]> Biopharma Manufacturing Execution Ontology This module contains terms and relations necessary for representing the actual occurrences of manufacturing processes with respect to recipes. Adlane Rebai, Millipore Sigma Ana Nikolov, OAGi Boonserm Kulvatunyou, NIST Cameron Gibbs, CrownPoint Technologies, LLC Gabriela Henning, NIST Jan Kemper, AstraZeneca Marie-Aude Coutouly, Millipore Sigma Melissa Weller, CrownPoint Technologies, LLC Milos Drobnjakovic, OAGi Stephen J. Granite, CrownPoint Technologies, LLC Stephen Kahmann, CrownPoint Technologies, LLC NIIMBL BD-1 Ontology Group http://opensource.org/licenses/MIT NIIMBL Manufacturing Execution Ontology

aeration process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ sparging of air into a bioreactor to supply oxygen for mammalian cell culture; sparging of oxygen-enriched gas into a microbial fermenter to support high oxygen demand; oxygen gas addition to a bioreactor to maintain dissolved oxygen within a target range; air addition through a gas inlet into a cell culture vessel to support oxygen transfer; oxygen-containing gas addition to an enzymatic reaction vessel to support an oxygen-dependent reaction

https://en.wikipedia.org/wiki/Aeration

AerationProcess(x) → MaterialAdditionProcess(x) ∧ ∃g ∃q ∃r ∃o (MaterialEntity(g) ∧ hasInput(x, g) ∧ GaseousAggregateState(q) ∧ hasQuality(g, q) ∧ TransferredMaterialRole(r) ∧ hasRole(g, r) ∧ DioxygenMolecule(o) ∧ isMadeOfAtAllTimes(g, o))

true

material addition process in which an oxygen-containing gas is added to a defined recipient to provide oxygen or support gas exchange

There are insufficient constructs to create a set of necessary and sufficient conditions.

if x is an 'aeration process' then x is a 'material addition process' that 'has input' some 'material entity' that 'has quality' some 'gaseous aggregate state', 'has role' some 'transferred material role', and 'is made of at all times' some 'dioxygen molecule'

antifoam addition process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ polypropylene glycol addition in microbial fermentation to prevent foam overflow and support stable dissolved oxygen control; antifoam addition to a mammalian cell culture bioreactor in response to foam detection; silicone-based antifoam addition during mixing of a foaming process solution

https://www.biophorum.com/download/cvp-case-study-interactive-version/

AntifoamAdditionProcess(x) → MaterialAdditionProcess(x) ∧ ∃m ∃r (AntifoamingAgent(m) ∧ TransferredMaterialRole(r) ∧ hasInput(x, m) ∧ hasRole(m, r))

true

material addition process in which an antifoam agent is introduced into a defined recipient to suppress, reduce, or prevent foam formation

There are insufficient constructs to create a set of necessary and sufficient conditions.

if x is an 'antifoam addition process' then x is a 'material addition process' that 'has input' some 'antifoaming agent' that 'has role' some 'transferred material role'

batch process operating mode https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ batch process operating mode of Protein A capture chromatography with a finite clarified-harvest load processed as a single unit to generate a product pool; batch process operating mode of mammalian cell culture in which process material is introduced before or at the start of cultivation and processed as a single unit without additional process material addition during cultivation; batch process operating mode of API crystallization in which a finite solvent/solute quantity is processed as a single unit before solids recovery

https://www.cytivalifesciences.com/en/us/news-center/what-are-the-different-bioreactor-processes-10001 and https://gmpua.com/Process/ContinuousManufacturing/ContinuousManufacturing.pdf

In batch process operating mode, a finite quantity of process material is processed as a single unit. The defining feature is that the process material is introduced before or at the start of the main processing interval and is not supplemented by additional process material during that interval. This does not exclude sampling, gas exchange, venting, minor control additions, or other ancillary operations that do not change the batch mode character of the process. Batch process operating mode should be distinguished from fed batch process operating mode, where additional process material is intentionally introduced during the run, and from continuous process operating mode, where material is introduced while output material is concomitantly removed over an operating interval.

BatchProcessOperatingMode(x) → PlannedProcessOperatingMode(x)

true

process operating mode of a planned process in which a finite quantity of process material is introduced before or at the start of the main processing interval and processed as a single unit, without additional process material being introduced or removed during that interval

There are insufficient constructs to define a set of necessary and sufficient conditions

if x is a 'batch process operating mode' then x is a 'planned process operating mode'

biomanufacturing production process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ Biomanufacturing production process where Chinese Hamster Ovary (CHO) cells serve as the mammalian host platform for producing recombinant protein therapeutics; monoclonal antibody production in a bioreactor; viral vector production using HEK293 cells; fermentation process for production of penicillin by Penicillium chrysogenum; mRNA synthesis using enzymatic in vitro transcription;

1) The target products may include proteins, nucleic acids, metabolites, or whole cells 2) This construct is labeled as a biomanufacturing production process and is distinct from a full product production process. In a biomanufacturing production process, the desired biological product is synthesized, secreted, or accumulated by a biological system. At this stage, the product is typically present in a complex mixture containing process-related and product-related impurities. Additional processing steps such as purification, concentration, and formulation are generally required to isolate the product and prepare it in its final usable form.

BiomanufacturingProductionProcess(x) → ManufacturingProcess(x)

true

manufacturing process in which biological entities such as cells, enzymes, or organisms are used to synthesize, secrete, accumulate, or themselves serve as the target product

Insufficient constructs are present to create a set of necessary and sufficient conditions.

if x is a 'biomanufacturing production process' then x is a 'manufacturing process'

capture step Merck KGaA https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ A capture purification process uses protein A chromatography to retain monoclonal antibodies while host cell proteins flow through; A capture purification process applies ion exchange chromatography to bind recombinant proteins from cell culture supernatant; A capture purification process employs affinity membranes to isolate His-tagged proteins from bacterial lysates; A capture purification process uses mixed-mode chromatography to retain viral vectors while impurities are washed away;

A flowthrough chromatography process removes DNA and endotoxins while the target protein does not bind to the column; A depth filtration process removes cells and debris without selectively retaining the target molecule;

The reversible nature of retention implies that conditions such as buffer composition or pH can be adjusted to reverse the binding of the target molecule, allowing its release from the capture medium and enabling purification to continue.

CaptureStep(x) → PurificationProcess(x)

true

purification process in which target molecules are selectively and reversibly retained while impurities are allowed to pass through in the flowthrough or wash fractions

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'capture step' then x is a 'purification process'

cell banking Merck KGaA https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ establishing a master cell bank by freezing portions of a cloned HEK293 cell line under GMP conditions; banking the Vero cell line in cryopreservation medium supplemented with DMSO (dimethyl sulfoxide) and storing it in vapor-phase liquid nitrogen for future vaccine manufacturing; banking a hybridoma cell line after single-cell cloning and characterization to provide a preserved source of cells for monoclonal antibody production

1) Cell banking provides a reliable and consistent source of a cell line for future use, reducing the need for continued propagation and helping to mitigate risks associated with genetic drift or contamination. 2) Examples of future use include research, drug development, and manufacturing of biopharmaceuticals.

CellBanking(x) → PlannedProcess(x) ∧ ∃y (CellLine(y) ∧ hasParticipantAtSomeTime(x, y))

true

planned process of preserving and maintaining a cell line for future use

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'cell banking' then x is a 'planned process' that 'has participant at some time' some 'cell line'

cell bleed process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ In a perfusion culture of CHO cells producing a monoclonal antibody, a controlled daily bleed of 10% of the reactor volume is performed to maintain cell density within the target range (e.g., 20–30 × 10⁶ cells/mL). This prevents overgrowth, stabilizes residence time distribution, and avoids excessive accumulation of lactate and ammonia that could impair productivity or product quality.

https://documents.thermofisher.com/TFS-Assets/BPD/Reference-Materials/perfusion-terminology-white-paper.pdf

At the end of a fed-batch run, the entire bioreactor contents are removed to recover product (harvesting). Although this involves material removal, it is not considered bleeding because the goal is not to regulate culture properties during an ongoing process, but rather to terminate the culture and collect the final product.

A cell bleed process is commonly used in perfusion culture processes to regulate viable cell density or biomass concentration, but it is not limited to continuous process operating mode. It may also occur in semi-continuous or other ongoing culture processes when cell-containing culture material is deliberately withdrawn to regulate culture properties. It should be distinguished from terminal harvest, which removes culture material to collect product or conclude the culture process, and from sampling, which removes material for measurement or testing

CellBleedProcess(x) → MaterialRemovalProcess(x) ∧ ∃c ∃sr ∃o ∃tr ∃p (CellCulture(c) ∧ hasParticipantAtSomeTime(x, c) ∧ MaterialWithdrawalSourceRole(sr) ∧ hasRole(c, sr) ∧ MaterialEntity(o) ∧ hasSpecifiedOutput(x, o) ∧ ∃cp (CellPopulation(cp) ∧ hasContinuantPartAtAllTimes(o, cp)) ∧ TransferredMaterialRole(tr) ∧ hasRole(o, tr) ∧ PlannedProcess(p) ∧ occursDuring(x, p) ∧ hasParticipantAtSomeTime(p, c))

true

material removal process in which a portion of cell-containing culture material is withdrawn from a cell culture during an ongoing culture process to regulate culture properties such as viable cell density, biomass concentration, or metabolite accumulation

There are insufficient constructs to create a set of necessary and sufficient conditions

if x is a 'cell bleed process' then x is a 'material removal process' that 'has participant at some time' some 'cell culture' that 'has role' some 'material withdrawal source role', 'has specified output' some 'material entity' that 'has continuant part at all times' some 'cell population' and 'has role' some 'transferred material role', and 'occurs during' some 'planned process' that 'has participant at some time' that same 'cell culture'

cell culture expansion process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ Shake flask expansion of CHO cells with controlled feeding and monitoring; seed train expansion of hematopoietic stem cells under GMP conditions; fed-batch bioreactor expansion of hybridoma cells with automated pH and DO control; scale-up culture of mammalian cells in rocking bioreactors with defined agitation parameters; T cell expansion in gas-permeable bags with scheduled media additions

OBI:0001147

proliferation of cells caused by a contamination

Implicit in cell culture expansion is the assumption that cells in culture remain healthy and proliferative. This assumption is typically evaluated by monitoring cell viability, which serves as a key indicator of culture fitness.

Incidental or secondary cell proliferation during a cell culture recovery process or production culture production phase does not by itself make that process a cell culture expansion process.

CellCultureExpansionProcess(x) → PlannedProcess(x) ∧ ∃p (CellPopulationProliferation(p) ∧ hasOccurrentPart(x, p)) ∧ ∃c (CellCulture(c) ∧ hasParticipantAtSomeTime(x, c))

true

planned cell culture process during which cultivation is managed primarily to increase the total number of cells through cell proliferation

Insufficient constructs are present to create a set of necessary and sufficient conditions.

if x is a 'cell culture expansion process' then x is a 'planned process' that 'has occurrent part' some 'cell population proliferation' and 'has participant at some time' some 'cell culture'

cell culture inoculation process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ introducing resuspended cells into a shake flask containing fresh medium to initiate a recovery culture; adding thawed ultra-high-density CHO cell material from a working cell bank into a wave-mixed perfusion bioreactor to start culture growth; using seed culture to inoculate an N-1 perfusion bioreactor; inoculating fed-batch production bioreactors with cells from an N-1 perfusion bioreactor

https://database.ich.org/sites/default/files/Q7%20Guideline.pdf and https://database.ich.org/sites/default/files/ICH_Q5A%28R2%29_Guideline_2023_1101.pdf

A cell culture inoculation process typically involves introducing cell-containing inoculum from a cryovial, seed culture, or intermediate vessel into fresh culture medium or vessel contents under controlled conditions. It marks the start of a new cell culture process within recovery, expansion, seed train, N-1, or production culture. It should be distinguished from culture medium charging, which occurs before inoculation, and from culture feed addition, which occurs after the cell culture process has begun.

CellCultureInoculationProcess(x) → InoculationProcess(x) ∧ ∃m ∃c ∃ir ∃tr (MaterialEntity(m) ∧ CellPopulation(c) ∧ hasInput(x, m) ∧ hasContinuantPartAtAllTimes(m, c) ∧ InoculumRole(ir) ∧ hasRole(m, ir) ∧ TransferredMaterialRole(tr) ∧ hasRole(m, tr)) ∧ ∃p ∃cc (PlannedProcess(p) ∧ occurrentPartOf(x, p) ∧ CellCulture(cc) ∧ hasParticipantAtSomeTime(p, cc))

true

inoculation process in which a cell-containing inoculum is introduced to initiate a cell culture process

There are insufficient constructs to create a set of necessary and sufficient conditions

if x is a 'cell culture inoculation process' then x is an 'inoculation process' that 'has input' some 'material entity' that 'has continuant part at all times' some 'cell population' and 'has role' some 'inoculum role' and some 'transferred material role', and x is 'occurrent part of' some 'planned process' that 'has participant at some time' some 'cell culture'

cell culture recovery process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ Recovery of cryopreserved CHO Cells after thawing; Recovery of mammalian cells after transfer to serum-free medium

https://documents.thermofisher.com/TFS-Assets/BID/Handbooks/gibco-cell-culture-basics-handbook.pdf and https://www.atcc.org/the-science/culturing-cells/reviving-cells#:~:text=The%20viability%20for%20most%20cells,recover%20and%20enter%20exponential%20growth. and https://www.thermofisher.com/rs/en/home/life-science/cloning/cloning-learning-center/invitrogen-school-of-molecular-biology/molecular-cloning/transformation/bacterial-transformation-workflow.html

1) Recovery cultivation is applied when cells have experienced physiological stress that may compromise viability, metabolic activity, adaptation to culture conditions, or growth potential. Thawing from cryopreservation is a common example, because ice crystal formation, osmotic imbalance, and cryoprotectant exposure may require time for cells to stabilize after thaw. Similar recovery may be needed after other stress-inducing manipulations, such as shear exposure, nutrient deprivation, transfer between culture environments, or other handling stresses. 2) In post-thaw recovery cultivation, cells are often more vulnerable than during later expansion stages and may require careful handling under controlled conditions. Cells in post-thaw recovery are not necessarily in exponential growth; the focus is typically on stabilization, viability recovery, and adaptation to the culture environment. Acceptance criteria for advancing out of recovery may therefore differ from those used for exponential expansion, reflecting the physiological state of the cells during recovery. 3) Recovery cultivation should be distinguished from cell culture expansion process. Expansion is primarily directed toward increasing cell number through proliferation, whereas recovery cultivation is primarily directed toward restoring or stabilizing cell condition after stress. Some proliferation may occur during recovery, but proliferation is not the defining purpose of the process.

CellCultureRecoveryProcess(x) → PlannedProcess(x) ∧ ∃c (CellCulture(c) ∧ hasParticipantAtSomeTime(x, c))

true

planned process in which cells that have undergone a stress-inducing process are cultured under controlled conditions to restore or stabilize viability, metabolic activity, or growth potential

Insufficient constructs are present to create a set of necessary and sufficient conditions.

if x is a 'cell culture recovery process' then x is a 'planned process' that 'has participant at some time' some 'cell culture'

cell line development Merck KGaA https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ establishing cell line Cell line development that starts with transfecting a CHO population with a vector containing the genetic sequence for the cNIST mAb and ends with banking the cell line stemming from a clone that had the highest mAb productivity

https://www.sartorius.com/en/applications/biopharmaceutical-manufacturing/cell-line-development/what-is-cell-line-development and from OBI:establishing cell lines

1) Cell line development involves one or more clonal selection processes to isolate and expand a genetically stable monoclonal population with desirable traits. 2) A cell line development process ends with the banking of the resulting cell line. 3) Cell line development is one of the first steps in the process of developing a biopharmaceutical product. This step is time consuming and resource-intensive. 4) Engineering in this context includes experimental modification of an existing cell population or cell line to establish a new cell line with desired characteristics, such as introduction of genetic material, immortalization, or another stable genetic modification. 5) Regulatory standards in biologics require proof of monoclonality for a production cell line. This implies that it originates from a single progenitor cell, regardless of whether one calls it a clone or a line. In practice, a clone is the starting point for development: once selected and scaled, it becomes a permanent cell line with specific attributes used for product manufacture.

CellLineDevelopment(x) → PlannedProcess(x) ∧ ∃g∃c∃l∃b(GeneticTransformationProcess(g) ∧ CloneSelectionProcess(c) ∧ ClonedCellLine(l) ∧ CellBanking(b) ∧ hasOccurrentPart(x,g) ∧ hasOccurrentPart(x,c) ∧ precedes(g,c) ∧ temporallyStartedBy(x,g) ∧ hasSpecifiedOutput(c,l) ∧ hasSpecifiedOutput(x,l) ∧ hasParticipantAtSomeTime(b,l) ∧ (meets(x,b) ∨ temporallyOverlaps(x,b)))

true

planned process in which a cell line is engineered to produce a therapeutic biomolecule or biologic

There are insufficient constructs to create a set of necessary and sufficient conditions

if x is a 'cell line development' then x is a 'planned process' that is 'temporally started by' some 'genetic transformation process' g and 'has occurrent part' g and some 'clone selection process' c, where g 'precedes' c, and c 'has specified output' some 'cloned cell line' l that is also the 'specified output' of x, and x either 'meets' or 'temporally overlaps' some 'cell banking' that 'has participant at some time' that same l

cell population proliferation https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ cell population growth natural proliferation of skin fibroblasts during wound healing; proliferation of T cells upon antigen stimulation in immune response; bacterial population growth in a nutrient-rich medium; uncontrolled cancer cell proliferation in tumor tissue; multiplication of yeast cells during fermentation

GO:0008283

CellPopulationProliferation(x) → Process(x) ∧ ∃y (CellPopulation(y) ∧ hasParticipantAtAllTimes(x, y))

true

process in which cells reproduce or multiply, resulting in an increase in the number of cells

This term is expected to remain primitive. Details of cellular reproduction or multiplication are out of scope and should be utilized if needed from a biological ontology.

if x is a 'cell population proliferation' then x is a 'process' that 'has participant at all times' some 'cell population'

cell retention process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ cell retention process in a perfusion cell culture process, in which cells are retained in the culture system while product-containing harvest is removed through an alternating tangential flow device; cell retention process in a perfusion culture process, in which cells are retained by tangential flow filtration while spent medium is removed; cell retention process in a culture process, in which a spin filter retains cells while culture fluid is withdrawn

https://www.sigmaaldrich.com/RS/en/technical-documents/technical-article/pharmaceutical-and-biopharmaceutical-manufacturing/cell-retention-technology-intensified-upstream-processing?srsltid=AfmBOoqFH-ws3yWwAzIOto0QwogsWZ9HabmigGDMjpxvLiLAKJZ3UquQ

CellRetentionProcess(x) → PlannedProcess(x) ∧ ∃c ((CellCulture(c) ∧ hasInput(x, c)) ∧ ∃r (MaterialRemovalProcess(r) ∧ hasOccurrentPart(x, r)) ∧ ∃p (PlannedProcess(p) ∧ occurrentPartOf(x, p) ∧ hasParticipantAtSomeTime(p, c)))

true

planned process in which material is removed from a cell culture while cells are preferentially kept in or returned to the cell culture

Insufficient constructs are present to create a set of necessary and sufficient conditions.

if x is a 'cell retention process' then x is a 'planned process' that 'has input' some 'cell culture', 'has occurrent part' some 'material removal process', and is 'occurrent part of' some 'planned process' that 'has participant at some time' that same 'cell culture'

cell therapy production process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ manufacturing of autologous CAR-T cell therapy through patient-derived T-cell activation and expansion in culture bags; large-scale allogeneic NK-cell expansion in single-use bioreactors for immunotherapy

https://www.cellandgene.com/topic/cell-therapy-manufacturing and https://www.fda.gov/media/156896/download

CellTherapyProductionProcess(x) → BiomanufacturingProductionProcess(x) ∧ ∃o ((MaterialProduct(o) ∨ ProcessIntermediateMaterial(o)) ∧ hasSpecifiedOutput(x, o) ∧ ∃p (CulturedCellPopulation(p) ∧ hasContinuantPartAtAllTimes(o, p)))

true

biomanufacturing production process that results in a cell population which constitutes the targeted product material

There are insufficient constructs to create a set of necessary and sufficient conditions. In particular constructs for representing cells as the target product are still missing.

if x is a 'cell therapy production process' then x is a 'biomanufacturing production process' that 'has specified output' some 'material product' or some 'process intermediate material' that 'has continuant part at all times' some 'cultured cell population'

centrifugation process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ Latex is concentrated by centrifugation to separate rubber particles from field latex; Centrifugation is used to harvest CHO cells by separating them from spent culture media after production; Spinning blood samples to separate plasma for diagnostic testing; Centrifuging cell lysates to remove debris before protein quantification;

OBI:0302886

CentrifugationProcess(x) → PlannedProcess(x) ∧ ∃c(Centrifuge(c) ∧ hasParticipantAtSomeTime(x,c))

true

planned process in which particles such as cells, organelles, or molecules are separated based on size or density by applying centrifugal forces generated by a spinning rotor

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'centrifugation process' then x is a 'planned process' that 'has participant at some time' some 'centrifuge'

chemical synthesis process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ Benzene is produced by hydrodealkylation of toluene with hydrogen, yielding benzene and methane, and diphenyl as a by-product; Hydrogen chloride is produced by reacting chlorine and hydrogen in an exothermic process; Phthalic anhydride is synthesized by oxidizing ortho-xylene with oxygen at 320–400 °C, producing phthalic anhydride, water, and minor by-products like maleic anhydride and CO₂

https://en.wikipedia.org/wiki/Chemical_synthesis and https://www.chem.ox.ac.uk/synthesis

ChemicalSynthesisProcess(x) → ManufacturingProcess(x)

true

manufacturing process in which one or more chemical compounds are created through a set of chemical reactions

This class is expected to remain primitive as modeling chemical reactions is outside of the scope.

if x is a 'chemical synthesis process' then x is a 'manufacturing process'

chemostat culture process operating mode https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ chemostat operating mode of a microbial culture process, in which fresh medium containing a limiting nutrient is introduced while culture broth is concomitantly removed at a controlled dilution rate; chemostat operating mode of a continuous cell culture process, in which culture medium is introduced and culture material is removed over an operating interval so that dilution rate regulates culture growth

https://infors-ht.com/en/blog/the-difference-between-batch-fed-batch-and-continuous-processes

ChemostatCultureProcessOperatingMode(x) → ContinuousCultureProcessOperatingMode(x)

true

continuous culture process operating mode in which culture medium containing a growth-limiting component is introduced while culture material is concomitantly removed over an operating interval, with dilution rate used to regulate culture growth

There are insufficient constructs to define a set of necessary and sufficient conditions

if x is a 'chemostat culture process operating mode' then x is a 'continuous culture process operating mode'

chromatography process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ In the recombinant human insulin manufacturing process, a Size Exclusion Chromatography (SEC) process is used for the final polishing step using Sephadex G-25 to remove salts and ensure the proper molecular weight distribution of insulin; Industrial plants devoted to the processing of corn use a continuous simulated moving bed (SMB) chromatography process to separate fructose from glucose

CHMO:0001000

The phase moving in a definite direction is called a mobile phase and is a fluid

ChromatographyProcess(x) → PlannedProcess(x) ∧ ∃y (MobilePhase(y) ∧ hasParticipantAtSomeTime(x, y)) ∧ ∃z (StationaryPhase(z) ∧ hasParticipantAtSomeTime(x, z))

true

planned process that results in the separation of components in a mixture based on their distribution between two phases, one of which is stationary and the other moves in a definite direction

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'chromatography process' then x is a 'planned process' that 'has participant at some time' some 'mobile phase' and 'has participant at some time' some 'stationary phase'

clone selection process Merck KGaA https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ using microscope images from clone experiments as input to a predictive model to prioritize clones, followed by selecting candidates with optimal morphology and expression levels; selecting clones based on functional assays confirming high target protein activity and long-term culture stability; manually screening clones under a microscope and selecting those with optimal morphology and growth behavior

Desirable characteristics can be things such as high protein expression levels, consistent product quality, and robust growth

CloneSelectionProcess(x) → PlannedProcess(x) ∧ ∃y (ClonedCellLine(y) ∧ hasSpecifiedOutput(x, y))

true

planned process in which an optimal set of cell clones is identified and isolated based on the clones exhibiting desirable characteristics

Insufficient constructs are present to create a set of necessary and sufficient conditions.

if x is a 'clone selection process' then x is a 'planned process' and 'has specified output' some 'cloned cell line'

clone stability study Merck KGaA https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ clone stability study process Assessing the stability of a CHO cell clone by monitoring titer and cell growth during a 14-day fed-batch culture in a 5 L bioreactor; Evaluating the genetic, phenotypic, and productivity stability of CHO-K1 clone 3B7 producing anti-TNFα antibody over 70 days of continuous culture (equivalent to ~140 generations).

The results of such a study are often process dependent. Best practice would be to consider the results applicable only for the process that is used to obtain the data.

CloneStabilityStudy(x) → PlannedProcess(x) ∧ ∃y (ClonedCellLine(y) ∧ hasInput(x, y)) ∧ ∃z ((MeasurementProcess(z) ∨ MonitoringProcess(z)) ∧ hasOccurrentPart(x, z))

true

planned process composed of one or more measurement or monitoring processes, designed to evaluate whether a selected cell clone maintains its key phenotypic characteristics, genotypic traits, and genetic integrity over time and across multiple generations of cell division

Insufficient constructs are present to create a set of necessary and sufficient conditions.

if x is a 'clone stability study' then x is a 'planned process' that 'has input' some 'cloned cell line' and 'has occurrent part' some 'measurement process' or 'monitoring process'

continuous culture process operating mode https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ continuous culture operating mode of a chemostat culture process, in which fresh medium is introduced while culture broth is concomitantly removed to maintain culture volume and regulate growth by dilution rate; continuous culture operating mode of a turbidostat culture process, in which medium is introduced while culture broth is concomitantly removed, with flow adjusted to maintain a target cell density or turbidity; continuous culture operating mode of a perfusion culture process, in which fresh medium is introduced while spent medium or product-containing harvest is concomitantly removed and cells are retained in the culture system

https://www.cytivalifesciences.com/en/us/insights/what-are-the-different-types-of-bioreactors and https://infors-ht.com/en/blog/the-difference-between-batch-fed-batch-and-continuous-processes

ContinuousCultureProcessOperatingMode(x) → ContinuousProcessOperatingMode(x) ∧ ∃p (PlannedProcess(p) ∧ processCharacteristicOf(x, p) ∧ ∃c (CellCulture(c) ∧ hasParticipantAtSomeTime(p, c)))

true

continuous process operating mode of a culture process in which culture medium or other input material is introduced while culture material, spent medium, or product-containing harvest material is concomitantly removed over an operating interval

There are insufficient constructs to define a set of necessary and sufficient conditions

if x is a 'continuous culture process operating mode' then x is a 'continuous process operating mode' that is the 'process characteristic of' some 'planned process' that 'has participant at some time' some 'cell culture'

continuous process operating mode https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ continuous process operating mode of perfusion cell culture with fresh medium introduction and concomitant harvest removal through a cell retention device; continuous process operating mode of simulated moving-bed chromatography with feed introduction and concomitant product-stream removal; continuous process operating mode of single-pass TFF with feed and buffer introduction and concomitant product containing retentate removal; continuous process operating mode of crystallization with solute feed introduction and concomitant product slurry withdrawal; Continuous process operating mode of a hydrodealkylation (HDA) process where toluene reacts with hydrogen gas at high temperature (500–660 °C) and pressure (20–60 bar) to produce benzene and methane and diphenyl as a side-product; Continuous process operating mode of a Haber-Bosch process for the synthesis of ammonia from nitrogen and hydrogen gases reacting over an iron-based catalyst at high pressure (150–250 atm) and temperature (400°C–500°C)

https://www.ema.europa.eu/en/documents/scientific-guideline/ich-guideline-q13-continuous-manufacturing-drug-substances-and-drug-products-step-5_en.pdf and https://gmpua.com/Process/ContinuousManufacturing/ContinuousManufacturing.pdf

ContinuousProcessOperatingMode(x) → PlannedProcessOperatingMode(x) ∧ ∃p∃a∃r∃m (PlannedProcess(p) ∧ processCharacteristicOf(x,p) ∧ MaterialAdditionProcess(a) ∧ MaterialRemovalProcess(r) ∧ MaterialEntity(m) ∧ hasOccurrentPart(p,a) ∧ hasOccurrentPart(p,r) ∧ (occursSimultaneouslyWith(a,r) ∨ temporallyOverlaps(a,r) ∨ isTemporallyOverlappedBy(a,r)) ∧ hasSpecifiedOutput(r,m) ∧ isOutputOf(m,p))

true

process operating mode that characterizes a planned process in which input material is introduced into the process while output material is concomitantly removed from the same process over the whole operating interval

There are insufficient constructs to define a set of necessary and sufficient conditions

if x is a 'continuous process operating mode' then x is a 'planned process operating mode' that is the 'process characteristic of' some 'planned process' p that 'has occurrent part' some 'material addition process' a and some 'material removal process' r, where a either 'occurs simultaneously with', 'temporally overlaps', or 'is temporally overlapped by' r, and r 'has specified output' some 'material entity' that 'is output of' p

culture feed addition process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ addition of carbohydrate and amino acid feed to a CHO fed-batch culture; bolus addition of nutrient mix to maintain viable cell density during CHO production; controlled exponential glucose feeding in an E. coli high-cell-density culture; perfusion feed supplying fresh medium to a CHO bioreactor

A culture feed addition process occurs after a cell culture has been established by inoculation. It should be distinguished from initial medium charging before inoculation and from inoculation itself.

CultureFeedAdditionProcess(x) → MaterialAdditionProcess(x) ∧ ∃m ∃r ∃c ∃t∃p(NutrientFeed(m) ∧ TransferredMaterialRole(r) ∧ hasInput(x, m) ∧ hasRole(m, r) ∧ CellCulture(c) ∧ MaterialAdditionTargetRole(t) ∧ hasParticipantAtSomeTime(x, c) ∧ hasRole(c, t) ∧ PlannedProcess(p) ∧ occursDuring(x, p) ∧ hasParticipantAtSomeTime(p, c))

true

material addition process in which a nutrient feed is added to a cell culture during a culture process

There are insufficient constructs to create a set of necessary and sufficient conditions.

if x is a 'culture feed addition process' then x is a 'material addition process' that 'has input' some 'nutrient feed' that 'has role' some 'transferred material role', 'has participant at some time' some 'cell culture' that 'has role' some 'material addition target role', and 'occurs during' some 'planned process' that 'has participant at some time' that same 'cell culture'

culture feeding strategy https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ periodic bolus feeding strategy for CHO fed-batch cultures; dual-feed strategy combining separate carbohydrate and amino acid/vitamin feeds in CHO cultivation; exponential feeding strategy maintaining a defined specific growth rate in E. coli fed-batch process; model-predictive feeding strategy controlling nutrient supply in CHO perfusion culture

https://www.sigmaaldrich.com/deepweb/assets/sigmaaldrich/marketing/global/documents/315/296/t099.pdf?srsltid=AfmBOorDj4GQApYbLofXthe35elxKxxnoghM-lzOSFnGvMAqW5HEJnG1 and https://pubmed.ncbi.nlm.nih.gov/20014108/ and https://www.tandfonline.com/doi/full/10.1080/10826068.2021.1998112

A feeding strategy specifies how feeding processes are to be executed, rather than performing them. It defines scheduling and frequency and may also specify decision rules that determine feed additions, such as fixed pre-set schedules, condition-based triggers based on process measurements, or model-based rules. As a plan specification, it serves as a template guiding execution of one or more feeding processes. Feeding strategies are commonly used to maintain favorable culture conditions, sustain cell growth, and support or optimize product accumulation.

CultureFeedingStrategy(x) → PlanSpecification(x) ∧ ∃p (CultureFeedAdditionProcess(p) ∧ prescribes(x, p))

true

plan specification that prescribes how one or more feeding processes are to be executed during a cell culture process, including scheduling and amounts or rates, and any specified triggering conditions

There are insufficient constructs to create a set of necessary and sufficient conditions.

if x is a 'culture feeding strategy' then x is a 'plan specification' that 'prescribes' some 'culture feed addition process'

culture medium charging process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ charging medium into a production bioreactor before seed culture inoculation; adding recovery medium to a shake flask before thawed cell suspension inoculation; charging fermentation medium into a vessel before microbial inoculum addition.

https://www.emerson.com/documents/automation/article-electronic-workflow-for-a-bioreactor-deltav-en-56666.pdf and https://www.eppendorf.com/product-media/doc/en/897339/Fermentors-Bioreactors_Publication_Bioprocess_Bioprocessing-basics.pdf

A culture medium charging process establishes the culture medium contents that will receive inoculum. The charged medium may be complete culture medium, growth medium, seed medium, expansion medium, production medium, or another culture-medium formulation, depending on the culture process. It should be distinguished from cell culture inoculation, where inoculum is added to establish a cell culture, and from culture feed addition, where culture medium or nutrient feed is added to an already inoculated cell culture during a culture process.

CultureMediumChargingProcess(x) → MaterialAdditionProcess(x) ∧ ∃a∃c∃ar∃m∃mr∃i(MaterialArtifact(a) ∧ CellCultureHoldingCapability(c) ∧ hasCapability(a,c) ∧ MaterialAdditionTargetRole(ar) ∧ hasParticipantAtSomeTime(x,a) ∧ hasRole(a,ar) ∧ CultureMedium(m) ∧ TransferredMaterialRole(mr) ∧ hasInput(x,m) ∧ hasRole(m,mr) ∧ CellCultureInoculationProcess(i) ∧ precedes(x,i))

true

material addition process in which culture medium is added to a culture vessel in preparation for cell culture inoculation

There are insufficient constructs to create a set of necessary and sufficient conditions

if x is a 'culture medium charging process' then x is a 'material addition process' that 'has participant at some time' some 'material artifact' that 'has capability' some 'cell culture holding capability' and 'has role' some 'material addition target role', 'has input' some 'culture medium' that 'has role' some 'transferred material role', and 'precedes' some 'cell culture inoculation process'

culture medium exchange process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ Partial medium exchange in a T-cell expansion culture to restore nutrient levels and reduce lactate; Complete media change in adherent Vero cells before virus inoculation.

https://www.corning.com/worldwide/en/products/life-sciences/resources/stories/at-the-bench/cell-culture-media-change-protocol.html#:~:text=As%20a%20starting%20point%20for,Cell%20Culture%20Success%20with%20Corning and https://cellculturecompany.com/best-practices-for-media-preparation-and-exchange-in-mammalian-cell-culture/#:~:text=When%20and%20How%20to%20Perform,scale%2Dup%20and%20regulatory%20compliance.

Addition of fresh medium without removal of existing culture fluid

1) Culture medium exchange process includes both removal of existing culture medium or culture-medium-containing material and addition of fresh culture medium. 2) The process is distinct from feeding alone because feeding adds fresh material without requiring removal of existing culture medium. 3) Medium exchange may be partial or complete and is commonly applied in mammalian cell culture, virus production, and cell therapy to restore nutrient levels, reduce metabolite accumulation, remove inhibitory compounds, or otherwise adjust the culture environment.

CultureMediumExchangeProcess(x) → PlannedProcess(x) ∧ ∃a∃f∃t (MaterialAdditionProcess(a) ∧ hasOccurrentPart(x,a) ∧ CultureMedium(f) ∧ hasInput(a,f) ∧ TransferredMaterialRole(t) ∧ hasRole(f,t)) ∧ ∃r∃o∃m∃s (MaterialRemovalProcess(r) ∧ hasOccurrentPart(x,r) ∧ MaterialEntity(o) ∧ hasSpecifiedOutput(r,o) ∧ CultureMedium(m) ∧ SpentCultureMediumState(s) ∧ hasMaterialState(m,s) ∧ (o = m ∨ hasContinuantPartAtAllTimes(o,m))) ∧ ∃p∃c (PlannedProcess(p) ∧ occurrentPartOf(x,p) ∧ CellCulture(c) ∧ hasParticipantAtSomeTime(p,c))

true

planned process in which part or all of the spent culture medium associated with a cell culture is removed and fresh culture medium is added

There are insufficient constructs to create a set of necessary and sufficient conditions.

if x is a 'culture medium exchange process' then x is a 'planned process' that 'has occurrent part' some 'material addition process' that 'has input' some 'culture medium' bearing some 'transferred material role', 'has occurrent part' some 'material removal process' that 'has specified output' some 'material entity' that either is some 'culture medium' having some 'spent culture medium state' or 'has continuant part at all times' some 'culture medium' having some 'spent culture medium state', and is 'occurrent part of' some 'planned process' that 'has participant at some time' some 'cell culture'

degassing process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ vacuum degassing of culture medium prior to sterilization; nitrogen sparging to remove dissolved oxygen from buffer solution

https://en.wikipedia.org/wiki/Degassing

Degassing process separates material commonly described as dissolved, entrained, or adsorbed gas from a liquid or solid material. In this context, dissolved gas does not imply that the material is in a gaseous aggregate state while dissolved; for example, dissolved dioxygen molecule in culture medium is molecular material present in a liquid solution. Entrained gas may be present as gas bubbles, while adsorbed gas may be associated with a solid surface or solid material

DegassingProcess(x) → PlannedProcess(x) ∧ ∃m ∃q ∃g ∃gq (MaterialEntity(m) ∧ hasInput(x, m) ∧ hasSpecifiedOutput(x, m) ∧ ((LiquidAggregateState(q) ∨ SolidAggregateState(q)) ∧ hasQuality(m, q)) ∧ MaterialEntity(g) ∧ hasOutput(x, g) ∧ GaseousAggregateState(gq) ∧ hasQuality(g, gq))

true

planned process during which dissolved, entrained, or adsorbed gas is separated from a liquid or solid material

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'degassing process' then x is a 'planned process' that 'has input' some 'material entity' that 'has quality' some 'liquid aggregate state' or some 'solid aggregate state', that same 'material entity' is also the 'specified output' of x, and x 'has output' some 'material entity' that 'has quality' some 'gaseous aggregate state'

degasification process

depth filtration process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ A depth filtration process is used to clarify harvested cell culture by removing cells and large debris; A depth filtration process removes insoluble material after cell lysis before purification; A depth filtration process serves as the primary clarification step prior to sterile filtration;

DepthFiltrationProcess(x) → FiltrationProcess(x) ∧ ∃y (DepthFilter(y) ∧ hasParticipantAtSomeTime(x, y))

true

filtration process in which a fluid is passed through a depth filter

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'depth filtration process' then x is a 'filtration process' that 'has participant at some time' some 'depth filter'

diafiltration process Merck KGaA https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ After mAb purification, the protein solution undergoes diafiltration to exchange the buffer and remove residual salts before formulation; Whey is concentrated by ultrafiltration to retain proteins, followed by continuous water addition during filtration to remove residual lactose and salts through diafiltration.

Diafiltration can be conducted either in a continuous or discontinuous manner: Continuous diafiltration: Buffer is added continuously as filtrate is removed, maintaining a constant volume and concentration of the target molecule. Discontinuous diafiltration: Involves diluting the sample, concentrating it back, and repeating this process multiple times.

DiafiltrationProcess(x) → PlannedProcess(x) ∧ ∃y (DilutionProcess(y) ∧ hasOccurrentPart(x, y)) ∧ ∃z (FiltrationProcess(z) ∧ hasOccurrentPart(x, z)) ∧ (∃y ∃z (DilutionProcess(y) ∧ FiltrationProcess(z) ∧ hasOccurrentPart(x, y) ∧ hasOccurrentPart(x, z) ∧ (before(y, z) ∨ occursSimultaneouslyWith(y, z))))

true

planned process that consists of either multiple cycles of dilution followed by filtration, or of dilution and filtration occurring simultaneously, to remove unretained solutes or to exchange the solution's solvent or buffer environment

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'diafiltration process' then x is a 'planned process' and 'has occurrent part' some 'dilution process' and 'has occurrent part' some 'filtration process' and the 'dilution process' is such that it either 'occurs before' the 'filtration process' or 'occurs simultaneously with' the 'filtration process'

dilution process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ diluting a 10× phosphate-buffered saline (PBS) stock with water to make a 1× working solution

DilutionProcess(x) → SolutionPreparationProcess(x) ∧ ∃s∃v(Solution(s) ∧ Solvent(v) ∧ hasInput(x,s) ∧ hasInput(x,v))

true

solution preparation process in which a solvent is added to a solution to reduce the concentration of one or more solutes

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'dilution process' then x is a 'solution preparation process' that 'has input' some 'solution' and 'has input' some 'solvent'

direct flow filtration https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ dead-end filtration normal flow filtration In brewing, dead-end filtration separates wort from barley husks after mashing; Dead-end filtration removes particulates from buffer solutions before chromatography;

DirectFlowFiltration(x) ↔ FiltrationProcess(x) ∧ ∃y (PerpendicularFlowOrientation(y) ∧ hasProcessProfile(x, y))

filtration in which the fluid travels in the direction that is perpendicular to the surface of the filter

every instance of 'direct flow filtration' is defined as exactly an instance of 'filtration process' that 'has process profile' some 'perpendicular flow orientation'

drug product formulation process Merck KGaA https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ The drug formulation process of Simvastatin (drug used to lower cholesterol and triglycerides) tablets comprises the combination of the API with a selection of appropriate pharmaceutical excipients that ensure the tablet's structure, stability, proper absorption in the body, and manufacturability.

https://renejix.com/what-is-drug-formulation/

DrugProductFormulationProcess(x) → ManufacturingProcess(x)

true

manufacturing process in which various components are combined to create a drug product that is safe, effective, and stable for patient use

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'drug product formulation process' then x is a 'manufacturing process'

fed batch process operating mode https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ CHO culture with bolus glucose feeds to maintain viable cell density, harvested in a single terminal step; Semi-batch polymerization where monomer is added gradually to control heat release, then reactor is emptied;

https://www.cytivalifesciences.com/en/us/insights/what-are-the-different-types-of-bioreactors and https://gmpua.com/Process/ContinuousManufacturing/ContinuousManufacturing.pdf

Simple batch bioreactor run with no feeding; Perfusion culture

In fed batch process operating mode, the process remains organized around a finite quantity of process material processed as a single unit, but additional process material is intentionally introduced during the main processing interval. Fed batch process operating mode should be distinguished from batch process operating mode, where additional process material is not introduced during that interval, and from continuous process operating mode, where all input materials are introduced while all the output materials are concomitantly removed during the whole processing interval. Ancillary additions such as pH adjusters, antifoam, sparging gas, buffers, wash solutions, or cleaning solutions do not by themselves make the mode fed batch.

FedBatchProcessOperatingMode(x) → PlannedProcessOperatingMode(x) ∧ ∃p∃i∃m∃r(PlannedProcess(p) ∧ processCharacteristicOf(x,p) ∧ MaterialAdditionProcess(i) ∧ hasOccurrentPart(p,i) ∧ (ProcessIntermediateMaterial(m) ∨ RawMaterial(m)) ∧ hasInput(i,m) ∧ TransferredMaterialRole(r) ∧ hasRole(m,r))

true

process operating mode of a planned process in which a finite quantity of process material is introduced before or at the start of the main processing interval, and additional process material is introduced during that interval while the process material is retained and processed as a single unit

There are insufficient constructs to define a set of necessary and sufficient conditions

if x is a 'fed batch process operating mode' then x is a 'planned process operating mode' that is the 'process characteristic of' some 'planned process' that 'has occurrent part' some 'material addition process' that 'has input' some 'process intermediate material' or some 'raw material' that 'has role' some 'transferred material role'

filtration process Merck KGaA https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ depth filtration; TFF filtration; direct flow filtration; membrane filtration

http://purl.obolibrary.org/obo/CHMO_0001640

1) Passing can be conducted by using gravity or by using pressure. 2) According to the direction of the fluid feed in relation to the filter medium there are two broad types of filtrations. In conventional (a.k.a normal, direct, perpendicular) filtration, the fluid flows perpendicular to the medium which results in a cake of solids depositing on the filter medium. In tangential flow filtration the fluid flows parallel to the medium to minimize buildup of solids on the medium. Given that flow direction is the key differentiating characteristic, tangential flow filtration and normal flow filtration (direct flow filtration) are modeled as defined subclasses of filtration. 3) Filtration is a separation technique predominantly based on particle size, where components are retained or passed through a porous medium depending on their dimensions relative to the pore size. However, in some cases, additional characteristics such as particle shape and electrostatic charge can significantly influence retention behavior and selectivity of the filter used in the process.

FiltrationProcess(x) → PlannedProcess(x) ∧ ∃y (Filter(y) ∧ hasParticipantAtSomeTime(x, y))

true

planned process in which suspended solids or dissolved components are separated from a fluid by passing it through a filter

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'filtration process' then x is a 'planned process' and 'has participant at some time' some 'filter'

fluid flow orientation https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ the fluid flows perpendicular to the surface of a filter medium; in a tubular reactor, the direction of fluid flow is aligned with the central axis of the flow channel

FluidFlowOrientation(x) → ProcessProfile(x)

true

process profile that is the orientation of fluid movement in a process with respect to a reference surface or spatial axis

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'fluid flow orientation' then x is a 'process profile'

gas chromatography process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ analyzing residual solvents in a drug substance using gas chromatography with a flame ionization detector; separating volatile organic compounds in a pharmaceutical formulation using gas chromatography; detecting trace levels of benzene and toluene in environmental air samples by gas chromatography

AFO_/process#AFP:0000310

GasChromatographyProcess(x) → ChromatographyProcess(x)

true

chromatography process in which the phase moving in a definite direction (mobile phase) is a gas

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'gas chromatography process' then x is a 'chromatography process'

genetic transformation process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ transfection of a mammalian cell; transduction of a CHO cell by a retrovirus containing a genetic sequence of a particular mAb; Gene deletion by using the CRISPR-CAS9 gene editing technology;

GeneticTransformationProcess(x) → PlannedProcess(x)

true

planned process that results in the introduction, alteration, or integration of genetic material into a cell or organism

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'genetic transformation process' then x is a 'planned process'

harvesting process Merck KGaA https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ Harvesting was carried out by depth filtration of a CHO cell culture to remove cells and debris, yielding a clarified supernatant containing the secreted monoclonal antibody for downstream purification; Harvesting was performed by collecting E. coli cells at early log phase (OD₆₀₀ ≈ 0.3–0.4) during cultivation at 37 °C. The culture was rapidly chilled on ice and centrifuged at 4 °C and 4,000 × g for 10 minutes to separate the biomass from the culture medium;

https://books.google.rs/books?hl=sr&lr=&id=p-rKBQAAQBAJ&oi=fnd&pg=PP1&dq=bioseparation+processes+harvesting&ots=eFDtLSUJ0I&sig=XjzTFnAmknXNjFlSWHpkkTtpHg0&redir_esc=y#v=onepage&q=bioseparation%20processes%20harvesting&f=false

Harvesting utilizes one or more sequential unit operations, such as centrifugation, filtration, cell concentration and membrane separation. The specific unit operations depend on whether the target product is located inside the cells (intracellular) or secreted into the medium (extracellular), or the cells themselves.

HarvestingProcess(x) → PurificationProcess(x) ∧ ∃m∃p(ProcessIntermediateMaterial(m) ∧ BiomanufacturingProductionProcess(p) ∧ isSpecifiedOutputOf(m, p) ∧ hasInput(x, m))

true

purification process that has as input the specified output of a biomanufacturing production process and that results in the separation or recovery of biotechnology products from the associated process streams, typically through the isolation or removal of cells, cell debris, or other bulk impurities

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'harvesting process' then x is a 'purification process' that 'has input' some 'process intermediate material' which 'is specified output of' some 'biomanufacturing production process'

induction process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ IPTG (Isopropyl-β-D-1-thiogalactopyranoside) addition to induce recombinant protein expression under a lac promoter; Temperature downshift from 37 °C to 32 °C to initiate production phase

https://www.genscript.com/biology-glossary/1499/induction and https://www.healthcare.nikon.com/en/ss/cell-image-lab/glossary/induction.html

galactose addition to shift glycosylation profile

An induction process is intentionally designed to push the culture into a new physiological or metabolic state. This may include activation or repression of gene expression, initiation of a production phase, promotion of differentiation, or induction of a stress response that enhances productivity. The mechanism of induction can vary and may involve material addition (e.g., IPTG, tetracycline, retinoic acid), material depletion or starvation (e.g., serum withdrawal, nutrient limitation), environmental changes (e.g., temperature shift, pH shift), or physical stimuli (e.g., light pulse for optogenetic activation).

InductionProcess(x) → PlannedProcess(x)

true

planned process that is a part of a cultivation or production process and triggers a defined change in cellular function, pathway activity, production phase, or differentiation state

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is an 'induction process' then x is a 'planned process'

inoculation process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ After thawing, CHO cells are introduced into a shake flask containing fresh medium to initiate expansion; A starter culture of Saccharomyces cerevisiae is added to a fermenter to begin beer production; A viral stock is added to a mammalian cell culture to study infection dynamics; An inactivated influenza vaccine preparation is injected into a host organism to stimulate an immune response.

http://purl.obolibrary.org/obo/NCIT_C68774 and https://database.ich.org/sites/default/files/ICH_Q5A%28R2%29_Guideline_2023_1101.pdf

1) In the context of inoculation, biological preparations refer to non-living, biologically derived materials that are intentionally introduced to elicit a response or initiate a process. This category includes vaccines (live-attenuated, inactivated, or subunit), purified antigens, toxoids, inactivated microorganisms, viral particles, and similar immunobiological products. Unlike cells, microorganisms, or viruses, biological preparations do not replicate autonomously but are used to stimulate, test, or modulate biological systems. 2) Defined recipient in this case encompasses medium, host, or vessel.

InoculationProcess(x) → MaterialAdditionProcess(x) ∧ ∃m ∃r ∃tr (MaterialEntity(m) ∧ InoculumRole(r) ∧ TransferredMaterialRole(tr) ∧ hasInput(x, m) ∧ hasRole(m, r) ∧ hasRole(m, tr))

true

material addition process in which cells, microorganisms, viruses, or biological preparations are deliberately introduced into a defined recipient to initiate growth, infection, testing, production, or a biological response

There are insufficient constructs present to create a set of necessary and sufficient conditions.

if x is an 'inoculation process' then x is a 'material addition process' that 'has input' some 'material entity' that 'has role' some 'inoculum role' and 'transferred material role'

liquid chromatography process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ separating protein isoforms using ion exchange chromatography with a buffered liquid mobile phase; analyzing small molecule impurities in a drug product using reversed-phase High-Performance Liquid Chromatography (HPLC); quantifying monoclonal antibody titer using protein A affinity chromatography;

AFO_/process#AFP:0000225

LiquidChromatographyProcess(x) → ChromatographyProcess(x)

true

chromatography process in which the phase moving in a definite direction (mobile phase) is a liquid

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'liquid chromatography process' then x is a 'chromatography process'

media solution preparation Merck KGaA https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ dissolving CHO cell culture media powder in water for use in a fed-batch bioreactor; diluting a 10× Dulbecco's Modified Eagle Medium (DMEM) stock solution with water to prepare a 1× working media solution; preparing Glasgow Minimum Essential Medium (GMEM) by dissolving powdered GMEM in a sodium bicarbonate buffer

thawing pre-made liquid media before use in cell culture; sterilizing a commercially available ready-to-use media without any modification;

This process may involve adjusting pH, sterile filtration, or supplementation with additives depending on the application.

MediaSolutionPreparation(x) → SolutionPreparationProcess(x) ∧ ∃y(CultureMedium(y) ∧ hasSpecifiedOutput(x,y) ∧ ∃z(InputSpecification(z) ∧ satisfiesRequirement(y,z)))

true

solution preparation process in which a media powder, an input media solution, or individual media components are dissolved or diluted in water or a buffered solution to produce a media solution that satisfies the material input specification of a target process

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'media solution preparation' then x is a 'solution preparation process' that 'has specified output' some 'culture medium' that 'satisfies requirement' some 'input specification'

membrane filtration process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ A membrane filtration process is used to sterilize media solutions by removing microorganisms; A membrane filtration process clarifies protein solutions before column chromatography; A membrane filtration process removes aggregates and particulates from monoclonal antibody formulations;

MembraneFiltrationProcess(x) → FiltrationProcess(x) ∧ ∃y (MembraneFilter(y) ∧ hasParticipantAtSomeTime(x, y))

true

filtration process in which a fluid is passed through a membrane

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'membrane filtration process' then x is a 'filtration process' that 'has participant at some time' some 'membrane filter'

mixing process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ mixing a buffer solution; mixing a cell culture suspension; mixing two liquid process streams; maintaining a suspension by agitation

http://purl.obolibrary.org/obo/CHMO_0001685

Mixing may involve combining initially separate materials or redistributing parts of an existing material. It may be performed manually or mechanically and may involve liquids, solids, gases, suspensions, pastes or other materials. Homogeneity need not be absolute; the process may increase homogeneity or maintain it by preventing segregation.

MixingProcess(x) → PlannedProcess(x) ∧ ∃y∃c ((Agent(y) ∨ PieceOfEquipment(y)) ∧ MixingCapability(c) ∧ hasCapability(y,c) ∧ hasParticipantAtSomeTime(x,y))

true

planned process that combines material entities or redistributes parts of a material entity to increase or maintain the homogeneity of the material being processed

Insufficient constructs are present to create a set of necessary and sufficient conditions.

if x is a 'mixing process' then x is a 'planned process' and 'has participant at some time' some 'agent' or 'piece of equipment' that 'has capability' some 'mixing capability'

nanofiltration process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ A nanofiltration process is used to remove endotoxins while allowing most proteins to pass through; A nanofiltration process concentrates therapeutic peptides while separating out small salts and solvents; A nanofiltration process is applied after viral inactivation to clear potential viral contaminants; A nanofiltration process is used to reduce water content and impurities in antibiotic purification;

The stated pore-size values indicate the characteristic scale associated with nanofiltration and are not intended to establish exact lower or upper classification boundaries. A membrane filtration process may still be classified as a nanofiltration process when the nominal pore-size rating lies near or modestly outside this interval, provided that the membrane and its retention performance are recognized as nanofiltration.

NanofiltrationProcess(x) → MembraneFiltrationProcess(x)

true

filtration process in which a membrane filter that is used has pore size in the range of 0.001 to 0.01 μm

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'nanofiltration process' then x is a 'membrane filtration process'

normal phase chromatography process Merck KGaA https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ Chromatography process in which a phospholipid extract was separated into distinct lipid classes using a polar silica stationary phase and a mobile phase consisting of hexane and isopropanol; Chromatography process in which a racemic small molecule API was purified to isolate the active enantiomer using a chiral polar stationary phase and a mobile phase of heptane and ethanol; Chromatography process in which a glycan mixture derived from enzymatic deglycosylation was separated based on polarity using an amino-functionalized silica stationary phase and an acetonitrile–water mobile phase

AFO_/process#AFP:0002328

This process is commonly used to separate small, polar organic compounds. Components with higher polarity interact more strongly with the stationary phase and elute later, while less polar components elute earlier with the nonpolar mobile phase.

NormalPhaseChromatographyProcess(x) → LiquidChromatographyProcess(x)

true

liquid chromatography process in which the stationary phase is polar and the mobile phase is nonpolar, resulting in the separation of components based on their relative polarity

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'normal phase chromatography process' then x is a 'liquid chromatography process'

pH adjustment addition process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ Controlled dosing of sodium hydroxide (NaOH) into a mammalian cell culture bioreactor during production scale to neutralize acidity from lactate accumulation.

https://www.sciencedirect.com/science/article/pii/S1871678424005533 and https://pmc.ncbi.nlm.nih.gov/articles/PMC10818583/

Addition of nutrient feeds (e.g., glucose, amino acids) might indirectly affect pH, but their purpose is metabolic, not direct pH control.

PHAdjustmentAdditionProcess(x) → MaterialAdditionProcess(x) ∧ ∃m ∃r ∃a (MaterialEntity(m) ∧ TransferredMaterialRole(r) ∧ hasInput(x, m) ∧ hasRole(m, r) ∧ ((AcidifyingAgentRole(a) ∨ AlkalizingAgentRole(a)) ∧ hasRole(m, a)))

true

material addition process in which an acidifying or alkalizing material is introduced into a defined recipient to modify pH

There are insufficient constructs to create a set of necessary and sufficient conditions.

if x is a 'pH adjustment addition process' then x is a 'material addition process' that 'has input' some 'material entity' that 'has role' some 'transferred material role' and 'has role' some 'acidifying agent role' or some 'alkalizing agent role'

perfusion culture process operating mode https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ perfusion culture operating mode of a mammalian cell culture process, in which fresh medium is introduced while product-containing harvest is removed through a cell retention device; perfusion culture operating mode of a high-cell-density culture process, in which medium exchange supports cultivation while cells are retained in the culture system

https://www.cytivalifesciences.com/en/us/insights/what-are-the-different-types-of-bioreactors and https://infors-ht.com/en/blog/the-difference-between-batch-fed-batch-and-continuous-processes

PerfusionCultureProcessOperatingMode(x) → ContinuousCultureProcessOperatingMode(x) ∧ ∃p (PlannedProcess(p) ∧ processCharacteristicOf(x, p) ∧ ∃r (CellRetentionProcess(r) ∧ hasOccurrentPart(p, r)) ∧ ∃e (PerfusionMediumExchangeProcess(e) ∧ hasOccurrentPart(p, e)))

true

continuous culture process operating mode in which culture medium or other input material is introduced while spent medium or product-containing harvest material is concomitantly removed over an operating interval, with cell retention used to preferentially keep cells in the culture system

There are insufficient constructs to define a set of necessary and sufficient conditions

if x is a 'perfusion culture process operating mode' then x is a 'continuous culture process operating mode' that is the 'process characteristic of' some 'planned process' that 'has occurrent part' some 'cell retention process' and 'has occurrent part' some 'perfusion medium exchange process'

perfusion medium exchange process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ perfusion culture medium exchange in a CHO perfusion culture, where fresh medium is supplied while product-containing harvest is removed through an Alternating Tangential Flow (ATF) cell retention device; perfusion culture medium exchange in a high-cell-density mammalian cell culture, where fresh medium is added while spent medium or harvest is removed through tangential-flow filtration; perfusion culture medium exchange using a spin filter, where medium is exchanged while cells are preferentially kept in the culture

PerfusionMediumExchangeProcess(x) → CultureMediumExchangeProcess(x) ∧ ∃r (CellRetentionProcess(r) ∧ hasOccurrentPart(x, r))

true

culture medium exchange process in which fresh culture medium is added to a cell culture while material is continuously or quasi-continuously removed from the cell culture, with cell retention used to preferentially keep cells in the culture

There are insufficient constructs to create a set of necessary and sufficient conditions.

if x is a 'perfusion medium exchange process' then x is a 'culture medium exchange process' that 'has occurrent part' some 'cell retention process'

perpendicular flow orientation https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ normal flow orientation the fluid flows perpendicular to the surface of a filter medium

PerpendicularFlowOrientation(x) → FluidFlowOrientation(x)

true

fluid flow orientation that is the perpendicular (normal) orientation of fluid movement in a process with respect to a defined surface

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'perpendicular flow orientation' then x is a 'fluid flow orientation'

planned cell infection process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ Infecting HEK293 cells with an adenovirus vector at MOI 5, incubating for 2 hours at 37 °C for adsorption, replacing medium, and culturing for 48 hours to produce infected HEK293 cells

https://www.thermofisher.com/rs/en/home/references/protocols/proteins-expression-isolation-and-analysis/adenovirus-protocol/virapower-adenoviral-expression-system.html

Transfecting cells with plasmid DNA

1) This process specifically refers to the intentional exposure of a host cell culture (e.g., HEK293, MDCK) to virus, either as free virions or infected cells, under well-controlled and documented conditions such as multiplicity of infection (MOI), adsorption time, and temperature, in order to generate infected host cells. 2) Typical conditions specified include multiplicity of infection (MOI), adsorption/contact time, incubation temperature, and incubation duration. 3) The specified output of this process is a cell population containing infected host cells. This cell population may be part of a cell culture that is subsequently propagated, harvested for virus recovery, or used as inoculum for a subsequent culture stage.

PlannedCellInfectionProcess(x) ↔ PlannedProcess(x) ∧ ∃v (VirusInoculationProcess(v) ∧ hasOccurrentPart(x, v)) ∧ ∃p (CellPopulation(p) ∧ hasSpecifiedOutput(x, p) ∧ ∃c (InfectedHostCell(c) ∧ hasMemberPartAtAllTimes(p, c)))

planned process in which a cell culture is exposed to a virus inoculum under defined conditions in order to generate a population of infected host cells

every instance of 'planned cell infection process' is defined as exactly an instance of 'planned process' that 'has occurrent part' some 'virus inoculation process' and 'has specified output' some 'cell population' that 'has member part at all times' some 'infected host cell'

planned process operating mode https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ batch process operating mode of a Protein A capture chromatography process, in which a finite quantity of clarified harvest is processed as a single unit; fed-batch process operating mode of a mammalian cell culture process, in which additional process material is introduced during cultivation while the culture is processed as a single unit; continuous process operating mode of a simulated moving-bed chromatography process, in which material is introduced while output material is concomitantly removed; semi-continuous process operating mode of a draw-and-fill culture process, in which material is introduced and output material is removed in repeated discrete episodes

PlannedProcessOperatingMode(x) → ProcessCharacteristic(x) ∧ ∃p (PlannedProcess(p) ∧ processCharacteristicOf(x, p))

true

process characteristic of a planned process that characterizes the overall pattern by which process material is introduced into, retained in, and removed from the planned process over an operating interval

There are insufficient constructs to create a set of necessary and sufficient conditions.

if x is a 'planned process operating mode' then x is a 'process characteristic' that is the 'process characteristic of' some 'planned process'

planned transduction process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ Lentiviral transduction of primary human T cells in CAR-T manufacturing; AAV-mediated delivery of a therapeutic gene to retinal cells in gene therapy; Engineered phage transduction of E. coli in a laboratory setting

http://id.nlm.nih.gov/mesh/D014161 and https://www.sciencedirect.com/topics/medicine-and-dentistry/genetic-transduction

Lipofection of plasmid DNA into CHO cells; Natural bacteriophage transfer of genes between gut bacteria

This class is restricted to planned applications of transduction, such as therapeutic, manufacturing, or experimental procedures. Examples include lentiviral transduction of T cells in CAR-T therapy, adeno-associated viral (AAV) gene delivery in gene therapy, and bacteriophage-mediated gene transfer in synthetic biology. Natural occurrences of transduction (e.g., bacteriophage-driven horizontal gene transfer in the environment) are out of scope and can be captured through external biological process ontologies (e.g., transduction in GO).

PlannedTransductionProcess(x) → GeneticTransformationProcess(x)

true

genetic transformation process of introducing DNA or RNA into cells by a virus or viral vector to modify the cell's genetic material

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'planned transduction process' then x is a 'genetic transformation process'

polishing process Merck KGaA https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ anion exchange chromatography used to remove residual DNA and endotoxins from a monoclonal antibody solution; cation exchange chromatography applied to reduce host cell protein levels and achieve charge variant specification; nanofiltration performed as a polishing step to remove trace viral particles following prior inactivation;

protein A affinity chromatography used as a primary capture step for monoclonal antibodies; depth filtration of harvested cell culture fluid to remove cells and debris; anion exchange chromatography used early in a multi-step purification to remove bulk impurities;

Polishing typically follows primary capture and intermediate purification. It removes residual impurities such as host cell proteins, DNA, viruses, and product variants, and is performed prior to formulation and fill–finish step

PolishingProcess(x) → PurificationProcess(x)

true

purification process in which minute amounts of impurities are removed and that occurs as one of the final processes of a drug substance manufacturing process

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'polishing process' then x is a 'purification process'

pooling process Merck KGaA https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ A monoclonal antibody manufacturing process runs four separate 2,000 L bioreactor batches in parallel. The clarified harvests from each batch are then pooled into a single lot to ensure consistent quality before downstream processing; After completing viral inactivation and polishing chromatography for three monoclonal antibody production batches, the resulting drug substance pools are combined into a single lot prior to ultrafiltration and diafiltration.

combining individual patient samples for pooled testing in a diagnostic laboratory; mixing raw material samples solely for analytical testing purposes; combining process waste streams for disposal; preparing a media solution by mixing multiple components (not batches); combining excipients during drug formulation without prior batch identity;

1) This process is typically employed to reduce batch-to-batch variability or to ensure consistent quality attributes before further processing or final release. 2) Pooling can be used to define a lot of material for further processing or release, ensuring a consistent product stream. 3) Not to be confused with Test pooling, which is a testing strategy where individual samples are combined into a single pooled sample for initial testing. If the pooled sample tests negative/correct, all individuals in the pool are considered negative/correct. If the pooled sample tests positive/out of specification, individual samples within the pool are then re-tested to identify the positive/out of specification individual(s). This method is used to reduce testing costs and resources, particularly when dealing with a large number of samples and a low prevalence of the target condition.

PoolingProcess(x) → ∃m1∃m2(((MaterialProduct(m1) ∨ ProcessIntermediateMaterial(m1)) ∧ (MaterialProduct(m2) ∨ ProcessIntermediateMaterial(m2))) ∧ hasInput(x,m1) ∧ hasInput(x,m2) ∧ m1 ≠ m2)

true

manufacturing process in which two or more batches of a product or intermediate are combined to produce a single, larger volume that is more homogeneous

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'pooling process' then x 'has input' at least two distinct entities that are each a 'material product' or 'process intermediate material'

production culture growth phase https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ growth window before a scheduled production-phase transition; increasing-cell-density window before induction or production-focused feeding begins; early fed-batch culture window managed primarily to increase viable cell density

1) A production culture growth phase is an operational window within a production culture process, not the production culture process as a whole. It is distinguished from a production focused part of the same process because operating decisions and process monitoring are organized primarily around increase in cell number rather than target product accumulation. 2) The word "phase" here does not imply that this process is prescribed by an ISA88 phase

ProductionCultureGrowthPhase(x) ↔ CellCultureExpansionProcess(x) ∧ ∃s(ProductionCultureProcess(s) ∧ temporalPartOf(x, s))

cell culture expansion process that is a temporal part of a production culture process

every instance of 'production culture growth phase' is defined as exactly an instance of 'cell culture expansion process' that is 'temporal part of' some 'production culture process'

production culture process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ A production culture process grows HEK293 cells in suspension to generate viral vectors for gene therapy; A production culture process uses CHO cells in a fed-batch bioreactor to produce monoclonal antibodies;

https://www.fda.gov/media/170955/download and https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q7a-good-manufacturing-practice-guidance-active-pharmaceutical-ingredients

shake flask studies; seed train bioreactor runs; Cell-free protein synthesis;

ProductionCultureProcess(x) ↔ BiomanufacturingProductionProcess(x) ∧ ∃y (CellCulture(y) ∧ hasParticipantAtSomeTime(x, y)) ∧ ∃s (SeedTrain(s) ∧ precededBy(x, s)) ∧ ∃b (Bioreactor(b) ∧ hasParticipantAtSomeTime(x, b))

biomanufacturing production process during which a cell culture synthesizes, secretes, or accumulates the target product in a controlled environment provided by a bioreactor following expansion in a seed train

every instance of 'production culture process' is defined as exactly an instance of 'biomanufacturing production process' that 'has participant at some time' some 'cell culture', is 'preceded by' some 'seed train', 'has participant at some time' some 'bioreactor'

production culture production phase https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ production-focused window after a planned process transition; culture window managed primarily for target product production; production culture period where monitoring and control is organized around titer, productivity, viability, and product quality

1) A production phase is an operational window within a production culture process, not the production culture process as a whole. During this phase, process conditions are managed to support accumulation of the target product. It is distinguished from an expansion-focused part of the same process because operating decisions and process monitoring are organized around product accumulation rather than increase in cell number. 2) The word "phase" here does not imply that this process is prescribed by an ISA88 phase

ProductionCultureProductionPhase(x) → ManufacturingProcess(x) ∧ ∃c (CellCulture(c) ∧ hasParticipantAtSomeTime(x, c)) ∧ ∃p (ProductionCultureProcess(p) ∧ temporalPartOf(x, p))

true

manufacturing process that is a temporal part of a production culture process and during which process conditions are managed primarily to support target product production

There are insufficient constructs present to create a set of necessary and sufficient conditions.

if x is a 'production culture production phase' then x is a 'manufacturing process' that 'has participant at some time' some 'cell culture', and is a 'temporal part of' some 'production culture process'

purification process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ capture stage; harvesting process; polishing process

OBI:0001505 and CHMO:0002231

1) Impurities in this context may include process byproducts, unreacted reagents, degraded products or contaminating substances introduced during preceding steps. 2) "Further use" refers to the inclusion of an output fraction in subsequent steps of a workflow, which may involve additional purification, analysis, formulation, or other processing activities. These steps may be aimed at preparing the final product or characterizing the material for analytical purposes. Fractions not retained for further use are typically discarded, repurposed, or treated as waste depending on the objective of the purification process and the broader workflow it is a part of. 3) Higher proportion here is with respect to other fractions that are not used further

PurificationProcess(x) → ManufacturingProcess(x)

true

manufacturing process in which an input material is separated into multiple output fractions, such that one or more fractions are enriched in a target component, while the remaining fractions contain predominantly impurities and are discarded or excluded from further use

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'purification process' then x is a 'manufacturing process'

reverse phase chromatography process Merck KGaA https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ Chromatography process in which a synthetic peptide was purified to remove synthesis byproducts using a C18-bonded silica stationary phase and a mobile phase composed of water and acetonitrile with 0.1% trifluoroacetic acid (TFA); Chromatography process in which a monoclonal antibody digest was resolved to quantify fragment abundance using a hydrophobic C18 stationary phase and a mobile phase gradient of water and methanol with 0.1% formic acid

http://wolfson.huji.ac.il/purification/PDF/affinity/GE_Affinity_Chromatography_Handbook-Antibodies.pdf and http://purl.obolibrary.org/obo/CHMO_0002302 and https://www.sigmaaldrich.com/RS/en/technical-documents/protocol/analytical-chemistry/purification/reverse-phased-chromatography-in-practice?srsltid=AfmBOorOQim54doE5guL_YoH41EUR9xT6oikpa5rJhbNFAYeFTiIxs0I

Reverse-phase chromatography (RPC) is utilized for the purification, separation, and analysis of biological molecules, including proteins, peptides, antibodies, and other metabolites. It is also employed in the separation and purification of intermediates and final products in chemical synthesis processes.

ReversePhaseChromatographyProcess(x) → LiquidChromatographyProcess(x)

true

liquid chromatography process in which the stationary phase is nonpolar and the mobile phase is polar, resulting in the separation of components based on their relative hydrophobicity

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'reverse phase chromatography process' then x is a 'liquid chromatography process'

seed train Merck KGaA https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ a monoclonal antibody seed train expanded CHO cells through sequential steps in shake flasks, a 10 L bioreactor, and a 200 L seed bioreactor based on target inoculation density; a seed train progressing through shake flasks and seed bioreactors to generate inoculum for a 5,000 L production bioreactor

https://www.ema.europa.eu/en/documents/scientific-guideline/draft-ich-guideline-q12-technical-and-regulatory-considerations-pharmaceutical-product-lifecycle-management-step-2b-annexes-first-version_en.pdf and https://20669391.fs1.hubspotusercontent-na1.net/hubfs/20669391/social-uploaded-images/SUIS/MK_WP13194EN%20Regulatory%20Perspectives%20Implementing%20Seed%20Train%20Intensification%20using%20HCDC%20-%20MK.pdf

1) The seed train is a series of steps used to generate the sufficient amount of viable cells for large-scale production of vaccines, viral vectors, monoclonal antibodies and other biologics. The purpose of the seed train is to progressively grow and expand the initial small-scale cell culture to inoculate the large-scale bioreactor for higher capacity production. 2) A single cell culture expansion process within the seed train is also called a "passage" 3) The following terms are commonly used when discussing a seed train or inoculum expansion with multiple steps: “N” refers to the production vessel; “N-1” refers to the final expansion used to inoculate the production vessel; “N-2” refers to the expansion before that, used to inoculate the N-1, and so on

SeedTrain(x) ↔ ManufacturingProcess(x) ∧ ∃a (CellCulture(a) ∧ hasInput(x, a)) ∧ ∃b (CellCultureExpansionProcess(b) ∧ hasOccurrentPart(x, b)) ∧ ∃c (CellCulture(c) ∧ hasSpecifiedOutput(x, c) ∧ ∃i ∃p ∃y (InputSpecification(i) ∧ PlanSpecification(p) ∧ satisfiesRequirement(c, i) ∧ continuantPartOfAtAllTimes(i, p) ∧ ProductionCultureProcess(y) ∧ prescribes(p, y)))

manufacturing process composed of a sequence of cell culture expansion processes occurring at increasing scales and that has as its specified output a cell culture at the required density to inoculate a production culture process

every instance of 'seed train' is defined as exactly an instance of 'manufacturing process' that 'has input' some 'cell culture', 'has occurrent part' some 'cell culture expansion process', and 'has specified output' some 'cell culture' that 'satisfies requirement' some 'input specification' that is 'continuant part of at all times' some 'plan specification' that 'prescribes' some 'production culture process'

solution preparation process Merck KGaA https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ dissolving sodium chloride in water to prepare a saline solution; diluting a 10× phosphate-buffered saline (PBS) stock with water to make a 1× working solution; preparing a glucose solution by dissolving D-glucose powder in sterile water

1) A solvent can be an individual compound or it can be a mixture of one or more compounds 2) The substances being dissolved or diluted may include solids, liquids, or gases, and the resulting mixture is uniform in composition at the molecular level.

SolutionPreparationProcess(x) → PlannedProcess(x) ∧ ∃s(Solution(s) ∧ hasSpecifiedOutput(x,s))

true

planned process in which a homogeneous mixture is created by dissolving one or more solutes in a solvent, or by diluting an existing solution with additional solvent

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'solution preparation process' then x is a 'planned process' that 'has specified output' some 'solution'

splitting process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ An intermediate seed culture lot is divided into multiple separately managed portions for further parallel seed expansion; A bulk drug substance lot is divided into multiple separately managed portions for parallel processing; monoclonal antibody manufacturing process produces a single harvested intermediate batch that is divided into three separately managed portions for further downstream purification

1) This process is typically employed to create distinct manufacturing portions from a parent batch or lot for subsequent manufacturing activities. 2) The resulting portions remain traceable to the original parent batch or lot and are managed as distinct portions in further manufacturing. 3) Not to be confused with sampling or aliquoting, where material is subdivided solely for analytical, testing, or measurement purposes rather than to establish distinct manufacturing portions.

SplittingProcess(x) → ManufacturingProcess(x) ∧ ∃i ((MaterialProduct(i) ∨ ProcessIntermediateMaterial(i)) ∧ hasInput(x, i)) ∧ ∃o1 ∃o2 (MaterialEntity(o1) ∧ MaterialEntity(o2) ∧ hasSpecifiedOutput(x, o1) ∧ hasSpecifiedOutput(x, o2) ∧ o1 ≠ o2)

true

manufacturing process in which a batch or lot of a product or intermediate is divided into two or more separately managed portions for further processing, handling, storage or release

This term is expected to remain primitive as formalization in OWL requires cardinality constraints.

if x is a 'splitting process' then x is a 'manufacturing process' that 'has input' some 'material product' or some 'process intermediate material', and 'has specified output' at least two 'material entities'

sterilization process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ steam sterilization of stainless-steel bioreactor vessel prior to culture; autoclave sterilization of glassware and stainless-steel fittings used in upstream processing; filtration sterilization of culture medium through 0.22 µm membrane filter before inoculation; gamma irradiation of single-use tubing assemblies prior to installation

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/content-and-format-premarket-notification-510k-submissions-liquid-chemical-sterilantshigh-level

SterilizationProcess(x) → PlannedProcess(x) ∧ ∃m ∃s (MaterialEntity(m) ∧ hasInput(x, m) ∧ SterileMaterialState(s) ∧ hasPostMaterialState(x, s) ∧ hasMaterialState(m, s))

true

planned process in which a material entity is rendered free of all viable microorganisms

There are insufficient constructs to create a set of necessary and sufficient conditions.

if x is a 'sterilization process' then x is a 'planned process' that 'has input' some 'material entity' that 'has material state' some 'sterile material state' that is also the 'post material state' of x

tangential flow filtration https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ cross-flow filtration Tangential flow filtration is used to purify and concentrate viral vectors by separating them from residual DNA, cell debris, and small fragments; Tangential flow filtration is applied to concentrate monoclonal antibodies before anion exchange chromatography;

TFF

TFF can operate in batch mode (Batch TFF) and continuous mode (single-pass TFF)

TangentialFlowFiltration(x) ↔ FiltrationProcess(x) ∧ ∃y (TangentialFlowOrientation(y) ∧ hasProcessProfile(x, y))

filtration process in which the liquid travels tangentially across the surface of the membrane or bed filter

every instance of 'tangential flow filtration' is defined as exactly an instance of 'filtration process' that 'has process profile' some 'tangential flow orientation'

tangential flow orientation https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ cross-flow orientation the fluid flows tangentially to the surface of a filter medium during a tangential filtration process

TangentialFlowOrientation(x) → FluidFlowOrientation(x)

true

fluid flow orientation that is the tangential orientation of fluid movement in a process with respect to a defined surface

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'tangential flow orientation' then x is a 'fluid flow orientation'

thawing process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ Cryopreserved cells contained in cryovials are thawed in a 37°C water bath, with gentle swirling, to facilitate even thawing; A frozen dough, like puff pastry, is thawed in a refrigerator at 5°C, with air circulation, for a certain period of time, before baking; In the fish industry, frozen blocks of Cod are thawed into large tanks with water, which are designed to facilitate the continuous movement of the product through a counter-flow stream of temperature controlled, agitated water

ThawingProcess(x) → PlannedProcess(x) ∧ ∃y ∃c (PieceOfEquipment(y) ∧ ThawingCapability(c) ∧ hasCapability(y, c) ∧ hasParticipantAtSomeTime(x, y))

true

planned process in which the temperature of a material entity is raised in a controlled manner to a specified setpoint, typically to transition it from a solid or frozen state to a soft or liquid state

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'thawing process' then x is a 'planned process' and 'has participant at some time' some 'piece of equipment' that 'has capability' some 'thawing capability'

transfection process Merck KGaA https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ transfection of a mammalian cell by electroporation, sonoporation or microinjection

https://www.thermofisher.com/de/de/home/references/gibco-cell-culture-basics/transfection-basics/introduction-to-transfection.html

introducing a gene encoding a recombinant protein into a yeast cell by using a virus

Such introductions of foreign nucleic acid using various chemical, biological, or physical methods can result in a change of the properties of the cell, allowing the study of gene function and protein expression in the context of the cell.

TransfectionProcess(x) → GeneticTransformationProcess(x)

true

genetic transformation process of introducing DNA or RNA into eukaryotic cells by non-viral methods to modify the cell's genetic material

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'transfection process' then x is a 'genetic transformation process'

ultrafiltration process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ Ultrafiltration is used in cheese making to concentrate casein and whey proteins while removing water, lactose, and soluble components; In mAb production, ultrafiltration concentrates antibody solutions before formulation; Ultrafiltration is applied to remove host cell proteins and as part of buffer exchange before viral filtration

1) Ultrafiltration (UF) is a variety of membrane filtration in which forces such as pressure or concentration gradients lead to a separation through a semipermeable membrane. Suspended solids and solutes of high molecular weight are retained in the so-called retentate, while water and low molecular weight solutes pass through the membrane in the permeate (filtrate). 2) The stated pore-size values indicate the characteristic scale associated with ultrafiltration and are not intended to establish exact lower or upper classification boundaries. A membrane filtration process may still be classified as an ultrafiltration process when the nominal pore-size rating lies near or modestly outside this interval, provided that the membrane and its retention performance are recognized as ultrafiltration.

UltrafiltrationProcess(x) → MembraneFiltrationProcess(x)

true

filtration process in which a membrane filter that is used has pore size in the range of 0.01 to 0.1 μm

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is an 'ultrafiltration process' then x is a 'membrane filtration process'

upstream biomanufacturing process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ upstream process for monoclonal antibody production in CHO cells involving cell thaw, recovery, seed expansion, and production culture; upstream process for recombinant enzyme production in E. coli including inoculum preparation, fermentation, and harvest; upstream process of lentiviral vector manufacturing in HEK293 cells covering producer cell expansion, infection, and culture;

https://www.cytivalifesciences.com/en/us/solutions/emerging-biotech/knowledge-center/biopharma-process-development-introduction and https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-process-validation-manufacture-biotechnology-derived-active-substances-and-data-be-provided-regulatory-submission_en.pdf and https://www.biophorum.com/download/cvp-case-study-interactive-version/

1) Upstream biomanufacturing process produces biological or biologically derived material for subsequent downstream processing or final use. 2) In some industrial practices, upstream processing includes the harvest step that removes material from the production culture; in others, harvest is treated as the starting point of downstream processing. This variability reflects organizational conventions rather than technical differences. 3) Upstream biomanufacturing processes may include activities such as cell thaw and recovery, seed expansion, inoculum preparation, production culture, fermentation, cell infection, transfection, viral propagation, or harvest, depending on the product modality and process convention.

UpstreamBiomanufacturingProcess(x) → ManufacturingProcess(x) ∧ ∃p (BiomanufacturingProductionProcess(p) ∧ hasOccurrentPart(x, p)) ∧ ∃o ((MaterialProduct(o) ∨ ProcessIntermediateMaterial(o)) ∧ hasSpecifiedOutput(x, o))

true

manufacturing process that includes preparation, expansion, cultivation, or propagation of biological material under controlled conditions to produce a process intermediate material or material product

This term is expected to remain primitive because the exact boundary between upstream and downstream processing can vary by product modality, manufacturing method, and company-specific convention

if x is an 'upstream biomanufacturing process' then x is a 'manufacturing process' that 'has occurrent part' some 'biomanufacturing production process' and 'has specified output' some 'material product' or some 'process intermediate material'

viral clearance Merck KGaA https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ anion exchange chromatography operated in flow-through mode to remove retrovirus-like particles from CHO cell harvest; Viral inactivation was performed by incubating monoclonal antibody solutions in 50 mM citrate buffer at pH 3.0 for 40 minutes at low ionic strength, followed by neutralization to pH 5.0 under higher ionic strength conditions;

https://www.ema.europa.eu/en/documents/scientific-guideline/ich-q-5-r1-viral-safety-evaluation-biotechnology-products-derived-cell-lines-human-animal-origin_en.pdf

1) Virus Removal: Physical separation of virus particles from the intended product. 2) Inactivation: Reduction of virus infectivity caused by chemical or physical modification 3) Viral clearance is typically demonstrated through studies in which known quantities of viruses are deliberately added to the manufacturing process, and the ability of specific steps—such as filtration, chromatography, or chemical treatment—to reduce or eliminate viral infectivity is measured. These studies use relevant and model viruses to represent a broad range of possible contaminants and quantify effectiveness as a log reduction in viral load.

ViralClearance(x) → ManufacturingProcess(x)

true

manufacturing process that results in the elimination of a target virus by either removing viral particles or by inactivating its infectivity

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'viral clearance' then x is a 'manufacturing process'

viral filtration Merck KGaA https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ Viral filtration was carried out using a Planova BioEX filter after a 0.2 µm prefilter process, applied to a monoclonal antibody solution in defined buffer conditions.

https://www.ema.europa.eu/en/documents/scientific-guideline/ich-q-5-r2-viral-safety-evaluation-biotechnology-products-derived-cell-lines-human-or-animal-origin-step-2b_en.pdf and https://www.sigmaaldrich.com/deepweb/assets/sigmaaldrich/marketing/global/photometer-files/269/820/viral-clearance-study-wp8407en-ms.pdf?srsltid=AfmBOoqxcqPF9uWz0DC3JJc6T_VPSw48iogXw9vpj89IzaVMeeS-NE-b

1) This process relies on size-based exclusion to retain viruses on the filter surface while allowing the target product to pass through. It typically involves one or more filtration steps, which may be arranged in series or parallel, and can be combined with other virus removal processes such as chromatographic steps validated for virus clearance. Pre-filtration is often used to protect the virus filter and maintain performance. 2) The filtration uses membranes with nanometer-scale pore sizes and is predominantly performed via nanofiltration. While ultrafiltration may assist in removing larger viruses such as retroviruses, it is not accepted as a standalone method for regulatory purposes; therefore, a nanofiltration step is required. 3) The process is rigorously designed and validated under regulatory guidance to ensure robust virus removal (typically achieving ≥4 log₁₀ reduction) while maintaining product yield and scalability.

ViralFiltration(x) → ViralRemovalProcess(x) ∧ ∃n (NanofiltrationProcess(n) ∧ hasOccurrentPart(x, n))

true

viral removal process in which viral particles are physically separated from the input material through a nanofiltration process

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'viral filtration' then x is a 'viral removal process' and 'has occurrent part' some 'nanofiltration process'

viral inactivation Merck KGaA https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ Viral inactivation was performed by incubating monoclonal antibody solutions in 50 mM citrate buffer at pH 3.0 for 40 minutes at low ionic strength, followed by neutralization to pH 5.0 under higher ionic strength conditions; Viral inactivation was performed by treating the product stream with 0.3% Triton X-100 for 60 minutes at room temperature to disrupt lipid-enveloped viruses.

Merck Biopharmaceutical Application Guide and https://www.ema.europa.eu/en/documents/scientific-guideline/ich-q-5-r1-viral-safety-evaluation-biotechnology-products-derived-cell-lines-human-animal-origin_en.pdf

1) In viral inactivation the viral particles are not necessarily removed from the input 2) Common inactivation methods include heat (e.g., pasteurization), acidic pH, solvent-detergent treatment, or UV exposure. Effectiveness is validated through spiking studies: known amounts of virus are added to the process and their infectivity is monitored over time.

ViralInactivation(x) → ViralClearance(x)

true

viral clearance during which viral infectivity is reduced by physically or chemically modifying the input material

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'viral inactivation' then x is a 'viral clearance'

viral removal process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ anion exchange chromatography operated in flow-through mode to remove retrovirus-like particles from CHO cell harvest; nanofiltration of plasma-derived products to remove non-enveloped viruses; tangential flow filtration used to remove contaminating virus particles from a process intermediate during manufacture of a nonviral biological product

https://www.ema.europa.eu/en/documents/scientific-guideline/ich-q-5-r1-viral-safety-evaluation-biotechnology-products-derived-cell-lines-human-animal-origin_en.pdf

ViralRemovalProcess(x) → ViralClearance(x)

true

viral clearance during which viral particles are physically separated from the input material based on differences in physical properties such as size or charge

Insufficient constructs are present to create a set of necessary and sufficient conditions

if x is a 'viral removal process' then x is a 'viral clearance'

virus inoculation process https://spec.industrialontologies.org/ontology/biopharma/BiopharmaManufacturingExecution/ addition of working virus seed to a confluent Vero cell culture to initiate viral propagation; inoculation of Sf9 insect cells with baculovirus seed stock in a production bioreactor; infection of HEK293 cells with adenoviral vector for recombinant protein expression; co-culture of producer and target cells for lentivirus amplification

https://www.sciencedirect.com/science/article/pii/S0166093422002099 and https://www.bioprocessintl.com/assays/nucleic-acid-impurity-reduction-in-viral-vaccine-manufacturing and https://www.sigmaaldrich.com/deepweb/assets/sigmaaldrich/marketing/global/documents/165/693/vaccine-handbook-process-br5237en-mk.pdf?srsltid=AfmBOopAab20MIAUvkPCifVu5keJOr4OPkvV65xNUwgIB9Ji9xExNOPn

VirusInoculationProcess(x) → InoculationProcess(x) ∧ ∃c ∃tr (CellCulture(c) ∧ MaterialAdditionTargetRole(tr) ∧ hasParticipantAtSomeTime(x, c) ∧ hasRole(c, tr)) ∧ ∃m ∃ir ∃mr (((VirusSeed(m)) ∨ (CellPopulation(m) ∧ ∃h (InfectedHostCell(h) ∧ hasMemberPartAtSomeTime(m, h)))) ∧ InoculumRole(ir) ∧ TransferredMaterialRole(mr) ∧ hasInput(x, m) ∧ hasRole(m, ir) ∧ hasRole(m, mr))

true

inoculation process in which a virus seed or infected host-cell-containing material is deliberately introduced into a cell culture to initiate viral propagation

There are insufficient constructs to create a set of necessary and sufficient conditions

if x is a 'virus inoculation process' then x is an 'inoculation process' that 'has participant at some time' some 'cell culture' that 'has role' some 'material addition target role', and 'has input' some 'virus seed' or some 'cell population' that 'has member part at some time' some 'infected host cell', where that participant 'has role' some 'inoculum role' and some 'transferred material role'