Manufacturing Execution Ontology
This module contains terms and relations necessary for representing the actual occurrences of manufacturing processes with respect to recipes.
Cameron Gibbs, CrownPoint Technologies, LLC
Melissa Weller, CrownPoint Technologies, LLC
Stephen J. Granite, CrownPoint Technologies, LLC
Stephen Kahmann, CrownPoint Technologies, LLC
Copyright (c) 2022, 2023, 2024, 2025, 2026 Open Applications Group
biomanufacturing production process
recombinant protein expression using CHO cells; 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)
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
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) ∧ ∃r (RecipeProcessStage(r) ∧ prescribes(r, x))
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' and is 'prescribed by' some 'recipe process stage'
cell banking
establishing a master cell bank by freezing aliquots of a cloned HEK293 cell line under GMP conditions; banking the Vero cell line in cryopreservation medium supplemented with DMSO and storing it in vapor-phase liquid nitrogen for future vaccine manufacturing; banking a hybridoma cell line after single-cell cloning and characterization to preserve monoclonal antibody production capability
1) It ensures a reliable, consistent, and well-characterized source of cells, reducing the need for constant cell culture and mitigating risks associated with genetic drift or contamination. 2) Examples of future use include research, drug development, and manufacturing of biopharmaceuticals
CellBankingProcess(x) → StorageProcess(x) ∧ ∃y (CellLine(y) ∧ hasParticipantAtSomeTime(x, y)) ∧ ∃z (RecipeProcessOperation(z) ∧ prescribedBy(x, z))
storage process of preserving and maintaining cell lines for future use
if x is a 'cell banking process' then x is a 'storage process' that 'has participant at some time' some 'cell line' and is 'prescribed by' some 'recipe process operation' `
cell culture expansion process
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
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.
if x is a 'cell culture expansion process' then x is a 'planned process' that 'has input' some 'cell culture' and 'has occurrent part' some 'cell population proliferation'
planned process in which cells within a cell culture proliferate, resulting in an increase in the total cell number
CellCultureExpansionProcess(x) → PlannedProcess(x) ∧ ∃y (CellCulture(y) ∧ hasInput(x, y)) ∧ ∃z (CellPopulationProliferation(z) ∧ hasOccurrentPart(x, z))
cell line development
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) Cell line development process ends with the banking of the particular 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-intense. 4) Engineering in this context means that the cell line is created, either through passaging of a primary cell culture to relative genetic stability and compositional homogeneity, or through some experimental modification of an existing cell line to produce a new line with novel characteristics (e.g. immortalization or some other 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) → ManufacturingProcess(x) ∧ ∃g ∃c (GeneticTransformationProcess(g) ∧ CloneSelectionProcess(c) ∧ hasOccurrentPart(x, g) ∧ hasOccurrentPart(x, c) ∧ precedes(g, c)) ∧ ∃o (CellLine(o) ∧ hasSpecifiedOutput(x, o)) ∧ ∃r (RecipeProcess(r) ∧ prescribes(r, x)) ∧ temporallyStartedBy(x, g) ∧ (∃b (CellBanking(b) ∧ meets(x, b)) ∨ ∃b (CellBanking(b) ∧ temporallyOverlaps(x, b)))
manufacturing 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 'manufacturing process' and 'has occurrent part' some 'genetic transformation process' that 'precedes' some 'clone selection process' and 'has occurrent part' some 'clone selection process' and 'has specified output' some 'cell line' and is 'prescribed by' some 'recipe process' and is 'temporally started by' some 'genetic transformation process' and either 'meets' some 'cell banking' or 'temporally overlaps' some 'cell banking'
cell population proliferation
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
CellPopulationProliferation(x) → Process(x) ∧ ∃y (CellPopulation(y) ∧ hasParticipantAtAllTimes(x, y))
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 multiplications 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'
centrifugation process
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;
CentrifugationProcess(x) → PlannedProcess(x) ∧ ∃y(RecipeProcessOperation(y) ∧ prescribes(y, x))
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
if x is a 'centrifugation process' then x is a 'planned process' and is 'prescribed by' some 'recipe process operation'
chemical synthesis process
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)
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'
chromatography process
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
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)) ∧ ∃w (RecipeProcessOperation(w) ∧ prescribes(w, x))
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
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
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)) ∧ ∃z (RecipeProcessStage(z) ∧ prescribes(z, x))
planned processs in which an optimal set of cell clones is identified and isolated based on the clones exibiting desirable characteristics
if x is a 'clone selection process' then x is a 'planned process' and 'has specified output' some 'cloned cell line' and is 'prescribed by' some 'recipe process stage'
clone stability study
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))
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
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'
depth filtration process
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))
filtration process in which a fluid is passed through a depth filter
if x is a 'depth filtration process' then x is a 'filtration process' that 'has participant at some time' some 'depth filter'
diafiltration process
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 continous or discontinous 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)) ∧ ∃s (RecipeProcessStage(s) ∧ prescribes(s, x)) ∧ (∃y ∃z (DilutionProcess(y) ∧ FiltrationProcess(z) ∧ hasOccurrentPart(x, y) ∧ hasOccurrentPart(x, z) ∧ (before(y, z) ∨ occursSimultaneouslyWith(y, z))))
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
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 is 'prescribed by' some 'recipe process stage' and ('has occurrent part' some 'dilution process' that 'occurs before' some 'filtration process' or 'occurs simultaneously with' some 'filtration process')
dilution process
diluting a 10× phosphate-buffered saline (PBS) stock with water to make a 1× working solution
DilutionProcess(x) → SolutionPreparationProcess(x) ∧ ∃y (RecipeProcessOperation(y) ∧ prescribes(y, x))
solution preparation process in which a solvent is added to a solution to reduce the concentration of one or more solutes
if x is a 'dilution process' then x is a 'solution preparation process'
if x is a 'dilution process' then x is a 'solution preparation process' and is 'prescribed by' some 'recipe process operation'
direct flow filtration
In brewing, dead-end filtration separates wort from barley husks after mashing; Dead-end filtration removes particulates from buffer solutions before chromatography;
DirectFlowFiltrationProcess(x) ↔ FiltrationProcess(x) ∧ ∃y (PerpendicularFlowOrientation(y) ∧ hasProperOccurrentPart(x, y))
filtration in which the fluid travels in the direction that is perpendicular to the surface of the filter
if x is a 'direct flow filtration process' then x is a 'filtration process' that 'has proper occurrent part' some 'perpendicular flow orientation'
drug product formulation process
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.
DrugProductFormationProcess(x) → ManufacturingProcess(x) ∧ ∃r (RecipeProcessStage(r) ∧ prescribes(r, x))
manufacturing process in which various components are combined to create a drug product that is safe, effective, and stable for patient use
if x is a 'drug product formation process' then x is a 'manufacturing process' and is 'prescribed by' some 'recipe process stage'
filtration process
depth filtration; TFF filtration; direct flow filtration; membrane filtration
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) l 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 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)) ∧ ∃z (RecipeProcessOperation(z) ∧ prescribes(z, x))
planned process in which suspended solids or dissolved components are separated from a fluid by passing it through a filter
if x is a 'filtration process' then x is a 'planned process' and 'has participant at some time' some 'filter' and is 'prescribed by' some 'recipe process operation'
fluid flow orientation
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)
process profile that is the orientation of fluid movement in a process with respect to a reference surface or spatial axis
if x is a 'fluid flow orientation' then x is a 'process profile'
gas chromatography process
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
GasChromatographyProcess(x) → ChromatographyProcess(x)
chromatography process in which the phase moving in a definite direction (mobile phase) is a gas
if x is a 'gas chromatography process' then x is a 'chromatography process'
genetic transformation process
transfection of a mammalian cell; transduction of a CHO cell by a retrovirus containing a genetic sequence of a particular mAb; Gene deletion by CRISPR-CAS9; introducing mutation in the cells by error prone PCR
GeneticTransformationProcess(x) → PlannedProcess(x)
planned process that results in the introduction, alteration, or integration of genetic material into a cell or organism
if x is a 'genetic transformation process' then x is a 'planned process'
harvesting process
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;
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∃s(ProcessIntermediateMaterial(m) ∧ BiomanufacturingProductionProcess(p) ∧ isSpecifiedOutputOf(m, p) ∧ hasInput(x, m) ∧ RecipeProcessStage(s) ∧ prescribedBy(x, s))
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
every instance of 'harvesting process' is defined exactly as an instance of 'purification process' that 'has input' some 'process intermediate material' which 'is specified output of' some 'biomanufacturing production process' and that 'is prescribed by' some 'recipe process stage'
liquid chromatography process
separating protein isoforms using ion exchange chromatography with a buffered liquid mobile phase; analyzing small molecule impurities in a drug product using reversed-phase HPLC; quantifying monoclonal antibody titer using protein A affinity chromatography;
LiquidChromatographyProcess(x) → ChromatographyProcess(x)
chromatography process in which the phase moving in a definite direction (mobile phase) is a liquid
if x is a 'liquid chromatography process' then x is a 'chromatography process'
media solution preparation
dissolving CHO cell culture media powder in water for use in a fed-batch bioreactor; diluting a 10× 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.
MediaSolutionProcess(x) → SolutionPreparationProcess(x) ∧ ∃y (CultureMedium(y) ∧ hasSpecifiedOutput(x, y) ∧ ∃z (InputSpecification(z) ∧ satisfiesRequirement(y, z)))
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
if x is a 'media solution process' then x is a 'solution preparation process' that 'has specified output' some 'culture medium' and 'satisfies requirement' some 'input specification'
membrane filtration process
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))
filtration process in which a fluid is passed through a membrane
if x is a 'membrane filtration process' then x is a 'filtration process' that 'has participant at some time' some 'membrane filter'
nanofiltration process
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;
NanofiltrationProcess(x) → MembraneFiltrationProcess(x)
filtration process in which a membrane filter that is used has pore size in the range of 0.001 to 0.01 μm
if x is a 'nanofiltration process' then x is a 'membrane filtration process'
normal phase chromatography process
A phospholipid extract was separated into distinct lipid classes using a polar silica stationary phase and a mobile phase consisting of hexane and isopropanol; 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; 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
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)
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
if x is a 'normal phase chromatography process' then x is a 'liquid chromatography process'
perpendicular flow orientation
the fluid flows perpendicular to the surface of a filter medium
PerpendicularFlowOrientation(x) → FluidFlowOrientation(x)
fluid flow orientation that is the perpendicular (normal) orientation of fluid movement in a process with respect to a defined surface
if x is a 'perpendicular flow orientation' then x is a 'fluid flow orientation'
polishing process
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) ∧ ∃r (RecipeProcessStage(r) ∧ prescribes(r, x))
purification process in which minute amounts of impurities are removed and that occurs as one of the final processes of drug substance manufacturing process
if x is a 'polishing process' then x is a 'purification process' and is 'prescribed by' some 'recipe process stage'
pooling process
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 specs, individual samples within the pool are then re-tested to identify the positive/out of specs 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) → ManufacturingProcess(x) ∧ ∃r (RecipeProcessOperation(r) ∧ prescribes(r, x))
manufacturing process in which two or more batches of a product or intermediate are combined to produce a single, larger volume that is more homogenous
if x is a 'pooling process' then x is a 'manufacturing process' and is 'prescribed by' some 'recipe process operation'
production culture process
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)) ∧ ∃r (RecipeProcessStage(r) ∧ prescribes(r, x))
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', and is 'prescribed by' some 'recipe process stage'
purification process
capture stage; harvesting process;polishing process
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)
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
if x is a 'purification process' then x is a 'manufacturing process'
recipe process action occurrence
see the corresponding specification class as well as the inferred hierarchy when using a reasoner such as Hermit
RecipeProcessActionOccurrence(x) ↔ RecipeProcessElementOccurrence(x) ∧ ∃y (RecipeProcessAction(y) ∧ isPrescribedBy(x, y))
planned process that is prescribed by some recipe process action
every instance of 'recipe process action occurrence' is exactly an instance of 'recipe process element occurrence' that 'is prescribed by' some 'recipe process action'
This class is intended to be a defined class used for axiomatization and assertion convenience. It is not expected nor recommended that entities will be asserted as a subclass of this class.
recipe process element occurrence
RecipeProcessElementOccurrence(x) ↔ PlannedProcess(x) ∧ ∃y (RecipeProcessElement(y) ∧ isPrescribedBy(x, y))
planned process that is prescribed by some recipe process element
every instance of 'recipe process element occurrence' is exactly an instance of 'planned process' that 'is prescribed by' some 'recipe process element'
recipe process occurrence
RecipeProcessOccurrence(x) ↔ RecipeProcessElementOccurrence(x) ∧ ∃y (RecipeProcess(y) ∧ isPrescribedBy(x, y))
planned process that is prescribed by some recipe process
every instance of 'recipe process action occurrence' is exactly an instance of 'recipe process element occurrence' that 'is prescribed by' some 'recipe process'
recipe process operation occurrence
RecipeProcessOperationOccurrence(x) ↔ RecipeProcessElementOccurrence(x) ∧ ∃y (RecipeProcessOperation(y) ∧ isPrescribedBy(x, y))
planned process that is prescribed by some recipe process operation
every instance of 'recipe process operation occurrence' is exactly an instance of 'recipe process element occurrence' that 'is prescribed by' some 'recipe process operation'
recipe process stage occurrence
RecipeProcessStageOccurrence(x) ↔ RecipeProcessElementOccurrence(x) ∧ ∃y (RecipeProcessStage(y) ∧ isPrescribedBy(x, y))
planned process that is prescribed by some recipe process stage
every instance of 'recipe process stage occurrence' is exactly an instance of 'recipe process element occurrence' that 'is prescribed by' some 'recipe process stage'
reverse phase chromatography process
Merck KGaA
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% TFA;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 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)
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
if x is a 'reverse phase chromatography process' then x is a 'liquid chromatography process'
seed train
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;CHO suspension cells were expanded through a seed train process involving shake flasks, benchtop bioreactors, and 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 as 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 ∃s (InputSpecification(i) ∧ PlanSpecification(p) ∧ RecipeProcessStage(s) ∧ satisfiesRequirement(c, i) ∧ continuantPartOfAtAllTimes(i, p) ∧ prescribes(p, s) ∧ ProductionCultureProcess(y) ∧ prescribes(s, y))) ∧ ∃r (RecipeProcessStage(r) ∧ prescribes(r, x))
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 'recipe process stage' that 'prescribes' some 'production culture process', and is 'prescribed by' some 'recipe process stage'
solution preparation process
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)
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
if x is a 'solution preparation process' then x is a 'planned process'
storage process
the process of storing cutting tools in a tool cabinet for future use, the process of storing dishes in my kitchen cabinet, the process of storing products by a retailer for selling them in the future
this class refers to the storage process in a generic sense and it is not necessarily limited to industrial storage in a factory warehouse for example.
planned process of putting and keeping material entities in a specified location for future use
The required constructs for creation of a formal definition are not available in this release.
if x is a 'storage process' then x is a 'planned process'
tangential 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 can operate in batch mode (Batch TFF) and continuous mode Single-pass TFF)
TangentialFlowFiltrationProcess(x) ↔ FiltrationProcess(x) ∧ ∃y (TangentialFlowOrientation(y) ∧ hasProperOccurrentPart(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 process' is defined as exactly an instance of 'filtration process' that 'has proper occurrent part' some 'tangential flow orientation'
tangential flow orientation
the fluid flows tangentially to the surface of a filter medium during a tangential filtration process
TangentialFlowOrientation(x) → FluidFlowOrientation(x)
fluid flow orientation that is the tangential orientation of fluid movement in a process with respect to a defined surface
if x is a 'tangential flow orientation' then x is a 'fluid flow orientation'
thawing process
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)) ∧ ∃z (RecipeProcessOperation(z) ∧ prescribes(z, x))
planned process in which the temperature of a material entity is raised in a controlled manner to specified setpoint, typically to transition it from a solid or frozen state to a soft or liquid state
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' and is 'prescribed by' some 'recipe process operation'
transfection process
transfection of a mammalian cell by electroporation, sonoporation or microinjection
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)
genetic transformation process of introducing DNA or RNA into eukaryotic cells by non-viral methods to modify the cell's genetic material
if x is a 'transfection process' then x is a 'genetic transformation process'
ultrafiltration process
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 buffer exchange before viral filtration
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).
UltrafiltrationProcess(x) → MembraneFiltrationProcess(x)
filtration process in which a membrane filter that is used has pore size in the range of 0.01 to 0.1 μm
if x is an 'ultrafiltration process' then x is a 'membrane filtration process'
viral clearance
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;
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) ∧ ∃r (RecipeProcessStage(r) ∧ prescribes(r, x))
manufacturing process that results in the elimination of a target virus by either removing viral particles or by inactivating its infectivity
if x is a 'viral clearance' then x is a 'manufacturing process' and is 'prescribed by' some 'recipe process stage'
viral filtration
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))
viral removal process in which viral particles are physically separated from the input material through a nanofiltration process
if x is a 'viral filtration' then x is a 'viral removal process' and 'has occurrent part' some 'nanofiltration process'
viral inactivation
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 necessairly 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)
viral clearance during which viral infectivity is reduced by physically or chemically modifying the input material
if x is a 'viral inactivation' then x is a 'viral clearance'
viral removal process
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; use of tangential flow filtration to separate viral particles from cell lysate during vaccine production
ViralRemovalProcess(x) → ViralClearance(x)
viral clearance during which viral particles are physically separated from the input material based on differences in physical properties such as size or charge
if x is a 'viral removal process' then x is a 'viral clearance'