A Guide to the Biopharmaceutical Lexicon

[ BIOTERMINOLOGY ]

2018 Edition A GUIDE TO THE BIOPHARMACEUTICAL LEXICON

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acceptance of the results of analytical A procedures which the drug substance or absorption Removal of a particular drug product or materials at other stages molecule from a sample by accumulation of their manufacture should meet. [From into a bound water volume such as might ICH Q6B] be present in a densely fibrous material. In ACN Acetonitrile; the most frequently pharmacology (and more specifically phar- used solvent in HPLC, commonly used as macokinetics), absorption is the movement an eluent. of a drug into the bloodstream. Absorp- acidic variant A product variant that tion involves several phases. First, the exhibits a more negative charge character drug needs to be introduced via a route of by IEX or CE than the primary biotherapeu- administration (oral, via the skin, etc.) and tic form. in a specific dosage form such as a tablet, active starting material The raw ma- capsule, and so on. (See adsorption). terial that is identified as directly related accelerated stability tests Studies to the active chemical comprising the prod- in which the product is stored under stress uct, and is defined at the first stage during conditions (for example, 45 °C and high chemical synthesis at which part or most of humidity over three to six months) and the critical moieties are present. Defining observed for signs of degradation; used to active starting material defines the step at predict long-term storage patterns. which compliance with cGMP requirements acceptance criteria Numerical limits, begins during manufacturing. For biophar- ranges, or other suitable measures for maceuticals, this term is not used.

Following acronyms that appear in brackets throughout the guide represent the sources of definitions: • FDA PHS Act definition is the one that appears in the US Public Health Service Act. • FDA QSG definition is the one that appears in the US FDA’s Quality Systems guidance. • ICH Q6B definition is the one that appears in the International Conference on Harmonization (ICH) Q6B guideline, “Test Procedures and Acceptance Criteria for Biotechnological/Biological Products.” • ICH Q8 definition is the one that appears in the ICH Q8 guideline, “Pharmaceutical Development.” • ICH Q9 definition is the one that appears in the ICH Q9 guideline, “Quality Risk Management.” • IC H Q11 under review; definition is the one that appears in the ICH Q11 guideline, “Development and Manufacture of Drug Substances (chemical entities and biotechnical/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.”

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acute Describes a disorder as a one- time condition (an injury or infection), rather than as a chronic disease such as diabetes. ADME Absorption, distribution, metabolism, and excretion. adjuvant A chemical agent added to vaccines to boost the immune response to the vaccine antigen. ADR Adverse drug reaction, an undesirable One of the most frequently used effect that may be caused by a study drug (see solvents in chromatographic analysis is ACN, acetonitrile. also adverse events). adsorption Adherence of molecules affinity tag (or tail) An amino acid in solution or suspension to cells or other sequence added to a protein to facilitate molecules—or to solid surfaces, such as chro- purification by affinity chromatography. matography media. Compare to absorption. agarose A polysaccharide (sugar) obtained adventitious agents Acquired, accidental from seaweed and used as a solidifying agent contaminants in a cell line, such as viruses (agar) in microbial culture; also used in gel and toxins; often infectious agents. electrophoresis. adverse events (see also ADR) Unde- aggregate A clustered mass, as of protein sired effects or toxicity in a patient due to molecules; or to cluster together in such a exposure (often to a drug or medical device, way. Aggregates of cells (solid, fluffy, or pel- but not limited to those). Adverse events must letized) can clog the pores of filters or other be notified to the sponsor, who is required to fermentation apparatus. perform a written investigation into the root Ala Alanine; one of more than 20 natu- causes, and may need to take other corrective rally occurring amino acids. or preventive actions. (See complaints, CAPA) albumins Protein constituents of blood aerobic Growing in the presence of oxygen. plasma and serum also found in muscle, egg A strict aerobe grows only under such a white, and milk. condition. alkylation The introduction, by substitution affinity Attraction between particles or or addition, of an alkyl group into an organic substances; relatively speaking, a measure of compound; alkylating agents are various the attraction of one molecule toward another. substances that contain an alkyl radical and affinity chromatography A chromato- that can, therefore, replace a hydrogen atom graphic method that makes use of the specific in an organic compound; alkylation is used to binding of one molecule to another; immuno- prevent refolding of already reduced proteins affinity chromatography uses antibodies, for during peptide mapping. example, and metal affinity chromatography alpha helix (α-helix) A coil or spiral ele- uses chelation. ment of protein secondary structure.

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amino acid analysis Hydrolysis of a protein analyze or characterize a mixture, a compound, or peptide into its individual residues (free amino or an unknown material. acids), followed by chromatographic separation anion A negatively charged ion (having and UV-visible detection for analytical purposes. more electrons than protons). amino acids A class of 20 naturally oc- anion exchange chromatography A curring hydrocarbon molecules that combine method for separating molecules on the basis of to form proteins in living things. They include negative charge; it can use strong or weak anion alanine (A), arginine (R), exchangers. asparagine (N), aspartic acid (D), cysteine (C), anneal Complementary sequences of glutamic acid (E), glutamine (Q), glycine (G), single-stranded DNA or RNA are paired by histidine (H), isoleucine (I), leucine (L), lysine hydrogen bonds to form a double-stranded (K), methionine (M), phenylalanine (F), proline polynucleotide. (P), serine (S), threonine (T), tryptophan (W), annual review An evaluation, conducted tyrosine (Y), and valine (V). (Those are the at least annually, which assesses the quality so-called normal amino acids; others have standards of each drug product to determine the been synthesized and are used in medicinal need for changes in drug product specifications chemistry.) They are incorporated into proteins or manufacturing or control procedures. [From by transfer RNA according to the genetic code. FDAQSG] amorphous Having no apparent shape or anodes Positive electrodes; negative ions order; non-crystalline. (anions) migrate carrying electric current toward ampholyte An electrolyte that can be either positive anodes. positively or negatively charged, depending on Amino acid analysis can be used to the pH of its medium. quantitatively determine the amount of amphoteric A substance that has both acid protein and the proportions of amino acids in a sample. The Waters UPLC and base properties; amphoteric molecules can Amino Acid Analysis Solution is a accept or donate protons to act as an acid or a turnkey chromatographic system that provides accurate, high-throughput base. amino acid analysis. ampule A small, sterile glass vessel with an airtight seal that contains a single drug dose. amyloid Insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis and may play a role in various other neurodegenerative diseases. 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

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antibody An infection-fighting protein mol- antisense oligonucleotides Antisense ecule that tags, neutralizes, and helps destroy oligonucleotides interact with complementary foreign microorganisms or toxins. Also known strands of nucleic acids, modifying expression as immunoglobulins, antibodies are produced of genes. by the immune system in response to antigens. API Active pharmaceutical ingredient; Antibodies are composed of four subunits: two the chemical entity that has the drug activity heavy chains and two light chains. Each sub- and structure, but is not yet formulated with unit contains a constant region and a variable excipients. region. The constant regions remain the same aprotinin A polypeptide that inhibits within each type of immunoglobulin (i.e., all (blocks the action of) serine proteases. IgM’s have the same constant regions, all IgG’s aptamer Single-stranded RNA or double- have the same constant regions). The variable stranded DNA molecules made up of short regions contain the antigen binding sites. lengths of nucleic acids that form three- antibody dependent cell-mediated dimensional structures and can bind to specific cytotoxicity (ADCC) A biological pathway endogenous targets to produce its biological triggering the body’s immune system to target action. a specific cell recognized by the antibody. It is Arg Arginine; one of more than 20 natu- a common mechanism of action of antibody rally occurring amino acids. drugs targeting cancer cells. artificial chromosome DNA synthesized antibody drug conjugate (ADC) Bio- in chromosomal form for use as an expression therapeutics that combine the proven antigen- vector. specific selectivity and antitumor activity of aseptic Sterile, free from bacteria, viruses, monoclonal antibodies with the potency of and other pathogenic contaminants. cytotoxic molecules. Asn Asparagine; one of more than 20 antibody fluorophore conjugate (AFC) naturally occurring amino acids. An antibody that has been derivatized (la- Asp Aspartic acid; one of more than 20 beled) with a fluorophore. naturally occurring amino acids. antifoam agent A chemical added to a assay A technique (test) for measuring a fermentation broth to counteract the foaming biological response or for determining charac- (bubbles) that can be caused by mixing, sparg- teristics such as composition, purity, activity, ing, or stirring. and weight. antigen Any agent that reacts specifically ATD Arrival time distribution; mobility- with an antibody. Each antigen may contain separated ions show a spread of arrival times more than one site capable of binding to a at the detector, dependent on their shape. The particular antibody. (See immunogen) distribution of these arrival times can be used antigenicity The capacity of a substance to to determine the differences in shape. induce the formation of antibodies or to elicit ATP Adenosine 5’-triphosphate; helps cells an immune response when injected into an conserve and spend energy and often is used animal. in assays of various ATP-dependent enzymes.

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attenuated Weakened (attenuated) that prevents microbes from multiplying but viruses can be used as vaccines; they can does not reliably kill them. May be used during no longer produce disease but still stimulate processing, in raw materials, or in final prod- a strong immune response similar to the ucts, especially multiple dosage medicines. natural virus. Examples include oral polio, baculovirus A virus that replicates only in measles, mumps, and rubella vaccines. the cells of Lepidopteran insects; it has been AutoBlend In chromatography systems genetically engineered to force the insect cells manufactured by Waters, AutoBlend mode al- in culture to produce large amounts of a given lows the automatic blending of up to four buf- protein through its natural method of replica- fers, salts, or solvents in accurate proportions tion, that is, injecting DNA into each cell. reproducibly, which can simplify mobile phase baseline Observations or data used for preparation. Any sequence of isocratic, binary, comparison or as a control. ternary, and quaternary gradients (very useful base pair Two bases on different strands for SEC) can be used. The technique is useful of nucleic acid that join together. In DNA, for routine assays as well as automatic method cytosine (C) always pairs with guanine (G) and development or system flushing. adenine (A) always links to thymine (T). In AutoBlend Plus AutoBlend Plus technol- RNA molecules, adenine joins to uracil (U). ogy extends the capabilities of AutoBlend by basic variant A product variant that exhib- automatically managing pH and ionic strength its a more positive charge character by IEX or requirements for the mobile phase. The CE than the primary biotherapeutic form. software calculates the proportions of buffer batch A quantity of a drug substance or stocks required for desired conditions. Com- drug product with uniform character and qual- putation can be based on known pK values or ity, within specified limits, produced according on an empirical calibration table, making any to a single manufacturing run during the same possible buffer combination available. cycle of manufacture. batch culture Large-scale cell culture in which cell inoculum is cultured to a maxi- B mum density in a tank or airlift fermentor, Bacillus subtilus A Gram-positive, aerobic, harvested, and processed as a batch. endospore-forming, rod-shaped bacterium benchtop A term used to distinguish commonly found in soil, bodies of water, sew- between laboratory-scale or small-scale pro- ers, and in association with some green plants; cesses, those that can be performed “on the the second most common species used in bench” (in the lab or even on a tabletop) and recombinant fermentation; also known for its larger, pilot- or production-scale processes. ability to handle organic waste in other types of Benchtop equipment (a “benchtop bioreactor,” biotechnology such as bioremediation. for example) can fit on a table or in a confined bacteriophage A virus that infects bacte- laboratory area. ria, sometimes used as a vector. beta sheet (β-sheet) A structure result- bacteriostatic agent A chemical agent ing from the regular, accordion-like folding of

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the same disease as a control animal; other analytical methods that use living cells, tissues, or organisms as test subjects. bioavailability Describes the fraction of an administered dose of unchanged drug that reaches systemic circulation, one of the principal pharmacokinetic properties of drugs. Biopharmaceutical development, manu- biobetter A term for a follow-on facturing, and analytical methods use a biologic that implies some improvement variety of buffer solutions. on an existing biologic. This, and similar polypeptide chains; the chief alternative to the terms, are not generally used by regulatory alpha helix. authorities. (See biosimilar) BEVS Baculovirus expression vector bioburden The number of contaminating system; an insect cell culture method in which microbes (bacteria, yeast, mold, etc.) on or a genetically engineered virus transfers in a certain amount of material before that recombinant DNA to the insect cells it infects, material has been sterilized. which then produce the peptide or protein in bioburden assay Microbiological test large quantities. that enumerates microbial content of a BFS Blow–fill–seal; a type of fill-and- sample, but that is not validated to deter- finish system used in the pharmaceutical mine sterility. industry that forms a plastic container, fills bioequivalency “The absence of a sig- that container, and then seals it with in-line nificant difference in the rate and extent to machinery. which the active ingredient or active moiety BHK Baby hamster kidney cells; an estab- in pharmaceutical equivalents or pharma- lished mammalian cell line that is commonly ceutical alternatives becomes available at used for biotechnology. the site of drug action when administered at bioactivity A protein’s ability to function the same molar dose under similar condi- correctly after it has been delivered to the tions in an appropriately designed study,” active site of the body (in vivo). Center for Drug Evaluation and Research bioanalytical Sub-discipline of analytical (2003), Guidance for Industry: Bioavail- chemistry covering the quantitative measure- ability and Bioequivalence Studies for ment of xenobiotics (drugs and their metabo- Orally Administered Drug Products—Gen- lites, and biological molecules in unnatural eral Considerations. locations or concentrations) and biotics (mac- biogeneric A term used for a biophar- romolecules, proteins, DNA, large molecule maceutical product that is produced and drugs, metabolites) in biological systems. licensed by a different firm than the one bioassay Inoculation of an infective that originally licensed the molecule. A substance into an animal to see if it develops biogeneric is used for the same indications

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and may be produced by a substantially response, or a subpopulation of people with a similar process, or one that is different, but different drug activity or pharmacokinetics. results in comparable product. biomass The dry weight estimation of bioinformatics Use of computers in the organisms (usually microorganisms) in a life sciences: for instance, searching and given habitat or medium. analysis of electronic databases of genomes biometabolism Physical and chemi- and protein sequences, and computer mod- cal processes that occur within a cell or an eling of biomolecules and biologic systems. organism—the conversion of nutrients into biological activity The specific ability energy, for example. or capacity of a product to achieve a defined biopharmaceutical A therapeutic product biological effect. Potency is the quantitative created through the genetic manipulation of measure of biological activity. [From ICH Q6B] living things, including (but not limited to) biologics Products of living organisms used proteins and monoclonal antibodies, peptides, in the prevention or treatment of disease. and other molecules that are not chemically Biologics Price Competition and Innova- synthesized, along with gene therapies, cell tion (BPCI) Act In 2009, the US Congress therapies, and engineered tissues. passed the Biologics Price Competition and BiopharmaLynx™ Application Manager Innovation (BPCI) Act, authorizing FDA to for MassLynx™ Software; Software available oversee an abbreviated pathway for approval from Waters Corporation that automates of biologics that are biosimilar to already the data analysis and reporting of mass approved products. spectrometry data for peptide maps and Biological product A virus, therapeutic intact mass measurements. It automatically serum, toxin, antitoxin, vaccine, blood, blood analyzes and assigns results, defining the component or derivative, allergenic product, sequence/features of known proteins, and protein (except any chemically synthesized determining the ID of modified forms. Allows polypeptide), or analogous product, or users to edit assignments, annotate new arsphenamine or derivative of arsphena- peaks, and compare experimental samples mine (or any other trivalent organic arsenic to a reference by using tabular and graphical compound), applicable to the prevention, visualization tools. treatment, or cure of a disease or condition bioprocessing Using organisms or of human beings. [FDA, PHS Act] biologically derived macromolecules to carry biomarker In either small or large out enzymatic reactions or to manufacture molecules, the presence or absence of an products. enzyme, receptor, other protein or peptide, a bioreactor A vessel capable of sup- mutated mRNA, or a genetic mutation, that porting a cell culture in which a biological differentiates patient subpopulations and is transformation takes place (also called a indicative of a disease, the disease severity, fermenter or reactor). a stage in a disease, a subpopulation with the Bioseparations The use of chromato- disease that are differentiated by their drug graphic techniques to separate biomole-

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cules into discrete fractions for subsequent matrix (nylon, for example)—to which they analysis. bind. Blotting is achieved through capillary biosimilar A biopharmaceutical that diffusion (when the gel is placed between is produced using a different cell line or the paper or matrix and an absorptive pad) master cell bank and/or different process, or through electrophoresis (electroblot- yet meets criteria for comparability in ting). Of the three types of blots, Southern clinical activity. A biosimilar may differ in hybridization (or Southern blot) transfers its purity/impurity profile, and its potency DNA; Northern blots transfer RNA, and may differ in a definable way. (See also Western blots transfer proteins (also called biogeneric, follow-on biological) protein blots). biotechnology The industrial use of bolus A concentrated mass of injected living things, specifically genetically medication. engineered organisms. broth The contents of a microbial bioreac- biotransformation The chemical tor: cells, nutrients, waste, and so on. modification (or modifications) made by an BSA Bovine serum albumin; a protein organism on a chemical compound, such as derived from cow serum and commonly used nutrients, amino acids, toxins, and drugs as a growth additive for animal cell culture. in the body. Important in ADC bioanalysis, buccal delivery Transmucosal (across the where structural changes in a matrix can mucosal membranes) drug delivery by way cause complexity in vitro and in vivo. of the mouth. BLA Biologics license application; the re- buffer (buffering agent) A solution quired application for marketing a biologic containing a weak acid and a conjugate base product in the United States. Most biotech- of this acid; it resists change in pH near nology-derived drugs are approved through a specific value when an acid or a base is a BLA, rather than an NDA, although some added to it because the acid neutralizes any biologics, such as recombinant insulin and added base and vice versa. For example, human growth hormone, considered to be bicarbonates and some proteins in biological simpler in structure and well-characterized, fluids, when in solution, tend to stabilize the have been approved under NDAs. hydrogen–ion concentration by neutralizing blinding Clinical trial technique in (within limits) both acids and bases so the which, to eliminate bias in a research study, solution resists changes in pH. subjects (and sometimes clinical investiga- bulk active ingredient Also bulk drug tors) remain unaware of which therapeutic substance, the active ingredient that is for- approach (for example, investigational mulated with excipients to produce the drug product or standard treatment) is provided. product formulation. Biopharmaceuticals are blotting Transfer of nucleic acids produced “in bulk” through bioprocessing. or proteins from an electrophoresis gel bulking agent An additive that increases strip to a chemically reactive paper or the volume of a solution or a solid. membrane (such as nitrocellulose paper) or

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monosaccharides, such as glucose, galactose, C and fructose. Monosaccharides can be linked cake The solid sediment that has been together into what are called polysaccharides compacted in a centrifuge after removal of as (or oligosaccharides) in almost limitless ways. much liquid as possible; or the remaining solid Oligosaccharides contain a small number after completion of a lyophilization. (typically three to 10) of component sugars. calorimetry Analytical method that mea- carbonyl bond An oxygen atom double- sures heat loss or gain resulting from physical bonded to a carbon atom; the carbon atom or chemical changes in a sample. Differential then has two additional bonds to attach to the scanning calorimetry compares the results of rest of the molecule. heating a sample to those for heating a refer- carcinogenic Cancer-causing; many ence material—for example, to measure the agents that are carcinogenic are mutagens temperature at which the sample crystallizes, (agents that increase the occurrence of muta- changes phase, or decomposes. tion). campaigned production Continuous cascade effects A series of events that production of successive batches of the same result from one initial cause. product. catabolites Waste products of catabolism, CAPA Corrective and preventive action; a by which organisms convert substances into quality system defined by 21CFR 820.100; excreted compounds. the policies, procedures, and support systems cation A positively charged ion (having that enable a firm to assure that exceptions are fewer electrons than protons). followed up with appropriate actions to correct cation exchange chromatography A the situation, and with continuous improvement method for separating molecules on the basis tasks to prevent recurrence and eliminate the of positive charge; it can use strong or weak cause of potential nonconforming product and cation exchangers. other quality problems. [From FDAQSG] CBE Changes being effected; a regulatory capillary electrophoresis The miniatur- submission sent to FDA to notify them of ized instrumental version of traditional elec- minor changes in a manufacturing process or trophoresis using capillary column technology its control. The sponsor is permitted to make (that is, tiny fused-silica tubes with 20 to 100 the changes without waiting for FDA response, μm inner diameters) and light-absorbance or and the changes become part of the existing fluorescence detection. licensed process. (See PAS) capillary isoelectric focusing A method CBE-30 Changes being effected within 30 for separating molecules on the basis of days; a regulatory submission sent to FDA isoelectric point. to request minor changes in a manufacturing capsid The outer protein shell of a virus process or its control. FDA has 30 days in particle (virion). which to respond, after which the change is carbohydrates Molecules consisting of considered approved and the part of the exist- sugars. The basic carbohydrate units are called ing licensed process. (See PAS)

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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, Cell culture on the smallest scale uses and provides health education. petri dishes. CDER Center for Drug Evaluation and Re- search; the largest of FDA’s six centers, CDER CBER Center for Biologics Evaluation and regulates prescription and over-the-counter Research at the FDA; CBER regulates vaccines, drugs. Following a transfer of responsibility gene therapy, cellular products, allergenic for biologics that began in June 2003, CDER extracts, antitoxins, antivenins, venoms, and now also regulates therapeutic proteins and blood and blood products (clotting factors and monoclonal antibodies for in vivo use, which plasma derived products). were formerly regulated by CBER. CCD Charge-coupled device; semiconduc- CE Capillary zone electrophoresis; an tors connected so that the output of one serves analytical method in which a mixture is frac- as the input for the next (digital cameras, tionated using charge; analytes are detected video cameras, and optical scanners all use using optical density, mass, or other physical CCD arrays); a light-sensitive integrated circuit properties. Also called CZE. that stores and displays the data for an image. cell bank A defined population of cells, CCS Rotationally average collision such as an immortalized cell line, grown by cross-section; The CCS of an ion is used to a defined process and cryopreserved in a calculate the area of an ion in the gas phase defined process and within a defined passage and expressed in Omega (see also Omega). number range. The assumption is that each Omega can be calculated empirically through vial from a cell bank is comparable, and when the measurement of an ion’s drift time as it thawed and added to a manufacturing vessel passes through a gas filled drift tube or travel- (or an analytical assay), will perform in a ling wave ion guide (see also TWIG). consistent way. (See master cell bank, work- CD Circular dichroism; the absorption of ing cell bank) left and right circularly polarized light, a cell banking Developing, reproducing, ali- property of molecules that are optically active. quoting, and storing cells at a defined passage CD spectroscopy is a form of light-absorption and homogeneity for particular uses. spectroscopy that measures the difference cell culture Cells taken from a living in left and right circularly polarized light organism and grown in the lab (in “culture”). absorbed by a substance. The spectra can Methods used to grow animal cells in the lab

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are usually different from those used to grow chaotropic Disrupting the structure of microorganisms such as bacteria. water, macromolecules, or living systems to cell lines When cells from the first culture promote activities that would have been inhib- (taken from the organism) are used to make ited by the water, molecules, or systems. subsequent cultures, a cell line is established. characterization Precisely deciphering Thanks to genetic or other manipulations, im- and describing an entity’s properties (physical mortal cell lines can replicate indefinitely. and chemical properties in the case of a mo- cellulose A fibrous polysaccharide mate- lecular entity; genetic and stability properties rial, the main ingredient of plant cell walls. in the case of a cell line). centrifugation Spinning samples at charge The electrical state of an atom high speeds, using centrifugal force (up to or molecule, whether positive, negative, or 500,000 times the force of gravity) to sepa- neutral, according to the difference of protons rate substances with very small differences in (positively charged) to electrons (negatively density or weight. charged). centrifuge A laboratory or industrial appa- charge variant A form of a protein that ratus that separates mixed samples of differing differs with respect to its ionic charge as density by spinning them at high speed. observed by methods such as ion exchange certificate of analysis (COA) A batch- chromatography (IEC) or isoelectric focusing specific document that is used to list test (IEF) gel electrophoresis. Charge heterogeneity methods and results, including applicable provides important information about mono- specifications, and a final batch disposition clonal antibody product quality and stability. CFR Code of Federal Regulations; the US chelation The binding or holding of a regulations that directly apply to biopharma- metal ion (such as copper, zinc, cadmium, ceutical development are in Title 21 parts 58, nickel, or cobalt) by another molecule or by 210, 211, and 600. Parts 50, 56, and 312 another part of the same molecule; used in a apply to clinical trials. form of affinity chromatography called “metal cfu Colony forming units; a measurement of chelate chromatography.” the number of microorganisms present derived chelator A molecule used to bind a metal from the number of colonies that form in a test ion with more than one organic group to form culture. a highly stable structure. cGMP Current good manufacturing practice; chemical synthesis A non-biotech see GMP. method of manufacturing chemicals, including change control A system by which drugs. changes to facilities, equipment, and processes chemostat A growth chamber that keeps a are documented and approved. The change bacterial culture at a specific volume and rate control system ensures that changes are of growth by limiting nutrient medium and evaluated and approved prior to implementa- removing spent culture. tion to maintain the facilities, equipment, and chimera Chimeric proteins (or fusion processes in a validated state. proteins) are created through the joining of

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two or more genes that originally coded for ment) without moving them or taking them separate proteins. apart, using a high-pressure rinsing treatment, chirality The condition of being chiral, sometimes followed by steam-in-place (SIP) that is, a molecule in a configuration that is sanitization. Chemically cleaning and steril- symmetrical with its mirror image; a right- izing equipment or systems without removing handed chiral molecule rotates polarized them from their installed location. light rightward, a left-handed chiral molecule clarify To clear liquid of suspended rotates polarized light leftward. particles through filtration, extraction/precipi- CHO cells Chinese hamster ovary cells; in tation, or centrifugation. cell culture, the cells of a female hamster’s classical pharmaceuticals Small-mole- reproductive organs, which historically have cule, non-biotech drugs produced by chemical proven to be the basis for good expression synthesis. systems in analytical studies and for produc- clean room A room in which the ing pharmaceutical proteins. concentration of airborne particulate matter chromatography A technique used to is controlled at specific limits to facilitate separate molecules based on how they tend the manufacture of sterile and high-purity to bind to various solids, liquids, and gases; products. Clean rooms are classified according based on the differential distribution of the to the number of particles per volume of air to substances between a stationary phase (sticky meet standards of cleanliness. Contaminants material such as silica gel or silicic acid, on surfaces and people entering and exiting usually contained in a column, tube, or capil- the room also are controlled. lary) and a gaseous or liquid mobile phase clearance Clearance—in volume/unit (a medium that carries the sample through time—of a drug or chemical from a body the stationary phase). This very effective fluid, usually plasma or blood, by specified technique can separate substances that are route(s) and mechanism(s) of elimination, nearly identical. as indicated by a subscript (e.g., ClR, urinary chromophore A molecule that absorbs UV clearance; ClH, hepatic clearance, etc). ClT, or visible light. total clearance, indicates clearance by all chromosome A long and complex DNA routes and mechanisms of biotransformation chain containing the genetic information and excretion, operating simultaneously. ClT (genes) of a cell. Prokaryotes contain only a = kel • Vd. Following intravenous administra- single chromosome; eukaryotes have more than tion, ClT = D/AUC; following administration of one, made up of a complex of DNA, RNA, and drug by any route other than the intravenous, protein. The exact number of chromosomes is ClT = F D/AUC. species-specific. Humans have 23 pairs. clinical development The phases of chymotrypsin A digestive enzyme that drug development during which a drug is can cleave peptide bonds. tested in human subjects, also referred to CIP Clean-in-place; a way to clean large as clinical trials. vessels (tanks, piping, and associated equip- clinical endpoint An indicator (such as

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blood pressure) measured in a human subject tion of unknown colors in terms of standard to assess the safety, efficacy, or other objec- colors; techniques may be visual, photoelec- tive of a clinical trial. tric, or spectrophotometric; colorimetry is clinical hold Temporary cessation of a useful in determining the concentration of a clinical trial by FDA if the agency is concerned chemical with color in a solution by measur- about a drug or study protocol. The trial may ing the intensity of the color and relating that resume when the problem is solved. intensity to the concentration of the solution. clone To duplicate exactly, whether a column A vertical, cylindrical container or gene or a whole organism; or an organism vessel often used in separation processes such that is a genetically identical copy of another as extraction, distillation, and chromatography. organism. column aspect ratio The ratio of a cloning vectors Methods of transferring column’s height to its diameter. desired genes to organisms that will be used column chromatography A separation to express them. Cloning vectors are used to method in which the different components of a make recombinant organisms. mixture migrate through a column at different CM Carboxymethylcellulose; a weak ion- rates of speed based on their relative affinity exchanger that is often coupled to a resin used for the stationary phase. in charge based separation chromatography. It comparable Product made before and is a cation exchange resin. after a given process change is comparable if CMC Chemistry, manufacturing, and the change is shown to have no adverse effect controls; the section of a BLA, NDA, or IND on the key quality attributes of the product, describing the composition, manufacture, such as purity, potency, PK/PD, stability, and and specifications of a drug product and its safety. Small differences in, for example, the ingredients. impurity profile are permitted, as long as the CMO Contract manufacturing organization; function is not affected. (See equivalent) a company contracted to perform development comparability protocol A protocol that and/or manufacturing services. defines the experiments and acceptance codon A sequence of three nucleotide criteria that will be used to evaluate a product bases in mRNA that specifies production of an before and after a process change, and if met, amino acid or represents a signal to stop or will provide documented evidence that the start a function. products are comparable. collision induced dissociation (CID) complaint Also customer complaint; fragmentation Mechanism by which to frag- any oral or written communication from an ment molecular ions in the gas phase. The mo- end user of a medicinal product indicating lecular ions are usually accelerated by some that it had an adverse effect on a patient, did electrical potential to high kinetic energy and not function as specified, or appeared to be then allowed to collide with neutral molecules contaminated or defective in any way. The (often helium, nitrogen, or argon). sponsor must promptly investigate all such colorimetry The measurement and defini- complaints and document the investiga-

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tion in a retrievable file. If the complaint weight or volume, as weight per unit volume, is confirmed, corrective and preventive as molarity (a one-molar solution contains actions are required. Examples include one gram-mole of solute per liter of solu- FDA notification, product lot(s) withdrawal, tion), or as normality (a one-normal or one- product recall, and review of medical files molar solution contains one gram-equivalent of adverse events caused by the product. weight of solute per liter of solution). These requirements are found in US regula- conformation The shape of a molecule, tions in 21 CFR 314, the GCP regulations. produced by the specific spatial arrangement complement A group of proteins in of the units that compose it. the blood that work in concert with other consent decree Status imposed by FDA immune system proteins and cells (such as on a company in serious violation of federal antibodies) in attacking foreign substances. regulations and related safety and quality component 1. Raw materials and standards. A company must agree to a series components (tubing, stoppers, vials, filters) of measures aimed at bringing its manufac- having direct product contact during manu- turing standards into compliance with federal facturing, which are regulated under 21 CFR regulations. Until agreed-upon conditions 84. 2. Differentiated from raw materials are met, a company may be forbidden to dis- and excipients, which are chemical entities, tribute its products in interstate commerce, and usually rated as lower in risk to patient except for those products deemed essential and product quality. (Note: These terms for the public health. may be used interchangeably or loosely, contaminant A foreign agent or material and definitions vary between US, Europe, that is not introduced as part of processing, and WHO). (See raw material, starting such as airborne particulates or adventitious material, API) organisms. concentration The amount of a par- continuous process verification An ticular substance in a given quantity of alternative approach to process validation in solution, usually stated as a percentage by 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 Columns for bioseparations are avail- through various physicochemical means able in a wide variety of dimensions, chemistries, and pore sizes to best meet designed to provide well-defined pharmaco- separation requirements. kinetic profiles.

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Convergence Chromatography (CC) CRISPR/Cas9 A biological system uti- Due to advancements in the performance of lized for targeted editing of a genome. analytical instruments designed to manage critical micellar concentration (CMC) supercritical fluids, convergence chromatog- The concentration of detergent at which raphy is a viable separation technique that micelles begin to form; from a practical complements liquid and gas chromatography. point of view, the CMC defines the minimum

The primary mobile phase in CC is dense CO2 concentration of free detergent that must in either a supercritical or subcritical state, be present to keep membrane proteins which mitigates the use of harmful solvents in solution. CMC values are affected by necessary in normal-phase LC mobile phases. temperature, ionic strength, pH, and buffer Either reversed-phase (with water-compatible composition. The CMC is important in solvents) or normal-phase (with organic determining whether a detergent can be solvents) chromatographic stationary phases removed by dialysis. For example, a free may be used. detergent molecule may pass through the Coomassie blue dye A sensitive stain membrane but the largest micelle will not. for proteins used to visualize the bands in (Compare to CMC: chemistry, manufactur- SDS-PAGE; also Coomassie brilliant blue. ing, and controls.) COS, CV-1 African green monkey kidney critical process parameter An input cells, an established cell line that is com- parameter (process setpoint) to a unit opera- monly used for biotechnology. tion that must be tightly controlled by the cosmid An artificially constructed plas- operator, either manually or automatically, mid vector that contains a specific bacterio- and which must be kept within a specified phage gene, which allows it to carry up to range in order to produce output of accept- 45,000 base pairs of desired DNA. able quality within specifications. These cot1/2 DNA A curve that measures parameters are identified during process genome complexity by determining the time development. taken for half the DNA in a sample to rean- critical quality attribute A quality neal (renature); it is measured for any new characteristic that must be controlled within genome and compared to a standard such as defined limits to ensure acceptable product the E. coli genome. quality and performance. covalent bond Chemical bond in which CRO Contract research organization or two atoms share one or more electron(s). clinical research organization; a company Cp Process capability; a statistical contracted by a sponsor to perform preclini- measurement of the relation between the cal or clinical pharmaceutical research. observed variability of a process and the cryoconcentration When a solution is specifications or requirements for individual frozen, water freezes as pure ice crystals. lots. Computed by dividing the range by the The remaining liquid therefore has a higher process variability (sigma); a larger number solute concentration than the original indicates a more capable process. solution.

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cryogranulation Use of a stream of liquid nitrogen to quickly create frozen, discrete D pellets of a solution such as bulk or final drug Da Dalton; the unit of molecular mass, formulation. very nearly equal to that of a hydrogen atom cryopreservation Maintenance of frozen (precisely equal to 1 on the atomic mass scale), cells, usually in liquid nitrogen. named after John Dalton, who developed the C-terminal Carboxyl-terminal; the carboxyl atomic theory of matter (kDa, kilodalton). terminus of a protein chain, with a free car- data directed analysis (DDA) An MS ac- boxyl group. quisition approach that automatically switches culture medium A complex mixture of between MS and MS/MS acquisition modes organic and inorganic materials used as a upon detection of ion characteristics pertinent nutrient system for the cultivation of cells. to molecules of interest. Often used for the cuvette A transparent or translucent identification of proteins and peptides within box-shaped container with precisely measured complex mixtures, but also applicable for dimensions for holding liquid samples to be put detection and identification of small molecules into a spectrophotometer; also such a container within a complex sample matrix. with optical surfaces used to mold samples data independent acquisition (DIA) An so that their light-absorbing properties can be MS acquisition approach that can acquire a measured. single data set useful for both identification Cys Cysteine; one of more than 20 natu- and quantification of detectable peptides in a rally occurring amino acids. complex mixture. cytokine A protein that acts as a chemical DEAE Diethylaminoethyl; a weak ion- messenger to stimulate cell migration, usu- exchanger that is often coupled to a resin and ally toward where the protein was released. used in charge based separation chromatogra- Interleukins, lymphokines, and interferons are phy. It is an anion exchange resin. the most common. deamidation Removal of one or more cytopathic Damaging to cells, causing amide groups from the Gln or Asn residue in them to exhibit signs of disease. a protein, converting the residues to Glu, Asp, cytoplasm The protoplasm of a cell, found or isoAsp. Depending on the protein, this may outside the nucleus (inside the nucleus is have no effect, or major effects, on potency, the nucleoplasm). Protoplasm is a semifluid, stability, or solubility. viscous, translucent mixture of water, proteins, deglycosylation The enzymatic cleavage lipids, carbohydrates, and inorganic salts found of glycan structures from proteins so they in all plant and animal cells. can be further analyzed. cytostat Something that retards cellular degradants The smaller parts that are left activity and production. This can refer to cy- over after a molecule or solution degrades. tostatic agents or to machinery, such as those degradation Loss or reduction of quality, that would freeze cells. integrity, or character; a chemical reaction that cytotoxic Causing cell death. breaks down a molecule into smaller parts.

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delivery matrix A heterogeneous hydrophilic (water-attracted) properties that semisolid matrix (such as a biopolymer gel) can dissolve fats and oils. for the sustained delivery of drug substances dextran calibration ladder Used to cali- directly to the tissues; a matrix can be modi- brate and normalize labeled glycan retention fied to optimize the dosage or time period times on a chromatographic system. during which the drug is delivered. dialysis/diafiltration Membrane denaturation A condition in which a ultrafiltration in which a large solute (such as protein unfolds or its polypeptide chains a protein) is washed or dialyzed with another are disordered, rendering the molecule less solution; for example, changing buffer condi- soluble and usually nonfunctional. tions without affecting protein concentration. denature To unfold a protein or break it up, diastereomer A stereoisomer (one of two changing its usual three-dimensional structure. or more molecules with the same atoms in the Proteins can be denatured by chemical action, same order but different three-dimensional heat, or even agitation of a protein solution. shapes) having two or more chiral centers that denatured protein A protein having is not a mirror image of another stereoisomer unfolded or disordered polypeptide chains, of the same compound; glucose, galactose, which render the molecule less soluble and and mannose are all diastereomers. usually nonfunctional. Sometimes a dena- differential scanning calorimetry Ana- tured protein can be refolded (renatured). lytical method that independently measures derivatization A sampling technique; the rate of heat flow to a sample against a chemical conversion into a derivative form reference standard of the same temperature. for identification purposes. Data are obtained by monitoring the differ- design space The multidimensional ential heat flow as a function of temperature. combination and interaction of input vari- DSC can measure heat capacities, phase ables (e.g., material attributes) and process transitions, dehydration, and heats of reaction. parameters that have been demonstrated diluent A chemically inert substance added to provide assurance of quality. Working to a solution to increase the volume and reduce within the design space is not considered a the concentration; a diluting agent. change. Movement out of the design space dimer A polymer made up of two identical is considered to be a change and would molecules. When three monomers link up, the normally initiate a regulatory post-approval resultant polymer is called a trimer. Larger change process. Design space is proposed polymers are usually referred to by placing by the applicant and is subject to regulatory a number before the “-mer” suffix: 4-mer, assessment and approval. [From ICH Q8] 5-mer, 6-mer, and so on. desorption The opposite of adsorption; dissociation constant A specific type the release of adsorbed molecules, particles, of equilibrium constant that measures the or cells into the surrounding medium. propensity of a larger object to separate detergents Cleaning agents: chemicals (dissociate) reversibly into smaller com- with both hydrophobic (averse to water) and ponents, as when a complex falls apart

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in a protein; such bonds (links, bridges) contribute to the tertiary structure of the protein. 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. DMPK Drug Metabolism and Pharmaco- This is a simplistic model of the DNA kinetics. Determining the DMPK properties structure. of a drug allows the drug developer to into its component molecules, or when a understand the safety and efficacy data salt splits up into its component ions. The required for regulatory approval. dissociation constant is usually denoted Kd DMSO Dimethyl sulfoxide; a common and is the inverse of the affinity constant. cryoprotectant used to cryopreserve cells Dissociation constants are commonly used to and tissues. describe how tightly a ligand (such as a drug) DMT dimethoxytrityl; a protecting group binds to a protein. Such binding is usually used in oligonucleotide synthesis. Oligo- non-covalent, i.e., no chemical bonds are nucleotide purification can be done DMT on made or broken. Since the binding is usually (usually on a RP SPE cartridge) or DMT off. described by a two-state process P + L = C DNA Deoxyribonucleic acid; the nucleic the corresponding dissociation constant is acid based on deoxyribose (a sugar) and defined Kd = [P][L]/[C] where [P], [L], and [C] the nucleotides G, A, T, and C. Double- represent the concentrations of the protein, stranded DNA has a corkscrew-ladder shape ligand, and bound complex, respectively. The (the “double helix”) and is the primary dissociation constant has the units of molar component of chromosomes, which thus (M), and corresponds to the concentration carry inheritable characteristics of life. (See of ligand [L] at which the binding site on nucleotides, nucleic acids) the protein is half occupied, i.e., when the DNA array Spots of DNA, oligonucle- concentration of protein with ligand bound otide, or cDNA arranged on a solid support [C] equals the concentration of protein with such as a glass or silicon “DNA chip” (or no ligand bound [P]. The smaller the dis- microarray), which is used for screening, sociation constant, the more tightly bound sequencing, genetic mapping, and so on. the ligand is; for example, a ligand with a DNA fingerprinting Sequences of nanomolar (nM) dissociation constant binds nucleic acids in specific areas (loci) on a more tightly than a ligand with a micromolar DNA molecule are polymorphic, meaning (mM) dissociation constant. that the genes in those locations may differ disulfide bond A covalent bond formed from person to person. DNA fragments between sulfur atoms of different cysteines can be cut from those sequences using

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restriction enzymes. Fragments from vari- enough temperature (ie., above the melting ous samples can be analyzed to determine temperature of the double-stranded form). whether they are from the same person. The downstream processing Bioprocess- technique of analyzing restriction fragment ing steps following fermentation and/or length polymorphism (RFLP) is called DNA cell culture, a sequence of separation and typing or DNA fingerprinting. It is also now purification activities needed to obtain the possible to detect polymorphisms consist- required drug product at the necessary level ing of a single nucleotide. These are called of purity. single-nucleotide polymorphisms (SNP). DQ Design qualification; a documented DNase Deoxyribonuclease, the enzyme review of the design, at an appropriate that breaks up and destroys DNA sequences stage of stages in the project, for con- (a protective mechanism in higher organ- formance to operational and regulatory isms). expectations. DNA sequencing Determing the order drift time The drift time of an ion is of nucleotide bases in a DNA molecule. a measure of how long it takes to move DNA vaccine A nucleic acid vaccine: through a mobility region in a mass Genes coding for specific antigenic proteins spectrometer. For a travelling wave, this is are injected to produce those antigens and measured in low hundreds of milliseconds trigger an immune response. (see also TWIG). DOE Design of experiments; a term for drug discovery Methods for identifying experiments that are planned and analyzed new therapeutic molecules. High-throughput using statistical design tools. A structured, techniques include combinatorial chemistry, organized method for determining the genomics, and proteomics analysis as the relationship between factors affecting a starting point. Low-throughput methods process and the output of that process. include traditional disease research. [From ICH Q8] drug product The final dosage form of domain A structurally distinct subregion a pharmaceutical medicine containing drug of a protein. A particular domain may have substance formulated with selected excipi- a function associated with it, and may be ents and packaged for the end user. found in more than one protein. drug to antibody ratio (DAR) The rela- dosage group A group of subjects in a tive content of antibody and cytotoxic agent clinical trial receiving the same dosage of a in an antibody-drug conjugate (ADC). drug being tested. drug substance The active drug chemi- double-stranded oligonucleotide Two cal or biological substance in purified bulk oligonucleotide strands held together by form. The drug substance is further pro- hydrogen bonding between complimentary cessed to derive a drug product. Also known base pairs. The double-stranded oligo- as active pharmaceutical ingredient (API). nucleotide can be broken apart into the two duplex Double-stranded form of DNA complimentary single strands with a high or RNA.

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dwell volume The dwell volume com- proteins) by transferring electrons to them. prises all the system volume from the mixer electroosmotic The movement of a liquid to the head of the column. out of or through a porous material or a biological membrane under the influence of an electric field. E electrophoresis Analytical method in EBA Expanded-bed adsorption; a chroma- which an electric field is applied to a medium tography method that uses an upward flow of (paper, thin-layer plates, polyacrylamide or liquid in a column of suspended, dense chro- agarose gel), causing charged molecules to matography beads to allow passage of crude, move through it. In capillary electrophoresis, unclarified raw materials without clogging the samples move through a buffer-filled tube chromatography medium. (capillary). In gel electrophoresis, samples efficacy The ability of a substance (such move through a thin agarose or polyacryl- as a protein therapeutic) to produce a desired amide gel. Bigger biomolecules (and those clinical effect; its strength and effectiveness; carrying few electrically charged chemical usefulness; the power to produce an effect. groups) move slower through the medium efficiency of delivery The relative ef- than smaller molecules (and those with many fectiveness of a drug delivery system. electrically charge chemical groups). EHSS exact hard sphere scattering; An electrospray ionization Technique for ion is modeled by a collection of overlap- generation of charged ions for mass spectrom- ping hard spheres with radii equal to hard etry. Analyte containing solution is dispersed sphere collision distances (see also PA). The as a fine charged aerosol into the MS by orientationally averaged momentum transfer passage of the liquid through a electrically cross section is calculated by determining the charged capillary emitter. scattering angles between the incoming buffer electrostatic binding A chemical bond of gas atom trajectory and the departing buffer two atoms or molecules by an electrostatic force gas atom trajectory. (like static electricity) caused by one or more elastomeric closure A rubber or electrons moving from one atom to the other. rubber-like closure or stopper; a packaging elimination The rate at which drugs are component that may come into direct contact removed from the body. with the enclosed drug, which is usually an ELISA Enzyme linked immunosorbent injectable. assay; a test to measure the concentration of electrolytes Ionized salts in body fluids; antigens or antibodies. electrolyte solutions are solutions containing eluate Also called elution fractions; the charged atoms or molecules. separated components of a mixture that wash electron transfer dissociation (ETD) out from a chromatography column during fragmentation A method of fragmenting elution. ions in a mass spectrometer. ETD induces eluent The substance used to recover fragmentation of cations (e.g., peptides or samples from a chromatography column;

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sometimes an elution solvent. When a buff- encapsidation During formation of a virus ering agent is used, it is called an elution particle, the process by which nucleic acid buffer. Sometimes a solvent is used and just is incorporated (encapsidated) into the viral referred to as the eluent. capsid. (See also capsid) elution Washing out; removing adsorbed encapsulation To enclose in a capsule, material with a solvent or buffering agent. usually one made of a biodegradable polymer. elution profile A graph made to show endogenous Growing or developing from a how much material is being carried out cell or organism, or arising from causes within of the column by the eluent in column the organism. chromatography over time. The graph will endonuclease A restriction enzyme that show a number of different peaks; each peak breaks up nucleic acid molecules at specific represents a different separated material sites along their length. Such enzymes are from the original mixed substance. Also naturally produced by microorganisms as a called a chromatogram. defense against foreign nucleic acids. elution volume The amount of eluent endoplasmic reticulum A highly that passes through the column in column specialized and complex network of branch- chromatography before a particular peak ing, interconnecting tubules (surrounded by appears in an elution profile (that is, before membranes) found in the cytoplasm of most a specific substance of interest comes out animal and plant cells. The rough endoplasmic with it). Also, the volume during which a reticulum is where ribosomes make proteins. particular compound is eluted. It appears “rough” because it is covered with EM Electron microscopy; in which ribosomes. The smooth endoplasmic reticulum instruments focus electrons like optical is the site for synthesis and metabolism of lip- microscopes focus light. Scanning electron ids, and it is involved in detoxifying chemicals microscopy (SEM) and transmission electron such as drugs and pesticides. microscopy (TEM) are sometimes used in endotoxin A poison in the form of a fat/ bioanalytical laboratories. sugar complex (lipopolysaccharide) that EMA European Medicines Agency; the forms a part of the cell wall of some types of agency responsible for regulating biophar- bacteria. It is released only when the cell is maceuticals in the European Union. ruptured and can cause septic shock and tissue emulsification A process that creates a damage. Pharmaceuticals are tested routinely stable mixture of two liquids that normally for endotoxins. would not mix together (such as oil and engineering batch A batch run at the de- water) by forcing one to disperse in the fined cGMP production scale for the purpose of other as droplets. evaluating the performance of any or all of the enantiomer Either of a pair of chemical unit operations prior to initiating cGMP manu- compounds whose molecular structures have facturing. It is not intended to be released as a mirror-image relationship to each other a fully compliant cGMP batch. An engineering (see diastereomer). batch may be executed using a batch record,

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but need not comply with all instructions and eukaryotes Complex organisms, often requirements. multicellular, whose cells contain nuclei. enthalpy Heat content; enthalpy change exception A deviation from approved GMP of a chemical reaction equals the difference procedure; an out-of-specifications result or between the heat put into breaking bonds and unexpected or out of trend result; a customer the heat released by new bond formation. complaint. Exceptions must be detected, environmental monitoring A docu- investigated, and managed using quality mented series of sampling and testing per- systems such as CAPA (corrective and preven- formed on controlled environments to assure tive action). compliance with room classifications. Testing excipient A type of raw material that is typically includes monitoring of viables and present in the drug product and thus has direct non-viables via standardized sampling meth- patient contact; includes inert materials such ods performed at established time intervals. as bulking agents, stabilizing agents, preser- enzymes Proteins that catalyze bio- vatives, salts, solvents, or waters. An excipient chemical reactions by causing or speeding up must be evaluated for safety in animals, reactions without being changed in the process unless it has been approved as GRAS or is on a themselves. list of approved excipients. epithelium (epithelial) The layer(s) of exclusion limit In size-exclusion (or gel cells between an organism or its tissues or filtration) chromatography, the smallest size organs and their surrounding environment or dimension of molecule that is too large to (skin cells, inner linings of lungs or digestive enter the pores on gel particles. organs, outer linings of kidneys, and so on). excretion The elimination of substances epitope A molecular region on the surface from the body. In rare cases, some drugs ir- of an antigen that elicits an immune response reversibly accumulate in body tissue. and can combine with the specific antibody exogenous Developing from outside, produced by such a response; also called a originating externally. Exogenous factors can determinant or an antigenic determinant. be external factors such as food and light that equivalence Two lots of product are equiv- affect an organism. alent if, within experimental error, they are exoglycosidase A glycoside hydrolase essentially equal in purity/impurity, potency, enzyme that breaks the glycosidic bonds at the identity, and safety. A more stringent require- terminal residue. ment than comparability. (See comparable) express To translate a cell’s genetic Escherichia coli Bacteria normally found information, stored in its DNA (gene), into a in the intestinal tract and widely used in specific protein. biochemical and genetic studies and genetic expression system A host organism com- engineering. E. coli is often used as a vehicle bined with a genetic vector (such as a virus or for combining a segment of DNA with an unre- circular DNA molecule called a plasmid) that is lated segment, creating continuous DNA that loaded with a gene of interest. The expression does not occur naturally (recombinant DNA). system provides the genetic context in which

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a gene will function in the cell—that is, the intact IgG, which removes the Fc portion of gene will be expressed as a protein. the molecule. F(ab)’2 binds two moles of expression vector A virus, plasmid, antigen per mole. (See Fab) cosmid, or artificial chromosome that factors (coagulation factors) Protein delivers foreign genes to a host, creating a constituents of blood, numbered according to recombinant organism that will express the the order in which they were discovered, which desired protein. separate out in a traditional fractionation extractables 1. Substances withdrawn procedure (Cohn fractionation); Factor VIII, for (such as the medicinally active components example, is a blood serum protein involved in of plant or animal tissue) by a physical or clot formation that is also called antihemo- chemical process. 2. Materials that are actu- philic globulin. ally removed from a container or closure Fc Portion of an immunoglobulin molecule by a given formulation or product. (See that carries various effector functions, such as leachables) the ability to bind complement. Important in extraction Liquid-liquid extraction is a immunological activities, and separable from process in which a solute is removed from the antigen-binding portion by enzymatic or a liquid by transferring the solute into a chemical cleavage. (See Fab) second liquid phase. The two liquid phases Fc/2 An ~25 kDa IgG fragment correspond- must be insoluble with each other. Separa- ing to the heavy chain region of the Fc subunit. tion is based on different solubilities of Can be produce by means of IdeS digestion the solute in the two phases. Extraction is and subsequent reduction. Often analyzed in gentle and suitable for unstable molecules. middle-down/up LC/MS assays. extrusion A process of forming rods, Fd An ~25 kDa IgG fragment corresponding tubes, or other continuously formed pieces to the heavy chain region of the F(ab) subunit. by pushing hot or cold semisoft solid mate- Can be produce by means of IdeS digestion rial through a die; also any process of push- and subsequent reduction. Often analyzed in ing a substance through holes or a tube. middle-down/up LC/MS assays. FD&C Act Food, Drug and Cosmetic Act of 1938; the major legislation regulating F such products in the United States. It requires Fab Antigen-binding fragment of an companies to prove that their products are safe immunoglobulin. An IgG Fab is prepared by before marketing them, extends FDA oversight enzymatic cleavage of the intact tetrameric to cosmetics and therapeutic devices, explic- IgG, and reduction of the inter-chain disul- itly authorizes factory inspections, requires fide links, and binds one mole of antigen standards for food, and adds injunctions to per mole. [See F(ab)’2] previous penalties of seizure and criminal F(ab)’2 Dimeric antigen-binding frag- prosecution for violations of related laws. ment of an immunoglobulin. An IgG F(ab)’2 FDA United States Food and Drug is prepared by enzymatic digestion of the Administration.

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for industrial purposes, such as to produce therapeutic molecules or specialty foods and beverages. fermenter A large bioreactor used to grow bacteria or fungi in liquid culture. fill-and-finish The part of a manufacturing process concerned with packaging a product in its final form. filter Porous material through which a Liquid formulations are most common liquid or gas is passed so that particulates and for biopharmaceuticals. impurities are held in suspension and removed FDA-483 A form prepared at the conclu- from the feed stream. Some impurities may sion of an inspection (without review by FDA pass through. management) citing observations that may filtrate The part of a mixture that passes constitute violations of law, in the opinion of through a filter, also called permeate. the inspector. Originally intended to inform filtration Separation of solid particles companies of possible product adulteration so from a fluid by passing the mixture through a that prompt corrective action could be taken, porous, fibrous, or granular substance. 483s now list a host of observations. Ac- FISH Fluorescence in situ hybridization; an cessible through the Freedom of Information analytical method in which specific se- Act by competitors, potential customers, and quences of DNA are labeled with fluorescent the media, 483s can lead to withholding of molecules, hybridized (amplified), and then product approvals, may come into play in due detected with a fluorescence microscope. diligence phases of acquisitions and mergers, floc A fluffy aggregate that resembles a and can potentially cost companies money. woolly cloud. FDAMA FDA Modernization Act; enacted flocculant A precipitate (floc), sometimes in November 1997, this amends the FD&C Act a flaky or fluffy aggregate that resembles a to improve (facilitate) the regulation of food, woolly cloud; the aggregation (flocculation) of drugs, devices, and biological products. initially separate cells that form flocs. feedstock Also feed or feed stream; most flux Usually, the rate of flow. A lower often the raw broth containing particles to be flux means slower flow, usually caused by removed that is placed into a laboratory or clogging. manufacturing appliance such as a centrifuge fMet N-formyl methionine; a variant of the or chromatography column. amino acid methionine that many bacterial feed stream Also feed or feedstock; cells can produce. In mammals, fMet results in most often the solution fed into a reaction or a strong adverse reaction by the body. separation/purification process. FMEA Failure modes evaluation and analy- fermentation Large-scale cultivation of sis; a method used to perform risk assess- microorganisms or single-celled creatures ment and risk mitigation. A unit operation is

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analyzed, and all the potential modes by which modifier for HPLC separations of proteins and it might fail are mapped out. Then a control peptides, especially when the sample is being strategy is defined to reduce the probability prepared for mass spectrometry analysis. that a given mode of failure will occur. Used in formulation The method and process of the aerospace and other industries with much selecting the components of a mixture; the success. (See also HACCP) product of such a process; the form in which a folding A process in which a protein drug is given to patients (tablets or injections, spontaneously forms into its correct, knotted for example); developed in concert with a drug tertiary structure that is held in place by delivery system and targeting mechanism chemical bonds and by attractive forces needed to get the active ingredient to its site between atoms. of action. follow-on biologic Another term for FPLC Fast Protein Liquid Chromatograpy; biosimilar or biogeneric. preparative or semi-preparative chromatogra- for-cause inspection An FDA facility phy typically with low-pressure resins, used to inspection carried out because of specific analyze or purify mixtures of proteins. information such as the results of a sample fraction A separate portion of a mixture, analysis, observations made during previ- often used to describe the part that contains a ous inspections, product recall or market particular molecular species. withdrawal, consumer or employee complaint, fractionation range The range of molecu- adverse reaction report, or suspicion of fraud. lar sizes that can fit (or diffuse) into the pores Also, a similar inspection of a clinic or an IRB. of a gel filtration chromatography medium forced degradation Also known as particle. accelerated degradation, a process whereby free radicals Short-lived, highly reactive the natural degradation rate of a product or molecular fragments that are often capable material is increased by the application of an of initiating/continuing chemical reactions additional stress to rapidly screen material by means of a chain reaction mechanism. stabilities. They are usually formed by the splitting of formal experimental design A structured, molecular bonds, which requires energy input. organized method for determining the relation- Free radicals act as initiators or intermediates ship between factors affecting a process and the in oxidation, combustion, polymerization, and output of that process. Also known as design of photolysis. experiments. [From ICH Q8] FT-IR Fourier transform infrared spectros- formamide A colorless, oily, hygroscopic copy; an analytical method that measures the liquid used to denature nucleic acids and as a ability of a sample to absorb different wave- solvent, softener, or chemical intermediate. lengths of infrared radiation: How much is ab- formic acid The simplest carboxylic acid, sorbed at each wavelength indicates the types miscible with water and most polar organic of chemical bonds present in the molecules solvents, and somewhat soluble in hydrocar- of the sample. The Fourier-transformation is bons. It is used in laboratories as a solvent a mathematical method used to interpret the

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vibrations of functional molecular groups and highly polar bonds. FT-IR produces a “finger- G print” illustrating the vibrational features of gas chromatography Analytical method all sample components. in which a volatile substance to be separated fucosylation A common modification is introduced into a stream of nonreactive involving oligosaccharides on glycoproteins or gas or other stationary phase. For example, in glycolipids, it is the process of adding fucose capillary gas chromatography, the gas mixture sugar units to a molecule such as N-glycans, moves through a tube coated with liquid, and O-glycans, and glycolipids. Fucosylation of how fast it moves through the tube depends on glycoproteins regulates the biological func- the degree to which it stays in the nonreactive tions of adhesive molecules and growth factor gas or dissolves in the liquid (partitioning). receptors. GCP Good clinical practice; according to 21 functional genomics A method of select- CFR Parts 56, 312, and 314, the regulations ing among the thousands of drug leads that that govern the actions and environment of can come out of discovery efforts. Whereas those working in clinical testing of drugs and genomics studies the genetic basis of organ- medical devices on human beings. These regu- isms and their diseases, functional genomics lations include rules for obtaining informed challenges drug lead candidates derived from consent and data integrity requirements. genomic studies with early development- gel filtration chromatography Size style assays to build as much information exclusion chromatography with an aqueous as possible about the potential drug into the mobile phase that separates analytes on the discovery process. basis of size. fusion partner When making a small gel permeation chromatography Size protein or peptide in E. coli, it is often exclusion chromatography with a nonaqueous necessary to produce the protein fused to mobile phase. a larger protein to get high levels of stable gene The unit of inheritance consisting expression. The resulting fusion protein must of a sequence of DNA occupying a specific be cleaved (chemically or enzymatically) position within the genome. Three types of to yield the desired protein or peptide. The genes have been identified: structural genes non-product fusion partner is left over and encoding particular proteins; regulatory genes usually thrown away. controlling the expression of the other genes; fusion protein A protein containing and genes for transfer RNA or ribosomal RNA amino acid sequences from each of two instead of proteins. distinct proteins. It is formed by expression gene therapy Treats, cures, or prevents dis- of a recombinant gene in which two coding ease by changing the expression of a person’s sequences have been joined together. Typi- genes or inserting genes into the genome. In cally, this is accomplished by cloning a cDNA its infancy, current gene therapy is primarily into an expression vector in frame with an experimental, with most human clinical trials existing gene. only in the research stages. Gene therapy can

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target somatic (body) or germ (egg and sperm) lyophilization; any material that takes the cells. In somatic gene therapy, the recipient’s shape of its container and is formed by cooling genome is changed, but the change is not a liquid until it is rigid but not crystallized. passed along to the next generation. In germ- Gln Glutamine; one of more than 20 line gene therapy, the parents’ egg and sperm naturally occurring amino acids. cells are changed with the goal of passing on GLP Good laboratory practices; according to the changes to their offspring. 21 CFR Part 58, regulations to ensure quality genetic engineering Altering the genetic of nonclinical laboratory studies related to structure of an organism (adding foreign safety. All activity is recorded, trained staff genes, removing native genes, or both) uses only established procedures, and records through technological means rather than and samples are maintained. traditional breeding. Glu Glutamic acid; one of more than 20 genetic polymorphisms Gene altera- naturally occurring amino acids. tions, additions, omissions, or deletions that glucose A monosaccharide (or simple alter biologic functioning or changes in drug sugar) is an important carbohydrate in metabolism. biology. The living cell uses it as a source of genome The collection of all the genes for energy and metabolic intermediate. an organism. Glucose Unit (GU) The normalized genomics Study of the genetic make-up of elution position of 2AB labeled N-linked and organisms, including sequencing and mapping O-linked glycan structures determined by a of their DNA. The Human Genome Project combination of HPLC, UPLC, exoglycosidase was a government-coordinated effort of many sequencing and mass spectrometry (See also genomics researchers who sequenced and GlycoBase). mapped the entire human genome. Gly Glycine; one of more than 20 naturally genotoxicity Ability of a substance to occurring amino acids. damage the genome. glycan Refers to a polysaccharide or genotoxin A substance that causes dam- oligosaccharide that can be found attached to age to an organism’s DNA. proteins as in glycoproteins and proteoglycans. genotype The genetic composition of an or- glycan labeling Glycans are typically ganism (including expressed and non-expressed labeled with a fluorescent tag to enable genes), which may not be readily apparent. efficient separation and detection. Compare to phenotype, the outward characteris- GlycoBase An integrated HPLC/UPLC web- tics that result from gene expression. based resource that contains elution positions germ cell The “sex cells” in higher animals for more than 650 2-AB-labeled N-linked and and plants that carry only half of the organ- O-linked glycan structures determined by a ism’s genetic material and can combine to combination of HPLC, UPLC, exoglycosidase develop into offspring. sequencing and mass spectrometry. Developed glass state The amorphous solid that, for by Waters Corp. in collaboration with the example, contains the therapeutic protein in National Institute for Bioprocessing Research

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and Training (NIBRT). http://glycobase.nibrt.ie GRAS Generally recognized as safe; a special (See also Glycan Unit). status afforded by FDA to ingredients and meth- glycoform A form of a protein that differs ods that have a proven, longstanding history of only with respect to either the number or type causing no harm to humans or animals. of attached oligosaccharides. growth hormone A protein produced in the glycopeptide A peptide with an attached pituitary gland to control cell growth. glycan moity, often derived from a glycopro- Guidance for Industry The next regula- tein that has been digested with a protease. tory level up from a Points to Consider (PTC) glycoproteins Proteins that contain sugar document (and below official Code of Federal side chains added as a posttranslational Regulations law). process; presence of sugar side chains often GXP All-inclusive term for GCPs, GLPs, affects activity and in vivo stability. and GMPs. glycosidase An enzyme that catalyzes the hydrolysis of a glycosidic bond joining a sugar of a glycoside to an alcohol or other sugar unit. H glycosylation Adding one or more carbo- HACCP Hazard analysis and critical control hydrate molecules onto a protein (a glycopro- points analysis; a method used to perform tein) after it has been built by the ribosome; a risk assessment and risk mitigation. Each unit post-translational modification. operation is evaluated to define what critical GMPs Good manufacturing practices; accord- parameters must be kept within specified ing to 21 CFR Parts 210, 211, 600, 610, and ranges, and the process control strategy is (for devices) 820, current good manufacturing designed to monitor and control within that practices (cGMPs) influence the manner in which biopharmaceuticals and other drugs and medi- Visualization of a complex population cal devices are produced. Standard operating of PEG structures by HDMS. procedures must be followed, processes must be validated, equipment must be qualified, and properly trained staff must maintain a clean/ sterile environment. Gram’s stain/Gram’s method A method developed by Hans C.J. Gram for identifying bacteria. Bacteria are stained with gentian violet, then treated with Gram’s solution (water, potassium iodide, and water) and counter- stained. They are then treated with alcohol and washed with water. Gram-negative bacteria do not retain the purple dye (E. coli, for example); Gram-positive bacteria do retain the purple dye (Staphylococcus aureus, for example).

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range. Used in the food industry with much PEG that are conjugated to proteins, including success. (See also FMEA) determining partial sequence information of half-life (t1/2) Time required to decrease proteins, and differentiating by size and shape, the amount of drug in body by 1/2 during as well as mass. elimination (or during a constant infusion). heavy chain (of an antibody) See antibody. hapten A small, separable part of an HeLa Human cervical cancer cells; an antigen that reacts specifically with an anti- established cell line that is commonly used in body but is incapable of stimulating antibody biotechnology. production except in combination with a carrier hemocytometer A device for counting protein molecule. blood cells. harm Physical injury or damage to the health hemoglobin A complex protein (a 4-mer) in of people, or damage to property or the environ- red blood cells that binds and releases oxygen, ment. [From ISO 14971; see also ICH Q9] carrying it from the lungs to all other tissues. harmonization In regulatory parlance, HEPA filtration High-efficiency particulate harmonization refers to the effort between air filter used to remove contaminants or to multiple regulatory agencies to standardize prevent particles from entering a clean room. and streamline the approval of new drugs, e.g. heterogeneity A term used to describe a ICH or International Council for Harmonisation. biological component (i.e. protein) consisting As a corporate strategy, harmonization is the of multiple structural variations. effort to minimize organizational chaos, and HGH Human growth hormone; an early institute an integrated strategy for deploying biopharmaceutical. Formerly derived from and maintaining analytical and informatics cadaveric pituitary glands, this protein is now resources. produced by recombinant expression. hazard The potential source of harm [From HIC Hydrophobic interaction chromatog- ICH Q9; see also ISO/IEC Guide 51]. raphy; a type of liquid chromatography that HCIC Hydrophobic charge induction makes use of the relative solubility of proteins chromatography; a type of HIC that is based on and matrix materials. Hydrophobic interactions pH rather than salt concentration, allowing for are strongest at high ionic strengths, so salt is elution under relatively mild conditions and usually included to increase those levels. eliminating the requirement for an associated Higher Order Structure (HOS) Structure filtration step in early separations. relating to secondary, tertiary, or quaternary HDMSª (IMS-TOF MS) System High structure of a biomolecule, in contrast to its Definition Mass Spectrometry™ (HDMS); Waters primary structure, the amino acid sequence. MS Technology that couples high-efficiency HILIC Hydrophilic interaction chromatogra- ion mobility separations (IMS) with time-of- phy; normal phase liquid chromatography of flight (TOF) mass analysis. HDMS provides molecules so polar that they require mobile an additional dimension of information for phases containing water to elute them. For separations, providing additional details on example, carbohydrates (glycans) are analyzed glycopeptide, protein, and polymers such as using HILIC.

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His Histidine; one of more than 20 naturally occurring amino acids. histochemistry A science that combines the techniques of biochemistry and histology to deal with the chemical changes and chemical constitution of tissues. hormone A protein released by endocrine glands or sex organs to travel in the blood and act on tissues at another location in the body. Insulin, a hormone, was the ﬁ rst bio- host A cell or organism used for growth pharmaceutical approved by the FDA. of a virus, plasmid, or for the production of cloned substances. spectrometry (MS), also referred to as HX MS, is host cell protein(s) (HCP) Proteins from an important structural characterization tool for the host cell system used to manufacture a discovery and development stages. Uses in bio- biopharmaceutical drug. Host cells contain therapeutics include epitope mapping, binding, hundreds to thousands of host cell proteins and protein–drug interaction studies, aggrega- and other biomolecules that could contami- tion studies, effect of mutation on conformation, nate the final product. and localization of conformational changes. HDX HPLC High-performance liquid chromatog- provides information on the relative deuterium raphy or high-pressure liquid chromatography; uptake of different conformations of a protein, or a form of liquid chromatography in which locations within a protein. a sample is forced at high pressure through hydrolysis Literally “cleaved by water,” a a tube (column) that is packed tightly with reaction in which the chemical bond attach- chromatographic media. ing an atom or group of atoms to the rest of a human genome The complete set of hu- molecule is severed, followed by attachment man genetic instructions. of hydrogen at the same point. Most often in humanized antibody An antibody in biopharmaceuticals, the breakage of peptide which the constant region is entirely human bonds by addition of a water molecule. but the variable region is not. hydrophilic Having an affinity for water; hybridization The process of joining comple- attracting, dissolving in, or absorbing water; mentary strands of DNA to make an RNA-DNA readily absorbing moisture; having strongly hybrid; the partial pairing of DNA single strands polar molecular groups that readily interact from genetically different sources. with water. hybridoma An immortalized cell line (usu- hydrophobic Insoluble in water; the extent ally derived by fusing B-lymphocyte cells with of insolubility; not readily absorbing water; re- myeloma tumor cells) that secretes desirable sisting or repelling water, wetting, or hydration; antibodies. or being adversely affected by water. Hydrogen Deuterium Exchange (HDX) hydrophobicity The lack of an affinity for Hydrogen deuterium exchange (HDX) with mass water.

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hygroscopic Ready to take up and retain until their net charge is zero (their isoelectric moisture. point, pI). cIEF is a specialized form of electrophoresis that can be adapted to the capillary format. I–J IEX See also: IEC, ion-exchange ICH The International Council for Harmonisa- chromatography. tion of Technical Requirements for Pharmaceuti- Ile Isoleucine; one of more than 20 natu- cals for Human Use; a project bringing together rally occurring amino acids. the regulatory authorities of Europe, Japan, IMAC Immobilized metal affinity chromatog- and the United States with experts from the raphy; a specific form of affinity chromatog- pharmaceutical industry to discuss scientific raphy. and technical aspects of product registration. immortalize To alter cells (either chemi- Its purpose is to recommend ways to harmonize cally or genetically) so that they can reproduce the technical guidelines and requirements for indefinitely. product registration and reduce or obviate the immunoassay An antibody-based test need to duplicate testing during development of used most often for bioanalytical purposes. new medicines. immunodetection A process that identifies IdeS Immunoglobulin degrading enzyme and quantifies specific biological substances, from S. pyogenes. An enzyme that cleaves such as antigens. IgGs in the hinge region between a conserved immunogen A substance that provokes G-G bond to produce F(abÕ)2 and Fc/2 sub- an immune responseÑthat is, the body units. Upon reduction, an IdeS digest contains recognizes it as a foreign agent that must be ~25 kDa light chain, Fc/2 and Fd fragments expelled or destroyed. that are often analyzed in middle-down/up immunogenicity The ability of a molecule LC-MS assays. to generate an immune response. IEC Ion-exchange chromatography; immunoglobulin A protein produced by sometimes abbreviated IEX, a liquid chro- plasma cells that fights infection or takes matographic technique based on the electrical part in various immune responses. Immuno- phenomenon of ion exchange. The amphoteric globulins bind with other molecules with a high nature of proteins can be exploited to bind degree of specificity; divided into five classes them in cation-exchange (binding positively (IgM, IgG, IgA, IgD, and IgE) on the basis of charged proteins) or anion-exchange (binding structure and biological activity. negatively charged proteins). immunohistochemistry The staining of IEF Isoelectric focusing; analytical histology preparations using chromagen linked separations in an electrical field through a pH antibodies to specifically stain for specific gradient (therefore based on the net charge of proteins in a histology section/slide. the molecules); usually done in bioanalysis at impurity A foreign agent or material either a neutral pH so that proteins (for example) will introduced as part of processing (such as buf- move under the influence of the electric field fers or salts added during chromatography) or

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intrinsic to the nature of bioprocessing (such as intermediates Substances formed in the product variants and cellular debris). middle stages of a series of processing steps; in silico Studies done “in the computer.” “stepping stones” between a parent substance Modeling a protein in silico refers to providing an and a final product. integrated, computerized view of the molecule. intron Noncoding genetic information in vitro Performed using laboratory appara- removed from pre-RNA in the formation of tus rather than a living animal. mRNA in eukaryotes. in vivo Involving living animals or humans ion mobility separation (IMS) A as test subjects. technology that differentiates ions based on inclusion bodies Discrete structures a combination of factors: their size, shape and (virions, viral components, cellular material, charge, as well as their mass. IMS provides aggregated proteins) present either normally an orthogonal dimension of separation. or abnormally within cells. Coupling of ion mobility measurements and IND Investigational New Drug applica- separations with tandem mass spectrometry tion; process by which a company files a can be applied to the gas-phase structures of request with FDA for permission to expose its biomolecules. (See also HDMS) experimental drug to patients or healthy hu- iontophoretic delivery Introduction of man volunteers. This application must be filed drugs through intact skin using the transfer of for each individual clinical study performed, ions by applying a direct electric current. Phases 1 to 3. IQ Installation Qualification; documented infusion Introducing a solution into the verification that all aspects of a facility, utility, bloodstream or another solution; also refers to or equipment that can affect product quality the solution itself, such as a drug formulation, adhere to approved specifications and are when infused. correctly installed. innovator product The approved biologic isoelectric focusing An analytical tech- used as the standard to compare candidate nique that uses electrophoresis in a pH gradi- biosimilar products. ent (for example 4 to 10) to determine the inoculate To introduce cells into a culture isoelectric point (see also pI) of a polypeptide. medium; also to introduce material to sensi- May be performed in a gel, in a liquid, or in a tize patients (as in vaccination). capillary tube (cIEF). inoculum Material (usually cells) used to isoform A specific and distinct structure or inoculate. form of a biological molecule among a family intact mass analysis A characterization of biological molecules with very similar technique using mass spectrometry that pro- structures and comparable, but not necessar- vides a mass measurement and an estimate of ily equal, action for the same product. the overall heterogeneity of a protein. isolation chambers Laboratory chambers interleukins Cytokines produced by designed to protect workers from dangerous lymphocytes or macrophages that modulate chemicals, organisms, or substances they are the immune response. working with (or the reverse); includes hooded

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workstations, isolators, and clean rooms, for example. isomerization Changes that create isomers (molecules with the same chemical make-up but a different structure), which alters the activity of Waters most proteins. isopycnic Describes molecules that have the Biopharmaceutical same buoyant density in ultracentrifugation. Platform Solution Molecules of differing densities form different with UNIFI regions in equilibrium within a density gradient medium. Key Applications isotonic Having the same osmotic pressure as blood serum, thus easily mixed with the 21 applications covering blood. intact protein MS analysis, isotope An alternative form of an element peptide mapping, released having a different number of neutrons in its glycan analysis and atomic nucleus. bioseparations.

Download the compilation K–L at www.waters.com/ kDa kiloDalton; a thousand Daltons. biopharmunifiANB knockout Gene targeting; for instance, a knockout mouse is one in which a single gene

TION SOLU is inactivated (“knocked out”), leaving other PLATFORM

genes unaffected; provides the best way to BIOPHARMACEUTICAL delineate the function of a gene. LAL assay Limulus amebocyte lysate assay; Key Applications detects pyrogenic endotoxins using a reagent that was discovered in the blood of Limulus horseshoe crabs. laminar flow clean air device A clean bench, clean workstation, and wall or ceiling modules or other devices that incorporate a filter and motor blower for supplying clean air in one direction for a controlled work space; more correctly referred to as “unidirectional air- flow,” which is air flow having generally parallel streams operating in a single direction and with uniform velocity over its cross section.

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LC/MS systems Liquid chromatography/ light-scattering analysis Analytical mass spectrometry systems; laboratory instru- method that gives information about the size ments that combine two popular analytical and shape of molecules based on how they methods into one piece of equipment. disperse ultraviolet and visible light. LC/IMS/MS systems Liquid chromatogra- LIMS Laboratory information management phy/ion mobility/mass spectrometry systems; system; computers and software that handle all laboratory instruments that combine three the data produced by laboratory research and popular analytical methods into one piece of analytical methods. equipment. liquid chromatography Analytical method LC/MS/MS Liquid chromatography with used to separate mixtures of substances based tandem mass spectrometry detection; a on the differential distribution of the substances highly selective method using an atmospheric- between a stationary phase (material such as pressure ionization tandem mass spectrometer silica gel or silicic acid, usually contained in a to measure the difference in the mass-to-charge column, tube, or capillary) and a liquid mobile ratio of ionized molecules and fragments. phase (a medium that carries the sample leachable Chemical entity that has the through the stationary phase). This very effec- potential to be extracted from a container or tive technique can separate substances that are closure when exposed to certain conditions of nearly identical. solutions. Examples of common leachables liquid fractionation Any of several seen in pharmaceuticals include plasticizers, precipitation or phase-separation methods used metals, accelerating agents. Leachables are to determine the molecular weight distribution potential extractables, and may be evaluated by of polymers, based on the tendency of polymers USP standard tests. of high molecular weight to be less soluble than lead 1. A molecule that modulates the activ- those of low weight. ity of a receptor or other target protein. Suc- lot A GMP-defined word used to refer to an cessful lead compounds become candidates for entire batch of product. drug development. 2. Pb, a toxic heavy metal. lot release testing Samples from each legacy system Old hardware and software drug lot (batch) manufactured for clinical trials applications in which a company has already or (later on) for sale are tested to prove that invested considerable time and money, and the batch meets specifications for content and which is no longer state-of-the-art or compliant purity before it is released for use. with regulatory requirements. lymphocytes White blood cells that produce Leu Leucine; one of more than 20 naturally antibodies. occurring amino acids. lyophilization Freeze-drying; a procedure ligands Molecules or ions that chemically by which a liquid solution is frozen to a glassy bind to certain other molecules or ions. In a state (primary drying), then slightly heated to binding action, usually the smaller of the two remove the unfrozen water by sublimation. molecules is considered the ligand. Lys Lysine; one of more than 20 naturally light chain (of an antibody) See antibody. occurring amino acids.

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Lys-C A protease with cleavage specificity pharmaceutical excipient and in diagnostic tests on the C-terminus of Lysine residues. of kidney function. lysed-cell slurry A mixture of the debris mannose A sugar (an aldohexose) often formed by disintegrating or breaking cells. used as an excipient in drug formulations. lysis Disruption or breaking of the cellular mass spectrometry Mass spectrometry membrane of cells by chemical, enzymatic, or (MS) is an analytical technique that measures mechanical means. A solution containing the the mass-to-charge ratio of charged particles. contents of lysed cells is called a “lysate.” It is used for determining masses of particles, lysosomes Cell organelles containing for determining the elemental composition enzymes, responsible for degrading proteins of a sample or molecule, and for elucidating and other materials ingested by the cell. the chemical structures of molecules, such as peptides and other chemical compounds. The MS principle consists of ionizing chemical M compounds to generate charged molecules or mAb Monoclonal antibody; a highly specific, molecule fragments and measuring their mass- purified antibody that recognizes only a single to-charge ratios. epitope. master batch record The template that macrokinetics Movement of whole cells and describes the step by step procedures to be their media within a bioreactor. followed during manufacturing, with spaces macromolecules Very large molecules to record actual data. The master batch record (proteins, carbohydrates, nucleic acids), often is uniquely identified, under change control, formed by two or more identical molecules in a pre-approved by quality assurance, and used to chain configuration (polymers). generate each individual batch record that is is- MALDI-TOF Matrix-assisted laser desorption sued when a given batch is to be manufactured. ionization–time of flight; mass spectrometry master cell banks A master cell bank is pre- technique for determining molecular weight. pared by culturing a homogeneous population Electrons become excited after laser irradia- of cells, such as an established, cloned cell line, tion, transferring energy into the mixture and under defined conditions and then distributed causing molecules and ions to be ejected from into containers in a single operation, processed its surface. Commonly used in proteomic and together to ensure uniformity, and stored to peptide analyses. ensure stability. Each vial is presumed to have MALLS Multiangle Laser Light Scattering—a comparable properties, and thus the bank may technique for determining, independently, the be characterized by testing a representative absolute molar mass and the average size of number of individual vials. Cell cultures derived particles in solution by detecting how they from the master cell bank are used to prepare scatter light. working cell banks for manufacturing of a mannitol A sugar alcohol (found natu- biopharmaceutical. Both master and working cell rally in many plants, algae, and fungi) that is banks are extensively tested and characterized obtained by reducing mannose and used as a before use. (See working cell bank)

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media Plural form of medium, a (usually often automated. Microplates can have room sterile) preparation made for the growth, stor- for 96, 384, or even 1,536 tiny samples. age, maintenance, or transport of microorgan- Microassays measure small quantities of com- isms or other cells. ponents even when the sample size is large. melting temperature The temperature microbial fermentation Processes involv-

(Tm) at which half of the DNA strands are in the ing the use of microorganisms, such as E. coli, random coil or single-stranded (ssDNA) state. to produce a protein or other substance.

Tm depends on the length of the DNA molecule microbial testing Analytical methods and its specific nucleotide sequence. required by regulations to ensure sterility and Met Methionine; one of more than 20 to measure bioburden or identify microorgan- naturally occurring amino acids. isms in controlled, classified environments. metered dose inhaler (MDI) A device microbiology The study of microscopic life used to deliver a fixed volume or dose of an such as bacteria, viruses, yeast, and protozoa. aerosol form of an active drug substance to the microcarrier A microscopic particle (often lungs and/or bronchi. a 200 μm polymer bead) that supports cell metabolism Drug metabolism is the attachment and growth in suspension culture; biochemical modification of pharmaceutical alternative to microencapsulation. Cells anchor substances by living organisms, usually through into tiny pores on the beads for protection. specialized enzymatic systems. This is a form of microencapsulation In cell culture, trap- xenobiotic metabolism. Drug metabolism often ping cells inside a thin protective membrane to converts lipophilic chemical compounds into provide anchorage and protect them from harsh more readily excreted polar products. Its rate is conditions. Microspheres are often biodegrad- an important determinant of the duration and able. intensity of the pharmacological action of drugs. microfiltration A method of sterile metabolites Chemical products of metabo- filtration, clarification, or cell harvesting that lism, the chemical process of life. removes particles in the 0.1 to 10.0 μm range. micelle A spherical arrangement (bubble) microheterogeneity In biopharmaceuti- formed by a group of lipid molecules in an cals, usually small differences in the amino aqueous environment; hydrophobic ends of acid sequence or structure of a polypeptide the molecules are turned inward and hydro- chain. For example, to produce a recombinant philic ends are turned outward. A molecular protein in E. coli, a Met must be added to one aggregate that constitutes a colloidal particle end of the protein sequence to act as a signal (a substance consisting of particles dispersed that initiates protein synthesis. In most cases, throughout another substance with particles that Met is removed once the protein is made. too small for resolution with an ordinary light Sometimes the Met is removed from only some microscope, but that can pass through a semi- of the molecules. The purified product is then permeable membrane). a mixture of a protein with the native sequence microassays Assays usually run on very and a protein with the native sequence plus the small samples, often using “microplates,” and extra amino acid.

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microinjection Manually using tiny cell from an immunized animal that recognize needles to inject microscopic material (such a single epitope. as DNA) directly into cells or cell nuclei; video monomer A simple molecule that may screens provide a magnified view. combine with others to form polymers. micron See micrometer. The preferred term monosaccharide (see carbohydrate) is micrometer. mRNA Messenger RNA; which serves as micrometer One millionth of a meter’s a template for protein synthesis. It is made length. Abbreviated as μm. as a complement to a DNA sequence and microorganism A microbe; a free-living then transported from the cell nucleus to the organism too small to be seen by the naked ribosomes. eye. MSDS Material safety data sheets; docu- microspheres Tiny polymer spheres (usu- mentation (including data describing physical ally biodegradable) measured in micrometers. characteristics, toxicity, health effects, first aid, miRNA A single-stranded RNA molecule reactivity, storage, disposal, protective equip- of about 21 to 23 nucleotides in length, which ment, and spill/leak procedures) that provides regulates gene expression. workers and emergency personnel with the mitochondria Animal-cell organelles that proper procedures for handling or working with reproduce using their own DNA. They metabo- a particular substance. lize nutrients to provide the cell with energy MSEE The simultaneous acquisition of exact and are believed to have once been symbiotic mass data using alternating collision cell bacteria. Chloroplasts are their plant-cell energies. This technique is unique to Waters equivalents. mass spectrometers, which can perform this MOBCAL Software that calculates mobili- simultaneous data capture at UPLC speed (see ties. MOBCAL is an open-source software and also UPLC). The MSEE approach, when used to is command-line driven (www.indiana.edu/ acquire precursor and product ion information, nano/software.html). has the additional benefits of obtaining both moiety One of the portions into which types of data in one analytical run. Both the something is divided; a component, part, or precursor and product ion data are acquired in fraction. In chemistry, a specific section of a accurate mass mode so that elemental compo- molecule, usually complex, that has a charac- sition information can be generated from both teristic chemical effect or property. sets of data. Another advantage of MSEE is that mole The amount of a substance that neutral loss information from a comparison contains the same number of elements (such as of the two alternating collision energy scans atoms, molecules, or ions) as there are atoms can be obtained, eliminating the need for any of carbon in 12 grams of carbon-12; one mole further experimentation. The mode of operation contains Avogadro’s number of molecules also removes the need for time-consuming (6.02 x 1023). reanalysis to obtain both MS and MS/MS data. monoclonal antibody Antibodies produced Data acquired in MSEE mode can be mined at a either recombinantly or by isolating a single B- later date for different information.

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multi-attribute monitoring (MAM) An the cytoplasm, subtly altering properties of the analytical test intended to perform multiplexed cells, but escaping detection unless specifically quantitative assessment of quality attributes of monitored. In cell culture of biopharmaceu- a biotherapeutic. ticals, each lot must be tested at the end of multicellular Referring to organisms com- cell culture for mycoplasma contamination; a posed of more than one cell—often billions confirmed positive results in batch rejection. of them—arranged in various organs, tissues, myeloma Lymphocytic cancer; a malig- and systems. nancy found in bone marrow. multidimensional chromatography A separation technique employing more than one mode of chromatography for greater separa- N tion. native The natural state; in a biophar- multimer Any small polymer; in biopharmaceutical context, it usually refers to a maceuticals, usually a protein made up of more molecule’s normal three-dimensional structure than one polypeptide chain. under optimal conditions. multimer formation Association of peptide NDA New Drug Application; CDER’s or protein molecules to produce dimers (two equivalent of the BLA. It is used for small- linked identical molecules), trimers (three molecules and some biopharmaceuticals (such linked identical molecules), and so on depend- as hormones and small peptides), which are ing on how many identical molecules link up regulated by CDER rather than CBER. together nebulizer A device, pressurized by an mutagen An agent (chemicals, radiation) oxygen or nitrogen tank, for the purpose that reacts with DNA to produce mutations. of converting a liquid (such as a medicinal mutagenicity The degree to which a formulation) into a fine mist (to be inhaled, for substance can cause a change in an organism’s example). DNA. nick translation A technique used to mutation A permanent change in DNA introduce radioactively and nonradioactively sequence or chromosomal structure. labeled nucleotides into DNA; the new nucleo- MW molecular weight; refers to the mass of tide is added at the position where the original a molecule, usually stated in Daltons. nucleotide was excised; nick translation can be mycoplasma Parasitic microorganisms used for a number of hybridization techniques, that infect mammalian cells, possessing some such as gel blots and colony plaque lifts. characteristics of both bacteria and viruses. NIH National Institutes of Health; the US Prokaryotic microorganisms, family Myco- government agency that conducts and sup- plasmataceae, with no cell walls (therefore ports medical research and dissemination of resistant to many antibiotics) and needing information. One of eight agencies in Public sterols for maintenance and growth. Potential Health Services, which is in turn part of the US contaminants of mammalian cell cultures, they Department of Health and Human Services. may grow attached or close to cell surfaces in NIR spectroscopy Near-infrared spec-

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troscopy; a bioanalytical technique that uses nucleotides Molecules composed of a radiation in the near-infrared range to provide nitrogen-rich base, phosphoric acid, and a rapid, nondestructive analysis of materials. sugar. The bases can be adenine (A), cytosine NIST National Institutes of Standards and (C), guanine (G), thymine (T), or uracil (U). Technology; a federal agency that develops and These molecules comprise the basic structural certifies standard reference materials for use in units of RNA and DNA. various US industry applications nucleus The largest organelle, a NMR spectroscopy Nuclear magnetic membrane-bounded compartment found in resonance spectroscopy; an analytical method eukaryotes that contains most of the cell’s that generates a spectrum (based on the genetic material and a nucleolus that builds electromagnetic environment surrounding the ribosomes. nucleus of each atom in a molecule) that serves as the chemical signature of each molecule and aids in structure determination. O N-linked glycan A glycan attached to a oligomer A short polymer consisting of protein through an Asparagine (Asn) residue. a few monomers, typically refers to small nonconformity A deficiency in a character- nucleotide polymer. istic, product specification, process parameter, oligonucleotide A short nucleotide poly- record, or procedure that renders the quality mer, typically with 30 or fewer bases. of a product unacceptable, indeterminate, or oligosaccharide (see carbohydrate) not according to specified requirements. [From O-linked glycan A glycan attached to a FDAQSG] protein through either a Serine (Ser) or Threo- norleucine An amino acid, not produced nine (Thr) residue. by mammalian cells, but may be produced Omega (Ω) The value of Omega is square by many bacteria, especially under condi- angstroms (Å2). Omega can be calculated tions of nutrient-poor media. NorLeu may be theoretically for any ionic structure based a substituted for Leu when a mammalian protein three-dimensional structure. Historically, a is expressed in bacterial cells, creating new physical model of the molecule was construct- product variants that may be of safety concern. ed and mounted between a light source and a N-terminal Amino-terminal or amine screen. The area of the shadow was measured terminus; the amine terminus of a protein chain for many orientations and then an average cal- (with a free a-amino group). culated. The measurement of Omega provides nucleic acids DNA or RNA: chainlike a mechanism for comparison of different (ionic) molecules composed of nucleotides. species for this attribute. nucleosides Glycosylamines consisting of oncogene A gene that, when expressed, a nucleobase bound to a ribose or deoxyri- can lead cells to become cancerous, by remov- bose sugar. The most prevalent examples of ing the normal constraints on their growth. nucleosides are adenosine, cytidine, guano- OOS Out-of-specifications result; a result sine, thymidine, and uridine. that is outside the range of an approved

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operon A group of functionally related, adjacent genes found in prokaryotes that operate as a unit to synthesize functionally related proteins (enzymes). An operon group includes an operator region, a regulator gene, and structural genes equivalent to the number of enzymes in the system. optimization Determining and implementing process operation at the best possible and most affordable efficiency. OQ Operational Qualification; documented verification that all aspects of a facility, utility or equipment that can Peptide mapping provides detailed struc- affect product quality operate to Intended tural information for a protein; it is a chal- lenging application because of the number throughout all anticipated ranges. of peaks that must be baseline-resolved. organelle A structurally discrete compo- The Waters ACQUITY UPLC H-Class Bio nent that performs a certain function inside a System, with Peptide Separation Technol- ogy Columns, provides maximum LC reso- eukaryotic cell. lution and sensitivity for more conﬁ dence organic In chemistry, any molecule con- in protein characterization studies. taining carbon atoms is considered an organic specification. An OOS result must be molecule (from the Greek for “work”). Organic investigated to determine whether it is due chemistry is the chemistry of life because to laboratory error, operator error, or process carbon interacts in myriad ways with a large error; and a judgment made whether the number of other elements to form complex result itself is valid (accurate estimate of the molecules (RNA, DNA, amino acids, proteins, true value of the analyte) or invalid. Usually, and so on) that perform the intricate actions confirming an OOS result as valid results in that make life “work.” affected lot(s) of product being rejected. organism A single, autonomous living OOT Out of tolerance; 1. refers to equip- thing. Bacteria and yeasts are organisms; ment or instrument which, when its calibration mammalian and insect cells used in culture is checked, is outside of a defined range and are not. requires adjustment or repair. 2. Out of trend; orphan drug A US product that treats a a test result that is unexpected or outside of its rare disease affecting fewer than 200,000 historical or statistical trends but within speci- people. fications; and must be investigated as a type orthogonal At right angles or differing of exception. The investigation is very similar completely. Sometimes used to mean occur- to an OOS investigation, with the difference ring stepwise rather than simultaneously. that product disposition may not be affected osmolarity The concentration of osmoti- by a confirmed out of trend result. cally active particles in a solution (expressed

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in osmoles of solute per liter of solution). pharmaceutical company’s filing an NDA. (See Osmosis is flow through a semipermeable prelicense inspection) membrane under the influence of an osmotic paratope The part of an antibody that binds gradient. Osmotic pressure is the pressure that to the antigen’s epitope. must be applied to a solution to prevent osmo- parenteral delivery Drug delivery by sis. Osmotic shock is a rapid change in osmotic injection; subcutaneous, intra-muscular, and pressure on a cell or virus, usually causing it to intravenous delivery are most common. Drug discharge its contents. must be sterile. outsourcing Having research, laboratory particle filtration Particle filtration is testing, clinical trials, or manufacturing done by used to filter macro particles, which are visible another firm, usually called the contract organi- to the naked eye and range in size from 50 zation. (See sponsor; quality agreement) μm to 1000 μm. Examples of particles in overflow The liquid portion of a broth after this size range include beach sand, granular centrifugation when solid particulates have activated carbon, human hair, mist, pollen, settled out; describes the part of the centrifuge milled flour, and precipitates formed during apparatus that holds the liquid separate from the bioprocessing. solids (the underflow). passage number When cells are cultured, oxidation Chemical reaction in which a the passage number is a theoretical number of compound or atom loses valence electrons; due cell generations, or how many times the cells to reaction with an oxidizing agent (e.g., oxygen, have been “passaged” in vitro. peroxides, metal ions, or others). Many proteins PAS Pre-approval supplement; a regula- are prone to oxidation on exposure to air (such as tory submission to FDA used for biologics and oxidation of the Met amino acid into methionine biopharmaceuticals when major changes to sulfide or sulfone). (See also redox) the process, facility, or quality control system are desired. The sponsor must wait for full FDA review and approval before any product manu- P factured may be placed in distribution. Often, PA projection approximation; an ion is a PAS or a CBE-30 may be part of a compa- modeled by a collection of overlapping hard rability protocol, and the type of submission spheres with radii equal to hard sphere colli- required for a given package of changes is sion distances. The orientationally averaged negotiated with FDA by RA personnel. geometric cross section is determined by PAT See process analytical technology. averaging the geometric cross section over all payload distribution In an antibody possible collision geometries. drug conjugate (ADC), refers to the number PAGE polyacrylamide gel electrophoresis; a and amount of drug molecules bound to an method for separating proteins on the basis of antibody. Loading can be random, where a mass to charge ratio. population of cysteine or lysine residues are PAI Preapproval inspection; an FDA facility modified, or site-selective, using site-specific inspection performed in response to a bio- antibody mutants.

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PCR Polymerase chain reaction; a process is most efficient in cleaving bonds involving that exponentially amplifies (reproduces) a the aromatic amino acids, phenylalanine, short piece of DNA having a specific nucleotide tryptophan, and tyrosine. sequence, making possible many research and peptide bioanalysis The use of analytical clinical applications involving that DNA (used techniques to quantitatively measure peptide extensively in forensics). PCR may be qualita- drugs and their metabolites in biological tive or quantitative (qPCR). systems. Formerly performed using ligand- peak An individual component of a mixture binding assays such as radioimmunoassay and that is washed out of the chromatography col- ELISAs, LC/MS/MS is now being applied to pep- umn during elution (the elution fraction). The tide bioanalysis for its higher accuracy levels. sharp rise in the line graph of a chromatogram A successful, highly sensitive method for the that represents this phenomenon. analysis of peptides relies upon a combination peak capacity A theoretical measurement of high-performance chromatography, mass of separation capability, typically derived spectrometry, and sample preparation. from an average peak width measurement. peptide bond The carbon-nitrogen The greater the peak capacity, the greater the covalent bond (link) between an amino group separation. of one amino acid and a carboxyl group of PEG Polyethylene glycol; a polymer that another, formed by removing water and result- usually consists of a size distribution of various ing in the group RCO-NH. This linkage does not molecular weight compounds. Physical and allow free rotation, and it is the important bond chemical properties vary with the molecular that connects amino acid monomers to form weight (liquid to solid, viscosity, etc.). PEGs the polymer known as a polypeptide. are used as surfactants in industry (for foods, peptide mapping Bioanalytical method cosmetics, and pharmaceuticals); and in in which proteins are selectively cleaved by biomedicine as dispersing agents, solvents, enzymes to create a characteristic pattern of ointment and suppository bases, vehicles, and peptides that is elucidated through chromato- excipients. In pharmaceutical development, analysts PEGylation Covalent attachment of generate information-rich and reliable analytical methods to support IND and NDA polyethylene glycol molecule(s) to a protein submissions for innovative medicines. molecule via selected amino acid side groups, for example free amino or sulfhydryl groups. May be done to decrease toxicity or improve its solubility and circulating half-life in the body. pepsin An enzyme whose zymogen is release by chief cells in the stomach and that degrades food proteins into peptides. One of three principal protein-degrading, or proteolytic, enzymes, the other two being chymotrypsin and trypsin. A digestive protease, pepsin

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graphic separations and spectroscopic or and therapeutic effects. A PD study seeks to spectrometric detection. determine where a drug penetrates in the body peptides Short polymers formed from the and by means of what mechanisms. linking, in a defined order, of amino acids. The pharmacokinetics Sometimes abbrevi- link between one amino acid residue and the next ated as PK, (from Ancient Greek pharmakon is known as an amide bond or a peptide bond. “drug” and kinetikos “to do with motion”; see perfusion Sometimes perfusion propaga- chemical kinetics) is a branch of pharmacology tion; a cell culture or fermentation process dedicated to the determination of the fate of commonly used in antibody production, in substances administered externally to a living which high concentrations of mammalian cells organism. The substances of interest include inside a chamber have fresh growth media pharmaceutical agents, hormones, nutrients, continually circulated around them for continu- and toxins. (See also ADME.) ous addition of nutrients and removal of waste Phe Phenylalanine; one of more than 20 products. naturally occurring amino acids. permeate Also called filtrate, the part of a phenotype The observable characteristic mixture that passes through a filter. that results from the action of an organism’s pH Power of hydrogen or the log of the genes. Phenotype varies depending on which concentration of H+ ion in a solution. Measure- alleles of each gene are present. ment of the relative alkalinity or acidity of a phosphoramidite or nucleoside phosphora- solution. Pure water is pH neutral (7), acidic midites The individual base building blocks solutions have pH values between 0 and 7, that are used to synthesize short nucleic acid and alkaline or basic solutions have pH values chains also known as oligonucleotides. between 7 and 14. Often a critical control phosphorothioate A variant in which one parameter in biopharmaceutical processes. or more of the nonbridging phosphate oxygens phage A virus-like parasite that infects in an oligonucleotide is replaced by sulphur, bacteria; also bacteriophage. which increases the lifetime of the oligonucle- pharmaceutical development Col- otide in the body. lected information from development studies phosphorylation Addition of a phosphate conducted to establish that the dosage form, (PO4) group to a molecule, usually enzymati- formulation, manufacturing process, and qual- cally done by transferring a phosphate group ity attributes are appropriate for the product. from ATP (adenosine triphosphate). The development process should identify and physical state The form that matter takes, describe the critical quality attributes and criti- whether solid, liquid, gas, or plasma. cal process parameters that influence product pI Isoelectric point; the pH at which a quality and performance. substance has no net charge, above which a pharmacodynamics Study of the reac- substance acts as a base and below which tions between drugs and living structures, it acts as an acid. A solution of proteins or including the processes of bodily responses to amino acids has its minimum conductivity pharmacological, biochemical, physiological, and viscosity at the isoelectric point.

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pichia pastoris An alternative yeast species proposed as a recombinant expression system. It performs post-translational modifications that are more similar to human protein modifications than those performed by other yeasts used in fermentation. pilot plant A medium-scale bioprocessing facility used as an intermediate in scaling up Laboratories rely on the high purity processes from the laboratory to commercial and recovery achieved with preparative production. chromatography columns. placebo A fake treatment (usually the support and separations matrix in electrophore- same formulation used for the real product, but sis and gel chromatography. without the active ingredient) administered to polyclonal antibodies A mixture of anti- the control group in a controlled clinical trial so bodies targeting different parts of an antigen that the specific and nonspecific effects of the that are produced by an immunized animal. experimental treatment can be distinguished. polymer A large molecule formed by the The experimental treatment must produce combination of at least five (and sometimes better results than the placebo to be considered as many as 1,000) identical smaller mol- effective. ecules (monomers). plasmid Hereditary material that is not part polymerase An enzyme that catalyzes of a chromosome. Plasmids are circular and the production of nucleic acid molecules. self-replicating and found (naturally in bacteria polymerize To undergo or subject to and some yeasts) in the cytoplasm of cells. polymerization, a chemical reaction in which They can be used as vectors for introducing two or more molecules combine to form up to 10,000 base-pairs of foreign DNA into larger molecules that contain repeating recipient cells. structural units. PNGase F An enzyme that specifically polymorphism A single mutation in a cleaves N-linked glycans from proteins. gene at one nucleotide locus that potentially polar solvent A solvent for molecules that changes gene expression with a modified have permanent electric dipoles. protein that may possess different properties, polishing The final purification step(s) in for example, the activity of an enzyme with a biopharmaceutical manufacturing process, a drug. usually involving an affinity or other refined polypeptide a peptide typically contain- chromatography method. Often this step uses ing between 10 and 100 amino acids. the most expensive technique in the process polysaccharide A kind of complex car- because it handles the smallest amount of bohydrate (macromolecule composed of long material. chains of simple sugars). Several polysaccha- polyacrylamide A high molecular-weight rides from microorganisms have important polymer of acrylamide (a neurotoxin) used as a commercial uses.

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polysorbate 80 and polysorbate 20 or other molecules. This protein processing is Hydrophilic non-ionic surfactants and emusli- done by the Golgi bodies after proteins have fiers often used as pharmaceutical excipients. been constructed by ribosomes. Commonly referred to as Tween 80 and potency The measure of the biological Tween 20. (Tween is a registered trademark activity using a suitably quantitative biological of ICI Americas, Inc.) assay (also call potency assay or bioassay), polysorbates Complex mixtures of based on the attribute of the product that is polyoxyethylene ethers used as emulsifiers or linked to the relevant biological properties. dispersing agents in pharmaceuticals. [From ICH Q6B] polyvinyl A polymer prepared from PQ Performance qualification; Documented polyvinyl acetates by replacement of the verification that all aspects of a facility, utility acetate groups with hydroxyl groups. It is used or equipment perform as intended in meeting as a pharmaceutic aid (a substance with little predetermined acceptance criteria. or no therapeutic value that is necessary in pre-license inspection An FDA facil- the manufacture, compounding, or storage of ity inspection performed in response to a pharmaceutical preparations or drug dosage biopharmaceutical companyÕs filing of a BLA to forms). Polyvinyls are used as solvents, dilut- confirm claims made in the license application ing agents, suspending agents, and emulsify- and assess the readiness and cGMP compliance ing agents. of the manufacturing plant. polyvinyl alcohol A synthetic polymer precipitation Process causing a solid to used as a fixative and an adhesive and as an settle out of solution (as in centrifugation) by emulsifying agent, thickener, and stabilizer. the action of gravity or by a chemical reaction; Specimens can remain in PVA without damage a reaction between a soluble antibody and for long periods of time. a soluble antigen, resulting in the formation postapproval changes Changes (scale-up, of a substance (known as a precipitate) that for example) made to a biopharmaceutical separates, in solid particles, from a liquid. manufacturing process after the drug has been preformulation An exploratory activ- approved for marketing. ity that begins early in biopharmaceutical postmarketing surveillance Phase 4 development, involving studies designed to clinical trials, which provide additional details determine the compatibility of initial excipients about a productÕs safety (while the product is with the active substance for a biopharmaceuti- on the market) and efficacy and may be used cal; physicochemical and bioanalytical inves- to evaluate formulations, dosages, durations tigation in support of promising experimental of treatment, medicine interactions, additional formulations. indications, and other factors. preparative chromatography Chroma- post-translational modification (PTM) tography methods used in manufacturing After a DNA sequence has been interpreted rather than analytical applications, larger in and a protein has been created, it may be modi- scale and intended to purify a product; also fied by the addition of sugar (glycosylation) called process chromatography. Chromato-

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graphic methods were first used in analytical process control 1. The means by which a laboratories, and only later in the 20th century process is monitored and operated, and is de- were they adapted to industrial separations signed to maintain critical parameters within use. (Contrast with small-scale analytical set ranges determined to be safe. 2. A consis- chromatography.) tent process that follows predictable statistical preservative A chemical additive that trends and is monitored using control charts is prevents spoilage by killing or inactivating said to be in a state of “statistical control.” microorganisms; also stabilizes molecules such process development The step in the life as when using antioxidants or sulfhydyls to cycle of a product that starts with information stabilize proteins. (Contrast with bacteriostatic from research, and delivers a scalable process agent, which prevents microbes from multiply- to manufacturing plants that can be validated, ing but does not kill them). operated under cGMP controls, and be com- primary recovery The early steps in separa- mercially viable. During process development, tion and purification of a biopharmaceutical, in preclinical and clinical trials supplies of the which a complex biological solution containing product are manufactured. the protein of interest is concentrated and clari- process knowledge A compilation of all fied, usually by means of filtration, centrifuga- facts about a manufacturing process from tion, or extraction (precipitation); and the pro- development through full-scale manufacture. tein of interest is isolated from residual debris, process-related impurities Impurities cells, and other macromolecular materials. that are derived from the manufacturing pro- primary structure The amino acid sequence cess. They may be derived from cell substrates of a biomolecule. (e.g., host cell proteins, host cell DNA), cell prion Believed to be the smallest, simplest culture (e.g., inducers, antibiotics, or media infectious particle consisting of a hydrophobic components), or downstream processing (e.g., protein (no nucleic acid, DNA, or RNA), sug- processing reagents of column leachables). gested as a possible model for the causal agent [From ICH Q6B] of scrapie and related diseases, called TSEs. process robustness Ability of a process to (Term originally derived from proteinaceous tolerate variability of materials and changes infectious particle.) of the process and equipment without negative Pro Proline; an imino acid often grouped impact on quality. [From ICH Q8] with the 20 naturally occurring amino acids. process understanding Comprehen- process analytical technology (PAT) A sion of process knowledge such that all system for designing, analyzing, and control- critical sources of variability are identified ling manufacturing through timely measure- and explained; variability is managed by ments (i.e., during processing) of critical the process; and product quality attributes quality and performance attributes of raw and can be accurately and reliably predicted in-process materials and processes with the over the design space established for the goal of ensuring final product quality. [From materials and process. Through process ICH Q8] understanding, process performance and

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product attributes can be explained logically form (charge isoform, n- or c- terminal form, and scientifically as a function of process eglycoform, etc.) that is considered part of parameters, inputs, and input material at- the product definition. tributes. prokaryotes Simple organisms, such as product lifecycle All phases in the life bacteria, with no cell nuclei and only a few cell of the product, from the initial development organelles. through marketing until the product’s discon- protease An enzyme that cleaves the tinuation. [From ICH Q9] peptide bonds linking amino acids in protein prodrug A modified version or precursor molecules, classified according to the most of a parent compound designed to enhance prominent functional molecular group (such delivery properties and be converted to the as serine or cysteine) at the active site; also parent compound in the body. called proteinase. product-related impurities Molecular protein One or more amino acid chains, of- variants of the desired product (e.g., precur- ten produced by gene expression. Proteins can sors, aggregates, certain degradation product be produced within a cell, in cell-free systems, arising during manufacture and/or storage) or through synthetic methodologies. Polypep- that do not have properties comparable to tide chains greater than 40 amino acids are those of the desired product with respect to generally termed as proteins. activity, efficacy, and safety. [From ICH Q6B] proteinase K A serine protease (used product-related substances Molecular in molecular cloning and DNA sequencing, variants of the desired product formed during nucleic acid research, and protein and peptide manufacture and/or storage that are active structural analysis) with broad specificity to- and have no deleterious effect on the safety ward aliphatic, aromatic, and other hydrophobic and efficacy of the drug product. These amino acids, cleaving their peptide bonds. variants possess properties comparable to protein conformation The characteristic the desired product and are not considered three-dimensional shape of a protein, includ- impurities. [From ICH Q6B] ing the secondary, tertiary, and quaternary product specification A list of tests and structure of the peptide chain. acceptance criteria (limits) that are used to protein folding A rapid biochemical define the quality of a drug substance or reaction involved in the formation of proteins. drug product. The specification is often listed It begins even before a protein has been on the Certificate of Analysis along with completely synthesized and proceeds through results for a specific batch or lot. discrete intermediates (primary, secondary, product variant A molecule that is and tertiary structures) before the final struc- related to the product but differs from it ture (quaternary structure) is developed. chemically, such as a degradation product, protein truncation Shortening a intermediate, or different configuration of polymeric chain of amino acids; the protein the protein of interest due to deamidation or truncation test developed by Dutch researchers other chemical reactions. A product variant is screens proteins to identify abnormally short

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molecules that suggest the location of genetic purification A central part of downstream mutations. processing that takes a crude fermentation su- protein variants Proteins with the same pernatant or cell homogenate (a chaotic slurry amino acid sequences but different folds or of tissues and cells) and isolates the product different carbohydrate residues. They must be from it in a fairly pure form. separated from the therapeutic proteins. pyrogen Any fever-inducing (pyrogenic) proteolysis Separation (cleavage) of pep- substance; more specifically, a lipopolysac- tide bonds in proteins by proteases (enzymes charide (the major constituents of the cell that recognize and cut specific peptide bonds) walls of Gram-negative bacteria). The major or other means. endogenous pyrogen in mammals is probably proteolytic Capable of lysing (denaturing, interleukin-1, production of which is stimulated or breaking down) proteins. by lipopolysaccharide. proteome The complete listing and descrip- pyrogenic endotoxins Components of tion of all the proteins and their functions for bacteria (such as lipopolysaccharides) that an organism. induce a feverish immune response in higher proteomics Study of protein function and organisms. structure. protocols Documentation (submitted to FDA or other agency in support of regulatory Q–R filings) that directs the work performed in an QA Quality assurance; 1. The quality sys- FDA-regulated company. Protocols tell who tems and processes used to control every step directs which activities, who approves what, of pharmaceutical manufacturing to ensure and who is allowed to sign off on materials that the product meets all of its specifications and products, even where to find specific files and quality attributes, and that all steps were and documents—all tying together numerous done and documented in compliance with SOPs. cGMP. 2. The sole work unit that is empowered PTC Points to Consider; PTC documents to disposition drug product and drug substance are not regulations with the force of law, but (release or reject) for use in humans; and that are instead guidelines on issues that FDA provides and sustains quality systems such as believes should be considered by regulated document control, corrective and preventive industry. These documents are not definitive actions, audits and oversight. or all-inclusive. In fact, they are presented QC Quality control; 1. the system of testing as drafts subject to further modification, and that confirms and measures the quality of raw readers are invited to submit comments. They materials, process intermediates, final product, acknowledge that processes and associated and environmental samples, during ongoing knowledge change with time. They suggest and production as well as during start-up and vali- recommend procedures that manufacturers dation. 2. The work unit that usually performs should consider during development of new testing regulated under cGMP and evaluates drugs and biologics. results against specifications, action limits, or

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targets, and makes technical recommendations Quality by Design (QbD) A term defined to QA. May be in the same department as QA by the ICH quality guidelines, meaning the in some organizations. use of science, engineering, and statistical QTof A hybrid mass spectrometer design tools, as appropriate, to design quality into a that couples time-of-flight (TOF) instrument process or product, or device; and to ‘mistake- with a quadrupole. This pairing results in a proof’ or design out common errors. combination of performance characteristics: quality risk management A systematic accurate mass measurement, the ability to carry process for the assessment, control, com- out fragmentation experiments, and high quality munication and review of risks to the quality quantitation. of the drug (medicinal) product across the quadrupole mass analyzer One type of product lifecycle. [From ICH Q9] mass analyzers used in mass spectrometry. It quality system A series of processes that consists of four circular rods, set perfectly paral- are linked together and controlled centrally lel to each other. Ions are separated in a quadru- to increase assurance of product or manu- pole based on the stability of their trajectories in facturing process quality. Term used by FDA, the oscillating electric fields that are applied to ICH, and ISO to define those systems that the rods, thus filtering the sample ions based on are created and maintained by QA to support their mass-to-charge ratio. GMP operations. Examples include documen- qualification 1. Documenting that a piece tation, facility, equipment, packaging, and of equipment does what it was designed to labeling. do, was installed correctly, and continues to quaternary protein structure The de- operate within specified parameters over time. fined organization of two or more macromol- 2. A term used during process or analytical ecules with tertiary structure such as a protein development to describe the experiments that that are held together by hydrogen bonds and are done prior to validation of the assay or van der Waals and coulombic forces. process, that define the critical parameters radiolabeled Covalently labeled with a and design space. 3. Analytical instruments radioactive isotope or substance. are qualified to ensure fitness for intended use RapiFluor-MS A proprietary glycan label- (USP <1058>). See also DQ, IQ, OQ, PQ. This ing reagent from Waters that enables both term sometimes is used interchangeably with fluorescent detection and MS detection. “validation.” RapiGest A proprietary detergent from quality The suitability of either a drug Waters that accelerates deglycosolation of substance or drug product for its intended proteins. use. This term includes such attributes as the raw material Term with differing defini- identity, strength, and purity (from ICH Q6A tions in different documents; commonly Specifications: Test Procedures and Acceptance means all materials that are used to manu- Criteria for New Drug Substances and New facture a drug substance or drug product, and Drug Products: Chemical Substances). [From regulated by 21 CFR 84. (See also compo- ICH Q8] nents, starting materials).

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reanneal The process of renaturing Public Health Service Act (PHS Act) against complementary single-stranded DNA mol- which a biological product is evaluated in a ecules to yield duplex molecules. 351(k) application. [From PHS Act] recall Product recall; the act of locating Reference standard Highly-characterized all units of a given lot of product that have physical specimens used in testing by pharma- been placed in the distribution chain for ceutical and related industries to help ensure human use and “recalling” them, for cause. the identity, strength, quality, and purity of Recalls are classified based on a risk assess- medicines (drugs, biologics, and excipients), ment. (See also withdrawal) dietary supplements, and food ingredients. The recombinant Refers to DNA (or the pro- USP Reference Standard collection consists of tein resulting from such DNA) that has been more than 3,100 items ranging from drug sub- genetically engineered to contain genetic stances, related impurities, residual solvents, material from another organism. Genetically biologics, excipients, botanicals, polymers, altered microorganisms are usually referred Near-IR and dissolution calibrators, photomicro- to as recombinant, whereas plants and graphs, and melting point standards. animals so modified are called transgenic. regeneration (of a column) The act of (See also transgenics) stripping and cleaning a chromatographic recovery Purifying a molecule of interest resin of any bound product or contaminants, from the mix of biological components pro- then stabilizing the surrounding environment duced by a biotech manufacturing fermenta- in preparation for reuse, usually done by a tion or cell culture process. sequence of various solvents or buffers. redox Equilibrium reaction of oxida- regulatory affairs Drug companies must tion/reduction, for example, thioldisulfide show that their products consistently meet exchange, a step used during refolding standards set by government agencies and of recombinant proteins that contain Cys that manufacturing stays within approved residues, in order to form correct pairing boundaries defined in the license application. of sulfhydryl groups (–SH) and form stable Regulatory affairs departments document those disulfide (S–S) bonds. activities, submit proposals, and follow those reducing agent A molecule that donates proposals through completion or approval. RA an electron in an oxidation-reduction reac- provides regulatory strategy, and sets up meet- tion, which is a chemical change in which ings with regulatory bodies, and determines one species is oxidized (loses electrons) and when formal notification or submissions to another species is reduced (gains electrons). FDA and other regulatory bodies are required. Reducing agents such as active metals RA is also involved during product recalls or (sodium, magnesium, aluminum, and zinc) withdrawals. can be used to take the place of proteins and released glycan analysis The analysis of keep them from being oxidized. glycans that have been enzymatically cleaved Reference product The single biological from their parent protein. product licensed under section 351(a) of the reproductive toxicology Studies of a drug

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substance in certain animal models to look for e.g., a microporous silica-based material any impact on the test animals’ reproductive with alkyl chains chemically bonded to its function. accessible surface. requirements The explicit or implicit needs RIA Radioimmunoassay; a bioanalytical or expectations of the patients or their surro- method that uses specific antibodies and ra- gates (e.g., healthcare professionals, regulators diolabeled detector molecules to quantitate and legislators); includes not only to statutory, a defined analyte in mixtures. For safety legislative, or regulatory requirements, but also considerations, many immunoassays are now such needs and expectations. [From ICH Q9] performed using dyes or other markers in residue An amino acid when referred to as lieu of the radioactive label. part of a polypeptide chain. RNA Ribonucleic acid; the nucleic acid resin Any of several solid or semi-solid based on ribose (a sugar) and the nucleotides inflammable substances, of natural or synthetic G, A, U, and C. It translates the information organic origin; usually translucent polymers encoded by DNA into amino acid sequences that do not conduct, that break like glass, the cell uses to make proteins. Similar to and that are soluble in ether, alcohol, and DNA but based on ribose, and with the base essential oils but not in water. The word is used uracil (U) in place of thymine (T). Various generically to describe chromatographic media, forms of RNA are found: mRNA (messen- particularly polymer beads. ger RNA); tRNA (transfer RNA); and rRNA resolution A measure of the distinguishabil- (ribosomal RNA). Most RNA molecules are ity of individual elements (the component parts single-stranded, although they can form of a mixture, for example). In chromatography, double-stranded units. the quality of separation measured in terms of RNAi RNA interference; a system that the purity of the resulting component fractions regulates what genes are active and how (higher resolution means greater purity). active they are. Two types of RNA molecules, restriction enzyme A bacterial enzyme microRNA (miRNA) and small interfering that cuts DNA molecules at discrete base-pair RNA (siRNA), are central to RNA interfer- locations. ence. retentate The part of a mixture that is risk The combination of the probability held back by a filter because of its size, of occurrence of harm and the severity of shape, and/or charge. that harm. [From ICH Q9; see also ISO/IEC retention time The period of time be- Guide 51] tween initial application of an elution buffer risk acceptance The decision to accept and the exit from the column of a particular risk. [From ICH Q9; see also ISO Guide 73] sample component. risk analysis The estimation of the risk reversed-phase chromatography An associated with the identified hazards. [From elution procedure used in liquid chromatog- ICH Q9] raphy in which the mobile phase is signifi- risk assessment A systematic process cantly more polar than the stationary phase, of organizing information to support a risk

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decision to be made within a risk manage- bottles have been replaced by microcarrier ment process. It consists of the identification culture systems that offer the advantage of of hazards and the analysis and evaluation scale-up, minimizing contamination. of risks associated with exposure to those R subgroup (or side chain) The group of hazards. [From ICH Q9] atoms that differs among different amino acid risk communication The sharing of molecules and thus determines their diverse information about risk and risk management chemical properties; for example, the R sub- between the decision maker and other stake- group on a Gly molecule is simply a hydrogen holders. [From ICH Q9]. atom, on an Ala it is a methyl complex (a risk control Actions implementing risk carbon atom and three hydrogens), and on Glu management decisions. [From ICH Q9; see it is a combination of carbon, oxygen, nitrogen, also ISO Guide 73] and hydrogen atoms. risk evaluation The comparison of the estimated risk to given risk criteria using a quantitative or qualitative scale to determine S the significance of the risk. [From ICH Q9] Saccharomyces cerevisiae Brewer’s yeast, risk identification The systematic use of familiar to cooks as the yeast used to leaven information to identify potential sources of bread, was the first and is still the most widely harm (hazards) referring to the risk question or used yeast species in biotechnology. Certain problem description. [From ICH Q9] strains are used in the manufacture of alcoholic risk management The systematic applica- beverages and fermented foods—and also tion of quality management policies, proce- for expression of genes. Biologically active dures, and practices to the tasks of assessing, interferons, for example, have been produced controlling, communicating, and reviewing in it and it can be used in the manufacture of risk. [From ICH Q9] biologics. Commonly abbreviated: S. cerevisiae. risk reduction Actions taken to lessen scale-down To model a biopharmaceuti- the probability of occurrence of harm and the cal manufacturing process (or section of that severity of that harm. [From ICH Q9] process) at the laboratory scale, usually for risk review Review or monitoring of validation or other study purposes. Scale-down output/results of the risk management process requires holding the critical parameters con- considering (if appropriate) new knowledge stant, and may be confounded by differences and experience about the risk. [From ICH Q9] in equipment dead volumes, performance, or roller bottle A container with large materials of construction. growth surfaces in which adherent cells can scale-up To transfer a biopharmaceutical be grown in a confluent monolayer. The manufacturing process from the laboratory bottles are rotated or agitated to keep cells scale to a manufacturing scale while holding in contact with growth media, but they re- critical parameters constant. quire extensive handling, labor, and media. Schizosaccharomyces pombe The second In large-scale vaccine production, roller most commonly used yeast species in biotech-

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nology, originally used in east Africa to brew secondary structure In proteins, millet beer, but which is typically unsuitable the folding, twisting, coiled, sometimes for other types of fermentation because of the spring-like chain that results when hydrogen large amount of sulfurous compounds it emits. bonds form between the adjacent parts of a SDMS Scientific Data Management System; molecule, as in an alpha helix or beta sheet. an automated, electronic repository that stores seed stock The initial inoculum or the and manages all types of scientific data to a cells placed in growth medium from which centralized database, offering integration with other cells will grow. a multitude of research applications. sensitivity The lowest level of detection SDS Sodium dodecyl sulfate; an ionic (LOD) that can be reliably measured above detergent that binds to and denatures proteins, background noise. and binds in rough proportion to the size of the sequence The precise order of bases in a protein; used to aid analytical separations. nucleic acid or amino acids in a protein. SDS-PAGE Sodium dodecyl sulfate- sequence variant Variant peptides contain- polyacrylamide gel electrophoresis; the SDS ing primary sequence differences due to muta- detergent denatures and binds to proteins, tion or amino acid misincorporation. aiding in their separation. Analytical sepa- Ser Serine; one of more than 20 naturally ration technique, often used to characterize occurring amino acids. proteins or mixtures, that uses a charged serum The watery portion of an animal gel environment through which molecules of or plant fluid (such as blood) remaining after varying sizes and electric charges migrate coagulation. from one pole to the other. Unlike gel- shear Tearing force (to cells), such as that filtration chromatography, larger molecules caused by blending or stirring. move more slowly than smaller molecules shelf life The period of time during which a because migration rate is not dependent on drug can be stored without decreasing in qual- diffusion into and out of particles. ity, safety, or efficacy. SEC Size-exclusion chromatography; An sialic acid Acidic monosaccharide found as analytical method that uses porous particles a terminal residue of N-linked and O-linked oli- to separate molecules of different sizes. gosaccharide chains of glycoproteins. The two Molecules that are smaller than the pore most commonly found forms of sialic acid are size can enter the particles and therefore N-acetylneuraminic and N-glycolylneuraminic have a longer path and longer transit time acid. Sialic acid imparts negative charge to than larger molecules that cannot enter glycoproteins. the particles. SEC can separate biological sialylated oligosaccharides N-linked and molecules and help scientists determine the O-linked oligosaccharides that contain sialic molecular weights and molecular weight acid moieties. distributions of polymers. silica Silicon dioxide, SiO2, occurring SNP Single-nucleotide polymorphism (See naturally in crystalline, microcrystalline, and DNA fingerprinting). amorphous form; used to make glass and

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ceramics, and used in pharmaceuticals. Silica Southwestern blot Analytical blotting gel is a jelly-like form of silicon dioxide that is technique for studying DNA-protein interac- widely used as a solid medium, as a dehu- tions using labeled DNA to detect proteins midifying and dehydrating agent, and in many transferred to membrane filters. chemical processes. sparge To spray. A sparger is the com- SIP Steam-in-place; using steam to clean and ponent of a fermentor that sprays air into sterilize equipment or systems without removing the broth. them from their installed location. (See CIP) species In chemistry, a particular kind of siRNA Small interfering RNA, short atomic nucleus, atom, molecule, or ion. interfering RNA, or silencing RNA; a class of specifications Tests, analytical procedures, 20 to 25 nucleotide-long double-stranded and appropriate acceptance criteria that are RNA molecules that play a variety of roles numerical limits or ranges that establish a in biology. Most notably, siRNA is involved set of criteria to which a raw material, drug in the RNA interference (RNAi) pathway, substance, or drug product must conform to be where it interferes with the expression of a considered acceptable for its intended use. specific gene. (See RNAi) specificity The degree to which a substance SMB Simulated moving bed; a method in exerts a definitive and distinctive influence on liquid chromatography of making separations a particular part of the body and on the course constant rather than in a batch process. of a particular disease. sodium hydroxide A highly caustic, alka- spectrometry Spectroscopy methods line chemical (NaOH) used to neutralize acids related to measurements of mass. and destroy soft body tissues (with potassium spectroscopy Study of the molecular hydroxide, the most widely used caustic agent absorption of light using optics. Different in industry). wavelengths and types of light can tell differ- solubility The degree to which a solute can ent things about the molecules’ identity and be dissolved in a defined solvent (sometimes condition. Proteins are often studied using describes the opposite of hydrophobicity). fluorescence and infrared (see FT-IR) spec- solute A substance that is dissolved in a troscopy. Fluorescence spectroscopy induces solvent; the part of a solution that is uniformly molecules to emit light by the application of dispersed in another substance. laser energy. somatic cell In higher organisms, a cell spike Adding a known amount of analyte that (unlike germ cells) carries the full genetic from a laboratory standard, sometimes with make-up of an organism. something highly reactive (such as a radioac- SOPs Standard operating procedures; tive or fluorescent dye) to act as a tracer. Used detailed (step-by-step), instructions to achieve to check a method for recovery or accuracy. uniformity in the performance of a specific sponsor Organization that takes primary process or piece of equipment, which are ap- ownership and responsibility for a product, and proved by the quality control unit and used for usually will be the license holder. A sponsor GMP operations. may outsource testing, clinical trials, or manu-

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facturing to other entities (CLO, CRO, CMO) sterile Absolutely free of any microbio- but retains oversight of the program. The exact logical contamination; an absolute state that division of roles is specified in contracts and in cannot be proven unless all of a material the quality agreement, a key GMP document. is consumed in the test. In practical terms, spray-drying Creation of a fine powder sterility assurance is demonstrated by by passing a bulk or final drug formulation showing that less than 1 in 106 units may be through a hot air stream to evaporate dispersed contaminated. (See USP Sterility Test) droplets; contrast with freeze-drying. stoichiometry The study of proportional stability 1. Ability to maintain constant (quantitative) relationships between two or characteristics in the presence of forces more substances during a chemical reaction. that threaten to disturb them; resistance to strain A population of cells all descend- change. Resistance to structural, chemi- ed from a single cell. cal, and biological changes in composition structural isomers Any isobaric species caused by such factors as light, temperature, that has the same elemental composition and storage (shelf) time. 2. A defined char- (and assumed basic structure) but dif- acteristic of a given product; stability profile fers in the arrangement of the elements, means the types of chemical degradations, often assumed to be functional groups for rates, and expected shelf life that character- biomolecules. ize a product. subcutaneous Referring to the layer stabilizer A chemical additive that helps of tissue (subcutis) directly underlying the maintain solution stability or drug product cutis, which is mainly composed of adipose stability. tissue. Subcutaneous (abbr: subq or sc) staining A procedure of labeling tissues, injections are given by injecting a fluid into organisms, or molecules (such as DNA or the subcutis. It is relatively painless and an proteins) with colored or fluorescent dyes effective way to administer particular types to allow visualization by microscopic or of medication. Certain depot injections are macroscopic techniques. a solid or oil-based medication, which is ad- starting material European term mean- ministered subcutaneously where it releases ing raw materials used in cGMP manufac- its agent slowly over a period of weeks. turing, but excluding components. (See sublimation Passing directly from a solid component, active starting material, raw to a vapor state without first melting into a material) liquid. statistical process control Monitoring substrate Reactive material, the sub- and controlling a process using statistical stance on which an enzyme acts. analysis with the aim of managing variabil- substratum The solid surface on which a ity at critical process control steps. cell moves or on which cells grow. stereoisomer Any of a group of isomers sulfhydryl group Any compound of in which atoms are linked in the same order sulfur and another element, usually made by but differ in their spatial arrangement. direct reaction of the elements.

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supernatant Material floating on the surface of a liquid mixture (often the liquid component that has the lowest density); the overlying fluid layer that remains after precipitation of a solid component through centrifugation. supercritical fluids Common gases, such as carbon dioxide, when under pressure contain a liquid form of the gas. This liquid is useful in a variety of biotechnology applications. In high-throughput laboratories, batches of samples are processed for screening, surface plasmon resonance A phenom- conﬁ rmation, or proﬁ ling purposes. enon used in analytical chemistry whereby plasmons (electromagnetic waves formed by and other methods of sustained delivery for electrons) propagating along the surface of a biomolecules. thin metal layer resonate with light coming symbiotic Living together for mutual benefit. through a prism at a specific angle, stopping synthesis Creating products through chemi- that light from reflecting. The electrical field cal and enzymatic reactions. Bioprocessing lets thus created is very sensitive to chemical living cells or organisms do this work. changes (such as molecular interactions) in a solution interfacing with the surface, which causes specific measurable differences in the angle of light necessary for the phenomenon to T–U perpetuate. SPR biosensors detect and measure tangential flow filtration A separation those changes. method that transfers components of one system surfactant Any substance that changes (stream) into another. The stream the product is the nature of a surface, such as lowering the being extracted from crosses the stream that the surface tension of water. product is being transferred to multiple times. suspension Particles floating in (not target Organ, tissue, or molecule involved necessarily on) a liquid medium, or the mix of in a disease that is modified or affected by a particles and liquid itself. potential therapeutic. sustained delivery Drug delivery in which targeted delivery Drug delivery that is the duration of release, action, and bioavail- specifically directed to the therapeutic molecule’s ability are controlled and reproducible; usually site of action by one of various means such as a depot (reservoir) of drug is created in the a targeting monoclonal antibody (that binds body (at the injection site, for example), and specifically to a particular kind of receptor) or the delivery matrix releases the therapeutic surgery (in which a drug formulation is injected molecules over a period of time. Biodegradable into a particular location, such as the liver). polymers are under study as microspheres T cell A synonym for T lymphocyte, T cells

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are a type of leukocyte (white cells of the blood titer A measured sample. (To draw a and lymphoid system) that (along with the less measured, representative sample from a larger numerous B lymphocytes in the bloodstream) amount is to titrate.) are necessary for conferring antibody-inde- TOC analysis Total organic carbon analy- pendent cellular immunity. Of their subsets, sis; an analytical method whereby organic cytotoxic or killer T cells can kill cells bearing carbon is oxidized to produce CO2, the amount specific antigens, helper T cells can help B of which produced is directly proportional to cells form antibodies, and suppressor T cells the amount of carbon present. Measurement suppress the activity of other cells involved in of CO2, as a result, indicates the presence immune responses. of organic molecules. The biopharmaceuti- Team Biologics A partnership between cal industry uses TOC analysis to test pure FDA’s Office of Regulatory Affairs (ORA) and water and to evaluate and validate cleaning CBER to focus on inspection and compliance procedures. issues in biologics. Its goal is to ensure the top-down sequencing The identification quality and safety of biologic products and and characterization of intact protein from tan- resolve inconsistencies. dem mass spectrometry experiments, enabling tertiary structure The three-dimensional the identification of post-translation modifica- folding (its normal state) of a polypeptide chain tions. The top-down approach provides direct in a protein molecule. measurement of the intact mass of the protein, Thr Threonine; one of more than 20 natu- as well as fragment ion information relating to rally occurring amino acids. the amino acid sequence. thrixotropy The property of some non- toxicology Study of harmful substances: Newtonian pseudoplastic fluids to show a what they are composed of and which part is time-dependent change in viscosity. harmful, how they exert their effect, whether an time-of-flight (TOF) mass spectrometer A antidote exists, and how the antidote works. mass analyzer that separates ions of different TM trajectory method; The trajectory mass-to-charge ratios by their time of travel method treats the ion as a collection of atoms, through a field-free vacuum region after having each one represented by a 12-6-4 potential. been give the same kinetic energy. The velocity The effective potential is obtained by summing of the ions is dependent on the mass-to-charge over the individual atomic contributions; then ratio and, as the ions are traveling over a fixed trajectories are run in this potential to obtain distance, the time taken to reach the detector al- the scattering angle (the angle between the lows the mass-to-charge ratios to be determined incoming and departing buffer gas atom tra- with heavier ions taking longer. jectory). The orientationally averaged collision tissue culture Growing plant or animal integral is determined by averaging over all tissues outside of the body, as in a nutrient possible collision geometries. medium in a laboratory; similar to cell culture, transcription Synthesis involving RNA but cells are maintained in their structured, polymerase of complementary RNA from a tissue form. sequence of DNA.

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transdermal delivery Drug delivery across trehalose A sugar (non-reducing disac- the skin, accomplished without breaking charide) found in certain algae and plants, the skin. For large molecules like proteins some bacteria, and some insects. It is used as a and peptides, this is possible only through preservative and stabilizer in some biopharma- iontophoresis. ceutical formulations. transduction The transfer of genetic mate- trend A statistical term referring to the rial from one cell or another by means of virus direction or rate of change of a variable(s). or phage vector. [From ICH Q9] transformation A change in the genetic trifluoroacetic acid A nonflammable, hy- structure of an organism by the incorporation groscopic (takes up moisture), colorless liquid of foreign DNA. used as a reagent, solvent, catalyst, and strong transgenics The alteration of plant or nonoxidizing acid. animal DNA so that it contains a gene from tRNA Transfer RNA; a type of RNA with another organism. There are two types of cells triplet nucleotide sequences that complement in animals and plants, germ line cells (the the nucleotide coding sequences of mRNA. In sperm and egg in animals, pollen and ovule in protein synthesis, tRNA bonds with amino acids plants) and somatic cells (all of the other cells). and transfers them to the ribosomes, where Germ-line DNA is altered in transgenic animals proteins are assembled according to the genetic and plants so those alterations are passed on code carried by mRNA. to offspring. That is done to produce therapeu- Trp Tryptophan; one of more than 20 tics, to study disease, and to improve livestock naturally occurring amino acids. strains. Transgenic plants have been created for trypsin An enzyme capable of cleaving increased resistance to disease and insects as peptide bonds. It is used to remove adherent well as to make biopharmaceuticals. cells from a surface and to break up (digest) translation The process by which informa- purified proteins for analysis. tion transferred from DNA by RNA specifies tryptic fragment analysis Identifying and the sequence of amino acids in a polypeptide quantitating the peptides resulting from tryptic (protein) chain. digestion. transmucosal delivery Drug delivery TSE Transmissible spongiform encephalopa- across mucosal membranes, such as the nasal thies; neurological disease in mammals of lining, the inside of the mouth, or the rectal many species, generally believed to be caused wall. by prions. treatment IND An IND that makes a prom- turbidostat A variation on a chemostat. ising new drug available to desperately ill pa- Whereas a chemostat is designed for constant tients as early in the drug development process input of medium, a turbidostat is designed to as possible. FDA permits the drug to be used if keep the organisms at a constant concentration. there is preliminary evidence of efficacy and it A turbidity sensor measures the concentration treats a serious or life-threatening disease, or if of organisms in the culture and adds additional there is no comparable therapy available. medium when a preset value is exceeded.

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turbulent flow field The state that results UPLC® Technology The use of a high- from mixing the contents of a fermentor or effiency LC system holistically designed bioreactor to provide oxygen to the cells. by Waters Corporation to accommodate That must be balanced against the shear that sub-2 μm particles and very high operating causes cell damage and death. pressure is termed UltraPerformance Liquid turnkey system A piece of equipment, Chromatography¨. The major benefits of this process train, or manufacturing plant that is technology are significant improvements delivered to the customer in a ready-to-run in resolution over HPLC, and/or faster run condition, specialized for the customerÕs times, while maintaining the resolution seen application, with no additional equipment or in an existing HPLC separation. modifications required. upstream processing The cell-culture or TWIG travelling wave ion guide; the fermentation process used to express pro- mechanism by which mobility is implemented teins. The output of upstream processing is in an ion mobility capable mass spectrom- an aqueous solution containing 1Ð10 g/L of eter, i.e., Waters SYNAPTª Systems. Ions the recombinant protein, cells, amino acids, are moved through a pressurized region by buffer salts, nutrients, and other additives. the action of a continuous train of transient USP or USP-NF The United States Phar- voltage pulses, or travelling waves. macopeial Convention, Inc.; establishes and Tyr Tyrosine; one of more than 20 natu- disseminates officially recognized standards rally occurring amino acids. of quality and authoritative information for ultrafiltration Filtration under pressure. the use in the manufacture and testing of underflow The dewatered solids that drugs, excipients, and raw materials. Also result from compaction during centrifugation. called one of the compendia. Other compen- unfolding A form of protein degradation dia include, for example, Ph.Eur (Pharmaco- in which the three-dimensional structure of peia Europa), JP (Japanese Pharmacopeia). a molecule unravels to something that more The USP, which defined specifications for closely resembles a basic chain of amino approved drugs as well as general methods acids. and guidances, merged with the NF, National unicellular A single-cell organism. Formulary, which focused on specifications unit operation A distinct chemical or for raw materials and excipients. General physical step in a downstream process, such chapters are not legally binding, but specific as ultrafiltration, centrifugation, or chroma- chapters are considered to be binding, and tography. defined USP methods are accepted by the UPC2® Technology UltraPerformance FDA as an appropriate standard. Convergence Chromatography¨, available USP sterility test A method defined in with the Waters ACQUITY UPC2¨ System. the USP and Ph.Eur, and considered accept- A broad-based analytical platform that able for per-lot testing of parenteral drugs is complementary to GC and UPLC. (See to test for sterility. By itself, this test does Convergence Chromatography) not prove a given lot is sterile; rather, taken

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together with all other validation, GMP through the jacket to heat (or cool) the fluid controls, and product/process testing, it in the vessel. Because biopharmaceuti- increases confidence that a given lot is safe. cal products are so sensitive and vessel (See sterility) jackets can cause uneven heating (hot or UV-vis Ultraviolet-visible spectroscopy; an cold spots), shell-and-tube or plate-and- analytical method that measures the absorp- frame heat exchangers are more common in tion of light in the 200 to 750 nm range biopharmaceutical production systems. of the electromagnetic spectrum. It is used viability The extent to which cells and tis- in determining protein concentration and is sues are living. Cells can be metabolically viable often applied to HPLC detection. even if they are not reproductively viable. viral clearance step Process step which separates a given class of virus, if any are V–Z present, from the desired product. A clear- vaccines Preparations that elicit an ance factor may be estimated by performing immune response (production of antibodies) scaled-down experiments using a model to protect a person or animal from a disease- virus, to determine process capability. causing agent. viral inactivation step Process step, val Valine; one of more than 20 naturally which inactivates the activity of a given class occurring amino acids. of virus to provide assurance of safety. An validation 1. Documented evidence that inactivation factor may be estimated by per- shows that an assay or process, when operated forming scaled-down experiments using a within specified ranges of critical parameters, model virus, to determine process capability. has a high probability of meeting specifica- virus The simplest form of life: RNA or tions. 2. The process of determining the DNA wrapped in a shell of protein, some- degree of validity; the procedures involved in times with a means of injecting that genetic checking data for correctness, compliance with material into a host organism (infection). standards, and conformance with the require- Viruses cannot reproduce on their own, but ment specifications. A series of experiments require the aid of a host (bacteria, plant, or performed using a pre-approved protocol that animal). The host cell’s synthesis is often will generate adequate documented evidence inhibited by the infecting virus, which may to support a claim of a validated state. or may not result in disease (more than vector The plasmid, virus, or other vehicle 200 viruses are known to produce human used to carry recombinant DNA into the cell of disease). An individual virus particle is another species. called a virion, and virions vary in structure, Vero An established cell line derived from complexity, and size (ranging from 20 to the kidney of the African green monkey. 25 nm or less to 2,000 nm or more). Six vessel jacket A temperature control classes of virus are defined by whether they method consisting of a double wall outside are single or double stranded, DNA or RNA, the main vessel wall. Liquid or steam flows or positive or negative.

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virus-like particles Also RVLP withdrawal Product withdrawal; a recall (retrovirus-like particles); particles that of a lot of product that is done voluntarily by resemble retroviruses, yet lack infectivity, a firm, when there is concern about product and usually are found in established lines of quality that is not proven. A recall may be mammalian cells. Cell bank characterization mandated by FDA or regulatory bodies. (See seeks to determine whether viral activity also recall) is present, as a means of assessing risk. Not working cell bank A cell bank that is usu- present in nonmammalian cells or cell lines. ally made from a single vial of the master cell viscosity Thickness of a liquid; determines bank, in which each vial has comparable con- its internal resistance to shear forces. tents and is expected to perform consistently warning letter The most serious FDA when introduced into a process or assay. Both post-audit (after inspection) letter, notifying a master and working cell banks are extensively manufacturer of adverse inspection findings tested and characterized before use. Manufac- and giving it 15 days to reply with a concrete turing usually starts when a vial of working cell plan for remediation. May or may not be as- bank is thawed and added to a reactor. (See sociated with other actions, such as injunction, master cell bank) consent decree, or product seizure. xenobiotic A chemical found in an organ- washing (of a column) Flushing a column ism but which is not normally produced or with a large volume of a solvent or buffering expected to be present in it. It can also cover agent before selective elution of the desired substances which are present in much higher analyte. concentrations than are usual. Specifically, well-characterized A chemical entity whose drugs such as antibiotics are xenobiotics in identity, purity, impurities, potency, and quan- humans because the human body does not tity can be determined and controlled; most produce them itself, nor are they part of a well-characterized biologics are recombinant normal diet. DNA-derived proteins or monoclonal antibodies. YAC Yeast artificial chromosome; a vector Western blot An immunochemical method used to clone DNA fragments up to 100,000 for identifying proteins in a complex mixture, base-pairs long. YACs are constructed from proteins separated by electrophoresis are the telomeric, centromeric, and replication transferred (blotted) from the gel medium to sequences of yeast cells. a protein-binding nitrocellulose or polymeric yeast A single-celled fungus (eukaryote). membrane; the transferred proteins are then Waters, UltraPerformance Liquid Chromatography, UPLC, detected by their relative binding to labeled ACQUITY, ACQUITY UPLC, UltraPerformance Convergence antibodies. (See blotting) Chromatography, UPC2, High Definition Mass Spectrometry, WFI Water for injection; very pure water MassLynx, SYNAPT, and The Science of What’s Possible are registered trademarks of Waters Corporation. BiopharmaL- that meets specifications defined by the USP or ynx, AutoBlend, AutoBlend Plus, RapiFluor-MS, and Rapid- other compendia; suitable for parenteral uses. Gest are trademarks of Waters Corporation.

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suggested resources If you are looking for additional information (or terms not included in our glossary), here are some places to begin your search.

BOOKS Process Validation in Manufacturing of Biophar- maceuticals, Anurag S. Rathore and Gail Sofer, Characterization of Protein Therapeutics using Eds. (CRC Press, Taylor & Francis Group, Boca Mass Spectrometry, Guodong Chen, Ed. (Springer Raton, FL 2005) Science+Business Media, New York 2013) J.D. Watson et al., Recombinant DNA: Genes Biopharmaceutical Drug Design and Development, and Genomes-A Short Course, Third Edition (Cold S. Wu-Pong and Y. Rojanasakul, Eds. (Humana Spring Harbor Laboratory Press, co-published Press Inc., Totowa, NJ 1999) with W.H. Freeman, NY, 2007)

W. Bains, Biotechnology from A to Z, 3rd ed. ORGANIZATIONS (Oxford University Press, Oxford, UK 2004) American Association of Pharmaceutical Scientists (AAPS) Expediting Drug and Biologics Development: A Arlington, VA; aaps.org Strategic Approach, 3rd ed., Steven E. Linberg, Ed. (Parexel International Corporation, Waltham, Biotechnology Industry Organization (BIO), MA 2006) Washington, DC; bio.org California Separation Science Society FDA-Speak: A Glossary and Agency Guide, 2nd (CASSS) ed. D.E. Snyder, Ed. (CRC Press, Boca Raton, FL San Francisco, CA; casss.org 2001) US FDA Handbook of Biopharma Industry Acronyms & US Food and Drug Administration Terms, Ronald P. Even, Ed. (Jones and Bartlett Rockville, Maryland Publishers, Sudbury, MA 2009) Center for Biologics Evaluation and Research, www.fda.gov/cber/index.html J.F. Huxsoll, Quality Assurance for Biopharmaceu- Center for Drug Evaluation and Research, ticals (John Wiley & Sons, Inc., New York 1994) www.fda.gov/cder Electronic Freedom-of-Information Reading J.M. Walker and M. Cox, The Language of Biotech- Room, www.fda.gov/foi/ nology: A Dictionary of Terms, 2nd ed. (American Chemical Society, Washington, DC 1995) European Medicines Agency (EMA) www.ema.europa.eu/ema The Merck Index: An Encyclopedia of Chemicals, Health Canada Drugs, and Biologicals,14th Edition (Merck & Co., Health Products and Food Branch Inspectorate, Inc., Whitehouse Station, NJ, 2006) Ottawa, ON; hc-sc.gc.ca The Merck Manual of Medical Information Second International Conference on Harmonisation Home Edition (Merck & Co., Inc., Whitehouse Sta- of Technical Requirements for Registration of tion, NJ 2003) Pharmaceuticals for Human Use (ICH), Geneva, Switzerland; www.ich.org P. Singleton and D. Sainsbury, Dictionary of International Federation of Pharmaceutical Microbiology and Molecular Biology, 3rd ed. (John Manufacturers & Associations, Wiley & Sons, New York 2002) Geneva, Switzerland; www.ifpma.org

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International Pharmaceutical Web MD Excipient Council of the Americas www.webmd.com Arlington, VA; ipecamericas.org Merck publications online (searchable) International Society for www.merck.com/pubs Pharmaceutical Engineering Tampa, FL; ispe.org BioSpace National Center for Biotechnology www.biospace.com Information National Library of Medicine, Biopharmaceutical News Source, Bethesda, MD; ncbi.nlm.nih.gov Thomson Reuters National Human Genome Research www.bioworld.com Institute National Institutes of Health, NCBI’s PubMed Bethesda, MD; www.genome.gov www.ncbi.nlm.nih.gov or pubmed.org Parenteral Drug Association, Bethesda, MD; pda.org Barnett Institute of Chemical and Biological Analysis, Northeastern University, Pharmaceutical Research and Boston, MA Manufacturers of America (PhRMA), www.northeastern.edu/barnett Washington, D.C.; phrma.org Biomanufacturing Training and Education Center ADDITIONAL INDUSTRY & (BTEC), North Carolina State University, TRAINING RESOURCES Raleigh, NC www.btec.ncsu.edu “A Hundred Years of Antibody Therapy” users.path.ox.ac.uk/~scobbold/tig/new1/mabth.html Bioinformatics Resource Portal, ExPASy Swiss Institute of Bioinformatics (SIB) Antibody Resource Page www.expasy.org www.antibodyresource.com The Biotechnology Institute, Biotechnology Biopharmaceutical Glossary and Industry Organization (BIO) Taxonomies,Cambridge Healthtech Institute (CHI) Washington, D.C. www.genomicglossaries.com www.biotechinstitute.org Human Genome Project Information Archive Institute for Bioscience & Biotechnology http://web.ornl.gov/sci/techresources/ Research (IBBR), University of Maryland and Human_Genome National Institute of Standards and Technology, Medical Transcription Desk Style Guide Refer- Rockville and College Park, MD ence: Medical terms, terminology, transcription www.ibbr.umd.edu samples and words National Institute for Bioprocessing www.mtdesk.com Research & Training (NIBRT), Dublin, Ireland- MedicineNet.com, See Med Term dictionary www.nibrt.ie www.medicinenet.com Northeastern University Biopharmaceutical Online Medical Dictionary Analysis Training Laboratory, Burlington, MA www.online-medical-dictionary.org www.northeastern.edu/batl TechTarget’s glossary of IT-related words Univ. of Penn Dept. of Medical Ethics Whatis.techtarget.com & Health Policy Physician’s Desk Reference medicalethics.med.upenn.edu www.pdr.net

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PEER-REVIEWED PUBLICATIONS FEATURING WATERS TECHNOLOGY Hilliard M., et al. “Glycan characterization of Lauber MA, et al. “Rapid Preparation of Released the NIST RM monoclonal antibody using a total N-Glycans for HILIC Analysis Using a Labeling analytical solution: From sample preparation to Reagent that Facilitates Sensitive Fluorescence data analysis,” mAbs, 2017, 9:8, 1349-1359, and ESI-MS Detection,” Anal. Chem. 2015, 87, DOI: 10.1080/19420862.2017.1377381 5401-5409. Chen L. et al., “In-depth structural charac- Doneanu CE, Chen W. “Analysis of host-cell proteins terization of Kadcyla® (ado-trastuzumab in biotherapeutic proteins by LC/MS approaches,” emtansine) and its biosimilar candidate,” Methods Mol Biol. 2014;1129:341-50. doi: mAbs, 2016, 8 (7), 1210-1223, DOI: 10.1007/978-1-62703-977-2_25. 10.1080/19420862.2016.1204502 Characterization of Protein Therapeutics using Mass Fang J. et al., “Advanced assessment of the Spectrometry. Chen G ed. Chen W, Chakraborty physicochemical characteristics of Remicade® A; chapter: “Applications of Ion Mobility Mass and Inflectra® by sensitive LC/MS tech- Spectrometry for Characterization of Protein niques,” mAbs, 2016, 8 (6), 1021-1034, DOI: Therapeutics” (Springer Science+Business Media, 10.1080/19420862.2016.1193661 New York 2013). Birdsall R. E. et al., “Reduction of metal adducts Cosgrave EFJ, McCarthy SM. “Running Legacy HPLC in oligonucleotide mass spectra in ion-pair Methods with UPLC: Details on How Two Methods reversed-phase chromatography/mass spectrom- were Transferred with Minimal Adjustment.” Genetic etry analysis,” Rapid Commun. Mass Spectrom. Engineering News, 2013 Nov 1; Tutorial 33(19): 2016, 30, 1667–1679 48-49. Chen W. et al., “Improved Identification and Williams JP, et al. “Characterisation of glycoproteins Quantification of Host Cell Proteins (HCPs) in using a quadrupole time-of-flight mass spectrom- Biotherapeutics Using Liquid Chromatography- eter configured for electron transfer dissociation.” Mass Spectrometry” In State-of-the-Art and Rapid Commun Mass Spectrom., 2013 Nov 15; Emerging Technologies for Therapeutic Monoclonal 27(21): 2383-90. doi: 10.1002/rcm.6684. Antibody Characterization Volume 3. Defining the Next Generation of Analytical and Biophysical Houel S, et al. “N- and O-Glycosylation Analysis of Techniques: John E. Schiel, Darryl L. Davis, Oleg Etanercept Using Liquid Chromatography and Quad- V. Borisov. Ed. American Chemical Society 2015, rupole Time-of-Flight Mass Spectrometry Equipped Chapter 13, pp 357-393; DOI: 10.1021/bk-2015- with Electron-Transfer Dissociation Functionality.” 1202.ch013 Anal. Chem. 2014; 86 (1): 576-84. Doneanu CE, et al. “Enhanced Detection of Low- Ahn J, Engen JR. “The use of hydrogen/deuterium Abundance Host Cell Protein Impurities in High- exchange mass spectrometry in epitope mapping.” Purity Monoclonal Antibodies Down to 1 ppm Chimica Oggi (Chemistry Today). 2013 Jan/Feb; Using Ion Mobility Mass Spectrometry Coupled 31(1): 25-39. with Multidimensional Liquid Chromatography,” Lauber MA, et al. “High-resolution peptide map- Anal. Chem., 2015, 87, 10283-10291. ping separations with MS-friendly mobile phases Birdsall R, et al. “A rapid on-line method for and charge-surface-modified C18.” Anal Chem. mass spectrometric confirmation of a cysteine- 2013 Jul 16; 85(14):6936-44. doi: 10.1021/ conjugated antibody-drug-conjugate structure ac401481z. using multidimensional chromatography,” mAbs, Ahn J, et al. “Pepsin immobilized on high-strength 2015, 7:6, 1036-1044 hybrid particles for continuous flow online diges- Birdsall R, et al. “A sensitive multidimensional tion at 10,000 psi.” Anal Chem. 2012 Aug 21; method for the detection, characterization, and 84(16):7256–62. doi: 10.1021/ac301749h. quantification of trace free drug species in Berkowitz SA, et al. “Analytical tools for character- antibody-drug conjugate samples using mass izing biopharmaceuticals and the implications for spectral detection,” mAbs 2015, 8:2 DOI:10.108 biosimilars.” Nat Rev Drug Discov. 2012 Jun 29; 0/19420862.2015.1116659 11(7):527-40. doi: 10.1038/nrd3746.

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