PDA Glossary

A. laidlawii is a mycoplasma in class Mollicutes and order Acholeplasmatales. (TR75)

An established microbial or airborne particle level that, when exceeded, indicates a process is outside of its normal operating range. A response to such an excursion should involve a documented investigation and corrective actions based on the results of that investigation. (TR13)

An established microbial or non-viable particle level that, when exceeded, should trigger appropriate investigation and corrective action based on the investigation. (TR22)

An established microbial or airborne particle level for environmental, water or gas monitoring that, when exceeded, indicates that a facility process is outside of its normal operating range. The response to such an excursion involves a documented investigation and corrective actions based on the results of that investigation. The prescribed action level is often specified in guidance or standards relating to environmental monitoring and water quality. (TR69)

An established microbial or nonviable particle level for environmental, water, or gas monitoring that, when exceeded, indicates a facility or process is outside of its normal operating range. The response to such an excursion may involve a documented investigation and corrective actions based on the results. The prescribed action level is often specified in guidances or standards relating to environmental monitoring and water quality (3-6). (TR88)

An established microbial or non-viable particle level that, when exceeded, should trigger appropriate investigation and corrective action based on the investigation. (TR22)

An internal (in-house) value used to assess the consistency of the process. The cause of the excursion should be investigated and documented and corrective action is generally required. Action limits are not specifications. (TR42)

An established internal (in-house) data-based value which is part of the control strategy and used to assess the consistency of the manufacturing process. An action limit excursion result in an investigation, identification of recovered isolates, root-cause analysis, assessment of a systemic failure and impact on product quality and patient safety. (TR69)

An established internal (in-house) data-based value that is part of the control strategy and used to assess the consistency of the manufacturing process. An action limit excursion result in an investigation, identification of recovered isolates, root-cause analysis, assessment of a systemic failure and impact on product quality and patient safety. (TR74)

A limit that, when exceeded, indicates a process is outside of its normal operating range. A response to such an excursion should involve a documented investigation and corrective actions based on the results of that investigation. (TR60)

A written plan consisting of elements to be accomplished to achieve a specific result. The plan describes responsibility for each element and a target date for completion. (TR22)

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)

Any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of 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. (TR60)

Any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and when used in the production of a drug, becomes an active ingredient of the drug product (also called “drug substance”). (TR29)

Any substance or mixture of substances 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 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. (TR54-3)

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 or 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)

A raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API Starting Material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API Starting Materials normally have defined chemical properties and structures. (TR60)

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)

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)

A foreign material that is introduced inadvertently; not natural or hereditary (as in microbial, chemical, or biochemical contamination of a purified substance). (TR 69)

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)

A microorganism that utilizes oxygen as the final electron acceptor during metabolism; a microorganism that will grow primarily in the presence of oxygen. For the purpose of this report, this definition encompasses facultative anaerobes. (TR22) (TR62)

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)

A moist heat sterilization process that operates at a controlled pressure greater than saturated steam pressure and typically uses compressed air to bring the chamber to the desired pressure. (TR01) (TR48)

A moist heat sterilization process that operates at a controlled pressure greater than saturated steam pressure and typically uses compressed air to bring the chamber to the desired pressure. (TR01) (TR48)

A test used to evaluate air removal and steam penetration in an empty sterilizer that is used for porous/hard goods load sterilization (e.g., Bowie-Dick Test, DART, Lantor Cube, Browns’ Test). (TR01) (TR 48)

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)

A room that controls the airflow between two rooms of different classification. (TR 70)

An established microbial or nonviable particle level giving early warning of potential drift from normal operating conditions; not necessarily grounds for definitive corrective action but typically requires follow-up investigation. (TR13) (TR22) (TR69)

An established level that, when exceeded, is giving an early warning of a potential drift from normal operating conditions; while not necessarily grounds for definitive corrective action, it typically requires follow-up review. (TR 60)

An established microbial or nonviable particle level giving early warning of potential drift from normal operating conditions; not necessarily grounds for definitive corrective action, but typically requires follow-up investigation (3, 4, 7). (TR88)

An established internal (in-house) data-based value giving early warning of potential drift of manufacturing process from normal operating conditions and triggers appropriate follow-up investigations. Alert limits are always lower than action limits. (TR69)

A novel, modern and/or fast microbiological testing method that is different from a classical or traditional growth-based method, such as agar-plate counting or recovery in liquid broth media. The alternative or rapid method may utilize instrumentation and software to manage the testing and resulting data, and may provide quantitative, qualitative and/or microbial identification test results. Automated technologies that utilize classical growth-based methods may also be designated as being novel, modern or rapid, based on their scientific principle and approach to microbial detection. The terms alternative, rapid microbiological method, rapid method and the acronym RMM are used interchangeably within this technical report. (TR33)

A segment of double stranded DNA formed as the product of polymerase chain reaction or other amplification based techniques such as TMA or NASBA. (TR50)

An organism that has the ability to grow in the absence of oxygen. (TR51)

A general statistical approach to data analysis (i.e., comparison of means) in which the variation in a method’s results is partitioned among explanatory factors in order to systematically assess factor influence and/or variance components. (TR57)

Substance (usually a residue) for which an analysis is being performed. (TR29) (TR49) (TR70)

A specific chemical moiety being measured, which can be intact drug, biomolecule or its derivative, impurity, and/or excipients in a drug product. [Synonym: measurand] (TR57)

Material used to monitor the performance of a method to assess the integrity and validity of the results. (TR57-2)

The qualification of the analytical instrument(s) used as part of the analytical procedure. (TR57)

Equivalence study that measure the same property of two methods and that shows that replacing one of these methods with the other would not adversely affect the test’s use or results. (TR57-2)

Collection of activities performed to define the intended purpose of the method, select the appropriate technology to implement the method, and identify the critical method variables that need to be controlled to ensure that the method is robust and rugged. (TR57-2)

Collection of activities performed to select an appropriate technique and method conditions to meet the Analytical Target Profile (ATP) requirements. (TR57-2)

Formal or informal study performed to assess initial method performance prior to full ICH Q2(R1) validation; assessment activity that culminates in a scientifically sound method that has an acceptable level of performance, is documented to be suitable for its intended use, and is demonstrated to have “adequate capability … to meet appropriate standards of performance for its purpose” (TR57-2)

Documented process that qualifies a laboratory (receiving unit) to use an analytical test procedure that originates in another laboratory (the transferring unit, also known as the sending unit), thus ensuring that the receiving unit has the knowledge and ability to perform the transferred analytical procedure as intended. (TR57-2)

An analytical method that is used for multiple products and/or types of sample matrix without modification of the procedure. Similar to compendial methods, an APT method may not require full validation for each new product or sample type. (TR57)

That which is performed in order to obtain a reportable result. The procedure should describe in detail the steps necessary to perform the analytical test. This may include but is not limited to: the sample, the reference standard and the reagents preparations, use of the apparatus, generations of the calibration curve, use of the formulae for the calculation [Synonym: Method, Assay] (TR57)

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 membrane in which the pore size and structure differ from one face to the other. These membranes are usually considered “directional” because of the difference in flow characteristics, depending on which surface of the membrane faces the feed stream. (TR15)

A temperature designed to allow primers to attach to single-stranded DNA or RNA to initiate amplification. The annealing temperature is usually kept a few degrees lower than the melting temperature of the primers to avoid non-specific amplification. See “Melting Temperature”. (TR50)

Substance used to destroy or suppress the growth of microorganisms, whether bacteria, fungi, or viruses, on inanimate objects and surfaces. (TR70)

Disinfection of floors, walls, ceilings, and other surfaces. (TR70)

Free from disease-producing microorganisms. (TR28)

Free from disease-producing microorganisms. An operation performed in a controlled environment designed to prevent contamination through the introduction of microorganisms. (TR26)

The part of aseptic processing where a pre- sterilized product is filled and/or packaged into sterile containers and closed. (TR22) (TR28) (TR62) (TR13)

A process in which sterile materials are handled in an environment in which the air supply, materials, equipment and personnel are controlled to prevent microbial and particulate contamination. (TR44) (TR51)

Handling sterile materials in a controlled environment, in which the air supply, facility, materials, equipment and personnel are regulated to control microbial and particulate contamination to acceptable levels. (TR28) (TR62) (TR69)

Handling of sterile product, containers, and/ or devices in a controlled environment in which the air supply, materials, equipment, and personnel are regulated to maintain (product) sterility. (TR13)

Controlled environment, consisting of several zones, in which the air supply, facility, materials, equipment and personnel are regulated to control microbial and particulate contamination to acceptable levels. (TR22) (TR28) (TR62) (TR70)

A means for establishing the capability of an aseptic process as performed using a growth medium. (TR22) (TR62)

A physical, chemical, or microbiological property or characteristic of an input or output material. (TR60)

An output variable or outcome that cannot be directly controlled, but is an indicator that the process performed as expected.(Synonym - Process Performance Parameter) (TR60)

A molecular or product characteristic that is selected for its ability to indicate the quality of the product. Collectively, the quality attributes define identity, purity, potency and stability of the product, and safety with respect to adventitious agents. Specifications measure a selected subset of the quality attributes. (TR60)

Particles that should not be present in excipients, APIs, intermediates, and final oral dosage forms, and their presence should always trigger an investigation. These particles consist of foreign matter that is not intended/designed to be in direct contact with the product/manufacturing process. These particles commonly originate from materials which accidently or unintentionally come into contact with the product or a process stream. (TR78)

A chamber for steam sterilization. (TR45)

Residual pressure opposing the free flow of liquid or gas at the outlet side of the filter. (TR45)

Pressure applied downstream of a filter or other piece of equipment. (TR26)

Feature that enhances the area to hold the syringe and is usually designed to avoid accidental removal of the plunger from the back. By design, it may also serve as a flange extender to facilitate holding of the syringe during injection. (TR 73)

Endotoxins are fever producing substances commonly found in the cell wall of certain Gram-negative bacteria. (TR3)

Assay for measuring active endotoxin by combining a liquid test sample with Limulus amebocyte lysate (LAL) reagent and measuring the resulting proportional reaction via visual, turbidimetric, chromogenic, or other validated means of detection. (TR3)

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)

Small glass beads (spheres) obtainable in a range of sizes, used in the recovery of spores from paper carriers. (TR51)

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)

A convection oven with a chamber or chambers where items are dry-heat sterilized or depyrogenated as a single load in a discontinuous process. The oven typically uses one or more filters to remove air particles. (TR3)

A process where there are no streams flowing into or out of a controlled volume, as opposed to a continuous process. In a batch filtration process, the feed solution is reduced in volume due to permeation of filtrate through the filter. There is no continuous addition of feed solution to the feed vessel. (TR45)

Homopolymers of glucose connected by (1→3)-β-D- glycosidic linkages. (TR45)

The total number of microorganisms per unit of material prior to sterilization. (TR13)

Total number of viable microorganisms on or in a health care product prior to sterilization. (TR22)(TR61)(TR62)

A population of viable microorganisms in a fluid prior to sterilizing filtration. (TR26)

A measure of the contaminating organisms found in or on a given amount of material before it undergoes a sterilization process. (TR45) (TR70)

The number of detectable microorganisms (bacteria and fungi) with which an object is contaminated. It is measured in CFU (colony forming units). (TR47)

The number of viable, contaminating microorganisms present on a product immediately prior to decontamination. (TR51)

Viable microbial contaminants associated with personnel manufacturing environments (air and surfaces), equipment, product packaging, raw materials (including water), in-process materials, and finished products. (TR 67) (TR 69)

Manufactured biological active substances and medicinal products involving biological process­es and materials, such as cultivation of cells or extraction from living organisms. (TR56)

Property that describes the specific ability or capacity of a product to achieve a defined biological effect. (TR57)

An inoculated carrier contained within its primary pack ready for use and providing a defined resistance to the specified sterilization process. (TR51)

A test system containing viable microorganisms of a pure and specified strain providing a defined resistance to a specified sterilization process (TR1)(TR3) (TR30) (TR61)

A product (therapeutic or prophylactic) for human use that has been manufactured in or from a biological source. Examples include recombinant therapeutic proteins or vaccines. Biological medicinal products are also referred to as: biological medicines, biological products, biologics and biologic drugs. (TR 71)

A component of performance qualification that demonstrates, by use of biological indicators, that the required lethality (F_BIO) is achieved consistently throughout the load. (TR1) (TR3) (TR30)

A component of performance qualification that demonstrates, by use of biological indicators, that the required lethality (F_BIO) or spore log reduction (SLR) is achieved consistently throughout the sterilized or sanitized portion of the SIP system. (TR61)

An enclosed, ventilated workspace with engineering controls designed to remove or minimize exposure to hazardous biological materials. A BSC is a principle device to provide containment of infectious splashes or aerosols generated by many microbiological procedures. BSCs are designed to provide personnel, environmental and product protection when appropriate practices and procedures are followed. A cabinet that is designed to protect the operator and the environment from the hazards of handling infected material and other dangerous biological. (TR62)

Biological tests include animal, cell culture, or biochemical based testing that measures a biological, biochemical, or physiological response. (TR38)

An application, filed with the US Food and Drug Administration (FDA), which contains specific information on the manufacturing processes, chemistry, pharmacology, clinical pharmacology and the medical effects of the biologic product (similar function as the Marketing Authorization Application in Europe). (TR56)

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)

The grouping of related experimental units used in design of experiments (DOE). (TR57)

A thin layer of fluid near the membrane surface in which the tangential velocity changes from zero at the surface to the free stream value away from the surface. (TR15)

Coating of fluid in the immediate vicinity of a bounding surface where the effects of viscosity are significant (TR 69)

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)

Energy required to initiate plunger movement within the syringe barrel upon injection. (TR 73)

A filtration operation resulting in a significant rise in filtrate turbidity accompanied by a small increase in differential pressure. This occurs when the adsorptive capacity of the filter is reached, resulting in the passage of particles smaller than the pore size of the filter that would normally be removed by adsorption. (TR45)

Small bacteria (0.3–0.4 &;mum in diameter by 0.6–0.1 &;mum long) used to challenge a sterilizing grade filter during validation testing. [Formerly Pseudomonas diminuta](TR45)

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)

Solids deposited on the upstream side of filter media. (TR15) (TR45) (TR26)

The demonstration that an instrument or device produces results within specified limits when compared to those produced by a reference standard or a standard that is traceable to national or international standards, over an appropriate range of measurements (calibration range). (TR 1) (TR 30) (TR 48) (TR 61) 

The demonstration that a particular instrument or device produces results within specified limits by comparison with those produced by a refer­ence or traceable standard over an appropriate range of measurements. (TR 54-5)

The CE marking is a key indicator of a product’s compliance with EU legislation and enables the free movement of products within the European market. (TR58)

Type of cell population with defined characteristics that originates by serial subculture of a primary cell population that can be banked. (TR83)

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)

The certification by a supplier of the performance of the material tested against a set of specifications, such asidentity, purity, moisture content, pH, color, bioburden, endotoxin, etc. (TR56)

The relationship between the number of colony forming units counted on solid media and the number of genome copies measured using a method suitable for quantitative assessment of genomic DNA. (TR50)

The concentration in Colony Forming Units/mL of the test microorganism in the challenge fluid. (TR75)

The carrier fluid in which the test microorganism is suspended and delivered to the test filter. (TR75)

The concentration of the test microorganism applied to the test filter (per centimeter squared) or the total number of cells applied to the test filter at the completion of the challenge. (TR75)

The volume of challenge fluid applied to the test filter. (TR75)

The primary component of a sterilizer that contains the items to be sterilized. The chamber is a pressure rated vessel. (TR1) (TR 48)

The primary structural element of a sterilizer that contains the products to be sterilized. The chamber is a pressure (positive and/or negative) rated vessel. (TR30)

The location(s) within the load zone that achieves the lowest process lethality (F₀) and/or the lowest distribution temperatures during the sterilization process. (TR01)

The elapsed time measured from the introduction of steam in the heat-up phase (“steam on”) to the point when the temperature of the heating medium within the chamber reaches the exposure temperature set point. (TR01)

A test conducted to evaluate possible air infiltration to the chamber under vacuum. [Synonym: Vacuum Leak Test] (TR1) (TR48)

A formal program that describes evaluation and actions to be taken if a change is proposed or completed to facilities, materials, equipment, and/or processes used in the fabrication, packaging, and testing of drugs, or a proposed or completed change that may affect the operation of the quality or support systems. (TR22) (TR39) (TR52) (TR58) (TR64) (TR 70)

The steps taken for switching multiproduct equipment from the manufacture of one product to the manufacture of a different product. (TR29) (TR49)

Scientifically sound method of a generally complex nature that is used for nonroutine assessment of specific biochemical, chemical, physicochemical, immunochemical, microbiological, and biological characteristics or inherent properties of a compound. (TR 57-2)

A series of tests designed to increase process knowledge by examining proposed operational ranges and their individual and/or combined impact on the chromatography process. (TR14)

A late-stage study that evaluates the process to increase process knowledge and examines proposed operational ranges and their individual and/or combined impact on target protein quality. (TR42)

The relative stability of filter materials and/or filter assembly components when exposed to process fluids and process parameters. (TR45)

Test system that reveals change in one or more predefined process variables based on a chemical or physical change resulting from exposure to a process. (TR01) (TR30)

A device that is designed to react in a quantitative manner to multiple sterilization variables, (typically, time and temperature and, in some instances, moisture). (TR01) (TR30)

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)

Data recorded during performance of a chromatography unit operation typically includes UV absorption (280 nm), pH, and conductivity, as well as other data (e.g., flow rates or pressure). (TR14)

The passage of a solute (mobile phase) through resin (stationary phase) to achieve purification of substances based on the chemical, physical, and biological properties of the molecules involved. (TR14)

Material used to interact with the process stream in order to purify the target protein. Chromatography resin usually consists of porous particles within a defined particle size range that are insoluble in the process stream (e.g., ceramic beads, agarose). (TR14)

The removal of solid particulates from a liquid through filtration, sedimentation, centrifugation or other means. (TR45)

A situation in which there is a reasonable probability that the use of or exposure to a violative product will cause serious adverse health consequences or death. (TR55)

A situation in which use of or exposure to a violative product or may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequence is remote.(TR55)

A situation in which use of or exposure to a violative product is not likely to cause adverse health consequences.(TR55)

A physician, psychiatrist, etc., who specializes in clinical work as opposed to one engaged in laboratory or experimental studies. (TR58)

The process of creating identical copies of DNA fragments or a homogeneous preparation of cells, viruses or other organisms. (TR47)

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)

The location within an SIP system that achieves the lowest process lethality (F₀) during a SIP process. Note: When lethality values are not available or not applicable (e.g., a sanitization process operating at less than 100 °C) the cold spot is the location with the lowest temperature profile during the SIP cycle. (TR61)

A mixture with properties between those of a solution and a fine suspension. (TR45)

Growth (division) of adherent microorganisms on a surface (TR 69)

One or more microorganisms that produce a visible, discrete growth entity on a semi-solid, agar-based microbiological medium. (TR22) (TR62)

Visible outcome of growth of microorganisms arising from a single or multiple cells. (TR28)

A single microorganism or an aggregate of many that forms a single discrete colony on solid agar media after suitable incubation. Colony forming units are used for bacterial titer (total bacteria load in a sample) determination on solid media. (TR50) (TR75)

The quantity of mycoplasma contained in the highest dilution of a test article that produces a color change in a pH-sensitive liquid medium (typically containing phenol red) within a specified time of incubation, used for end-point determination of growth. (TR50)

The solute that is passed through the column for separation. (TR14)

Preparation of a column that includes the addition of resin slurry into a column to create a bed suitable for its intended use. Characteristics of a packed column bed include bed height and diameter, backpressure, and number of theoretical plates. (TR14)

A well planned, documented and managed engineering approach to the start-up and transfer of facilities, systems and equipment to the end-user that results in a safe and functional environment that meets established design and user requirement specifications. Commissioning precedes Qualification and includes three phases:
1. Inspection, testing, and regulation
2. Adjustment and setting of work
3. Functional testing (TR 3)

A prescribed number of activities designed to take equipment and systems from a static, substantially complete state to an operable state. (TR 48)

A well planned, documented, managed engineering approach to the start-up and turnover of facilities, systems, and equipment to the end-user, that results in a safe and functional environment that meets established design requirements and stakeholder expectations.(TR 54) (TR 54-5)

A protocol submitted by an applicant under CFR 601.12(e) and 314.70 (g) that describes the specific tests and validation studies and acceptable limits to be achieved to demonstrate the lack of adverse effect for specified types of manufacturing changes on the identity, strength, quality, purity, and potency of the product as they may relate to the safety or effectiveness of the product. Any such protocols, or change to a protocol, shall be submitted as a supplement requiring approval from FDA prior to distribution of the product. The supplement, if approved, may justify a reduced reporting category for the particular change because the use of the protocol for that type of change reduces the potential risk of an adverse effect. (TR38)

An assessment of the similarities between the critical parameters and output results of two or more separate processes or methods. (TR50)

Transfer of a method that involves the analysis of a predetermined number of samples of the same lot by both the sending and the receiving unit. (TR 57-2)

Proof that no adverse interaction between the filter and the process fluid has occurred. (TR26)

A term used in relation to the non-reactivity of filter materials with the substance to be filtered. (TR45)

The ability of a filter to be used with a particular process fluid without a change in the inherent properties of the filter. (TR41)

A method that is considered validated as published in one of the recognized compendia. (TR57)

(a) As defined by 21 CFR Part 211.198- Complaint Files. (b) A written record of each complaint shall be maintained in a file designated for drug product complaints. The file regarding such drug product complaints shall be maintained at the establishment where the drug product involved was manufactured, processed, or packed, or such file may be maintained at another facility if the written records in such files are readily available for inspection at that other facility.
1.The written record shall include the following information, where known: the name and strength of the drug product, lot number, name of complainant, nature of complaint, and reply to complainant .
2.Where an investigation under 211.192 is conducted, the written record shall include the findings of the investigation and follow-up. The record or copy of the record of the investigation shall be maintained at the establishment where the investigation occurred in accordance with 211.180. (TR55)

Element of the assembled prefilled syringe (needle, plunger stopper and tip closure, or adhesive) directly in contact with the drug. (TR 73)

Element of the assembled prefilled syringe (plunger rod, backstop, or safety system) that interacts with the primary components and provides functionality to the delivery system. (TR 73)

A membrane consisting of multiple layers. (TR15)

A process in which a bulk drug substance is combined with one or more excipients and/or another bulk drug substance to produce a drug product. (TR22)

A process wherein bulk drug substance is combined with one or more excipients and/or another bulk drug substance to produce a drug product. (TR62)

The preparation, mixing, assembling, altering, packaging, and labeling of a drug, drug-delivery device, or device in accordance with a licensed practitioner’s prescription, medication order, or initiative based on the practitioner/patient/pharmacist/compounder relationship in the course of professional practice. Compounding includes the following:
• Preparation of drug dosage forms for both human and animal patients
• Preparation of drugs or devices in anticipation of prescription drug orders based on routine, regularly observed prescribing patterns
• Reconstitution or manipulation of commercial products that may require the addition of one or more ingredients
• Preparation of drugs or devices for the purposes of, or as an incident to, research (clinical or academic), teaching, or chemical analysis
• Preparation of drugs and devices for prescriber’s office use where permitted by federal and state law. (TR63)

The concentrated feed solution after the removal of filtered liquid through the membrane and into the filtrate. [Synonym: retentate, retentate solution] (TR15)

The ratio of the initial feed volume to the retentate volume. (TR15)

A phenomenon in which the concentration of retained solutes increases in the region adjacent to the membrane surface due to limitations in particle transport back into the bulk solution. (TR15)

This refers to items (e.g., SUS, storage bags, tubing, filters, diaphragms, flasks, etc.) that form or are a part of process equipment and are used on a per batch basis. (TR66)

Any adventitiously or externally introduced material(s) (e.g., chemical, biochemical, or microbial species) not intended to be part of the process. (TR14) (TR15) (TR70)

An undesired impurity of a chemical or microbiological nature that is introduced into a raw material, intermediate, or API (drug substance) during manufacture. (TR14) (TR15)

Any adventitiously introduced materials (e.g., chemical, biochemical, or microbial species) not intended to be part of the manufacturing process of the drug substance or drug product. (TR69) (TR74)

Any adventitiously introduced material (e.g., chemi­cal, biochemical) or microorganisms including viruses not intended to be included in the manufacturing process of the drug substance or drug product. (TR83)

The percentage of units filled in a process simulation that are positive for microbial growth after incubation. (TR22)

Following comprehensive assessments of scientific evidence and risk, quality attributes are ranked according to the degree of criticality. The continuum, as opposed to binary classifications of Critical and Non-Critical, is thought to “more accurately reflect complexity of structure-function relationships and the reality that there is some uncertainty around attribute classification”. (TR60)

A non-discrete scale where parameters or attributes are evaluated relative to their impact on drug substance and drug product quality. (TR60)

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)

A planned set of controls, derived from current product and process understanding, which ensures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control. (TR 54) (TR 60) (TR 54-5) (TR56)

Actions taken to eliminate the cause of an existing (corrective) or potential (preventative) non-conformity to prevent its recurrence. (TR52)

Action to eliminate the cause of a detected non-conformity or other undesirable situation. (TR54)

A response taken to remediate the effect of an excursion or product failure. (TR13)

Action taken to eliminate the causes of an existing deviation or other undesirable situation to prevent recurrence. (TR88)

Action to eliminate the cause of a detected nonconformity or other undesirable situation. NOTE: Corrective action is taken to prevent recurrence, whereas preventive action is taken to prevent occurrence. (TR 52) (TR 54-2) (TR 54-3) (TR 54-5)

A subsystem used to collect and analyze information, identify and investigate product and quality problems, and take appropriate and effective measures to prevent recurrence of the identified problem (8). (TR88)

A measure of covariation, the square root of the coefficient of determination. (TR57)

A small, generally flat portion of a defined material of construction (such as stainless steel or PTFE) and of a defined surface finish, typically used for laboratory cleaning evaluations and/or for laboratory sampling recovery studies. (TR29) (TR49)

Sending and receiving laboratories participate in the AMV study execution. (TR57)

Describes a process step, process condition, test requirement, or other relevant parameter or item that must be controlled within predetermined criteria to ensure that the drug substance meets its specification. (TR38)

An area designed to maintain sterility of sterile materials. Sterilized product, containers, closures, and equipment may be exposed in critical areas. (TR13) (TR22) (TR44) (TR62)

A step at which control can be applied and that is essential to prevent or eliminate a pharmaceutical quality hazard or reduce it to an acceptable level. (TR54-4) (TR61)

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.

A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality. (TR54) (TR54-4) (TR56) (TR54-5) (TR60-2) (TR5 6) (TR 81)

An input process parameter that should be controlled within a meaningful operating range to ensure that drug substance critical quality attributes meet their specifications. Although parameters with wide operating ranges may also impact product quality, they are generally easily controlled and not as likely to result in excursions that impact quality and are therefore low risk of occurrence. (TR60-3)

A physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. (TR14)(TR54)(TR54-4)(TR57)(TR57-2)(TR60)(TR01)

Product attributes that affect product safety, identity, strength, quality and purity.(TR15)

Attributes that describe a parameter or item that must be controlled within predetermined criteria to ensure that the medicinal product meets its specifications .(TR39)

A defining characteristic of the product, including purity, strength, identity and safety.(TR44)

A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.(TR74)(TR 54-5)(TR81)

A physical, chemical, biological or microbio­logical property or characteristic that should be within an appropriate limit, range, or distribu­tion to ensure the desired product quality, as de­fined in ICH Quality Guidance Q8. (TR56)

A physical, chemical, biological, or microbio­logical property or characteristic that should be within an appropriate limit, range, or distribu­tion to ensure the desired product quality. (TR60-2)

A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. (TR84)

A component of the test method that may have a substantial impact on the consistency and reliability of method performance. Features of critical reagents include: 1. A reagent that requires qualification of each new batch prior to routine use in an analytical procedure, or 2. A material whose method performance characteristics may change over time, during handling, or from lot to lot. 3. An analytical reagent that may be purchased only from a single vendor. Reagent Examples: antibodies or enzymes that require titration prior to use, tissue culture treated plates when only one vendor’s plates give acceptable results for a bioassay, growth factors for bioassay cells, conjugated proteins that require custom preparations, or reference or system suitability standards. (TR57)

Function related: assay reagents that have been shown through development and/or robustness studies to have the potential to generate measurable differences that can significantly affect assay performance, such as sensitivity, specificity, and precision. (TR57-2)

A classification of an item (e.g., process, equipment, parameter) that expresses the significance given to the impact of that item, and should therefore be controlled or monitored to ensure product quality, safety or efficacy. (TR54)

A classification of an item (e.g., product, process, equipment, parameter) that expresses the significance given to the impact of that item, and should therefore be controlled or monitored to ensure product quality, safety or efficacy. (TR68)

The International Genetic Standardization System designator for Sprague Dawley (SD) rats. The SD (Crj:CD) is a general multipurpose rat model, used for safety and efficacy testing, aging, nutrition, diet-induced obesity, oncology. (TR55)

See Tangential Flow Filtration. (TR15)

Volumetric rate of fluid flow parallel to the membrane surface. (TR15)

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

The nutritional medium which supports the growth of the given microorganism. (TR75)

Practices and systems that are required to be followed for pharmaceutical manufacturing to ensure that the products produced meet specific requirements for identity, strength, quality, and purity. (TR54)

Refers to the Current Good Manufacturing Practice regulations enforced by the FDA and as described in the ICH guidance (ICH Q7 and WHO GMP, for API manufacturing). Current GMP provides for systems that assure proper design, monitoring, and control of manufactur­ing processes and facilities. Adherence to cGMP regulations assures the identity, strength, quality, and purity of drug products by requiring that manufacturers of medications adequately control manufacturing operations. (TR56)

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)

For small molecules, the date of manufacture of a drug product is considered to be the initial date that an active ingredient has been added during manufacturing. For biologics the date of manufacture can be determined in multiple ways and should be consistent with internal quality systems and the product license application. (TR53)

Person(s) with the competence and authority to make appropriate and timely quality risk management decisions.(TR54) (TR54-2)

A planned and orderly removal of a facility, operation or system from use. (TR48)

The process of retiring equipment/systems/facili­ties from production use. (TR54-5)

A process that is designed to remove soil (including microorganisms) and may consist of cleaning and/or disinfection. (TR51)

Equipment used exclusively for the manufacture of only one drug product, bulk drug substance, or intermediate. (TR29)

(1) A departure of a quality characteristic from its intended level or state that occurs with a severity sufficient to cause an associated product or service not to satisfy its intended normal or foreseeable usage requirements. (TR51)

(2) The nonfulfillment of intended usage requirements. The departure or absence of one or more quality characteristics from intended usage requirements. (TR43)

The nonfulfillment of intended usage requirements. The departure or absence of one or more quality characteristics from intended usage requirements. (TR76)

The breakdown (usually chemical) of material during manufacture, including during and after the cleaning process. (TR49) (TR70)

Molecular variants resulting from changes in the desired product or product-related substance brought about over time and/or by the action of light, temperature, pH, water, etc., or by reaction with an excipient and/or the immediate container/ closure system. Such changes may occur because of manufacture and/or storage (e.g., deamidation, oxidation, aggregation, proteolysis). Degradation products may be either product-related substance or product-related impurities. (TR57)

Water treated by passing through both cation- and anion-exchange resin beds, or a mixed-resin bed to remove both positive and negative ions. (TR45)

Activities involving the hands-on steps required to successfully assemble and make a system ready for use for a specific SUS application. (TR66)

The destruction and/or removal of bacterial endotoxins. A depyrogenation process should demonstrate at least 99.9% or a 3-log endotoxin reduction. (TR3)

Removal or destruction of pyrogens. (TR70)

A method for carrying out carefully planned experiments on a process. Usually, DoE involves a series of experiments that initially involves evaluating many variables and then focuses on a few critical ones. (TR54-4)

A structured, organized method for determining the relationship between factors affecting an assay and output of that assay. (TR57) (TR57-2) (TR74)

A structured, organized method for determining the relationship between factors affecting a process and the output of that process (8). (TR60)

A synthetic wetting agent and emulsifier that can be added to a solvent to improve its cleaning efficiency. (TR70)

Documentation and description of work done during the early phases of development. The goal is to document information about the way the process works and to document why key choices were made in selecting the specifics of the process (e.g., flow rate or temperature). These documents can serve as a reference during investigations of discrepancies and during the design of specific Validation and characterization studies.(TR14) (TR 42)

Documentation and description of work done during the early phases of development (Stage 1). The goal is to document information about the way the process works and to document why key choices were made in selecting the specifics of the process (e.g., flow rate or temperature). These documents can serve as a reference during investigations of deviations and during the design of specific validation and process characterization studies.(TR60)

Departure or digression from set parameters. (TR58)

Data or a result outside of the expected range or an unfulfilled requirement; it may be called nonconformity, defect, discrepancy, out-of-specification, out-of-limit, or adverse trend. (TR88)

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

The convective elimination of permeable solutes by the addition of fresh solvent to the retentate. (TR15)

A volume equal to the retentate volume to which a diafiltration buffer is added. (TR15)

The difference in pressure between the upstream (feed or influent) and downstream (effluent) sides of the filter. (May be modified with the terms: applied, available differential pressure, clean differential pressure, dirty differential pressure, initial differential pressure, or maximum differential pressure). [Synonym: Delta P (Δ P), PSID, Pressure Drop] (TR45) (TR26)

A test to determine the integrity of a filter. The test is based on the measurement of the diffusive (diffusional) flow of a gas through a wetted filter, along with any bulk flow of gas through open (unwetted) pores. Either the gas flow or the downstream liquid, displaced by the gas flow, may be measured. [Synonym: Forward Flow Test] (TR45)

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)

A test to determine the integrity of a filter. [Synonym: diffusive flow test, forward flow test.] (TR26)

The product conforms to the required drawing dimensions. (TR43)(TR76)

In direct flow filtration, all fluid is directed through the membrane in a single pass. (TR41)

Particles with diameters larger than the filter pore diameter that are prevented from passing through the filter. (TR26)

See Development Reports , Process Characterization Report , Process Validation Protocol, or Process Validation Report (TR14) (TR42)

The effluent side of the process step (filter). (TR45)

The filtrate or outlet side of the filter. (TR26)

A general term used to define the entire process of bringing a new drug to the Market. It includes drug discovery, process and product development, pre-clinical research (microorganisms/cell culture/animals) and Clinical trials (on humans). (TR56)

A pharmaceutical product type that contains a drug substance, generally, in association with excipients. [Synonym: Dosage Form; Finished Product] (TR57)(TR14)(TR42)

A finished dosage form (e.g., tablet, capsule, or solution) that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients.(TR38) (TR67) (TR88)

The dosage form in the final immediate packaging intended for marketing.(TR60)(TR82)

The active ingredient that is subsequently formulated with excipients to produce the drug product. It can be composed of the desired product, product-related substances, and product- and process-related impurities. It may also contain excipients, including buffers and other components. [Synonyms: bulk drug substance, bulk material, active pharmaceutical ingredient (API)] (TR14) (TR57) (TR74) (TR60)

Active pharmaceutical ingredient in a drug product that is responsible for that product’s therapeutic activity.(TR67) (TR82) (TR88)

See Active Pharmaceutical Ingredient (API). (TR56)

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)

Generally used to indicate the following clinical study activities: Microdosing Studies, Phase 1 Trials, Phase 2 Trials, and Phase 3 Trials. See any of the following studies for more information. (TR56)

Studies designed to speed up the development of promising drugs by establishing very early on whether the drug or agent behaves in human subjects as was expected from preclinical studies. May include the administration of single sub therapeutic doses of the study drug to a small number of subjects (10 to 15) to gather preliminary data on the agent’s pharmacokinetics (how the body processes the drug) and pharmacodynamics (how the drug works in the body). A microdosing study gives no data on safety or efficacy, being by definition a dose too low to cause any therapeutic effect. (TR56)

Phase 1 trials are the first stage of testing in human subjects. Often, a small (20-100) group of healthy volunteers will be selected. For life-threatening indications such as oncology, these can be patients that have the target disease but may not yet be the ideal target population. This Phase includes trials designed to assess the safety (pharmacovigilance), tolerability, pharmacokinetics, and pharmacodynamics of a drug. These trials are often conducted in an inpatient clinic, where the subject can be observed by full-time staff. (TR56)

Once the initial safety of the study drug has been confirmed in Phase 1 trials, Phase 2 trials are performed on larger groups (20-300) are designed to assess efficacy, as well as to continue safety assessments in a large group of volunteers and patients. Phase 2a is specifically designed to assess dosing requirements (how much drug should be given). Phase 2b trials are specifically designed to study efficacy (how well the drug works at the prescribed dose(s). (TR56)

Final clinical stage Phase 3 trials are designed to demonstrate the potential advantages of the new therapy over other therapies already on the market; safety and efficacy of the new therapy are studies over a long period of time and many more patients (1,000-3,000) are enrolled into the study with less restrictive eligibility criteria; phase 3 studies are intended to help scientists identify rarer side effects of treatment and prepare for a broader application of the product; phase 3 trials enroll patients to verify efficacy and monitor adverse reactions during longer-term use. (TR56)

The fraudulent, intentional substitution or addition of a substance in a product for the purpose of increasing the apparent value of the product or reducing the cost of its production (i.e., for economic gain). (TR54-3)

A device that produces vacuum by means of the Venturi effect. [Synonym: Aspirator, ejector pump] (TR48)

The liquid flowing out of a column. (TR14)

Fluid that flows out of a process step. (TR26)

Thermoplastic material formulation (that may or may not contain rubber/natural latex) derived from elastic polymer; often used interchangeably with the term “rubber.” (TR73)

A record used for GMP purposes or for regulatory submission that is stored electronically for the purposes of reproduction, retrieval or archival. (TR48)

Solution (effluent) that flows out of the chromatographic column containing the drug substance. [Synonym: collected product fractions] (TR14)

Desorption of a drug substance from a chromatographic column. (TR14)

A tool or process which provides the means to achieve an objective (ICH Q10). (TR54)

Cells cultured (under conditions comparable to those used in production) from the MCB or WCB to a passage level or population doubling level comparable to or beyond the highest level reached in production. Note: The ICH term is: “Cells at Limit of invitro Cell Age Used for Production”.
Note: The term as defined in ICH Guidance Q5 D is “Cells at Limit of in vitro Cell Age Used for Production”; also abbreviated as EPC. (TR56)

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 type of spore formed intracellularly by some bacterial genera. (TR51)

Lipopolysaccharides from the cell walls of bacteria, the most potent of which derive from Gram-negative organisms. When injected, they are known to cause a febrile, or fever-producing reaction that can cause severe patient reactions, and on occasion, can be fatal. (TR26) (TR44)

Pyrogenic lipopolysaccharide component of Gram-negative bacterial cell walls. (TR69)

An article challenged with a vial of endotoxin (or a carrier spiked with endotoxin) designed for use in depyrogenation studies. The endotoxin (a purified lipopolysaccaride) is validated for use in or on an endotoxin indicator. The carrier is made from a material appropriate for the intended depyrogenation processes to which it will be subjected. The endotoxin on a carrier is added at a concentration sufficient to allow recovery of a minimum of 1000 USP endotoxin units/carrier. The endotoxin indicator would allow for accurate indication of at least a 3-log reduction in USP endotoxin units during depyrogenation process challenges. (TR3)

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)

Microorganisms associated with a processing environment. (TR22)

Describes the processes and activities that need to take place to characterize and monitor the quality of the environment. (TR70)

Monitoring for nonviable particulates and/or microorganisms where the result meets or exceeds the alert and/or action level or limit. (TR88)

Defined documented program which describes the routine particulate and microbiological monitoring of processing and manufacturing areas, and includes a corrective action plan when action levels are exceeded. It includes assessment of environmental air, surfaces and personnel. (TR22) (TR28) (TR62)

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

Column washing with a solution or buffer(s) in preparation for the column load. (TR14)

The period that elapses between the attainment of the minimum exposure temperature at the reference measurement point (typically the drain) and the attainment of the sterilization temperature at all points within the load. This period is an indication of the ability to properly remove air and heat the load items; consequently, it is typically only evaluated by placing heat penetration probes in porous/hard goods loads. (TR01) (TR48)

The moisture content of wood below the fiber saturation point is a function of both the relative humidity and the temperature of surrounding air. The equilibrium moisture content (EMC) is the moisture content at which the wood is neither gaining nor losing moisture; this however, is a dynamic equilibrium and changes with relative humidity and temperature. (TR55)

Automated or non-automated, mechanical or non-mechanical equipment used to produce the drug product, including equipment used to package the drug product. (TR38)

The sequence of equipment through which a product is produced or processed. (TR29) (TR49)

See Comparability. (TR38)

A comparison with the primary objective of showing that the results from two methods differ by an amount which has negligible impact on fitness for use. This is usually demonstrated by showing that the true difference is likely to lie between a lower and an upper equivalence margin of acceptance differences. (TR57)

The largest difference between the results from two methods that is considered as being scientifically and statistically acceptable. (TR57)

Test of conformance to interval-based target acceptance criteria; differs from most common statistical tests in the nature of the statistical hypothesis. In equivalence testing, the alternative hypothesis is that the difference is sufficiently small that no important difference exists. A common statistical procedure used for equivalence testing is the two one-sided T-test. (TR57-2)

A measure of how similar the test results are when compared with the existing method. (TR33)

Deviation from expected value. Error may be random or systematic. (TR57)

A systematic technique that employs forward logic to construct a graphical representation of consequences from an initiating event. (TR54)

A component of a drug formulation that has no active pharmacologic function. Excipients are commonly used in drug formulations as modulators of pH or osmolality for parenteral administration and as stabilizers for APIs. (TR54-4)

An ingredient added intentionally to the drug substance that should not have pharmacological properties in the quantity used. (TR57)

Inactive pharmaceutical ingredients in a product formulation that are responsible for the product’s manufacturability and physicochemical attributes. (TR67) (TR88)

The capacity of an assay not to detect microorganisms closely related to a target microorganism. (TR33)

A temperature or humidity deviation from conditions such as those specified by product labeling or shipping specifications. (TR53)

Measurement that exceeds an alert, concern, or action level/limit by either a discreet value or an increasing/decreasing trend. (TR69)

Lipopolysaccharides from the cell walls of bacteria, the most potent of which derive from Gram-negative organisms. When injected, they are known to cause a febrile, or fever-producing reaction that can cause severe patient reactions, and on occasion, can be fatal. (TR26) (TR44)

Pyrogenic lipopolysaccharide component of Gram-negative bacterial cell walls.(TR69)

The major constituent of the outer membrane of Gram-negative bacteria is composed of lipid A, the core polysaccharide, and the O-antigen polysaccharide; endotoxin is also known as lipopolysaccharide (LPS).(TR82)

Refers to a legislative requirement that packaging manufacturers “take back” their packaging, or otherwise ensure (through a tax) that it is collected and properly disposed of. (TR46)

Product of microbial growth, particularly in biofilms, composed of polysaccharides, lipids, proteins, and nucleic acids; produced by bacteria and fungi; is an important mediator of microbial attachment to surfaces and biofilm formation. (TR69)

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)

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)

Those particles that are not part of the formulation, package, or assembly process but rather are foreign and unexpected. Materials such as rubber, metal, and plastic are defined as extrinsic in cases where the specific material identified is not a product-contact material. (TR78)

Foreign material that comes from outside the primary process.  Often these are from the manufacturing environment or incomplete cleaning of components. They are uncontrolled. (TR85)

Filled syringe delivery force (that does not include break-loose force) quantified as the highest non-break-loose force to complete the injection stroke. (TR73)

Independent QRM expert who facilitates risk assessment; guides documentation, risk control, and risk review; and helps present risk assessment results and risk control proposals. (TR54-2) (TR54-5)

A physical building with a defined building number or name. (TR38)

Independent variables that may influence assay outcome. (May be modified with confounded, crossed, fixed, interaction, level, modifying, nested, random). (TR57) (TR57-2)

A test typically conducted by the sterilizer manufacturer after the system has been assembled and before the system is shipped to the installation site. (TR48) (TR54-5)

The condition or fact of not achieving expected results; a cessation of proper functioning or performance. (TR44)

An impact on customer requirements. Generally, failure effect has an external customer focus, but it can also include downstream processes. (TR58)

A method of assessing and evaluating risk. (TR44)

A systematic method for identifying, analyzing, prioritizing and documenting potential failure modes, their effects on system, product and process performance, and the possible causes of failure in order to prevent defects from occurring. (TR54) (TR54-2) (TR54-3) (TR54-4) (TR74) (TR54-5)

A tool for analyzing processes or systems to evaluate all operating steps in order to identify and assess the risk associated with any potential failures. (TR65)

An analytical technique that results in a rankordered list of concerns to take action on. (TR72)

A test result that is erroneously classified in a negative category (e.g., the absence of a viable microbial detection result when viable microorganisms are present). (TR33)

A test result that is erroneously classified in a positive category (e.g., a viable microbial detection result when viable microorganisms are not present). (TR33)

A population of microorganisms having complex nutritional requirements and thus difficult to cultivate. (TR50)

A deductive technique used to analyze the causes of faults (defects). The technique visually models how logical relationships between failures, human errors, and external events can combine to cause specific faults. (TR54) (TR54-2) (TR54-3) (TR54-5)

Inspectional observation sheet used by FDA investigators to document their findings. (TR67)

A modification of the batch filtration process in which a separate (typically larger) reservoir feeds a smaller recycle tank. The retentate stream is returned to the recycle tank. (TR15)

The starting solution prior to filtration. (TR15)

The fluid introduced into a process. (TR41)

The pressure measured at the inlet of the tangential flow filter device. (TR15)

The fluid and all constituents in a fermentation vessel prior to separation. (TR45)

A porous medium used for the separation of components in a fluid stream.(TR15)

The effective surface area of a filter that is available for filtration; not the internal pore surface area, but rather the surface of one side of a filter. (TR45)

A numerical rating of filter performance based on the ability of the filter to retain an appropriate model microorganism under given test conditions. (TR75)

Fluid that has been passed through a process step (filter). [Synonym: Permeate] (TR15) (TR26)

The pressure measured at the outlet side of the tangential flow filter device containing filtered material. [Synonym: permeate pressure] (TR15)

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)

This term refers to items such as drug substances, drug products, finished product held in bulk before final packaging, and clinical trial materials that are likely to be stored for significant periods of time and are also subject to the risks of distribution. (TR53)

Refers to the air exiting at the face of HEPA filters. Based on the airflow through HEPA filters and its unidirectional air flow the air exiting at the filter face is for the purposed of aseptic processing free of particulate contamination (both viable and non-viable). (TR70)

The work location first in the path of HEPA filtered air. (TR62)

A method of controlling inventory to ensure that the material with the shortest remaining shelf-life is distributed first. (TR52)

A flexible-wall container designed with 2 sides (two dimensional or “pillow” shape) or 6 sides (three dimensional cuboid shape) designed to hold process fluids or product. (TR66)

Decrease in flow rate at constant pressure as a result of filter fouling. (TR45)

An experiment to determine flow rate and throughput of a filter type or combination of filters on a specific liquid, usually by using a small area filter, to determine the sizing of a filter system by extrapolation. (TR45)

The volumetric rate of flow of a solution, expressed in units of volume per time (e.g., L/min or gal/day). (TR15) (TR26)

Effluent that may contain the product that is not retained by chromatography resin during column loading. (TR14)

The rate of transfer of fluid through a cross-sectional area often applied to filtrate flow rate; expressed in units of volume per time per unit area (e.g., LMH: liters per square meter per hour). (TR15)

The rate of filtrate flow divided by the membrane area. (TR26)

Instantaneous or current flux relative to initial or buffer flux. (TR41)

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)

A structured, organized method for determining the relationship between factors affecting a process and the output of that process. (TR60)

Observed actual or simulated use of early prototypes to help reliably identify product conceptspecific, use-related hazards that may have been missed by other methods. (TR73)

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)

No visible water pool in the equipment or line when viewed under appropriate lighting conditions (but may contain water droplets). (TR29)

A study designed to determine the effect of repeated freezing (typically to -20 °C), and thawing back to labeled storage conditions (typically +5 °C for refrigerated products, and +25 °C for temperature products). Freeze-thaw studies are designed to evaluate the impact of short-term excursions where product may be exposed to sub-zero temperatures, followed by standard shipping conditions. (TR53)

The pressure measured by a pressure gauge. Typically expressed in units of psig, bar or kilopascal. (TR45)

Gauge pressure is the difference between a given fluid pressure and that of the atmosphere. (TR26)

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)

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)

Defined as that part of quality assurance that ensures that the quality of the pharmaceutical product is maintained by means of adequate control of numerous activities which occur during the distribution process. (TR55)

(commonly abbreviated GDP, or as GDocP to distinguish from “Good Distribution Practice”) Describes standards by which documents are cre­ated and maintained. (TR56)

Documented proven and accepted engineering methods and practices that applied throughout the project life-cycle to deliver solutions that are cost effective, are compliant with regulations and meet the requirements of the user. (TR48)

Those established engineering methods and standards that are applied throughout the lifecycle to deliver appropriate and cost-effective solutions. (TR60) (TR54-5)

An organism that retains the Gram stain. (TR51)

Test performed to demonstrate that media will support microbial growth. (TR22) (TR28)

Damage to health, including damage occurring from loss of product quality or availability. (TR44) (TR54) (TR54-2) (TR54-4) (TR68)

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

The potential source of harm. (TR44) (TR54) (TR54-2) (TR58) (TR61)

A systematic, proactive, and preventative tool for assuring product quality, reliability, and safety (TR54-3) (TR54)

A management system in which potential hazards are addressed through the identification and control of key risk factors (critical control points) of the biological, chemical, and physical hazards from raw material production, procurement and handling, to manufacturing, distribution and consumption of the finished product. (TR55)

A structured, systematic and qualitative technique for examination of a planned or existing process or operation in order to identify and evaluate problems that may represent risks to personnel or equipment, or prevent efficient operation. (TR54)

Circumstances in which people, property, or the environment is exposed to a hazard. (TR54-2)

A tool for classifying a voluntary recall by a firm. The HHE guides the US FDA in determining the risk to the public from the defective product and appropriate actions for the firm and the FDA to take to protect public health. (TR55)

Refers to technology of indoor and automated environmental control. (TR70)

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)

A linear polymer, HDPE is prepared from ethylene by a catalytic process. The absence of branching results in a more closely packed structure with a higher density and somewhat higher chemical resistance than low-density polyethylene (LDPE). (TR55)

A type of air filter that must satisfy certain standards of efficiency such as those set by the United States Department of Energy (DOE). The air filter must remove 99.97% of all particles greater than 0.3 micrometer from the air that passes through it. (TR62) (TR70)

For purposes of this guidance, data on impurities or physical attributes from three or more consecutive, representative pre-modification batches. (TR38)

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)

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

Use of an analytical procedure to determine the chemical and biochemical identity of a material. (TR57)

A technique used to determine or confirm the identity of an organism (virus, bacteria, cells). (TR47)

Any component present in the drug substance or drug product that is not the desired product, a product-related substance, or excipient including buffer components. It may be either processor product-related. (TR14) (TR57) (TR74)

Any component present in the drug substance or drug product which is not the desired product, a product-related substance, or excipient. It may be either process- or product-related (17). (TR60)

A description of the identified and unidentified impurities present in a drug substance (ICH A3A). (TR38)

Any event that occurs during the shelf life of a product that may have an adverse effect on quality (e.g., temperature excursion, missing temperature monitor when required, shipment time in excess of qualified packout duration, wet/ crushed packaging). (TR58)

Part of the Quality Management System that handles incidents, deviations, excursions, and exceptions in the supply chain. (TR58)

The ability of an assay to detect a target microorganism. (TR33)

A preventative program where parts or products are subjected to evaluation upon receipt.(TR43)

A program where, upon receipt, parts or products are subjected to measuring, examining, testing, or gauging one or more characteristics of a product or service, and comparing the results with specified requirements in order to establish whether conformity is achieved for each characteristic.(TR 76)

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

Term defines when a chemical is administered through the peritoneal cavity (area that contains the abdominal organs). (TR55)

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)

A pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial. (TR29)

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 chemical component that migrates from a contact surface into a drug product or process fluid during storage or normal use conditions. The term leachable is often erroneously used to describe an extractable. (TR14) (TR26)

Leachables are organic and inorganic chemical entities that migrate from a packaging/delivery system, packaging component, or packaging material of construction into an associated drug product under normal conditions of storage and use or during accelerated drug product stability studies. Leachables are typically a subset of extractables or are derived from extractables. (TR54-4)

Chemical substances that are leached, from product-contact or non-product-contact materials, under typical process conditions and detected in final dosage. Leachables may be a subset of extractables, and can include their reaction or breakdown products. (TR66)

Organic or inorganic chemical entity that migrates from pharmaceutical container closure system components into a drug product formulation. (TR73)

A functional molecule (small molecule or protein) coupled to the chromatography resin that selectively interacts with the target protein, impurities, or other molecules from the process stream. (TR14)

Endotoxin detection and quantitation can be accomplished at high sensitivity and specificity using reagents manufactured from Limulus Amebocyte Lysate, a biological reagent prepared from horseshoe crabs and offered in a variety of formulations. (TR45)

A biologically based assay for the detection and quantitation of bacterial endotoxin. (TR69)

A component of the cell wall of Gram-negative bacteria.(TR3)

Component of the outer cell wall of Gram-negative bacteria that is pyrogenic. (TR69)(TR82)

The amount of target molecules per volume of resin (e.g., gram protein per milliliter resin). (TR14)

Freeze-dried product typically in the form of a solid plug or cake in the container. (TR79)

A purification method based on sequence-specific hybridization of labeled nucleic acid probes with targeted regions of test article nucleic acids, followed by magnetic bead capture. (TR50)

Specialized filling needles on certain BFS machines which also act to form the container. (TR77)

A type of interference that may result in low endotoxin recovery.(TR82)

The MCB represents a collection of cells of uniform composition derived from a single source prepared under defined culture conditions. (TR 54-4)

The MCB represents a collection of cells of uni­form composition derived from a single source pre­pared under defined culture conditions, aliquoted into multiple vials, cryopreserved and stored in the vapor phase of liquid nitrogen. (TR 83)

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)

Reference culture of a microorganism derived from an authenticated source such as American Type Culture Collection (ATCC) and used to produce working seed lots. (TR51)

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)

Those values where activity is confirmed by interpolation from a reference standard curve.(TR82)

A substance that is either the result of metabolism or a requirement for a metabolic process. (TR70)

The demonstration of analytical method comparability (AMC) for method replacements. A study to demonstrate that a modification to an existing method either improves or does not significantly change the analytical procedure’s characteristics relative to the methods’ validation and intended use. (TR57)

A test performed to quantify the number of microorganisms present in a sample of material. Standard microbial methods are utilized to estimate the number of colony forming units (CFU) per unit mass or volume. (TR28)

Compendial test for microbial counts using the plate-count, membrane-filtration or most probable number methods described in USP <61> Microbiological Examination of Nonsterile Products: Microbial Enumerations Tests. (TR67)

The compendial tests for microbial enumeration and absence of specified microorganisms as found in USP <61> Microbiological Examination of Nonsterile Products: Microbial Enumerations Tests and USP <62> Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms. (TR67)

Biochemical characterization of isolated colonies to determine the isolate genus and, where feasible and appropriate, the species. (TR22)

Pressure-driven, membrane-based separation process in which particles and dissolved macromolecules (typically 0.1 &;mum or larger) are retained. (TR15)

A microbe; a free-living organism too small to be seen by the naked eye. (TR45) (TR26)

A bacterium, yeast, or mold that, due to it prominence in product recalls, infection outbreaks, nosocomial infections, and the clinical literature, results in a multifactor risk assessment to determine whether the microorganism is objectionable if it is present in a specific nonsterile product. (TR67)

A class of bacteria which lack a cell wall. Mollicutes are small, typically about 0.1-0.5 &;mum in size, and vary in form (trivial name: mycoplasma) (TR50)

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)

An engineered process equipment solution for process management and unit operations designed for repeated use. (TR66)

Small, flexible bacteria that lack a cell wall. Mycoplasma can pass through 0.2 μm and some 0.1 μm rated filters and are unaffected by some antibiotics, such as penicillin. (TR70) (TR47)

A sterilizing grade filter that also provides a log reduction value (or a titer reduction value) for a specified test mycoplasma according to the PDA Mycoplasma Consensus Method. (TR75)

Endotoxin prepared from Gram-negative bacteria produced under defined conditions and with minimal nonchemical processing, e.g., centrifugation and filtration.(TR82)

A test article used to assess the performance of an assay in the known absence of a targeted microorganism or nucleic acid. Negative controls are used to minimize a risk of false positive results, which could occur due to non-specific signals. (TR50)

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)

The assumed activity of an endotoxin preparation, dilution, or "spike"; based on label-claim information.(TR82)

Procurement of a product such as liquid or powder format culture media or buffer and that has been supplied in single-use technology. (TR66)

The “tube” of polymer extruded by the BFS machine from which the containers are formed. (TR77)

Suspended in the bulk phase of a fluid as opposed to being attached to surfaces. (TR69)

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 report that includes results from a study characterizing the performance of a unit operation and/or operations conducted in a process characterization study. The report describes process characteristics, the operational parameters (e.g., critical, key, and non-key) and their acceptable ranges (limits), and acceptance criteria for Validation

protocols. (TR14) (TR42)

A report that includes results from a process characterization study with information on the performance of one or several unit operation(s). The report describes process characteristics, the parameters (e.g., critical or noncritical) and their studied ranges (limits) and may outline acceptance criteria for process performance qualification protocols.(TR60)

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)

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)

Technologies that allow users to obtain microbiology test results more quickly than traditional microbiological methods, which are usually culture/ growth based. (TR69)

Starting materials, reagents, and solvents used in the production of intermediates or APIs/drug substance. (TR54-4) (TR83)

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)

Operation performed to remove residual proteins, impurities, or contaminants from the resin. [Synonym: strip] (TR14)

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)

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)

To make physically clean and to remove and destroy, to the maximum degree that is practical, agents injurious to health. (TR70)

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)

Studies used to assess sizing for the appropriate performance of filter media at increased process volumes. (TR45)

The process of decreasing the column volume. (TR38)

A small-scale process step that has been demonstrated to be representative of a production-scale operation. (TR14)

The process of increasing the column volume (TR38)

Microorganisms that are attached to animate or inanimate surfaces, as opposed to planktonic organisms. (TR69)

Having a general likeness. (TR38)

The chemical or microbiological materials left on process equipment after completion of process manufacturing, but before initiation of the cleaning process. (TR29)

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)

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)

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)

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 solution typically selected to control bioburden during column storage. (TR14)

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)

Filtration in which a fluid (feed) stream runs tangential to a membrane. A pressure differential causes some fluid to pass through the membrane. (TR41)

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)

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)

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 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)

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)

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)

The WCB is derived from one or more vials of cells from the MCB, which are expanded by serial subculture. The pooled cells are dispensed into individual vials and cryopreserved to form the WCB. (TR54-4)

The WCB is derived from one or more vials of cells from the MCB, which are expanded by serial subculture. The pooled cells are dispensed into in­dividual vials and cryopreserved and stored in the vapor phase of liquid nitrogen. (TR83)

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)

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

A system fitted to a BFS machine to direct a flow of HEPA-filtered air over the Critical Processing Zone of the machine. (TR77)