Critical Process (CP)
A process that impacts a critical quality attribute of the intermediate, drug substance or drug product being manufactured and therefore should have established critical process parameters that can be monitored or controlled to ensure that the process produces the desired quality.
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Chemistry Manufacturing and Controls (CMC)
The body of information that defines the technical development, manufacturing facility and support utilities; the process equipment and materials used in manufacturing; the manufacturing process itself; the personnel involved in manufacturing and quality; the chemistry of the product; QC in process and release testing, specifications, and stability of the product; all of the controls, documentation, and training necessary to ensure that all of these listed activities are properly and effectively carried out. (TR56)
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Biological Active Substance
Manufactured biological active substances and medicinal products involving biological processes and materials, such as cultivation of cells or extraction from living organisms. (TR56)
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Host Cells/Parental Cells
A non-transfected cell substrate that is generally well-characterized and banked. It can be manipulated to generate a cell substrate for production of a biological medicinal product. (TR83)
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Cell Line
Type of cell population with defined characteristics that originates by serial subculture of a primary cell population that can be banked. (TR83)
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Animal-Derived Raw Materials (Secondary)
Non-animal in origin but may be derived from processes that include materials from animal components that come in direct contact with the raw material, for example, a recombinant protein produced in an E. coli fermentation that uses fermentation medium containing tryptone, or a recombinant protein expressed in plants that are exposed to bovine manure fertilizer. (TR83)
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Animal-Derived Raw Materials (Primary)
Contains in the final raw material or uses in the manufacturing process of the final raw material, any raw material derived directly from bovine or other animal tissues, for example, bovine serum, porcine-derived trypsin, and animal-tissue-derived hydrolysates. (TR83)
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Technically Unavoidable Particles (TUPs)
Particles that are visibly different from the bulk of the material when viewed with the naked eye within the container or against a suitable background (e.g., size, shape, color, number, texture) and are inherent to the manufacturer’s process, product, or raw materials. The unintended presence of a small quantity of particles, stemming from impurities of natural or synthetic ingredients, the manufacturing process, storage, or migration from packaging that is technically unavoidable in good manufacturing practice, and do not pose a risk to patient safety. (TR78)
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Intrinsic Particles
Those particles that arise from sources related to the formulation, packaging, or assembly processes. In each of these cases, the particle material (e.g., glass, stainless steel, rubber, or gasket material) could be identified as a known product-contact material. (TR78)
A particle that comes from within the primary process. These are qualified product contact materials and are often associated with the primary packaging components. They are unplanned but not unexpected.(TR85)
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Zone of Protection/Machine Shroud
A system fitted to a BFS machine to direct a flow of HEPA-filtered air over the Critical Processing Zone of the machine. (TR77)
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Static (at rest)
BFS machine line with conveyor belts at rest but with air shower and room ventilation in operation, extruder (heated, not running) and mold carriage in standby. No operating personnel present. (TR77)
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Parison
The “tube” of polymer extruded by the BFS machine from which the containers are formed. (TR77)
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Mandrel
Specialized filling needles on certain BFS machines which also act to form the container. (TR77)
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Air Shower
A device fitted to a BFS machine which provides, at a minimum, a continuous flow of Grade A quality air supply over the filling needles and the point-of-fill. The air shower is also known as a nozzle shroud in shuttle type machines. (TR77)
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Advanced Aseptic Process
A process in which direct intervention with open product containers or exposed product contact surfaces by operators wearing conventional cleanroom garments is not required and never permitted. (TR77)
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Defect (ISO def.)
The nonfulfillment of intended usage requirements. The departure or absence of one or more quality characteristics from intended usage requirements. (TR76)
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Nominal Value
The assumed activity of an endotoxin preparation, dilution, or "spike"; based on label-claim information.(TR82)
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Naturally Occurring Endotoxin (NOE)
Endotoxin prepared from Gram-negative bacteria produced under defined conditions and with minimal nonchemical processing, e.g., centrifugation and filtration.(TR82)
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Measured Values
Those values where activity is confirmed by interpolation from a reference standard curve.(TR82)
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Masking
A type of interference that may result in low endotoxin recovery.(TR82)
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Reference Standard Endotoxin (RSE)
The primary standard from USP, EDQM, JP and WHO for use in the harmonized compendial bacterial endotoxins test (BET). The current 3rd International Standard (WHO), USP, and EDQM RS are lyophilized formulation that contains highly purified LPS that is chemically extracted and purified from E. coli strain O113:H10:K(-) and further formulated with stabilizers and excipients.(TR82)
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Control Standard Endotoxin (CSE)
Endotoxin preparations other than the international or national reference standards that are traceable in their calibration to the international endotoxin reference standard. A CSE is a secondary or tertiary standard, commonly purified from Escherichia coli, and is usually manufactured and certified by an LAL reagent manufacturer for use with a specific lot of reagent under defined assay conditions.(TR82)
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Working Cell Bank (WCB)/Working Virus Bank (WVB)
A stock of cells or virus derived from the MCB/MVB and used to produce production cells, assay cells or virus production lots. (TR 47)
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Working Seed Lot
A seed lot generated from the master seed stock by a single passage. (TR51)
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Toxicity Studies (also referred to as “Tox” studies)
In vivo or in vitro experiments in which test articles are studied prospectively in test systems under laboratory conditions with the primary goals of identifying the following: 1) an initial safe dose and subsequent dose escalation schemes in humans; 2) potential target organs for toxicity and for the study of whether such toxicity is reversible; and, 3) safety parameters for clinical monitoring after the appropriate dosing and administering schedule is followed (relevant to the drug being studied). In toxicity studies, the test animals are examined by histological or serological methods in order to identify toxic, mutagenic, or teratogenic effects of the drug. It is sometimes possible to collect physiological data from the animals prior to sacrifice. Some toxicity studies may be performed using cell culture methods. Toxicity studies are also described by the U.S. FDA as “nonclinical laboratory studies” and by ICH as “preclinical safety evaluations”.
The definition does not include studies using human subjects or clinical studies, field trials in animals, or any basic exploratory studies carried out to determine whether a test article has any potential utility or to determine physical or chemical characteristics as described in ICH S6 and 21 CFR Part 58 (GLP). (TR56)
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Tissue Culture Infectious Dose – TCID50
The dilution of virus that results in the probability of infection of 50% in replicate tissue-culture inoculations. (TR41)
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Transcription-Mediated Amplification (TMA)
An isothermal NAT method that can amplify RNA or DNA targets a billion-fold in less than one hour. TMA technology uses two primers and two enzymes: RNA polymerase and reverse transcriptase. (TR50)
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Touchdown PCR
A technique to reduce appearance of non-specific amplicons in PCR reactions. The earliest cycles of a touchdown PCR method have high annealing temperatures. The annealing temperature is decreased in increments for subsequent cycles until a fixed point is reached. (TR50)
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Titer
The concentration of infectious virus calculated, taking into account the dilution factor. (TR41)
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Viral Removal
Physical separation of virus particles from the intended product. (TR47) (TR83)
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Viral Inactivation
Reduction of virus infectivity caused by chemical or physical modification. (TR41) (TR83)
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Toll-like Receptor (TLR)
A class of single membrane-spanning non-catalytic receptors that recognize structurally conserved molecules derived from microbes. They can activate immune cell responses when microbes have breached physical barriers such as the skin or intestinal tract mucosa. (TR50)
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Tangential Flow Filtration
Filtration in which the product stream is introduced parallel to the membrane surface and flows in a direction perpendicular to the filtrate flow. (Synonym:cross-flow filtration) (TR15)
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Tangential or Cross Flow Filtration (TFF or CFF)
Filtration in which a fluid (feed) stream runs tangential to a membrane. A pressure differential causes some fluid to pass through the membrane. (TR41)
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TCld50 Assay
Quantal assays for determining the titer of a virus. The 50% tissue culture infective does (TCID50) is the dilution of virus that results in the infection of 50% of cell cultures that have been infected with the same dilution of the virus sample. (TR47)
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Specification
A list of tests, references to analytical procedures, and appropriate acceptance criteria that are numerical limits, ranges, or other criteria for the test described. It establishes the set of criteria to which a material should conform to be considered acceptable for its intended use. (TR14)
A list of tests, references to analytical procedures, and appropriate acceptance criteria that are numerical limits, ranges, or other criteria for the test described. It establishes the set of criteria to which a material should conform to be considered acceptable for its intended use. Drug product and drug substance specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities (TR38) (TR57)
A list of tests, references to analytical procedures, and appropriate acceptance criteria that are numerical limits, ranges, or other criteria for the test described. It establishes the set of criteria to which a material should conform to be considered acceptable for its intended use. Drug product and drug substance specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities (TR69)
A list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which a drug substance, drug product, or materials at other stages of its manufacture should conform to be considered acceptable for its intended use. “Conformance to specification” means that the drug substance and drug product, when tested according to the listed analytical procedures, will meet the acceptance criteria. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of approval. (TR56) (TR74)
A list of tests, references to analytical procedures, and appropriate acceptance criteria that are numerical limits, ranges, or other criteria for the test described. It establishes the set of criteria to which a material should conform to be considered acceptable for its intended use (17). (TR60-3)(TR88)
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Specificity
The ability of an analytical procedure to accurately measure or detect a target analyte in the presence of other components in the sample matrix. (TR50) The ability to assess unequivocally the analyte in the presence of components that may be expected to be present. Typically these might include impurities, degradants, matrix, etc. Lack of specificity of an individual analytical procedure may be compensated by other supporting analytical procedure(s). (TR57) The ability to detect a range of microorganisms, which demonstrate that the method is fit for its intended use. (TR33)
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Soil
The chemical or microbiological materials left on process equipment after completion of process manufacturing, but before initiation of the cleaning process. (TR29)
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Storage Solution
A solution typically selected to control bioburden during column storage. (TR14)
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Stirred-Cell Filtration
A surrogate for tangential flow filtration where shear is achieved by rapidly stirring the solution immediately adjacent to the membrane. Typically the stirring is accomplished by mechanical means, such as through the use of a stir bar or impeller. (TR15)
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Scalability Studies
Studies used to assess sizing for the appropriate performance of filter media at increased process volumes. (TR45)
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Scale-Down
The process of decreasing the column volume. (TR38)
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Scale-Down Model
A small-scale process step that has been demonstrated to be representative of a production-scale operation. (TR14)
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Sanitizer
A compound that will reduce the number of vegetative microorganisms to a safe level as determined by public health requirements. Normally a reduction of 103 in vegetative microorganisms is obtained. (TR70)
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Sanitization
Reduction of microbial contaminants to safe levels as judged by public health requirements for the specific country. (TR13) A significant reduction in bioburden, achieved in chromatography by the use of bactericidal agents, such as sodium hydroxide (NaOH), hydrochloric acid (HCl), ethanol (EtOH), and isopropanol (IPA). (TR14) The process of reducing microbial levels by treatment at less than defined sterilizing conditions. Typically water at 80 °C or a chemical treatment is used to perform sanitization of process components. (TR45) A process that reduces the number of viable microorganisms to a defined level. (TR61) (TR69)
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Rapid Microbiological Methods (RMMs; Alternative Microbiological Methods)
Technologies that allow users to obtain microbiology test results more quickly than traditional microbiological methods, which are usually culture/ growth based. (TR69)
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Process Validation Protocol
A written plan pre-approved by the quality unit that specifies critical steps, controls, and measurements. The process validation protocol states how validation will be conducted, identifying sampling, assays, specific acceptance criteria, production equipment, and operating ranges. Results obtained for each study described in the protocol should be evaluated in an associated process Validation report. (TR14) (TR42)
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Raw Materials
Starting materials, reagents, and solvents used in the production of intermediates or APIs/drug substance. (TR54-4) (TR83)
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Process Validation Report
A report approved by the quality unit that summarizes specific tests performed, compares the test results with the protocol acceptance criteria, and addresses deviations encountered during the study. (TR14) (TR42)
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Polymerase Chain Reaction (PCR)
A technique widely used in molecular biology in which a DNA polymerase is used to amplify a piece of DNA by in vitro enzymatic replication. As PCR progresses, the DNA thus generated is itself used as a template for replication. This sets in motion a chain reaction in which the DNA template is exponentially amplified. This technique may be used to quantify virus. (TR41) (TR47)
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