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2018 Edition
A GUIDE TO THE
BIOPHARMACEUTICAL
LEXICON
Gain confidence in glycan,
peptide, and oligonucleotide
analysis with mass detection.
PHARMACEUTICAL Q
HEALTH SCIENCES Q
FOOD Q
ENVIRONMENTAL Q
CHEMICAL MATERIALS
©2018 Waters Corporation. Waters, ACQUITY QDa and The Science of What’s Possible
are registered trademarks of Waters Corporation.
[ BIOTERMINOLOGY ]
BIOTERMINOLOGY AND
DEFINITIONS
A
absorption Removal of a particular
acceptance of the results of analytical
procedures which the drug substance or
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.”
• ICH 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.”
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
C
cake The solid sediment that has been
monosaccharides, such as glucose, galactose,
and fructose. Monosaccharides can be linked
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)
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
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
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-
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, designed to provide well-defined pharmaco-
chemistries, and pore sizes to best meet
separation requirements. kinetic profiles.
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.
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
E electric field.
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;
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
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
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
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
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
HDMS™ (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.
hygroscopic Ready to take up and retain until their net charge is zero (their isoelectric
moisture. point, pI). cIEF is a specialized form of electro-
phoresis that can be adapted to the capillary
I–J format.
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(ab’)2 and Fc/2 sub- an immune response—that 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
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
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.
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.
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
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 an-
alytical 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 proteo-
lytic, enzymes, the other two being chymotryp-
sin and trypsin. A digestive protease, pepsin
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
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
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
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).
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
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
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-
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.
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.
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 customer’s 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 1–10 g/L of
eter, i.e., Waters SYNAPT™ 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
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
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