal immunoglobulin composition is prepared in less than 48 hours, less than 36 hours, less than 30 hours, and less than 24 hours.

[0270] A further embodiment includes the features of previous embodiments, wherein the modular system can be transported to an area of less than 500 square feet.

[0271] A further embodiment includes the features of previous embodiments, wherein the chromatography column comprises a single-use chromatography column.

[0272] A further embodiment includes the features of previous embodiments, wherein the filtering station comprises a single-use virus filter.

[0273] A further embodiment includes the features of previous embodiments, personal protective equipment, and buffers necessary to perform the process of previously described embodiments.

[0274] A further embodiment includes a method of treating plasma for pathogen reduction, the method comprising: receiving a batch of plasma packaged as a plurality of plasma samples containing a raised level of one or more antibodies; introducing riboflavin to the batch of plasma; exposing the batch of plasma containing the riboflavin to ultraviolet radiation to reduce pathogens contained in the batch of plasma to obtain a treated batch of plasma; and using the treated batch of plasma in a process to concentrate the one or more antibodies to manufacture a hyperimmune composition of antibodies.

[0275] A further embodiment includes the features of previous embodiments, introducing the riboflavin includes introducing the riboflavin to the plurality of plasma samples, and exposing the batch of plasma containing the riboflavin to the ultraviolet radiation includes exposing the plurality of plasma samples to the ultraviolet radiation.

[0276] A further embodiment includes the features of previous embodiments, pooling the plurality of plasma samples to generate a pooled plasma sample; and obtaining individual aliquots of plasma from the pooled plasma sample; wherein introducing the riboflavin to the plurality of plasma samples includes introducing the riboflavin to the individual aliquots, and wherein exposing the batch of plasma containing the riboflavin to the ultraviolet radiation includes exposing the individual aliquots to the ultraviolet radiation.

[0277] A further embodiment includes the features of previous embodiments, freezing the individual aliquots; receiving the individual aliquots at a modular manufacturing unit configured for manufacture of the hyperimmune composition of antibodies; thawing the individual aliquots; and pooling the individual aliquots prior to employing the treated batch of plasma in the process to concentrate the one or more antibodies.

[0278] A further embodiment includes the features of previous embodiments, wherein employing the treated batch of plasma in the process to concentrate the one or more antibodies to manufacture the hyperimmune composition of antibodies includes filtering the treated batch of plasma via a depth filter including activated carbon to remove at least a portion of the riboflavin.

[0279] A further embodiment includes a method of preparing pathogen reduced plasma for hyperimmune antibody composition manufacturing, the method comprising: receiving a plurality of treated plasma samples, the plurality of treated plasma samples containing riboflavin introduced during in a pathogen reduction operation utilizing ultraviolet radiation; pooling the plurality of treated plasma samples to generate a pooled treated plasma sample; filtering the pooled treated plasma sample via a depth filter including activated carbon to remove at least a portion of the riboflavin to generate a filtered plasma sample; and using the filtered plasma sample in a process to concentrate one or more antibodies contained in the filtered plasma sample to manufacture a hyperimmune composition of the one or more antibodies.

[0280] A further embodiment includes the features of previous embodiments, wherein filtering the pooled treated plasma sample further includes removing riboflavin degradants.

[0281] A further embodiment includes the features of previous embodiments, wherein filtering the pooled treated plasma sample further includes removing at least 98% of the riboflavin in the pooled treated plasma.

[0282] A further embodiment includes the features of previous embodiments, further comprising transferring the filtered plasma sample to an isolation station via a transfer system configured to prevent exposure of the filtered plasma sample to a local environment.

[0283] A further embodiment includes a modular manufacturing unit for manufacturing a hyperimmune antibody composition comprising: a transfer system configured to transfer products between stations without exposure to a local environment; an isolation station including at least one chromatography column configured to isolate at least one antibody in a pooled plasma sample to create an isolated antibody composition; a filtering station including a virus filter configured to reduce viral contaminants in the isolated antibody composition obtained from the isolation station via the transfer system to create a filtered antibody composition; a concentration station including a concentration receptacle configured to concentrate and formulate the filtered antibody composition obtained from the filtering station via the transfer system to create a concentrated antibody composition; and a sterilization station including a sterilizing filter configured to sterilize the concentrated antibody composition obtained from the concentration station via the transfer system to create the hyperimmune antibody composition.

[0284] A further embodiment includes the features of previous embodiments, further comprising a packaging station configured to distribute the hyperimmune antibody composition obtained from the sterilization station to individual packages.

[0285] A further embodiment includes the features of previous embodiments, a pooling station including a pooling receptacle configured to receive a plurality of plasma samples containing raised levels of the at least one antibody to create the pooled plasma sample; and a filtering station including a depth filter containing activated carbon configured to filter the pooled plasma sample prior to transfer via the transfer system to the isolation station.

[0286] A further embodiment includes the features of previous embodiments, wherein the transfer system is configured for removable attachment to the isolation station, the filtering station, the concentration station, and the sterilization station.

[0287] A further embodiment includes the features of previous embodiments, wherein the transfer system is configured for disposability.

[0288] A further embodiment includes the features of previous embodiments, wherein the transfer system is configured to provide a continuous flow between the isolation station, the filtering station, and the concentration station.

[0289] A further embodiment includes the features of previous embodiments, further comprising: a control unit; and a plurality of pumps, wherein the control unit is configured to control the plurality of pumps to maintain the continuous flow between the isolation station, the filtering station, and the concentration station.

[0290] A further embodiment includes the features of previous embodiments, wherein the concentration station is configured to receive an excipient provided in a liquid solution to formulate the hyperimmune antibody composition without exposing the hyperimmune antibody composition to the local environment.

[0291] A further embodiment includes a method for manufacturing a hyperimmune antibody composition comprising: receiving pooled plasma containing raised levels of at least one antibody at an isolation station that includes a chromatography column; isolating the at least one antibody in the pooled plasma utilizing the chromatography column of the isolation station to create an isolated antibody composition; transferring, via a transfer system, the isolated antibody composition from the isolation station to a filtering station without exposure to a local environment; filtering the isolated antibody composition to reduce viral contaminants in the isolated antibody composition to create a filtered antibody composition; transferring the filtered antibody composition from the filtering station to a concentration station without exposure to the local environment; concentrating the filtered antibody composition at the concentration station to create a concentrated antibody composition; transferring the concentrated antibody composition from the concentration station to a sterilization station without exposure to the local environment; and sterilizing the concentrated antibody composition at the sterilization station to create the hyperimmune antibody composition.

[0292] A further embodiment includes the features of previous embodiments, further comprising: transferring the hyperimmune antibody composition to a packaging station without exposure to the local environment; and distributing the hyperimmune antibody composition obtained from the sterilization station to individual packages.

[0293] A further embodiment includes the features of previous embodiments, further comprising: receiving a plurality of plasma samples containing raised levels of the at least one antibody at a pooling station including a pooling receptacle to create the pooled plasma; and transferring the pooled plasma to a filtering station including a depth filter containing activated carbon configured to filter the pooled plasma prior to transferring the pooled plasma to the isolation station via the transfer system.

[0294] A further embodiment includes the features of previous embodiments, further comprising providing a continuous flow between the isolation station, the filtering station, and the concentration station.

[0295] A further embodiment includes the features of previous embodiments, further comprising operating a plurality of pumps controlled by a control unit to maintain the continuous flow between the isolation station, the filtering station, and the concentration station.

[0296] A further embodiment includes the features of previous embodiments, further comprising formulating the hyperimmune antibody composition by providing an excipient in a liquid solution to the hyperimmune antibody composition without exposing the hyperimmune antibody composition to the local environment. [0297] A further embodiment includes the features of previous embodiments a thawing drape comprising: a panel comprising a water-resistant material, the panel having a top and a bottom; a plurality of pockets disposed on a first side of the panel, the plurality of pockets having openings oriented towards the top of the panel and comprising a permeable material permitting fluid flow; and a trough disposed at the bottom of the panel on the first side, the trough configured to catch and collect liquid exiting the plurality of pockets.

[0298] A further embodiment includes the features of previous embodiments, further comprising a plurality of fasteners disposed at the top of the panel and configured to hang the panel vertically.

[0299] A further embodiment includes the features of previous embodiments, further comprising a collection device connected to the trough and configured to drain the liquid.