PDA Glossary

Retention of solutes, suspended colloidal particles or microorganisms to fluid contact surfaces, e.g., the surfaces of pores in the filter medium. (May be modified with the following terms: electrokinetic, charge-rated, surface charge, hydrophobic or ionic strength. (TR45)

The retention of solutes, suspended colloidal particles or microorganisms to fluid contact surfaces, e.g., the surfaces of pores in filtration membranes. (TR26)

An exogenously introduced infectious virus that is unintentionally present in a biological product or its manufacturing process. (TR71) (TR83)

The American Society of Hospital Pharmacists (ASHP) defines a significant ADR as any unexpected, unintended, undesired, or excessive response to a drug that:
(1) Requires discontinuing the drug (therapeutic or diagnostic) Requires changing the drug therapy
(2) Requires modifying the dose (except for minor dosage adjustment)
(3) Necessitates admission to a hospital
(4) Prolongs stay in a healthcare facility
(5) Necessitates supportive treatment
(6) Significantly complicates diagnosis
(7) Negatively affects prognosis
(8) Results in temporary or permanent harm, disability, or death.
The World Health Organization (WHO) defines ADR as any noxious, unintended, and undesired effect of a drug which occurs at doses used for prophylaxis, diagnosis, or therapy, excluding therapeutic failures, intentional and accidental overdose and drug abuse. It does not consider errors in drug administration to be adverse events. (TR55)

An AE report is a communication to the U.S. FDA of an undesirable sign or symptom associated with use of a drug as required and detailed by 21 CFR 314.80. These reports are logged into the U.S. FDA’s Adverse Event Reporting System (AERS). Drug manufacturers are required to report adverse event information to FDA. These reports may also may be voluntarily submitted to the FDA directly by healthcare professionals or the general public at Med Watch. The reports are reviewed, safety issues are monitored, and data are periodically analyzed and assessed by the Center for Drug Evaluation and Research (CDER). (TR55)

A series of alert-level or action-level excursions that indicates the system or areas are not in control and have the potential to affect the product quality. (TR 70)

An increase in the frequency of alert- and action-level excursions or repeated recovery of low levels of microorganisms below the alert level during microbial monitoring or of pharmaceutical ingredient or finished product failure that is indicative of a loss of process control. (TR88)

Clumping of proteins, viruses, or bacteria that may arise from several mechanisms and may be classified in numerous ways, including soluble/insoluble, covalent/noncovalent, reversible/irreversible, and native/denatured. (TR47)

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)

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)

A bacteriophage is any one of a number of viruses that infect bacteria. The term is commonly used in its shortened form, “phage”. (TR41) (TR 47)

In a batch filtration process, the entire volume to be filtered is held in a single feed tank. The retentate stream is recycled back to that single feed tank. (TR15)

The enzyme chlorophenol o-methyltransferase responsible for fungal methylation has been isolated in cell-free extracts. Biomethylation, in this context, may be seen as a detoxification mechanism, although it plays a role in the production of mycotoxins by secondary metabolism. Slightly xerophilic fungi frequently associated halophenol biomethylation include Trichoderma longibrachiatum, Trichoderma virgatum, Aspergillus sydowii, and Penicillium islandicum. (TR55)

A demonstration of unit operation performance at two different values of a given parameter (e.g., ionic strength, dwell time or temperature), allowing the use any values of that parameter falling within this range. (TR41)

A scientific approach for defining product/load characteristics (e.g., viscosity, container sizes, container fill volumes, item sizes, loading configurations) that are tested (in a qualification study or validation study) at upper and/or lower limits. (TR1) (TR61)

A validation method that tests the extremes of a process or product. The method assumes the extremes will be representative of all the samples between the extremes. (TR26)

The host cells that are used to propagate or detect viruses. (TR 47)

Cells used for the manufacture of a biological medicinal product. (TR 71) (TR 83)

Cells used for production which are at the limit of their invitro cell age. Note Also known as, “End-of-Production-Cells”. (TR56)

An isolated system that has no interaction with its external environment, preventing contamination and release of the material contained.(TR28) (TR 66)

A measure of the proportion of the variation of one variable determined by the variation of the other. (TR57)

A process where cells, viruses or whole tissues are preserved by cooling to low sub-zero temperatures, typically -1960C. (TR47)

Morphological changes induced by viruses in infected cells in invitro culture. They are usually localized around a site of initial infection and vary in appearance based on the virus and the cultured cell. (TR47)

Viruses where infection of cells results in microscopically visible degeneration of the cells or other morphological changes. (TR47)

Assembly of short reads of a sequence to generate a contiguous sequence (contig). (TR71)

Complex, branched, high molecular weight polysaccharides made of many glucose molecules joined into chains of varying lengths and branches. (TR41)

A technique used to measure the size and size distribution of particles. Particles suspended in a solution will cause scattering of light and the extent of the scattering is related to the size and shape of the particles. (TR47)

A virus that pre-exists in the genome of the cell substrate. (TR71)

A virus that integrates into the genome of the cell substrate. (TR83)

Virus-like entity whose genetic material is stably integrated into the germ line of an organism or cell line. Cell lines (notably CHO) may constitutively produce virus-like particles, which are typically noninfectious but still of safety concern. Model retroviruses are generally used as surrogates to measure virus-like particle clearance. (TR41)

A classical PCR method based on repeated cycling of the reaction mixture between two or three temperatures (denaturing, annealing, and extension) with detection of the amplified product after reaction completion (e.g., by agarose gel electrophoresis). (TR50)

A biochemical technique used to detect or measure the presence of an antibody or an antigen in a sample. (TR41) (TR47)

A known test article processed with a nucleic acid extraction procedure in order to ensure the proper extraction of nucleic acid. (TR50)

The efficiency of extraction of target analyte from a test matrix. It is usually measured as ratio (percentage) of analyte amount extracted from the matrix to that originally present in the matrix before extraction. (TR50)

A measure of virus infectively based on formation of a region or “focus”, of infected cells within a monolayer culture that is caused by viruses that do not kill their host, but rather transform them. The number of foci is directly correlated to the number of infectious virus particles. (TR47)

Microorganisms responsible for infection in healthy individuals (i.e., individuals with normal operative and functional host defense mechanisms) that may be acquired from exposure to other infected people or animals, environmental reservoirs (exogenous) or the individual’s normal (endogenous) microbial flora. (TR67)

A gene or DNA sequence within a chromosome which can be used for discrimination of one mycoplasma species or strain from another. (TR50)

An amount of nucleic acid equivalent to the genetic complement present in the genome of a single microorganism. (TR50)

Relating to those characters that reside in the genetic complement of a specific strain of a specific organism. (TR51)

A compound that destroys all vegetative microorganisms. (TR70)

The screening of a biopharmaceutical bulk cell culture harvest for any adventitious contaminants, including mycoplasma, before further processing. (TR50)

Adherence of red blood cells to virus-specific antigens on the surface of infected cells. In cellbased in vitro assays the reaction is used as an end point for virus detection. (TR47) (TR71)

A clumping together or agglutination of red blood cells. In the context of this Technical Report hemagglutination indicates presence of virus that binds to erythrocytes. (TR47)

The clumping of red blood cells by binding to virus particles. The hemagglutination reaction is used in cell-based in vitro assays as an end point for virus detection. (TR71)

The formation of a double-stranded complex of complementary strands of nucleic acids (e.g., a primer and single-stranded DNA or RNA) (TR50)

Cell lines that are used in in vitro assays to detect the presence of viral agents. (TR71)

A measure of quantity of infectious virus. An infectious unit does not necessarily reflect the number of virus particles, as virus preparations also contain noninfectious virus particles and, depending on the cellular host, more than one virus particle may be necessary to infect a cell. (TR47)

A carrier upon which a defined number of test organisms have been deposited. (TR51)

The capacity of a substance to affect the quantitation of virus in the assay. (TR47)

A reaction performed to provide confirmation of adequate performance of the NAT assay including preparation of nucleic acid, its amplification using appropriate amplification technology, and analysis of amplified products. An example is the amplification of a housekeeping gene from the production cell line which provides a positive signal even in the absence of contaminant DNA. (TR50)

A RNA copy synthesized using a double-stranded DNA as template. The RNA polymerases of bacteriophage T7 or SP6 are usually used to perform the in-vitro transcription. (TR50)

Latency is the ability of a virus to be dormant (latent) within a cell (for example, genetic episomes; provirus). Under certain conditions the virus may become active and produce particles. (TR71)

A filter made up of a series of biconvex cells that are stacked on top of one another with rings between them to prevent bypass between the cells. End-caps are then placed at the top and bottom of the assembly and are held in place with a central core. [Synonyms: Lenticular Cartridge, Modules, Filter Elements, Filter Devices] (TR45)

In the context of this Technical Report the limiting dilution technique is used for virus cloning. The virus suspension is diluted until virus is no longer detectable. The dilution immediately before the dilution where infection of cells is no longer detectable is considered to contain only one virus particle or a very low number of virus particles. (TR47)

Log reduction is defined as the first log being 90%, the second log being 9% and the third log being 0.09% of the original inoculums. (TR70)

The logarithm to the base 10 of the ratio of organisms in the feed to organisms in the filtrate. (i.e., Log10(109/2) = 9.7). [Synonym: Log Titer Reduction] (TR45)

Titer Reduction (TR) expressed as a base 10 logarithm. (TR75)

The virus reduction factor of an individual purification or inactivation step is defined as the log10 of the ratio of the virus titer or total load in the prepurification material and the virus titer or load in the post-purification material which is ready for use in the next step of the process. (TR41)

A stock of cells or virus used to produce the Working Cell Bank or the Working Virus Bank. Cell/virus banking is used to enhance biological consistency. (TR47)

An internal control in which an amplifiable amount of nucleic acid is added to a test article to determine inhibition of the PCR. This addition is usually performed pre-extraction and should provide a weak signal 100% of the time. Also known as “interference control”. (TR50)

The part of the filter through which fluid passes that retains particles during filtration. (TR45)

The calculated or observed temperature for a primer/nucleic acid mixture at which 50% of primer-binding sites are in single strand form. (TR50)

A finely porous structure having lateral dimensions much greater than its thickness, through which mass transfer may occur by the application of driving forces like pressure or electro-osmotic. (TR15)

The effective surface area of a membrane device that is available for filtration. (TR15)

An individual unit consisting of multiple membranes in any format within a frame structure containing integral channels and ports for feed, retentate, filtrate and air connections. (TR15)

Filter element that is incorporated into a cartridge or capsule. (TR26)

Particles of uniform size in a dispersed phase. In the case of viruses, this term refers to free virus particles not agglomerated to other viruses or proteins in solution. (TR41)

A statistical method of estimating the number of viable organisms suspended in a liquid. (TR51)

The average number of infectious units added per cell in an infection. (TR41)

A manufacturer’s measure of an ultrafiltration membrane based on a defined solute-retention coefficient. (TR15)

A filter rating with an arbitrary value, indicating a particulate size range at which the filter manufacturer claims the filter removes some percentage. Nominal ratings vary from manufacturer to manufacturer and may not be suitable to compare filters among manufacturers. Processing conditions, such as operating pressure and concentration of contaminant may have a significant effect on the retention efficiency of the nominally rated filters. (TR41)

Nonfiber-releasing filter means any filter, which after any appropriate pretreatment, such as washing or flushing, will not release fibers into the component or drug product that is being filtered. All filters composed of asbestos are deemed to be fiber-releasing filters. (TR45)

A virus used for characterization of viral clearance of the process when the purpose is to characterize the capacity of the manufacturing process to remove and/or inactivate viruses in general (i.e., to characterize the general viral clearance capacity of the purification process.) (TR41)

An enzyme capable of cleaving the phosphodiester bonds between the nucleotide subunits of nucleic acids. (TR47)

A method for detection, and in some cases, quantification of target organisms via detection of organism specific nucleic acid. PCR or polymerase chain reaction is a common NAT method that is based on amplification of targeted sequences using primers and specialized DNA polymerases. (TR50)

An isothermal amplification method targeting RNA in which amplifications of RNA occurs via DNA intermediates. Each of the DNA templates can make 100 to 1000 copies of RNA amplicons, potentially resulting in the production of greater than a billion amplicons. (TR50)

A sample with a precisely measured content of specific nucleic acid. A nucleic acid standard can be serially diluted to assess the limit of detection of an NAT assay or to create a standard curve for Q-PCR to determine the concentration of target nucleic acid. (TR50)

A measure of virus infectively based on formation of a region, or “plaque” of lysed cells within a monolayer culture caused by viruses that kill and disrupt their host cell. The number of plaques is directly correlated to the number of infectious virus particles. (TR47)

The process of extracting virus from a lawn of plaque for growth in cell culture. By performing several rounds of plaque purification a virus clone can be isolated. (TR47)

An extra-chromosomal DNA molecule in bacteria which is capable of replicating independently of the host chromosomal DNA. Plasmids are often used as positive controls for NAT assays. (TR50)

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)

A short synthetic single-stranded nucleic acid complementary to a specific sequence of a target gene, DNA or RNA. It usually serves to initiate the de novo synthesis of nucleic acid from a template. (TR50)

Viral clearance studies in which nonspecific model viruses are used to assess the general virus clearance capacity of the manufacturing process to remove and/or inactivate viruses. (TR41)

Viral clearance studies in which relevant and/or specific “model” viruses are used to determine the ability of the manufacturing process to remove and/or inactivate these viruses. (TR41)

A class of UV photoactivated chemicals able to covalently modify nucleic acids. Psoralens may be used to reduce contaminating nucleic acid in NAT reagents. (TR50)

Any substance capable of eliciting a febrile (or fever) response upon injection or infection (as in endotoxin released in vivo by Gram-negative bacteria. (TR3)

Fever-producing substance (TR69)

A material that elicits a pyrogenic response (fever). (TR70)

A synthetic, chemically-labeled single-stranded nucleic acid complementary to a selected sequence within a DNA sequence to be amplified using forward and reverse primers in a Q-PCR reaction. A probe is typically labeled with both a fluorophor and quencher. The latter inhibits fluorescence until the quencher and fluorophore are separated by the exonuclease activity of DNA polymerase. (TR50)

A virus used in process evaluation studies that either is the identified virus, or of the same species as the virus known to or likely to contaminate the cell substrate or any other reagents or materials used in the production process. (TR41)

A coding sequence linked to a gene or promoter of interest. It is generally used to determine activation of the promoter or expression of the gene of interest in a cell or organism. (TR50)

RNA viruses containing a virally-encoded reverse transcriptase enzyme able to transcribe the RNA genome into DNA, which can then be incorporated into the host DNA. (TR47)

A technique for amplifying a defined segment of a RNA molecule. The RNA is first reverse-transcribed into complementary DNA (cDNA), followed by amplification of the cDNA using PCR. (TR50)

Virus that is closely related to the known or suspected virus (same genus or family), having similar physical and chemical properties as those of the observed or suspected virus. (TR41)

A filter intended for terminal processing of sterile liquids that has been tested under worst-case actual processing conditions for the ability to retain a minimum challenge of 10⁷ cells of Brevundimonas diminuta per cm² of filter area. (TR41)

A filter that reproducibly removes all test microorganisms from the process stream, producing a sterile effluent. (TR75)

A filter that reproducibly removes test microorganisms from the process stream, producing a sterile filtrate. (TR26)

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)

A model process fluid used in a small-scale validation study. The fluid is intended to either match or resemble an actual process fluid as closely as is feasible. (TR41)

A clumping of fused neighboring cells (syncytia) caused by viral infection when viral fusion proteins are transported to the surface of the infected cells and cause the host cell membrane to fuse with neighboring cells. The number of syncytia is directly correlated to the number of infectious virus particles. (TR47)

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)

Repetition of the PCR reaction steps of denaturing, annealing, and extension. Each step is characterized by different temperatures and reaction times. Some PCR methods combine the annealing and extension steps (i.e., two step PCR). (TR50)

The dilution of virus that results in the probability of infection of 50% in replicate tissue-culture inoculations. (TR41)

The concentration of infectious virus calculated, taking into account the dilution factor. (TR41)

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)

The capacity of a substance to confer morbidity or mortality. In the context of virus assays, the ability of a buffer or other process components to kill or otherwise harm the functionality of indicator cell lines. This is independent of the infection by the virus. (TR41)

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)

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)

Cells expressing exogenous proteins or reporter genes, produced by the transfection of continuously growing cells with gene expression constructs. (TR50)

A microscopy technique whereby a beam of electrons is transmitted through an ultra-thin specimen, interacting with the specimen as it passes through it. An image is formed from the electrons transmitted through the specimen, which are magnified and focused by an objective lens, and appear on an imaging screen. (TR41)

Subjection of material to an exceedingly high g-force. The technique can be used to band or sediment virus particles. (TR47)

A pressure-driven, membrane-based separation process in which a semipermeable membrane is used to retain high molecular weight solutes, while low molecular weight solutes are allowed to pass through the membrane. (TR15)

Membranes that retain particles whose sizes are measured by molecular weight, with retention ranges from 1,000 to 1,000,000 (Daltons). (TR41)

Elimination of a target virus by removal of viral particles or by inactivation of viral infectivity. (TR41)

Reduction of virus infectivity caused by chemical or physical modification. (TR41) (TR83)

Physical separation of virus particles from the intended product. (TR47) (TR83)

A simple, potentially pathogenic organism composed of a single type of nucleic acid (DNA or RNA) encased in a protein shell (called a capsid) and, in some cases, a lipid membrane (called an envelope). Viruses are incapable of independent replication and therefore must infect a host cell in order to propagate. (TR41)

Obligate, intercellular, replicating, infectious agents that are potentially pathogenic, possessing only a single type of nucleic acid (either RNA or DNA). They use the host cells for propagation as they are unable to grow independently, for example by binary fission, and multiplying their genomic material. (TR47) (TR83)

Unintentionally introduced contaminant viruses. (TR47)

Viral entity whose genome is part of the germ line of the species of origin of the cell line and can be produced in culture by cell lines from these species. (TR47)

A virus used for characterization of viral clearance of the process when the purpose is to characterize the capacity of the manufacturing process to remove and/or inactivate viruses in general, i.e., to characterize the robustness of the purification process. (TR47)

A virus used in process evaluation studies that either is the virus, or of the same species as a virus known to or possible to contaminate the cell substrate or any other reagents or materials used in the production process. (TR47)

Virus that is closely related to the known or suspected virus (same genus or family), having similar physical and chemical properties as those of the observed or suspected virus. (TR47)

According to the mode of preparation the following terms are used:
Crude Virus Preparation: A virus preparation that has undergone minimal processing post propagation. The virus is usually separated from cells which are lysed as the result of virus replication or are freezed/thawed in one or several cycles to release the virus from infected cells. The preparation is typically purified from cell debris by low speed centrifugation.
Purified Virus Preparation: A virus that has undergone purification process by one or more techniques, such as density ultracentrifugation, chromatography or membrane adsorber. The purity of the virus preparation varies depending on the purification technique and should be characterized by appropriate analytical methods. (TR47)

A virus preparation that is used directly in a clearance study. It can be crude or purified. Typically a large volume is produced, tested and qualified. This volume is divided into multiple aliquots for individual clearance studies. (TR47)

Physical separation of virus particles from the intended product. (TR41)

An initial virus stock produced after a new virus is introduced into a laboratory. Its purpose is to create a Master Virus Bank. (MVB) (TR47)

The maximum volume that can be processed through a filter area. It is the volumetric capacity of the filter for a given process fluid and generally expressed in L/m². (TR41) (TR47)

A seed lot generated from the master seed stock by a single passage. (TR51)