Process Characterization of Viral Clearance
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)
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Process Evaluation Studies of Viral Clearance
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)
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Pressure Hold Test (or Leak Test)
A test for leaks and gross defects in which the system is held at a defined pressure for a defined time. Failure is indicated by the observation of a steady stream of air bubbles downstream of the filter. (TR41)
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Volumetric Throughput (Vmax)
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)
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Virus Removal
Physical separation of virus particles from the intended product. (TR41)
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Transmission Electron Microscopy (TEM)
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)
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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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Ultrafiltration Membranes
Membranes that retain particles whose sizes are measured by molecular weight, with retention ranges from 1,000 to 1,000,000 (Daltons). (TR41)
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Virus
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)
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Titer
The concentration of infectious virus calculated, taking into account the dilution factor. (TR41)
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Viral Inactivation
Reduction of virus infectivity caused by chemical or physical modification. (TR41) (TR83)
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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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Size Exclusion
A technique which separates particles based on diameter. (TR41)
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Steam-in-Place (SIP)
The process of applying clean pressurized steam to a stationary piece of equipment in order to sterilize it. (TR41)
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Specific Model Virus
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)
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Surrogate Fluid
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)
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Relevant Virus
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)
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Processing Time
The duration of time for a phase of a manufacturing unit operation or the entire operation. (TR41)
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Pore
The channel(s)/path(s) in a membrane through which a fluid or a gas may pass. (TR41) (TR26)
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Porosimetry (Gas-Liquid and Liquid-Liquid)
An analytical technique used to determine various quantifiable aspects of a material’s porous nature, such as pore diameter, total pore volume, surface area, and bulk and absolute densities. (TR41)
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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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Optical Density (OD)
A unitless measure of the absorption of light of a given wavelength in media of a given path length. (TR41)
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Permeate
The fluid which passes through a membrane. (see also filtrate) (TR41)
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Permeability
The degree to which a fluid will pass through a permeable substance under specified pressure and temperature conditions. (TR41) (TR26)
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Monodispersed particles
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)
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Nonspecific Model Virus
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)
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Nominal Pore Size Rating
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)
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Limit of Detection (LOD)
The lowest concentration of microorganisms in a test sample that can be detected, but not necessarily quantified, under the stated experimental conditions. (TR33) The lowest amount of analyte in a sample that can be distinguished from the absence of analyte. (TR41) The lowest concentration of analyte that can be unambiguously detected in a sample. For qualitative and for quantitative NAT methods, this value is conventionally expressed as a 95% positive cut-off value, representing the target concentration detected in 95% of repeated tests using a certain assay. (TR50)
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Irradiation
The process by which an item is exposed to ionizing radiation (typically gamma) to reduce or eliminate bioburden. (TR41)
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GMPs
Best practices in manufacturing of pharmaceuticals or biopharmaceuticals. From a regulatory standpoint, GMPs are regarded as the minimum current good manufacturing practice for methods to be used in, and the facilities or controls to be used for, the manufacture, processing, packaging, or holding of a drug to assure that such drug meets requirements of safety, identity and strength and meets the quality and purity characteristics that it purports or is represented to possess. (TR41) (TR 79)
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Feed (or Load or Feedstock or Feedstream)
The fluid introduced into a process. (TR41)
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Filtration
A process of removing particles from a fluid by passing it through a permeable material, such as a membrane film. (TR41) The process by which particles are removed from a fluid by passing the fluid through a porous material. (TR26)
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Extractable
A chemical component that is removed from a material by application of an artificial or exaggerated force (e.g., solvent, temperature, time). The term extractable is often erroneously used to describe a leachable. (TR14) (TR15) (TR26) (TR41) (TR45) Chemical substances that can be extracted from components of material process fluid contact surfaces by exertion of an exaggerated force (e.g., organic solvent, extreme elevated temperature, ionic strength, pH, contact time, etc.) Extractables may represent most but not all of the potential leachables that may be seen in process fluids. (TR66) Extractables are organic and inorganic chemical entities that can be released from a pharmaceutical packaging/delivery system, packaging component, or packaging material of construction under laboratory conditions. (TR54-4) Organic or inorganic chemical entity that is forced out of container closure system materials and components under laboratory experimental conditions. (TR73)
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Endogenous Virus-Like Particles – (e.g., Type C endogenous retroviruses)
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)
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Diffusion Test (or Forward Flow Test)
A test for membrane integrity that involves measuring the rate of gas diffusion through a liquid-wetted membrane.(TR15) An integrity test in which a filter is subjected to differential gas pressures below the bubble point and gas molecule migration through the water-filled pores of a wetted membrane is measured. This behavior follows Fick’s Law of Diffusion (i.e., the gas diffusional flow rate for a filter is proportional to the differential pressure and the total surface area of the filter). (TR41)
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Direct Flow Filtration (DFF) or Normal Flow Filtration (NFF)
In direct flow filtration, all fluid is directed through the membrane in a single pass. (TR41)
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Compatibility (Filter)
The ability of a filter to be used with a particular process fluid without a change in the inherent properties of the filter. (TR41)
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Bracketing
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)
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Cartridge Filter
Filter elements encased in a housing. Generally, the filter elements are disposable while the housing units are multi-use. In a few cases, both filter and housings are disposable. (TR26) (TR41)
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Bubble Point
The measured differential gas pressure at which a wetting liquid (e.g., water, alcohol, product) is pushed out of the largest pores of a wetted porous membrane, and a steady stream of gas bubbles or bulk gas flow is detected.(TR15) (TR26) The minimum pressure at which a wetting liquid is pressed out of the pore system of a membrane while forming a steady bubble chain. (TR41)
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Capsule Filter
Compact, self-contained filter assembly. Generally, the whole assembly is disposable. (TR26) (TR41)
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Bacteriophage
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)
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Active Pharmaceutical Ingredient (API)
Synonym: Drug Substance. (TR14) (TR42) A substance or mixture of substances that, when delivered in a finished drug product, directly affects the structure or function of the body. (TR54-4) Any substance or mixture of substance intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body. Note: also known as Drug Substance. (TR29) (TR56) (TR41) (TR54-3) (TR60) Any substance or mixture of substances intended to be used in the compounding of a drug preparation, thereby becoming the active ingredient in that preparation and furnishing pharmacological activity o other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans and animals or affecting the structure and function of the body. (TR63) (TR70) Any substance or mixture of substances intended to be used in the manufacture of a drug product, and that when used in the production of a drug, becomes an active ingredient in the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure and function of the body. (TR74)
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