Right First Time
The percentage of the time that a manufacturing process step, batch record, or in-process or laboratory test is successfully completed on the first attempt. (TR88)
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Out-of-Level Result (Out-of-Limit Result)
Any unexplained deviation or result that failed to meet set levels for environmental monitoring and other utilities. (TR88)
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Out-of-Specification Result
Any unexplained deviation or the failure of a pharmaceutical ingredient, drug substance, or drug product batch to meet any of its regulatory-release and shelf-life specifications. (TR88)
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Cross-Functional Team
An investigatory team, comprising representatives including QCU microbiologists, manufacturing, engineering, and maintenance personnel, and other appropriate SMEs, with the purpose of conducting a manufacturing investigation. (TR88)
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Error, Laboratory
A self-evident documented mistake that will bring the validity of a laboratory test into question. (TR88)
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Error, Manufacturing
A self-evident documented mistake that will bring the manufacturing process into question. (TR88)
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Invalid Test
Laboratory test that, as a result of the laboratory (Phase I) investigation, did not meet the test method requirements and whose results would not be deemed valid. This may also apply to a test which was aborted (e.g. breakdown of isolator during sterility testing). (TR88)
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Impact Analysis
Determination of how a product failure may extend an investigation “to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy” (10). (TR88)
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Contaminants (Contamination)
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 (16). The undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or onto a raw material, intermediate, or API [drug substance] during production [manufacture], sampling, packaging or repackaging, storage or transport (17).
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Rect A
The longest side length when a rectangle is constructed around the particle. (TR85)
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Critical Process (CP)
A process that impacts a critical quality attribute of the intermediate, drug substance or drug product being manufactured and therefore should have established critical process parameters that can be monitored or controlled to ensure that the process produces the desired quality.
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Pharmacodynamics
How the drug works in the body, the biochemical and physiological effects of drug and its mechanisms of their actions. (TR56)
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Pedigree
A statement of origin for a drug, active ingredient, or other critical starting material that identifies the original source of the material and each sale, purchase, or trade prior to receipt by the user, including the dates, names, and addresses of all parties involved in such transactions. Note: Also called a “batch tree.” (TR56)
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Phase 2 Clinical Trials
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) and are designed to assess efficacy, as well as to continue safety assessments in a larger 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)
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Phase 1 Clinical Trials
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)
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New Drug Application (NDA)
An application filed with the FDA used for the regulation and control of new drugs in the United States; the goal is to provide enough information to permit the FDA reviewer to reach the following key decisions: whether the drug is safe and effective in its proposed use(s), and whether the benefits of the drug outweigh the risks; whether the drugs proposed labeling (package insert) is appropriate, and what it should contain; whether the methods used in manufacturing the drug, and the controls used to maintain the drug’s quality are adequate to preserve the drug’s identity, strength, quality, and purity. (TR56)
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Microdosing Studies
Studies designed to speed up the development of promising drugs by establishing early on whether the drug or agent behaves in human subjects as was expected from preclinical studies. May include the administration of single subtherapeutic doses of the study drug to a small number of subjects (10 to 15) to gather preliminary data on the agent’s pharmacokinetics and pharmacodynamics. A Microdosing study gives no data on safety or efficacy, being by definition a dose too low to cause any therapeutic effect. (TR56)
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Early Phase
Generally used to indicate Phase 1 and A clinical studies.(TR 56)
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Chemistry Manufacturing and Controls (CMC)
The body of information that defines the technical development, manufacturing facility and support utilities; the process equipment and materials used in manufacturing; the manufacturing process itself; the personnel involved in manufacturing and quality; the chemistry of the product; QC in process and release testing, specifications, and stability of the product; all of the controls, documentation, and training necessary to ensure that all of these listed activities are properly and effectively carried out. (TR56)
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Biological Active Substance
Manufactured biological active substances and medicinal products involving biological processes and materials, such as cultivation of cells or extraction from living organisms. (TR56)
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Preliminary/Process Hazard Analysis (PHA)
A tool of analysis based on applying prior experience or knowledge of a hazard or failure to identify future hazards, hazardous situations and events that might cause harm, as well as to estimate their probability of occurrence for a given activity, facility, product or system. (TR54-5)
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Design Specification
Controlled documentation that clearly and explicitly defines the manufacturing system details, codes, and standards to be followed during fabrication and construction to meet associated requirements. (TR54-5)
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Design Reviews
Planned and systematic reviews of specifications, design, and design development and continuous improvement changes performed as appropriate throughout the lifecycle of the manufacturing system. Design reviews evaluate deliverables against standards and requirements, identify problems, and propose required corrective actions. (TR54-5)
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Critical Aspect Design Elements (CADE)
Critical aspect design elements are components, instruments, and process controls that comprise the critical aspect (e.g., temperature feedback loop). Critical aspect design elements are tested in commissioning and qualification. (TR54-5)
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Critical Aspects (CAs) of Manufacturing Systems
Critical aspects are constituent parts of a system or piece of equipment that provide the ability to control one or more critical process parameter of the associated process (e.g., temperature controller of a bioreactor). (TR54-5)
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Manual Inspection
Consists of manual handling and presentation of filled containers under controlled conditions of lighting and background to allow for human visual inspection. (TR79)
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Visible Particle Range
Particulate matter sized above the visible particle 70% probability of detection threshold are considered in the visible range, typically >100-150 μm. (TR79)
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Test Sets
A group of defect standards combined with good or blank units used to evaluate the probability of detection in visual inspection or testing system performance. Test sets can be used for inspector training, validation of automated systems, or other special studies as needed. (TR79)
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Tyndall Lighting
Collimated lighting at right angle to the viewing direction, typically against a black or dark background, which is useful during manual visual inspection to detect fine dispersions of small particulate that scatter the light making them more detectable. (TR79)
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Supplemental Testing or Inspection
Destructive reconstitution, dilution, transfer, clearing, solubilizing, filtration, screening, or sieving that allows a product to be visually examined or evaluated microscopically to determine the presence, type, and size of foreign particulate contamination present within the product, container, or device. (TR79)
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Probability of Detection
The likelihood of detecting a defective unit during an inspection process expressed as a probability, quantitatively as a number (0–1) or as a percentage (0–100%). (TR79)
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Manual Baseline
Data generated from visual inspection of a blinded set of seeded test containers that demonstrates the detection capability of human inspection. The test set is sometimes referred to as a “particle size threshold set,” where various foreign particulate types in a gradation of sizes are examined to yield a statistically significant probability of detection percentage for each unit. This allows the determination of what types and sizes of particulates can be reproducibly detected in a specific product/container system. (TR79)
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Automated Inspection
Consists of mechanical handling and presentation of product containers combined with automated inspection of the filled containers using image analysis and/or light obscuration. (TR79)
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Technically Unavoidable Particles (TUPs)
Particles that are visibly different from the bulk of the material when viewed with the naked eye within the container or against a suitable background (e.g., size, shape, color, number, texture) and are inherent to the manufacturer’s process, product, or raw materials. The unintended presence of a small quantity of particles, stemming from impurities of natural or synthetic ingredients, the manufacturing process, storage, or migration from packaging that is technically unavoidable in good manufacturing practice, and do not pose a risk to patient safety. (TR78)
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Intrinsic Particles
Those particles that arise from sources related to the formulation, packaging, or assembly processes. In each of these cases, the particle material (e.g., glass, stainless steel, rubber, or gasket material) could be identified as a known product-contact material. (TR78)
A particle that comes from within the primary process. These are qualified product contact materials and are often associated with the primary packaging components. They are unplanned but not unexpected.(TR85)
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Zone of Protection/Machine Shroud
A system fitted to a BFS machine to direct a flow of HEPA-filtered air over the Critical Processing Zone of the machine. (TR77)
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Mandrel
Specialized filling needles on certain BFS machines which also act to form the container. (TR77)
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Advanced Aseptic Process
A process in which direct intervention with open product containers or exposed product contact surfaces by operators wearing conventional cleanroom garments is not required and never permitted. (TR77)
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Nominal Value
The assumed activity of an endotoxin preparation, dilution, or "spike"; based on label-claim information.(TR82)
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Masking
A type of interference that may result in low endotoxin recovery.(TR82)
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Low Endotoxin Recovery (LER)
The inability to recover ≥50% activity over time when known amount of endotoxin is added to an undiluted product. LER cannot be overcome by dilution.(TR82)
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Reference Standard Endotoxin (RSE)
The primary standard from USP, EDQM, JP and WHO for use in the harmonized compendial bacterial endotoxins test (BET). The current 3rd International Standard (WHO), USP, and EDQM RS are lyophilized formulation that contains highly purified LPS that is chemically extracted and purified from E. coli strain O113:H10:K(-) and further formulated with stabilizers and excipients.(TR82)
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Activity
Ability of endotoxin (LPS) to initiate the LAL cascade in the compendial bacterial endotoxins test (BET) assay, or the ability to elicit a pyrogenic response in a compendial pyrogen test (2,10). Activity can be measured by other assays such as the monocyte activation test (MAT) or recombinant Factor C tests (rFc), if such tests have been validated, to demonstrate that decisions made from the results are comparable to or superior to the compendial assay. Activity is measured in endotoxin units (EU). In terms of activity, one EU = one IU, regardless of the source. Activity is generally expressed as a concentration, usually EU/mL.(TR82)
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Precision, Intermediate
The closeness of agreement between a series of measurements obtained within laboratory variations (e.g., different days, different analysts, different equipment). (TR57)
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Positive Unit
Unit filled in an aseptic processing simulation that exhibits detectable microbial growth after incubation. (TR22) (TR62)
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Precision
The degree of agreement among individual test results when the procedure is applied repeatedly to multiple samplings of the same suspension of microorganisms and using different suspensions across the range of the test. Also known as repeatability. (TR33)
The closeness of agreement (degree of scatter) between a series of measurements obtained from multiple sampling of the same homogeneous sample under the prescribed conditions. Precision may be considered at three levels: repeatability, intermediate precision, and reproducibility. It is usually expressed as the variance, standard deviation, or coefficient of variation of a series of measurements. (TR57)
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Probability of a Non-Sterile Unit (PNSU)
The number that expresses the probability of occurrence of a non-sterile unit after exposure to a sterilization process. Within the pharmaceutical industry, a design end point better than or equal to the probability of one non-sterile unit in a million units is expected, i.e., PNSU ≤ 10–6. [Synonym: Steriliy Assurance Level (SAL)] (TR01)
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Primary Contact Surfaces
All process surfaces that have a direct influence on the quality of the drug substance being manufactured, including surfaces processing equipment, storage containers, and of processing aids during manufacturing operations. (TR54-4)
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Primer
A short synthetic single-stranded nucleic acid complementary to a specific sequence of a target gene, DNA or RNA. It usually serves to initiate the de novo synthesis of nucleic acid from a template. (TR50)
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Precision, Reproducibility
The closeness of agreement between a series of measurements for the same sample obtained among different laboratories. (TR57)
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