This lexicon was generated by the editors of BioPharm International magazine. Please feel free to email your suggestions for terms that should be added, or definitions that you think could be refined to [email protected].
BIOTERMINOLOGY AND DEFINITIONS
The following acronyms that appear in brackets throughout the guide represent the sources of definitions:
FDAQSDG definition is the one that appears in the U.S. FDA’s Quality Systems Draft guidance.
ICH Q8 definition is the one that appears in the International Conference on Harmonization Q8 guideline, “Pharmaceutical Development.”
ICH Q9 definition is the one that appears in the International Conference on Harmonization Q9 guideline, “Quality Risk Management.”
ICH Q11 definition is the one that appears in the International Conference on Harmonization Q11 guideline, “Development and Manufacture of Drug Substances (chemical entities and biotechnological/biological entities)".
ISO 14971 Refers to the International Organization for Standardization’s standard 14971, “Medical Devices—Application of risk management to medical devices.”
ISO/IEC Guide 51 Refers to the the joint ISO and IEC (International Electrotechnical Commission) publication, “Safety aspects—Guidelines for their inclusion in standards.”
ISO Guide 73 Refers to ISO Guide 73, “Risk management—Vocabulary—Guidelines for their use in standards.”A
absorption Removal of a particular molecule from a sample by accumulation into a bound water volume such as might be present in a densely fibrous material. Compare to adsorption.
accelerated stability tests Studies in which the product is stored under stress conditions (for example, 45 °C and high humidity over three to six months) and observed for signs of degradation; used to predict long-term storage patterns.
acceptance criteria Numerical limits, ranges, or other suitable measures for acceptance of the results of analytical procedures which the drug substance or drug product or materials at other stages of their manufacture should meet. [From ICHQ6B]
acetylation Attachment of an acetyl group to the lysine residue of a protein, a common, reversible posttranslational modification. Acetylation of histone proteins is an important mechanism for regulating gene expression.
ACN Acetonitrile; the most frequently used solvent in HPLC, commonly used as an eluent.
acidic variant A product variant that exhibits a more negative charge character by IEX or CE than the primary biotherapeutic form.
active starting material The raw material that is identified as directly related to the active chemical comprising the product, and is defined at the first stage during chemical synthesis at which part or most of the critical moieties are present. Defining active starting material defines the step at which compliance with cGMP requirements begins during manufacturing. For biopharmaceuticals, this term is not used.
acute Describes a disorder as a one-time condition (an injury or infection), rather than as a chronic disease such as diabetes.
adjuvant A substance cointroduced with an antigen, usually in a vaccine, to boost the host’s immune response.
ADR Adverse drug reaction, an undesirable effect that may be caused by a study drug; also “adverse events.”
adsorption Adherence of molecules in solution or suspension to cells or other molecules—or to solid surfaces, such as chromatography media. Compare to absorption.
adventitious agents Acquired, accidental contaminants in a cell line, such as viruses and toxins; often infectious agents.
adverse events (see also ADR) Any untoward event temporally associated with exposure to a study drug or investigational device. Adverse events may be related or unrelated to the study drug/device. Adverse events must be notified to the sponsor, who is required to perform a written investigation into the root causes, and may need to take other corrective or preventive actions. (See complaints, CAPA)
adult stem cells Unspecialized cells obtained from adult tissue that can grow and divide and that can be induced to differentiate into a specialized tissue type.
aerobic Growing in the presence of oxygen. A strict aerobe grows only under such a condition.
affinity Attraction between particles or substances; relatively speaking, a measure of the attraction of one molecule toward another.
affinity chromatography A chromatographic method that makes use of the specific binding of one molecule to another; immunoaffinity chromatography uses antibodies, for example, and metal affinity chromatography uses chelation.
affinity tag (or tail) An amino acid sequence added to a protein to facilitate purification by affinity chromatography.
agarose A polysaccharide (sugar) obtained from seaweed and used as a solidifying agent (agar) in microbial culture; also used in gel electrophoresis.
aggregate A clustered mass, as of protein molecules; or to cluster together in such a way. Aggregates of cells (solid, fluffy, or pelletized) can clog the pores of filters or other fermentation apparatus.
Ala Alanine; one of more than 20 naturally occurring amino acids.
albumins Protein constituents of blood plasma and serum also found in muscle, egg white, and milk.
alkylation The introduction, by substitution or addition, of an alkyl group into an organic compound; alkylating agents are various substances that contain an alkyl radical and that can, therefore, replace a hydrogen atom in an organic compound; alkylation is used to prevent refolding of already reduced proteins during peptide mapping.
alpha helix (a-helix) A coil or spiral element of protein secondary structure.
amino acid analysis Hydrolysis of a protein or peptide into its individual residues (free amino acids), followed by chromatographic separation and UV-visible detection for analytical purposes.
amino acids A class of 20 naturally occurring hydrocarbon molecules that combine to form proteins in living things. (See table for a list of amino acids commonly found in human proteins and their abbreviations.)
amorphous Having no apparent shape or order; non-crystalline.
amphiphilic Referring to molecules, such as surfactants, that have a polar, water-soluble end and a non-polar, water-insoluble end.
ampholyte An electrolyte that can be either positively or negatively charged, depending on the pH of its medium.
amphoteric A substance that has both acid and base properties; amphoteric molecules can accept or donate protons to act as an acid or a base.
ampule A small, sterile glass vessel with an airtight seal that contains a single drug dose.
anabolism The metabolic process of creating complex molecules out of simple ones.
anaerobic Growing in the absence of air or oxygen. Some anaerobic organisms are killed by brief exposure to oxygen, whereas it may simply retard or stop the growth of others.
analytical methods Processes used to analyze or characterize a mixture, a compound, or an unknown material.
anion A negatively charged ion (having more electrons than protons).
annual review An evaluation, conducted at least annually, which assesses the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures. [From FDAQSDG]
anodes Positive electrodes; negative ions (anions) migrate carrying electric current toward positive anodes.
antibody An infection-fighting protein molecule that tags, neutralizes, and helps destroy foreign microorganisms or toxins. Also known as immunoglobulins, antibodies are produced by the immune system in response to antigens.
anticodon Three nucleotide bases of RNA on the transfer RNA strand that are complimentary to, and capable of binding with, the three nucleotide bases that make up a codon on the messenger RNA.
antifoam agent A chemical added to a fermentation broth to counteract the foaming (bubbles) that can be caused by mixing, sparging, or stirring.
antigen Any agent that reacts specifically with an antibody. Each antigen may contain more than one site capable of binding to a particular antibody. (See immunogen)
antigenicity The capacity of a substance to induce the formation of antibodies or to elicit an immune response when injected into an animal.
antisense oligonucleotides Antisense oligonucleotides interact with complementary strands of nucleic acids, modifying expression of genes.
aprotinin A polypeptide that inhibits (blocks the action of) serine proteases.
aptamer Single-stranded RNA or double-stranded DNA molecules made up of short lengths of nucleic acids that form three-dimensional structures and can bind to specific endogenous targets to produce its biological action.
aqueous solution A solvent solution made with water.
Arg Arginine; one of more than 20 naturally occurring amino acids.
artificial chromosome DNA synthesized in chromosomal form for use as an expression vector.
aseptic Sterile, free from bacteria, viruses, and other pathogenic contaminants.
Asn Asparagine; one of more than 20 naturally occurring amino acids.
Asp Aspartic acid; one of more than 20 naturally occurring amino acids.
assay A technique (test) for measuring a biological response or for determining characteristics such as composition, purity, activity, and weight.
ATD Arrival time distribution; Mobility-separated ions show a spread of arrival times at the detector, dependent on their shape. The distribution of these arrival times can be used to determine the differences in shape.
ATP Adenosine 5'-triphosphate; helps cells conserve and spend energy and often is used in assays of various ATP-dependent enzymes.
attenuated Weakened (attenuated) viruses often used as vaccines; they can no longer produce disease but still stimulate a strong immune response similar to the natural virus. Examples include oral polio, measles, mumps, and rubella vaccines.
autoradiography A technique that uses X-ray film to visualize radioactively labeled molecules or molecular fragments; used in analyzing the length and number of DNA fragments after separation by gel electrophoresis.B
Bacillus subtilus A Gram-positive, aerobic, endospore-forming, rod-shaped bacterium commonly found in soil, bodies of water, sewers, and in association with some green plants; the second most common species used in recombinant fermentation; also known for its ability to handle organic waste in other types of biotechnology such as bioremediation.
bacteriophage A virus that infects bacteria, sometimes used as a vector.
bacteriostatic agent A chemical agent that prevents microbes from multiplying but does not reliably kill them. May be used during processing, in raw materials, or in final products, especially multiple dosage medicines.
baculovirus A virus that replicates only in the cells of Lepidopteran insects; it has been genetically engineered to force the insect cells in culture to produce large amounts of a given protein through its natural method of replication, that is, injecting DNA into each cell.
baseline Observations or data used for comparison or as a control.
base pair Two bases on different strands of nucleic acid that join together. In DNA, cytosine (C) always pairs with guanine (G) and adenine (A) always links to thymine (T). In RNA molecules, adenine joins to uracil (U).
basic variant A product variant that exhibits a more positive charge character by IEX or CE than the primary biotherapeutic form.
batch A quantity of a drug substance or drug product with uniform character and quality, within specified limits, produced according to a single manufacturing run during the same cycle of manufacture.
batch culture Large-scale cell culture in which cell inoculum is cultured to a maximum density in a tank or airlift fermentor, harvested, and processed as a batch.
benchtop A term used to distinguish between laboratory-scale or small-scale processes, those that can be performed “on the bench” (in the lab or even on a tabletop) and larger, pilot- or production-scale processes. Benchtop equipment (a “benchtop bioreactor,” for example) can fit on a table or in a confined laboratory area.
beta sheet (b-sheet) A structure resulting from the regular, accordion-like folding of polypeptide chains; the chief alternative to the alpha helix.
BEVS Baculovirus expression vector system; an insect cell culture method in which a genetically engineered virus transfers recombinant DNA to the insect cells it infects, which then produce the peptide or protein in large quantities.
BFS Blow-fill-seal; a type of fill and finish system used in the pharmaceutical industry that forms a plastic container, fills that container, and then seals it with in-line machinery.
BHK Baby hamster kidney cells; an established mammalian cell line that is commonly used for biotechnology.
bioactivity A protein’s ability to function correctly after it has been delivered to the active site of the body (in vivo).
bioanalytical Analytical methods that pertain to biotechnology (that is, to proteins, peptides, and other biomolecules) are more specifically referred to as bioanalytical methods.
bioassay Inoculation of an infective substance into an animal to see if it develops the same disease as a control animal; other analytical methods that use living cells, tissues, or organisms as test subjects.
bioavailability Measure of the true rate and the total amount of drug that reaches the target tissue after administration; extent to which the active drug ingredient enters systemic circulation, thereby gaining access to the site of its action.
bioburden The number of contaminating microbes (bacteria, yeast, mold, etc.) on or in a certain amount of material before that material has been sterilized.
bioburden assay Microbiological test that enumerates microbial content of a sample, but that is not validated to determine sterility.
bioequivalency A scientific basis on which generic and brand-name drugs are compared with one another. Drugs are bioequivalent if they enter circulation at the same rate when given in similar doses under similar conditions.
biogeneric A biopharmaceutical that is produced and licensed by a different firm than the one that originally licensed the molecule. A biogeneric is used for the same indications and may be produced by a substantially similar process, or one that is different, but results in comparable product.
bioinformatics Use of computers in the life sciences: for instance, searching and analysis of electronic databases of genomes and protein sequences, and computer modeling of biomolecules and biologic systems.
biological activity The specific ability or capacity of a product to achieve a defined biological effect. Potency is the quantitative measure of biological activity. [From ICHQ6B]
biologics Products of living organisms used in the prevention or treatment of disease.
biomarker The presence or absence of an enzyme, receptor, other protein or peptide, a mutated mRNA, or a genetic mutation, that differentiates patient subpopulations and is indicative of a disease, the disease severity, a stage in a disease, a subpopulation with the disease that are differentiated by their drug response, or a subpopulation of people with a different drug activity or pharmacokinetics.
biomass The dry weight estimation of organisms (usually microorganisms) in a given habitat or medium.
biometabolism Physical and chemical processes that occur within a cell or an organism — the conversion of nutrients into energy, for example.
biopharmaceutical A therapeutic product created through the genetic manipulation of living things, including (but not limited to) proteins and monoclonal antibodies, peptides, and other molecules that are not chemically synthesized, along with gene therapies, cell therapies, and engineered tissues.
bioprocessing Using organisms or biologically derived macromolecules to carry out enzymatic reactions or to manufacture products.
bioreactor A vessel capable of supporting a cell culture in which a biological transformation takes place (also called a fermentor or reactor).
biosimilar A biopharmaceutical that is produced using a different cell line or master cell bank and/or different process, yet meets criteria for comparability in clinical activity. A biosimilar may differ in its purity/impurity profile, and its potency may differ in a definable way. (See also biogeneric, follow-on biological)
biotechnology The industrial use of living things, specifically genetically engineered organisms.
BLA Biologics license application; the required application for marketing a biologic product in the United States. Most biotechnology-derived drugs are approved through a BLA, rather than an NDA, although some biologics, such as recombinant insulin and human growth hormone, considered to be simpler in structure and well-characterized, have been approved under NDAs.
blotting Transfer of nucleic acids or proteins from an electrophoresis gel strip to a chemically reactive paper or membrane (such as nitrocellulose paper) or matrix (nylon, for example)—to which they bind. Blotting is achieved through capillary diffusion (when the gel is placed between the paper or matrix and an absorptive pad) or through electrophoresis (electroblotting). Of the three types of blots, Southern hybridization (or Southern blot) transfers DNA; Northern blots transfer RNA, and Western blots transfer proteins (also called protein blots).
blunt ends Double-stranded ends with no single-stranded overhang, which remains after DNA is cleaved by certain restriction enzymes.
bolus A concentrated mass of injected medication.
bond A mechanism through which atoms, ions, or groups of atoms are held together in a molecule.
broth The contents of a microbial bioreactor: cells, nutrients, waste, and so on.
BSA Bovine serum albumin; a protein derived from cow serum and commonly used as a growth additive for animal cell culture.
BSE Bovine spongiform encephalopathy; the TSE of cattle believed capable of crossing the species barrier to have become feline spongiform encephalopathy (FSE) in cats, transmissible mink encephalopathy (TME) in farmed mink, and vCJD in human beings.
buccal delivery Transmucosal (across the mucosal membranes) drug delivery by way of the mouth.
buffer (buffering agent) A solution containing a weak acid and a conjugate base of this acid; it resists change in pH near a specific value when an acid or a base is added to it because the acid neutralizes any added base and vice versa. For example, bicarbonates and some proteins in biological fluids, when in solution, tend to stabilize the hydrogen–ion concentration by neutralizing (within limits) both acids and bases so the solution resists changes in pH.
bulk active ingredient Also bulk drug substance, the active ingredient that is formulated with excipients to produce the drug product formulation. Biopharmaceuticals are produced “in bulk” through bioprocessing.
bulking agent An additive that increases the volume of a solution or a solid.
cake The solid sediment that has been compacted in a centrifuge after removal of as much liquid as possible; or the remaining solid after completion of a lyophilization.
calorimetry Analytical method that measures heat loss or gain resulting from physical or chemical changes in a sample. Differential scanning calorimetry compares the results of heating a sample to those for heating a reference material—for example, to measure the temperature at which the sample crystallizes, changes phase, or decomposes.
campaigned production Continuous production of successive batches of the same product.
CAPA Corrective and preventive action; a quality system defined by 21CFR 820.100; the policies, procedures, and support systems that enable a firm to assure that exceptions are followed up with appropriate actions to correct the situation, and with continuous improvement tasks to prevent recurrence and eliminate the cause of potential nonconforming product and other quality problems. [From FDAQSDG]
capillary electrophoresis The miniaturized instrumental version of traditional electrophoresis using capillary column technology (that is, tiny fused-silica tubes with 20 to 100 µm inner diameters) and light-absorbance or fluorescence detection.
carbohydrates Molecules consisting of sugars. The basic carbohydrate units are called monosaccharides, such as glucose, galactose, and fructose. Monosaccharides can be linked together into what are called polysaccharides (or oligosaccharides) in almost limitless ways. Oligosaccharides contain a small number (typically three to ten) of component sugars.
carbonyl bond An oxygen atom double-bonded to a carbon atom; the carbon atom then has two additional bonds to attach to the rest of the molecule.
carcinogenic Cancer-causing; many agents that are carcinogenic are mutagens (agents that increase the occurrence of mutation).
cascade effects A series of events that result from one initial cause.
catabolism The metabolic process of breaking down complex molecules into simpler ones.
catabolites Waste products of catabolism, by which organisms convert substances into excreted compounds.
cation A positively charged ion (having fewer electrons than protons).
CBE Changes being effected; a regulatory submission sent to FDA to notify them of minor changes in a manufacturing process or its control. The sponsor is permitted to make the changes without waiting for FDA response, and the changes become part of the existing licensed process. (See PAS)
CBE-30 Changes being effected within 30 days; a regulatory submission sent to FDA to request minor changes in a manufacturing process or its control. FDA has 30 days in which to respond, after which the change is considered approved and the part of the existing licensed process. (See PAS)
CBER Center for Biologics Evaluation and Research at the FDA; CBER regulates vaccines, gene therapy, cellular products, allergenic extracts, antitoxins, antivenins, venoms, and blood and blood products (clotting factors and plasma derived products).
CCD Charge-coupled device; semiconductors connected so that the output of one serves as the input for the next (digital cameras, video cameras, and optical scanners all use CCD arrays); a light-sensitive integrated circuit that stores and displays the data for an image
CCS Rotationally average collision cross-section; The CCS of an ion is used to calculate the area of an ion in the gas phase and expressed in Omega (see also Omega). Omega can be calculated empirically through the measurement of an ion’s drift time as it passes through a gas filled drift tube or travelling wave ion guide (see also TWIG).
CD Circular dichroism; the absorption of left and right circularly polarized light, a property of molecules that are optically active. CD spectroscopy is a form of light-absorption spectroscopy that measures the difference in left and right circularly polarized light absorbed by a substance. The spectra can be analyzed to learn the different secondary structural types in a protein: alpha helix, parallel and antiparallel beta sheet, turn, and so on.
CDC Centers for Disease Control and Prevention (Atlanta, GA); an agency of the Department of Health and Human Services. CDC develops and applies disease prevention and control, promotes environmental health, and provides health education.
CDER Center for Drug Evaluation and Research; the largest of FDA’s six centers, CDER regulates prescription and over-the-counter drugs. Following a transfer of responsibility for biologics that began in June 2003, CDER now also regulates therapeutic proteins and monoclonal antibodies for in vivo use, which were formerly regulated by CBER.
cDNA, complementary DNA DNA synthesized using an RNA strand (often, messenger RNA) as a primer. The base pairs on the DNA strand are complimentary to those on the RNA strand.
CE Capillary zone electrophoresis; an analytical method in which a mixture is fractionated using charge; analytes are detected using optical density, mass, or other physical properties. Also called CZE.
cell bank A defined population of cells, such as an immortalized cell line, grown by a defined process and cryopreserved in a defined process and within a defined passage number range. The assumption is that each vial from a cell bank is comparable, and when thawed and added to a manufacturing vessel (or an analytical assay), will perform in a consistent way. (See master cell bank, working cell bank)
cell banking Developing, reproducing, aliquoting, and storing cells at a defined passage and homogeneity for particular uses.
cell culture Cells taken from a living organism and grown in the lab (in “culture”). Methods used to grow animal cells in the lab are usually different from those used to grow microorganisms such as bacteria.
cell lines When cells from the first culture (taken from the organism) are used to make subsequent cultures, a cell line is established. Thanks to genetic or other manipulations, immortal cell lines can replicate indefinitely.
cellulose A fibrous polysaccharide material, the main ingredient of plant cell walls.
centrifugation Spinning samples at high speeds, using centrifugal force (up to 500,000 times the force of gravity) to separate substances with very small differences in density or weight.
central dogma The original postulate that genetic information can be transferred only from DNA to DNA, from DNA to RNA, and from RNA to protein (although information transfer from RNA to DNA was not excluded and is now known to occur [reverse transcription]).
centrifuge A laboratory or industrial apparatus that separates mixed samples of differing density by spinning them at high speed.
centromere the most constricted portion of a chromosome where the spindle attaches during cell division.
certificate of analysis (COA) A batch-specific document that is used to list test methods and results, including applicable specifications, and a final batch disposition.
CFR Code of Federal Regulations; the U.S. regulations that directly apply to biopharmaceutical development are in Title 21 parts 58, 210, 211, and 600. Parts 50, 56, and 312 apply to clinical trials.
cfu Colony forming units; a measurement of the number of microorganisms present derived from the number of colonies that form in a test culture.
cGMP Current good manufacturing practice; see GMP.
change control A system by which changes to facilities, equipment, and processes are documented and approved. The change control system ensures that changes are evaluated and approved prior to implementation to maintain the facilities, equipment, and processes in a validated state.
chaotropic Disrupting the structure of water, macromolecules, or living systems to promote activities that would have been inhibited by the water, molecules, or systems.
characterization Precisely deciphering and describing an entity’s properties (physical and chemical properties in the case of a molecular entity; genetic and stability properties in the case of a cell line).
charge The electrical state of an atom or molecule, whether positive, negative, or neutral, according to the difference of protons (positively charged) to electrons (negatively charged).
chelation The binding or holding of a metal ion (such as copper, zinc, cadmium, nickel, or cobalt) by another molecule or by another part of the same molecule; used in a form of affinity chromatography called “metal chelate chromatography.”
chelator A molecule used to bind a metal ion with more than one organic group to form a highly stable structure.
chemical synthesis A non-biotech method of manufacturing chemicals, including drugs.
chemostat A growth chamber that keeps a bacterial culture at a specific volume and rate of growth by limiting nutrient medium and removing spent culture.
chirality The condition of being chiral, that is, a molecule in a configuration that is symmetrical with its mirror image; a right-handed chiral molecule rotates polarized light rightward, a left-handed chiral molecule rotates polarized light leftward.
CHO cells Chinese hamster ovary cells; in cell culture, the cells of a female hamster’s reproductive organs, which historically have proven to be the basis for good expression systems in analytical studies and for producing pharmaceutical proteins.
chromatography A technique used to separate molecules based on how they tend to bind to various solids, liquids, and gases; based on the differential distribution of the substances between a stationary phase (sticky material such as silica gel or silicic acid, usually contained in a column, tube, or capillary) and a gaseous or liquid mobile phase (a medium that carries the sample through the stationary phase). This very effective technique can separate substances that are nearly identical.
chromophore A molecule that absorbs UV or visible light.
chromosome A long and complex DNA chain containing the genetic information (genes) of a cell. Prokaryotes contain only a single chromosome; eukaryotes have more than one, made up of a complex of DNA, RNA, and protein. The exact number of chromosomes is species-specific. Humans have 23 pairs.
chymotrypsin A digestive enzyme that can cleave peptide bonds.
CIP Clean-in-place; a way to clean large vessels (tanks, piping, and associated equipment) without moving them or taking them apart, using a high-pressure rinsing treatment, sometimes followed by steam-in-place (SIP) sanitization. Chemically cleaning and sterilizing equipment or systems without removing them from their installed location.
clarify To clear liquid of suspended particles through filtration, extraction/precipitation, or centrifugation.
classical pharmaceuticals Small-molecule, non-biotech drugs produced by chemical synthesis.
clean room A room in which the concentration of airborne particulate matter is controlled at specific limits to facilitate the manufacture of sterile and high-purity products. Clean rooms are classified according to the number of particles per volume of air to meet standards of cleanliness. Contaminants on surfaces and people entering and exiting the room also are controlled.
clearance Demonstrated removal of an impurity or potential contaminant from a product.
clinical development The phases of drug development during which a drug is tested in human subjects, also referred to as clinical trials.
clinical endpoint An indicator (such as blood pressure) measured in a human subject to assess the safety, efficacy, or other objective of a clinical trial.
clinical hold Temporary cessation of a clinical trial by FDA if the agency is concerned about a drug or study protocol. The trial may resume when the problem is solved.
clone To duplicate exactly, whether a gene or a whole organism; or an organism that is a genetically identical copy of another organism.
cloning vectors Methods of transferring desired genes to organisms that will be used to express them. Cloning vectors are used to make recombinant organisms.
CM Carboxymethylcellulose; a weak ion-exchanger that is often coupled to a resin used in charge based separation chromatography. It is a cation exchange resin.
CMO Contract manufacturing organization; a company contracted to perform development and/or manufacturing services.
codon A sequence of three nucleotide bases in mRNA that specifies production of an amino acid or represents a signal to stop or start a function.
colorimetry The measurement and definition of unknown colors in terms of standard colors; techniques may be visual, photoelectric, or spectrophotometric; colorimetry is useful in determining the concentration of a chemical with color in a solution by measuring the intensity of the color and relating that intensity to the concentration of the solution.
column A vertical, cylindrical container or vessel often used in separation processes such as extraction, distillation, and chromatography.
column aspect ratio The ratio of a column’s height to its diameter.column chromatography A separation method in which the different components of a mixture migrate through a column at different rates of speed based on their relative affinity for the stationary phase.
comparable Product made before and after a given process change is comparable if the change is shown to have no adverse effect on the key quality attributes of the product, such as purity, potency, PK/PD, stability, and safety. Small differences in, for example, the impurity profile are permitted, as long as the function is not affected. (See equivalent)
comparability protocol A protocol that defines the experiments and acceptance criteria that will be used to evaluate a product before and after a process change, and if met, will provide documented evidence that the products are comparable. A comparability protocol may be filed within another regulatory submission, such as a BLA; or may be filed on its own. One reason to file a comparability protocol is that FDA may grant a less stringent category to the change, so that what required a PAS now requires only a CBE-30.
complaint Also customer complaint; any oral or written communication from an end user of a medicinal product indicating that it had an adverse effect on a patient, did not function as specified, or appeared to be contaminated or defective in any way. The sponsor must promptly investigate all such complaints and document the investigation in a retrievable file. If the complaint is confirmed, corrective and preventive actions are required. Examples include FDA notification, product lot(s) withdrawal, product recall, and review of medical files of adverse events caused by the product. These requirements are found in U.S. regulations in 21 CFR 314, the GCP regulations.
complement A group of proteins in the blood that work in concert with other immune system proteins and cells (such as antibodies) in attacking foreign substances.
component 1. Raw materials and components (tubing, stoppers, vials, filters) having direct product contact during manufacturing, which are regulated under 21 CFR 84. 2. Differentiated from raw materials and excipients, which are chemical entities, and usually rated as lower in risk to patient and product quality. (Note: These terms may be used interchangeably or loosely, and definitions vary between U.S., Europe, and WHO). (See raw material, starting material, API)
concentration The amount of a particular substance in a given quantity of solution, usually stated as a percentage by weight or volume, as weight per unit volume, as molarity (a one-molar solution contains one gram-mole of solute per liter of solution), or as normality (a one-normal or one-molar solution contains one gram-equivalent weight of solute per liter of solution).
conformation The shape of a molecule, produced by the specific spatial arrangement of the units that compose it.
consent decree Status imposed by FDA on a company in serious violation of federal regulations and related safety and quality standards. A company must agree to a series of measures aimed at bringing its manufacturing standards into compliance with federal regulations. Until agreed-upon conditions are met, a company may be forbidden to distribute its products in interstate commerce, except for those products deemed essential for the public health.
contaminant A foreign agent or material that is not introduced as part of processing, such as airborne particulates or adventitious organisms.
continuous process verification An alternative approach to process validation in which manufacturing process performance is continuously monitored and evaluated. [From ICH Q8]
control group The group of subjects in a controlled study that receives no treatment, a standard treatment, or a placebo.
controlled delivery Drug delivery in which the duration (sustained delivery) and/or the site (targeted delivery) of drug release, action, and bioavailability are controlled through various physicochemical means designed to provide well-defined pharmacokinetic profiles.
Coomassie blue dye A sensitive stain for proteins used to visualize the bands in SDS-PAGE; also Coomassie brilliant blue.
COS, CV-1 African green monkey kidney cells, an established cell line that is commonly used for biotechnology.
cosmid An artificially constructed plasmid vector that contains a specific bacteriophage gene, which allows it to carry up to 45,000 base pairs of desired DNA.
cot1/2 DNA A curve that measures genome complexity by determining the time taken for half the DNA in a sample to reanneal (renature); it is measured for any new genome and compared to a standard such as the E. coli genome.
covalent bond Chemical bond in which two atoms share one or more electron(s).
Cp Process capability; a statistical measurement of the relation between the observed variability of a process and the specifications or requirements for individual lots. Computed by dividing the range by the process variability (sigma); a larger number indicates a more capable process.
critical micellar concentration (CMC) The concentration of detergent at which micelles begin to form; from a practical point of view, the CMC defines the minimum concentration of free detergent that must be present to keep membrane proteins in solution. CMC values are affected by temperature, ionic strength, pH, and buffer composition. The CMC is important in determining whether a detergent can be removed by dialysis. For example, a free detergent molecule may pass through the membrane but the largest micelle will not. (Compare to CMC: chemistry manufacturing, and controls.)
critical process parameter An input parameter (process setpoint) to a unit operation that must be tightly controlled by the operator, either manually or automatically, and which must be kept within a specified range in order to produce output of acceptable quality within specifications. These parameters are identified during process development.
critical quality attribute A quality characteristic that must be controlled within defined limits to ensure acceptable product quality and performance.
CRO Contract research organization or clinical research organization; a company contracted by a sponsor to perform preclinical or clinical pharmaceutical research.
cryoconcentration When a solution is frozen, water freezes as pure ice crystals. The remaining liquid therefore has a higher solute concentration than the original solution.
cryogranulation Use of a stream of liquid nitrogen to quickly create frozen, discrete pellets of a solution such as bulk or final drug formulation.
cryopreservation Maintenance of frozen cells, usually in liquid nitrogen.
C-terminal Carboxyl-terminal; the carboxyl terminus of a protein chain, with a free carboxyl group.
culture medium A complex mixture of organic and inorganic materials used as a nutrient system for the cultivation of cells.
cuvette A transparent or translucent box-shaped container with precisely measured dimensions for holding liquid samples to be put into a spectrophotometer; also such a container with optical surfaces used to mold samples so that their light-absorbing properties can be measured.
Cys Cysteine; one of more than 20 naturally occurring amino acids.
cytokine A protein that acts as a chemical messenger to stimulate cell migration, usually toward where the protein was released. Interleukins, lymphokines, and interferons are the most common.
cytopathic Damaging to cells, causing them to exhibit signs of disease.
cytoplasm The protoplasm of a cell outside the nucleus (inside the nucleus is the nucleoplasm). Protoplasm is a semifluid, viscous, translucent mixture of water, proteins, lipids, carbohydrates, and inorganic salts found in all plant and animal cells.
cytostat Something that retards cellular activity and production. This can refer to cytostatic agents or to machinery, such as those that would freeze cells.
cytotoxic Causing cell death.
Da Dalton; the unit of molecular mass, very nearly equal to that of a hydrogen atom (precisely equal to 1 on the atomic mass scale), named after John Dalton, who developed the atomic theory of matter (kDa, kilodalton).
DEAE Diethylaminoethyl; a weak ion-exchanger that is often coupled to a resin and used in charge based separation chromatography. It is an anion exchange resin.
deamidation Removal of one or more amide groups from the Gln or Asn residue in a protein, converting the residues to Glu, Asp, or isoAsp. Depending on the protein, this may have no effect, or major effects, on potency, stability, or solubility.
Declaration of Helsinki A set of recommendations or basic principles guiding medical doctors in the conduct of biomedical research involving human subjects.
deflashing The finishing procedure by which excess plastic (flash) is removed from a molding in BFS operations.
degradants The smaller parts that are left over after a molecule or solution degrades.
degradation Loss or reduction of quality, integrity, or character; a chemical reaction that breaks down a molecule into smaller parts.
delaminate To split apart into thin layers; the act of separating a laminate into layers.
delivery matrix A heterogeneous semisolid matrix (such as a biopolymer gel) for the sustained delivery of drug substances directly to the tissues; a matrix can be modified to optimize the dosage or time period during which the drug is delivered.
denaturation A condition in which a protein unfolds or its polypeptide chains are disordered, rendering the molecule less soluble and usually nonfunctional.
denature To unfold a protein or break it up, changing its usual three-dimensional structure. Proteins can be denatured by chemical action, heat, or even agitation of a protein solution.
denatured protein A protein having unfolded or disordered polypeptide chains, which render the molecule less soluble and usually nonfunctional. Sometimes a denatured protein can be refolded (renatured).
derivatization A sampling technique; chemical conversion into a derivative form for identification purposes.
design space The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post-approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval. [From ICH Q8]
desorption The opposite of adsorption; the release of adsorbed molecules, particles, or cells into the surrounding medium.
dialysis/diafiltration Membrane ultrafiltration in which a large solute (such as a protein) is washed or dialyzed with another solution; for example, changing buffer conditions without affecting protein concentration.
diastereomer A stereoisomer (one of two or more molecules with the same atoms in the same order but different three-dimensional shapes) having two or more chiral centers that is not a mirror image of another stereoisomer of the same compound; glucose, galactose, and mannose are all diastereomers.
differential scanning calorimetry (DSC) Analytical method that independently measures the rate of heat flow to a sample against a reference standard of the same temperature. Data are obtained by monitoring the differential heat flow as a function of temperature. DSC can measure heat capacities, phase transitions, dehydration, and heats of reaction.
diluent A chemically inert substance added to a solution to increase the volume and reduce the concentration; a diluting agent.
dimer A polymer made up of two identical molecules. When three monomers link up, the resultant polymer is called a trimer. Larger polymers are usually referred to by placing a number before the “-mer” suffix: 4-mer, 5-mer, 6-mer, and so on.
diploid Referring to a cell that has two copies of each chromosome.
disposables In pharmaceutical manufacturing, refers to single-use components (often made of plastic) that are used for single cycle or batch, then replaced, rather than being cleaned between batches and reused. See also single-use components.
dissociation constant A specific type of equilibrium constant that measures the propensity of a larger object to separate (dissociate) reversibly into smaller components, as when a complex falls apart into its component molecules, or when a salt splits up into its component ions. The dissociation constant is usually denoted Kd and is the inverse of the affinity constant. Dissociation constants are commonly used to describe how tightly a ligand (such as a drug) binds to a protein. Such binding is usually non-covalent, i.e., no chemical bonds are made or broken. Since the binding is usually described by a two-state process P + L = C the corresponding dissociation constant is defined Kd = [P][L]/[C] where [P], [L] and [C] represent the concentrations of the protein, ligand and bound complex, respectively. The dissociation constant has the units of molar (M), and corresponds to the concentration of ligand [L] at which the binding site on the protein is half occupied, i.e., when the concentration of protein with ligand bound [C] equals the concentration of protein with no ligand bound [P]. The smaller the dissociation constant, the more tightly bound the ligand is; for example, a ligand with a nanomolar (nM) dissociation constant binds more tightly than a ligand with a micromolar (mM) dissociation constant.
disulfide bond A covalent bond formed between sulfur atoms of different cysteines in a protein; such bonds (links, bridges) help hold proteins together.
divalent cations Cations with a net positive charge of +2.
DIW Deionized water; very pure water in which contaminants have been ionized and removed by special filtration.
DMSO Dimethysulfoxide; a common cryoprotectant used to cryopreserve cells and tissues.
DNA Deoxyribonucleic acid; the nucleic acid based on deoxyribose (a sugar) and the nucleotides G, A, T, and C. Double-stranded DNA has a corkscrew-ladder shape (the “double helix”) and is the primary component of chromosomes, which thus carry inheritable characteristics of life. (See nucleotides, nucleic acids)
DNA array Spots of DNA, oligonucleotide, or cDNA arranged on a solid support such as a glass or silicon “DNA chip” (or microarray), which is used for screening, sequencing, genetic mapping, and so on.
DNA fingerprinting Sequences of nucleic acids in specific areas (loci) on a DNA molecule are polymorphic, meaning that the genes in those locations may differ from person to person. DNA fragments can be cut from those sequences using restriction enzymes. Fragments from various samples can be analyzed to determine whether they are from the same person. The technique of analyzing restriction fragment length polymorphism (RFLP) is called DNA typing or DNA fingerprinting. It is also now possible to detect polymorphisms consisting of a single nucleotide. These are called single-nucleotide polymorphisms (SNP).
DNase Deoxyribonuclease, the enzyme that breaks up and destroys DNA sequences (a protective mechanism in higher organisms).
DNA sequencing Determining the order of nucleotide bases in a DNA molecule.
DNA vaccine A nucleic acid vaccine: Genes coding for specific antigenic proteins are injected to produce those antigens and trigger an immune response.
DOE Design of experiments; a term for experiments that are planned and analyzed using statistical design tools. A structured, organized method for determining the relationship between factors affecting a process and the output of that process. [From ICH Q8]
dosage group A group of subjects in a clinical trial receiving the same dosage of a drug being tested.
dose sparing Refers to strategies for reducing the dose of a drug necessary to produce a therapeutic effect. For vaccines this can involve the use of powerful adjuvants that decreases the requirement for antigen in order to induce a therapeutically useful immune response.
downstream processing Bioprocessing steps following fermentation and/or cell culture, a sequence of separation and purification activities needed to obtain the required drug product at the necessary level of purity.
DQ Design qualification; a documented review of the design, at an appropriate stage of stages in the project, for conformance to operational and regulatory expectations.
drift time The drift time of an ion is a measure of how long it takes to move through a mobility region in a mass spectrometer. For a travelling wave, this is measured in low hundreds of milliseconds (see also TWIG).
drug discovery Methods for identifying new therapeutic molecules. High-throughput techniques include combinatorial chemistry, genomics, and proteomics analysis as the starting point. Low-throughput methods include traditional disease research.
drug product The final dosage form of a pharmaceutical medicine containing drug substance formulated with selected excipients and packaged for the end user.
drug substance The active drug chemical or biological substance in purified bulk form. The drug substance is further processed to derive a drug product. Also known as active pharmaceutical ingredient (API).
EBA Expanded-bed adsorption; a chromatography method that uses an upward flow of liquid in a column of suspended, dense chromatography beads to allow passage of crude, unclarified raw materials without clogging the chromatography medium.
efficacy The ability of a substance (such as a protein therapeutic) to produce a desired clinical effect; its strength and effectiveness; usefulness; the power to produce an effect.
efficiency of delivery The relative effectiveness of a drug delivery system.
EHSS exact hard sphere scattering; An ion is modeled by a collection of overlapping hard spheres with radii equal to hard sphere collision distances (see also PA). The orientationally-averaged momentum transfer cross section is calculated by determining the scattering angles between the incoming buffer gas atom trajectory and the departing buffer gas atom trajectory.
elastomeric closure A rubber or rubber-like closure or stopper; a packaging component that may come into direct contact with the enclosed drug, which is usually an injectable.
electrolytes Ionized salts in body fluids; electrolyte solutions are solutions containing charged atoms or molecules.
electroosmotic The movement of a liquid out of or through a porous material or a biological membrane under the influence of an electric field.
electrophoresis Analytical method in which an electric field is applied to a medium (paper, thin-layer plates, polyacrylamide or agarose gel), causing charged molecules to move through it. In capillary electrophoresis, samples move through a buffer-filled tube (capillary). In gel electrophoresis, samples move through a thin agarose or polyacrylamide gel. Bigger biomolecules (and those carrying few electrically charged chemical groups) move slower through the medium than smaller molecules (and those with many electrically charge chemical groups).
electrospray ionization Technique for generation of charged ions for mass spectrometry. Analyte containing solution is dispersed as a fine charged aerosol into the MS by passage of the liquid through a electrically charged capillary emitter.
electrostatic binding A chemical bond of two atoms or molecules by an electrostatic force (like static electricity) caused by one or more electrons moving from one atom to the other.
ELISA Enzyme linked immunosorbent assay; a test to measure the concentration of antigens or antibodies.
eluate Also called elution fractions; the separated components of a mixture that wash out from a chromatography column during elution.
eluent The substance used to recover samples from a chromatography column; sometimes an elution solvent. When a buffering agent is used, it is called an elution buffer. Sometimes a solvent is used and just referred to as the eluent.
elution Washing out; removing adsorbed material with a solvent or buffering agent.
elution profile A graph made to show how much material is being carried out of the column by the eluent in column chromatography over time. The graph will show a number of different peaks; each peak represents a different separated material from the original mixed substance. Also called a chromatogram.
elution volume The amount of eluent that passes through the column in column chromatography before a particular peak appears in an elution profile (that is, before a specific substance of interest comes out with it). Also, the volume during which a particular compound is eluted.
EM Electron microscopy; in which instruments focus electrons like optical microscopes focus light. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) are sometimes used in bioanalytical laboratories.
EMA European Medicines Agency; the agency responsible for regulating biopharmaceuticals in the European Union.
embryonic stem cells (ESCs) Unspecialized cells obtained from embryos that can grow and divide and that can be induced to form specialized cells resembling those in many different tissue types.
emulsification A process that creates a stable mixture of two liquids that normally would no