Glossary

absorption The process of a drug's movement from the administration site into systemic circulation.

accelerated stability tests Studies in which the product is stored under stress conditions (usually 45°C and high humidity) over three to six months and observed for signs of degradation; used to predict long-term storage patterns.

acute During lyophilization, this describes the processing stage that includes both freezing and drying by pressure, but before the temperature is raised. In medicine, it describes a disorder that is usually severe and of short duration (viral fever, bacterial food poisoning), as opposed to a long-term, chronic disease, such as diabetes.

adsorption Adherence of molecules in solution or suspension to cells or other molecules — or to the walls of a vial or drug delivery device.

aggregate A clustered mass.

amorphous Having no apparent shape or order; noncrystalline.

aqueoussolution A solution that resembles or is made with water.

bioavailability Extent to which (sometimes the rate at which) the active drug ingredient enters systemic circulation, thereby gaining access to its site of action.

bolus A rounded mass; oral medication formed into a large soft pill; a concentrated mass of injected medication.

buffer (buffering agent) A substance or mixture of substances (such as bicarbonates and some proteins in biological fluids) that in solution tend to stabilize the hydrogen-ion concentration by neutralizing within limits both the acids and the bases, making the solution resistant to pH changes.

bulk active ingredient Any substance or mixture of substances used in the manufacture of a therapeutic that furnishes the pharmacological activity of the drug product.

bulking agent An additive that increases the volume of a solution.

cake The freeze-dried solid portion of a formulation that remains after as much water as possible has been removed.

calorimetry Analytical measurement of quantities of heat.

campaigned production A cost-effective, multistep production method for producing more than one product with the same equipment and in the same facilities; continuous production of successive batches.

characterization Precisely deciphering and describing a molecular entity's physical, chemical, and biological properties, as appropriate.

charge The electrical state of an atom or molecule (positive, negative, or neutral) according to the ratio of protons (positively charged) to electrons (negatively charged).

chelator A molecule used to bind a metal ion with more than one organic group to form a highly stable, ring-like formation.

chromatography Techniques used to separate molecules based on their relative affinity for various liquid or gas mediums.

circular dichroism (CD) The absorption of left and right circularly polarized light; a property of molecules that are optically active. CD spectroscopy is a form of light-absorption spectroscopy that measures the difference in CD by a substance. The spectra can be analyzed to learn the different structural types in a protein: alpha helix, parallel and antiparallel beta sheet, turn, and so on.

coacervation The process of forming a coacervate (a mass of small particles bound together by electrostatic attraction) by the partial mixing of two or more liquids.

concentration The amount of a particular substance in a given quantity of solution, usually stated as a percentage by weight or volume, as weight per unit volume, as molarity (a molar solution contains one gram-mole of solute per liter of solution), or as normality (a normal solution contains one gram-equivalent weight of solute per liter of solution).

conformation The shape of a molecule, produced by the specific spatial arrangement of the units that compose it.

contaminant A foreign agent or material that is not introduced as part of processing, such as airborne particulates or adventitious organisms.

controlled delivery Incorporation of one or more elements of control on the release of an active ingredient from a dosage form to obtain well-defined pharmacokinetic profiles.

convection A transfer of heat that occurs when a fluid flows inside a channel of a different temperature; heat is transferred through the fluid because of the difference in motion between it and the flow boundary.

cryoconcentration When temperature is decreased at a sufficiently slow rate, ice formation occurs below the freezing temperature, which can cause cryoinjury to the solution, and the ice crystals will function as an additional solute; a cryoprotectant is often used to prevent this.

dalton (Da) A unit of mass very nearly equal to that of a hydrogen atom (precisely equal to 1 on the atomic mass scale), named after John Dalton, who developed the atomic theory of matter. It is 1.660 3 10^-24 gram. A kilodalton (kDa) is 1,000 daltons.

deamidation Removal of one or more amide groups from a polypeptide molecule.

deflashing The finishing procedure by which excess plastic (flash) is removed from a molding.

degradation Loss or reduction of quality, integrity, or character; a chemical reaction that breaks down a molecule into smaller parts.

degradants The smaller parts that are left over after a molecule or solution degrades.

delaminate To split apart into thin layers; the act of separating a laminate into layers.

delivery matrix A heterogeneous semisolid matrix (such as a biopolymer gel) for the sustained delivery of drug substances directly to the tissues; a matrix can be modified to optimize the dosage or time period during which the drug is delivered.

denaturation A condition in which a protein unfolds or its polypeptide chains are disordered, rendering the molecule less soluble and usually nonfunctional.

dendritic ice Ice that branches like a tree; if water is cooled slowly, it forms dendritic ice crystals.

differential scanning calorimetry (DSC) Analytical method that independently measures the rate of heat flow to a sample against a reference standard of the same temperature. Data are obtained by monitoring the differential heat flow as a function of temperature. DSC can measure heat capacities, phase transitions, dehydration, and decomposition reactions.

diluent A chemically inert substance added to a solution to increase the volume and reduce the concentration; a diluting agent.

disulfide bond A covalent bond formed between two sulfur atoms of different cysteines in a protein.

efficacy Usefulness; the power to produce an effect.

efficiency of delivery The relative effectiveness of a drug delivery system.

elastomeric closure A rubber or rubber-like closure or stopper; a packaging component that may come into direct contact with the enclosed drug, which is usually an injectable.

electrophoresis Movement of suspended particles through a fluid or gel under the influence of an electrical charge.

emulsification A process that creates a stable mixture of two liquids that normally would not mix together (such as oil and water) by forcing one to disperse in the other as droplets.

encapsulation To enclose in a capsule, usually one made of a biodegradable polymer.

excipient A relatively inert substance, such as a syrup, that is added to a drug to make it easier to ship, store, or administer.

extractables Substances withdrawn (such as the medicinally active components of plant or animal tissue) by a physical or chemical process.

extrusion A process of forming rods, tubes, or other continuously formed pieces by pushing hot or cold semisoft solid material through a die; also any process of pushing a substance through holes or a tube.

flash The material that oozes from the joint line of the mold cavity in plastics production.

folding A process in which a protein spontaneously forms into its correct, knotted tertiary structure that is held in place by chemical bonds and by attractive forces between atoms.

formulation The method and process of selecting the components of a mixture; the product of such a process.

glass state The amorphous solid that contains the therapeutic protein in lyo-philization; any material that takes the shape of its container and is formed by cooling a liquid until it is rigid but not crystallized.

glycoproteinA conjugated (joined together) protein in which the nonprotein group is a carbohydrate (such as sugar, starch, or cellulose).

half-life The time it takes for 50% of a drug or drug formulation given to a patient to be eliminated or disintegrated by natural processes.

HEPA filtration Use of a high-efficiency particulate air filter to remove contaminants from a clean room.

high-pressure liquid chromatography (HPLC) Also high-performance liquid chromatography; a form of liquid chromatography for separating compounds dissolved in solution. A liquid sample is forced at high pressure through a tube (column) that is packed tightly with chromatographic media (see The BioPharm Guide to Separation and Purification, December 2000, for a detailed discussion of chromatographic methods and terminology).

hydrolysis Literally "cleaved by water," a reaction in which the chemical bond attaching an atom or group of atoms to the rest of a molecule is severed, followed by attachment of a hydrogen atom at the same point.

hydrophilic Having an affinity for water; attracting, dissolving in, or absorbing water.

hydrophobicity The degree to which something repels water.

immunogen A substance that induces or elicits an immune response — that is, the body recognizes it as a foreign agent that must be expelled.

impurity A foreign agent or material either introduced as part of processing (such as buffers or salts added during chromatography) or intrinsic to the nature of bioprocessing (such as product variants and cellular debris).

infusion Introducing a solution into the bloodstream or another solution; also refers to the solution itself, such as a drug formulation, when infused.

iontophoreticdelivery Introduction of drugs through intact skin using the transfer of ions by applying a direct electric current.

isoelectric focusing An analytical technique that uses electrophoresis in a pH gradient to determine the isoelectric point (pI, see below) of a polypeptide.

isoelectric point (pI) The pH at which a protein has no net charge. At a pH above the isoelectric point, a protein acts as a base. At a pH below the isoelectric point, it acts as an acid. A solution of proteins or amino acids has its minimum conductivity and viscosity at pI.

isomerization Changing into an isomeric form (with the same chemical makeup but a different molecular structure — for proteins, therefore, altering their activity).

isotonic Having the same osmotic pressure as blood serum, thus easily mixed with the blood.

laminar flow clean air device A clean bench, clean workstation, and wall or ceiling modules or other devices that incorporate a HEPA/ULPA filter and motor blower for supplying clean air in one direction for a controlled work space; more correctly referred to as "unidirectional airflow," which is air flow having generally parallel streamlines operating in a single direction and with uniform velocity over its cross section.

ligands Molecules that bind to other molecules. In a binding action, usually the smaller of the two molecules is considered the ligand.

Luer-lock A pressure-locked connection between a needle and syringe body.

lyophilization Freeze-drying; a procedure by which a liquid solution is frozen and then placed under lowering pressure to remove ice crystals (primary drying), then heated to remove the unfrozen water by sublimation.

mass spectrometry Analytical method that measures the difference in mass-to-charge ratio (m/e) of ionized atoms or molecules to separate them from each other. Mass spectrometry is useful for counting atoms or molecules and also for determining chemical and structural information about molecules (molecules have distinctive fragmentation patterns). In the study of proteins, mass spectrometry data are often combined with liquid chromatography results.

melting temperature (Tm) The melting temperature refers to the midpoint in the transition from one state to another; for example, from folded to unfolded, or, in the case or a powder, from rigid to viscous.

metered dose inhaler (MDI) A metal canister containing a drug formulation and propellants and placed in a plastic holder that precisely measures out a formulation dose for inhalation.

microheterogeneity Heterogeneity that is localized to a relatively small region, as in an amino acid sequence or the structure of a polypeptide chain.

microspheres Tiny polymer spheres (usually biodegradable) measured in micrometers.

multimer formation Association of peptide or protein molecules to produce dimers (two linked molecules), trimers (three linked molecules), and so on depending on how many identical molecules link together.

multiphase solidification Material, such as the plastic used in blow-fill-seal, is heated to suitable viscosity, squeezed through a nozzle by a pumping system, and deposited layer by layer; the molten material solidifies when it contacts the previous layer; the contact of the liquefied material leads to partial remelting of the previous layer for good bonding of the layers.

native The natural state; in biopharmaceutical development, it usually refers to a molecule's normal three-dimensional structure under optimal conditions.

nebulizer A device, pressurized by an oxygen or nitrogen tank, for the purpose of converting a liquid medication into a fine mist for inhalation.

oxidation Combination with oxygen or subjection to its action.

parenteral delivery Drug delivery by injection; subcutaneous, intramuscular, and intravenous delivery are most common.

parison a hot quantity of soft or molten polymer (or glass) that is partly blown or formed into a shape before its final shaping in a mold.

PEGylation Attachment of a polyethylene glycol molecule to a protein molecule.

peptide bond A covalent bond (link) between an amino group of one amino acid and a carboxyl group of another. This linkage does not allow free rotation, and it is the important bond that holds amino acid monomers together to form the polymer known as a polypeptide.

peptide mapping Obtaining a characteristic pattern of peptides by partial hydrolysis (cleavage, digestion) of a protein and separation by chromatographic means to produce a "fingerprint" of it.

pH Measurement of the relative alkalinity or acidity of a solution based on a chemical logarithm. Pure water is pH neutral (7), acidic solutions have pH values between 0 and 7, and alkaline or basic solutions have pH values between 7 and 14.

pharmacokinetics Study of a drug and its metabolites in the body after administration by any route.

physical state The form that matter takes, whether solid, liquid, gas, or plasma.

placebo A fake treatment (often the same formulation used for the real product, but without the active ingredient) administered to the control group in a controlled clinical trial so that the specific and nonspecific effects of the experimental treatment can be distinguished. The experimental treatment must produce better results than the placebo to be considered effective.

polyethylene glycol (PEG) A polymer that varies in consistency from liquid to solid depending on its molecular weight (indicated by a number following the name). PEGs are used as surfactants in industry (for foods, cosmetics, and pharmaceuticals) and in biomedicine as dispersing agents, solvents, ointment and suppository bases, vehicles, and excipients.

polysorbates Complex mixtures of polyoxyethylene ethers used as emulsifiers or dispersing agents in pharmaceuticals.

precipitation Process causing a solid to settle out of solution by the action of gravity or by a chemical reaction, which forms a substance (precipitate) that separates as solid particles in the liquid.

preservative A chemical additive that prevents spoilage by killing or inactivating microorganisms; an additive that prevents microbial contamination, usually employed in multi-dose containers.

protein collapse Mild denaturation, in which a protein's native structure falls out of equilibrium.

proteolysis Separation (cleavage) of peptide bonds in proteins by proteases (enzymes that recognize and cut specific peptide bonds) or other means.

residue An amino acid when referred to as part of a polypeptide chain.

shear Tearing force, such as that caused by blending or stirring.

shelf life The period of time during which a drug can be stored without significant loss in quality, safety, or efficacy.

size-exclusion chromatography (SEC) Also gel-filtration or gel-permeation chromatography; an analytical method that uses porous particles to separate molecules of different sizes. Molecules that are smaller than the pore size can enter the particles and therefore have a longer path and longer transit time than larger molecules that cannot enter the particles. SEC can separate biological molecules and help scientists determine the molecular weights and molecular weight distributions of polymers.

spectroscopy Study of the molecular absorption of light. Different wavelengths and types of light can tell different things about the molecules' identity and condition. Proteins are often studied using fluorescence and infrared spectroscopy. Fluorescence spectroscopy induces molecules to emit light by the application of laser energy. Fourier-transform infrared (FTIR) spectroscopy uses a mathematical logarithm to interpret the vibrations of functional molecular groups and highly polar bonds. It can produce a biochemical "fingerprint" illustrating the vibrational features of all sample components, and it can be used to learn about protein structure.

stability Ability to maintain constant characteristics in the presence of forces that threaten to disturb them; resistance to change.

stabilizer A chemical additive that helps maintain solution or drug stability.

sublimation Passing directly from a solid to a vapor state without first melting into a liquid.

surfactant Any substance that changes the nature of a surface, such as by lowering the surface tension of water.

sustaineddelivery Controlled delivery that is engineered to release the active ingredient over an extended period in a well-defined and reproducible way.

targeted delivery Drug delivery that is specifically directed to the therapeutic molecule's site of action by one of various means such as a monoclonal antibody that targets a specific kind of receptor or surgery in which a drug formulation is injected into a particular location, such as the liver.

tertiary structure The three-dimensional folding of polypeptide chains in a protein molecule.

transdermal delivery Drug delivery across the skin, accomplished without breaking the skin. For large molecules like proteins and peptides, this is possible only through iontophoresis.

transmucosal delivery Drug delivery across mucosal membranes, such as the nasal lining, the inside of the mouth, or the rectal wall.

unfolding A form of protein degradation in which the knotty structure of a molecule unravels to something that more closely resembles a chain of amino acids.