Escolar Documentos
Profissional Documentos
Cultura Documentos
A Guide to the
Biopharmaceutical
Lexicon
2012 edition
[ BIOTERMINOLOGY ]
BIOTERMINOLOGY AND
DEFINITIONS
A
absorption Removal of a particular
tance of the results of analytical procedures
which the drug substance or drug product or
materials at other stages of their manufac-
molecule from a sample by accumulation ture should meet. [From ICH Q6B]
into a bound water volume such as might ACN Acetonitrile; the most frequently
be present in a densely fibrous material. In used solvent in HPLC, commonly used as
pharmacology (and more specifically phar- an eluent.
macokinetics), absorption is the movement acidic variant A product variant that
of a drug into the bloodstream. Absorption exhibits a more negative charge character
involves several phases. First, the drug needs by IEX or CE than the primary biotherapeu-
to be introduced via a route of administra- tic form.
tion (oral, via the skin, etc.) and in a specific active starting material The raw materi-
dosage form such as a tablet, capsule, and so al that is identified as directly related to the
on. (See adsorption). active chemical comprising the product, and
accelerated stability tests Studies in is defined at the first stage during chemical
which the product is stored under stress con- synthesis at which part or most of the critical
ditions (for example, 45 C and high humidity moieties are present. Defining active starting
over three to six months) and observed for material defines the step at which compli-
signs of degradation; used to predict long- ance with cGMP requirements begins during
term storage patterns. manufacturing. For biopharmaceuticals, this
acceptance criteria Numerical limits, term is not used.
ranges, or other suitable measures for accep- acute Describes a disorder as a one-time
Following acronyms that appear in brackets throughout the guide represent the sources of definitions:
FDA QSG definition is the one that appears in the US FDAs 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 Standardizations standard 14971,
Medical DevicesApplication of risk management to medical devices.
ISO/IEC Guide 51 Refers to the the joint ISO and IEC (International Electrotechnical Commission) publication,
Safety aspectsGuidelines for their inclusion in standards.
ISO Guide 73 Refers to ISO Guide 73, Risk managementVocabularyGuidelines for their use in standards.
alpha helix (-helix) A coil or spiral anaerobic Growing in the absence of air
element of protein secondary structure. or oxygen. Some anaerobic organisms are
amino acid analysis Hydrolysis of a killed by brief exposure to oxygen, whereas
protein or peptide into its individual residues it may simply retard or stop the growth of
(free amino acids), followed by chromato- others.
graphic separation and UV-visible detection analytical methods Processes used to
for analytical purposes. analyze or characterize a mixture, a com-
amino acids A class of 20 naturally oc- pound, or an unknown material.
curring hydrocarbon molecules that combine anion A negatively charged ion (having
to form proteins in living things. They more electrons than protons).
include alanine (A), arginine (R), annual review An evaluation, conducted
asparagine (N), aspartic acid (D), cysteine at least annually, which assesses the quality
(C), glutamic acid (E), glutamine (Q), glycine standards of each drug product to deter-
(G), histidine (H), isoleucine (I), leucine (L), mine the need for changes in drug product
lysine (K), methionine (M), phenylalanine specifications or manufacturing or control
(F), proline (P), serine (S), threonine (T), procedures. [From FDAQSG]
tryptophan (W), tyrosine (Y), and valine (V). anodes Positive electrodes; negative
(Those are the so-called normal amino acids; ions (anions) migrate carrying electric cur-
others have been synthesized and are used in rent toward positive anodes.
medicinal chemistry.) They are incorporated antibody An infection-fighting protein
into proteins by transfer RNA according to molecule that tags, neutralizes, and helps
the genetic code. Amino acid analysis can be used to
amorphous Having no apparent shape or quantitatively determine the amount of
order; non-crystalline. protein and the proportions of amino
acids in a sample. The Waters UPLC
ampholyte An electrolyte that can be Amino Acid Analysis Solution is a
either positively or negatively charged, turnkey chromatographic system that
provides accurate, high-throughput
depending on the pH of its medium. amino acid analysis.
amphoteric A substance that has both
acid and base properties; amphoteric mol-
ecules can accept or donate protons to act as
an acid or a base.
ampule A small, sterile glass vessel with an
airtight seal that contains a single drug dose.
amyloid Insoluble fibrous protein ag-
gregates sharing specific structural traits.
Abnormal accumulation of amyloid in
organs may lead to amyloidosis and may
play a role in various other neurodegenera-
tive diseases.
technology extends the capabilities of amounts of a given protein through its natu-
AutoBlend by automatically managing pH ral method of replication, that is, injecting
and ionic strength requirements for the DNA into each cell.
mobile phase. The software calculates the baseline Observations or data used for
proportions of buffer stocks required for comparison or as a control.
desired conditions. Computation can be base pair Two bases on different strands
based on known pK values or on an empiri- of nucleic acid that join together. In DNA, cy-
cal calibration table, making any possible tosine (C) always pairs with guanine (G) and
buffer combination available. adenine (A) always links to thymine (T). In
autoradiography A technique that RNA molecules, adenine joins to uracil (U).
uses X-ray film to visualize radioactively basic variant A product variant that
labeled molecules or molecular fragments; exhibits a more positive charge character
used in analyzing the length and number by IEX or CE than the primary biotherapeu-
of DNA fragments after separation by gel tic form.
electrophoresis. batch A quantity of a drug substance
or drug product with uniform character and
analysis of electronic databases of genomes not limited to) proteins and monoclonal
and protein sequences, and computer model- antibodies, peptides, and other molecules
ing of biomolecules and biologic systems. that are not chemically synthesized, along
biological activity The specific abil- with gene therapies, cell therapies, and
ity or capacity of a product to achieve a engineered tissues.
defined biological effect. Potency is the BiopharmaLynx Application Manager
quantitative measure of biological activity. for MassLynx Software; Software available
[From ICH Q6B] from Waters Corporation that automates
biologics Products of living organisms the data analysis and reporting of mass
used in the prevention or treatment of spectrometry data for peptide maps and
disease. intact mass measurements. It automatically
Biologics Price Competition and In- analyzes and assigns results, defining the
novation (BPCI) Act In 2009, the US sequence/features of known proteins, and
Congress passed the Biologics Price Compe- determining the ID of modified forms. Allows
tition and Innovation (BPCI) Act, authoriz- users to edit assignments, annotate new
ing FDA to oversee an abbreviated pathway peaks, and compare experimental samples
for approval of biologics that are biosimilar to a reference by using tabular and graphical
to already approved products. visualization tools.
biomarker In either small or large bioprocessing Using organisms or bio-
molecules, the presence or absence of an logically derived macromolecules to carry
enzyme, receptor, other protein or peptide, a out enzymatic reactions or to manufacture
mutated mRNA, or a genetic mutation, that products.
differentiates patient subpopulations and is bioreactor A vessel capable of sup-
indicative of a disease, the disease severity, porting a cell culture in which a biological
a stage in a disease, a subpopulation with transformation takes place (also called a
the disease that are differentiated by their fermenter or reactor).
drug response, or a subpopulation of people biosimilar A biopharmaceutical that
with a different drug activity or pharmaco- is produced using a different cell line or
kinetics. master cell bank and/or different process,
biomass The dry weight estimation of yet meets criteria for comparability in
organisms (usually microorganisms) in a clinical activity. A biosimilar may differ in
given habitat or medium. its purity/impurity profile, and its potency
biometabolism Physical and chemi- may differ in a definable way. (See also
cal processes that occur within a cell or an biogeneric, follow-on biological)
organismthe conversion of nutrients into biotechnology The industrial use of
energy, for example. living things, specifically genetically engi-
biopharmaceutical A therapeutic neered organisms.
product created through the genetic BLA Biologics license application; the
manipulation of living things, including (but required application for marketing a biologic
product in the United States. Most biotech- broth The contents of a microbial bioreac-
nology-derived drugs are approved through tor: cells, nutrients, waste, and so on.
a BLA, rather than an NDA, although some BSA Bovine serum albumin; a protein
biologics, such as recombinant insulin and derived from cow serum and commonly used
human growth hormone, considered to be as a growth additive for animal cell culture.
simpler in structure and well-characterized, BSE Bovine spongiform encephalopathy;
have been approved under NDAs. the TSE of cattle believed capable of cross-
blinding Clinical trial technique in which, ing the species barrier to have become feline
to eliminate bias in a research study, sub- spongiform encephalopathy (FSE) in cats,
jects (and sometimes clinical investigators) transmissible mink encephalopathy (TME) in
remain unaware of which therapeutic ap- farmed mink, and vCJD in human beings.
proach (for example, investigational product buccal delivery Transmucosal (across
or standard treatment) is provided. the mucosal membranes) drug delivery by
Blood-brain barrier To protect the way of the mouth.
brain from infection and from damage that buffer (buffering agent) A solution
could be caused by foreign chemicals, the containing a weak acid and a conjugate base
endothelial cell linings of its capillaries are of this acid; it resists change in pH near
tightly packed together. Nothing but water a specific value when an acid or a base is
and nutrients that are actively transported added to it because the acid neutralizes any
by cellular mechanisms can pass through. added base and vice versa. For example,
blotting Transfer of nucleic acids or bicarbonates and some proteins in biological
proteins from an electrophoresis gel strip fluids, when in solution, tend to stabilize the
to a chemically reactive paper or membrane hydrogenion concentration by neutralizing
(such as nitrocellulose paper) or matrix (within limits) both acids and bases so the
(nylon, for example) to which they bind. solution resists changes in pH.
Blotting is achieved through capillary bulk active ingredient Also bulk drug
diffusion (when the gel is placed between substance, the active ingredient that is for-
the paper or matrix and an absorptive pad) mulated with excipients to produce the drug
or through electrophoresis (electroblot- product formulation. Biopharmaceuticals are
ting). Of the three types of blots, Southern produced in bulk through bioprocessing.
hybridization (or Southern blot) transfers bulking agent An additive that in-
DNA; Northern blots transfer RNA, and creases the volume of a solution or a solid.
Western blots transfer proteins (also called
protein blots).
bolus A concentrated mass of injected C
medication. cake The solid sediment that has been
bond A mechanism through which atoms, compacted in a centrifuge after removal of
ions, or groups of atoms are held together as much liquid as possible; or the remaining
in a molecule. solid after completion of a lyophilization.
calorimetry Analytical method that mea- bonded to a carbon atom; the carbon atom
sures heat loss or gain resulting from physical then has two additional bonds to attach to
or chemical changes in a sample. Differential the rest of the molecule.
scanning calorimetry compares the results of carcinogenic Cancer-causing; many
heating a sample to those for heating a refer- agents that are carcinogenic are mutagens
ence materialfor example, to measure the (agents that increase the occurrence of
temperature at which the sample crystallizes, mutation).
changes phase, or decomposes. cascade effects A series of events that
campaigned production Continuous result from one initial cause.
production of successive batches of the catabolites Waste products of catabo-
same product. lism, by which organisms convert substances
CAPA Corrective and preventive action; a into excreted compounds.
quality system defined by 21CFR 820.100; cation A positively charged ion (having
the policies, procedures, and support systems fewer electrons than protons).
that enable a firm to assure that exceptions CBE Changes being effected; a regulatory
are followed up with appropriate actions to submission sent to FDA to notify them of
correct the situation, and with continuous minor changes in a manufacturing process
improvement tasks to prevent recurrence and or its control. The sponsor is permitted to
eliminate the cause of potential nonconform- make the changes without waiting for FDA
ing product and other quality problems. response, and the changes become part of
[From FDAQSG] the existing licensed process. (See PAS)
capillary electrophoresis The minia- CBE-30 Changes being effected within 30
turized instrumental version of traditional days; a regulatory submission sent to FDA
electrophoresis using capillary column to request minor changes in a manufactur-
technology (that is, tiny fused-silica tubes ing process or its control. FDA has 30 days
with 20 to 100 m inner diameters) and in which to respond, after which the change
light-absorbance or fluorescence detection. is considered approved and the part of the
capsid The outer protein shell of a virus existing licensed process. (See PAS)
particle (virion). CBER Center for Biologics Evaluation
carbohydrates Molecules consisting of and Research at the FDA; CBER regulates
sugars. The basic carbohydrate units are vaccines, gene therapy, cellular products,
called monosaccharides, such as glucose, allergenic extracts, antitoxins, antivenins,
galactose, and fructose. Monosaccharides venoms, and blood and blood products (clot-
can be linked together into what are called ting factors and plasma derived products).
polysaccharides (or oligosaccharides) in CCD Charge-coupled device; semiconduc-
almost limitless ways. Oligosaccharides tors connected so that the output of one
contain a small number (typically three to serves as the input for the next (digital cam-
10) of component sugars. eras, video cameras, and optical scanners all
carbonyl bond An oxygen atom double- use CCD arrays); a light-sensitive integrated
desired genes to organisms that will be used comparable Product made before and
to express them. Cloning vectors are used to after a given process change is comparable
make recombinant organisms. if the change is shown to have no adverse
CM Carboxymethylcellulose; a weak ion- effect on the key quality attributes of the
exchanger that is often coupled to a resin product, such as purity, potency, PK/PD,
used in charge based separation chromatog- stability, and safety. Small differences in,
raphy. It is a cation exchange resin. for example, the impurity profile are permit-
CMC Chemistry, manufacturing, and ted, as long as the function is not affected.
controls; the section of a BLA, NDA, or IND (See equivalent)
describing the composition, manufacture, comparability protocol A protocol that
and specifications of a drug product and defines the experiments and acceptance cri-
its ingredients. teria that will be used to evaluate a product
CMO Contract manufacturing organiza- before and after a process change, and if
tion; a company contracted to perform met, will provide documented evidence that
development and/or manufacturing services. the products are comparable.
codon A sequence of three nucleotide complaint Also customer complaint; any
bases in mRNA that specifies production of oral or written communication from an end
an amino acid or represents a signal to stop user of a medicinal product indicating that
or start a function. it had an adverse effect on a patient, did
colorimetry The measurement and not function as specified, or appeared to be
definition of unknown colors in terms of contaminated or defective in any way. The
standard colors; techniques may be visual, sponsor must promptly investigate all such
photoelectric, or spectrophotometric; colo- complaints and document the investigation
rimetry is useful in determining the concen- in a retrievable file. If the complaint is con-
tration of a chemical with color in a solution firmed, corrective and preventive actions are
by measuring the intensity of the color and required. Examples include FDA notification,
relating that intensity to the concentration of product lot(s) withdrawal, product recall, and
the solution. review of medical files of adverse events
column A vertical, cylindrical con- caused by the product. These requirements
tainer or vessel often used in separation are found in US regulations in 21 CFR 314,
processes such as extraction, distillation, the GCP regulations.
and chromatography. complement A group of proteins in
column aspect ratio The ratio of a the blood that work in concert with other
columns height to its diameter. immune system proteins and cells (such as
column chromatography A separation antibodies) in attacking foreign substances.
method in which the different components of component 1. Raw materials and compo-
a mixture migrate through a column at dif- nents (tubing, stoppers, vials, filters) having
ferent rates of speed based on their relative direct product contact during manufactur-
affinity for the stationary phase. ing, which are regulated under 21 CFR 84.
2. Differentiated from raw materials and bidden to distribute its products in interstate
excipients, which are chemical entities, and commerce, except for those products deemed
usually rated as lower in risk to patient and essential for the public health.
product quality. (Note: These terms may be contaminant A foreign agent or
used interchangeably or loosely, and defini- material that is not introduced as part of
tions vary between US, Europe, and WHO). processing, such as airborne particulates or
(See raw material, starting material, API) adventitious organisms.
concentration The amount of a particular continuous process verification An
substance in a given quantity of solution, alternative approach to process validation in
usually stated as a percentage by weight which manufacturing process performance is
or volume, as weight per unit volume, as continuously monitored and evaluated. [From
molarity (a one-molar solution contains one ICH Q8]
gram-mole of solute per liter of solution), or control group The group of subjects in a
as normality (a one-normal or one-molar so- controlled study that receives no treatment,
lution contains one gram-equivalent weight a standard treatment, or a placebo.
of solute per liter of solution). controlled delivery Drug delivery in
conformation The shape of a molecule, which the duration (sustained delivery)
produced by the specific spatial arrangement and/or the site (targeted delivery) of drug
of the units that compose it. release, action, and bioavailability are
consent decree Status imposed by controlled through various physicochemical
FDA on a company in serious violation of means designed to provide well-defined
federal regulations and related safety and pharmacokinetic profiles.
quality standards. A company must agree to Coomassie blue dye A sensitive stain
a series of measures aimed at bringing its for proteins used to visualize the bands in
manufacturing standards into compliance SDS-PAGE; also Coomassie brilliant blue.
with federal regulations. Until agreed-upon COS, CV-1 African green monkey kidney
conditions are met, a company may be for- cells, an established cell line that is com-
monly used for biotechnology.
cosmid An artificially constructed plas-
mid vector that contains a specific bacterio-
phage gene, which allows it to carry up to
45,000 base pairs of desired DNA.
cot1/2 DNA A curve that measures
genome complexity by determining the time
taken for half the DNA in a sample to rean-
neal (renature); it is measured for any new
Columns for bioseparations are avail- genome and compared to a standard such as
able in a wide variety of dimensions, the E. coli genome.
chemistries, and pore sizes to best meet
separation requirements. covalent bond Chemical bond in which
two atoms share one or more electron(s). cal or clinical pharmaceutical research.
Cp Process capability; a statistical cryoconcentration When a solution is
measurement of the relation between the frozen, water freezes as pure ice crystals.
observed variability of a process and the The remaining liquid therefore has a higher
specifications or requirements for individual solute concentration than the original
lots. Computed by dividing the range by the solution.
process variability (sigma); a larger number cryogranulation Use of a stream of
indicates a more capable process. liquid nitrogen to quickly create frozen,
critical micellar concentration (CMC) discrete pellets of a solution such as bulk or
The concentration of detergent at which final drug formulation.
micelles begin to form; from a practical cryopreservation Maintenance of frozen
point of view, the CMC defines the minimum cells, usually in liquid nitrogen.
concentration of free detergent that must C-terminal Carboxyl-terminal; the
be present to keep membrane proteins carboxyl terminus of a protein chain, with a
in solution. CMC values are affected by free carboxyl group.
temperature, ionic strength, pH, and buffer culture medium A complex mixture of
composition. The CMC is important in deter- organic and inorganic materials used as a
mining whether a detergent can be removed nutrient system for the cultivation of cells.
by dialysis. For example, a free detergent cuvette A transparent or translucent box-
molecule may pass through the membrane shaped container with precisely measured
but the largest micelle will not. (Compare dimensions for holding liquid samples to be
to CMC: chemistry, manufacturing, and put into a spectrophotometer; also such a
controls.) container with optical surfaces used to mold
critical process parameter An input samples so that their light-absorbing proper-
parameter (process setpoint) to a unit ties can be measured.
operation that must be tightly controlled Cys Cysteine; one of more than 20
by the operator, either manually or auto- naturally occurring amino acids.
matically, and which must be kept within a cytokine A protein that acts as a chemi-
specified range in order to produce output cal messenger to stimulate cell migration,
of acceptable quality within specifications. usually toward where the protein was
These parameters are identified during released. Interleukins, lymphokines, and
process development. interferons are the most common.
critical quality attribute A quality cytopathic Damaging to cells, causing
characteristic that must be controlled within them to exhibit signs of disease.
defined limits to ensure acceptable product cytoplasm The protoplasm of a cell
quality and performance. outside the nucleus (inside the nucleus is
CRO Contract research organization or the nucleoplasm). Protoplasm is a semi-
clinical research organization; a company fluid, viscous, translucent mixture of water,
contracted by a sponsor to perform preclini- proteins, lipids, carbohydrates, and inorganic
salts found in all plant and animal cells. delaminate To split apart into thin
cytostat Something that retards cellular layers; the act of separating a laminate
activity and production. This can refer to into layers.
cytostatic agents or to machinery, such as delivery matrix A heterogeneous
those that would freeze cells. semisolid matrix (such as a biopolymer gel)
cytotoxic Causing cell death. for the sustained delivery of drug substances
directly to the tissues; a matrix can be modi-
drift time The drift time of an ion is ion is modeled by a collection of overlap-
a measure of how long it takes to move ping hard spheres with radii equal to hard
through a mobility region in a mass sphere collision distances (see also PA). The
spectrometer. For a travelling wave, this is orientationally averaged momentum transfer
measured in low hundreds of milliseconds cross section is calculated by determining
(see also TWIG). the scattering angles between the incoming
drug discovery Methods for identify- buffer gas atom trajectory and the departing
ing new therapeutic molecules. High- buffer gas atom trajectory.
throughput techniques include combinato- elastomeric closure A rubber or rubber-
rial chemistry, genomics, and proteomics like closure or stopper; a packaging component
analysis as the starting point. Low- that may come into direct contact with the
throughput methods include traditional enclosed drug, which is usually an injectable.
disease research. electrolytes Ionized salts in body fluids;
drug product The final dosage form of electrolyte solutions are solutions containing
a pharmaceutical medicine containing drug charged atoms or molecules.
substance formulated with selected excipi- electroosmotic The movement of a liquid
ents and packaged for the end user. out of or through a porous material or a
drug substance The active drug chemical biological membrane under the influence of
or biological substance in purified bulk form. an electric field.
The drug substance is further processed to electrophoresis Analytical method
derive a drug product. Also known as active in which an electric field is applied to a
pharmaceutical ingredient (API). medium (paper, thin-layer plates, polyacryl-
amide or agarose gel), causing charged
electrically charged chemical groups) move elution volume The amount of eluent
slower through the medium than smaller that passes through the column in column
molecules (and those with many electrically chromatography before a particular peak
charge chemical groups). appears in an elution profile (that is, before
electrospray ionization Technique a specific substance of interest comes out
for generation of charged ions for mass with it). Also, the volume during which a
spectrometry. Analyte containing solution particular compound is eluted.
is dispersed as a fine charged aerosol into EM Electron microscopy; in which
the MS by passage of the liquid through a instruments focus electrons like optical
electrically charged capillary emitter. microscopes focus light. Scanning electron
electrostatic binding A chemical bond microscopy (SEM) and transmission electron
of two atoms or molecules by an electro- microscopy (TEM) are sometimes used in
static force (like static electricity) caused bioanalytical laboratories.
by one or more electrons moving from one EMA European Medicines Agency; the
atom to the other. agency responsible for regulating biophar-
elimination The rate at which drugs are maceuticals in the European Union.
removed from the body. emulsification A process that creates a
ELISA Enzyme linked immunosorbent stable mixture of two liquids that normally
assay; a test to measure the concentration would not mix together (such as oil and
of antigens or antibodies. water) by forcing one to disperse in the other
eluate Also called elution fractions; as droplets.
the separated components of a mixture that enantiomer Either of a pair of chemical
wash out from a chromatography column compounds whose molecular structures have
during elution. a mirror-image relationship to each other
eluent The substance used to recover (see diastereomer).
samples from a chromatography column; encapsidation During formation of a
sometimes an elution solvent. When a buff- virus particle, the process by which nucleic
ering agent is used, it is called an elution acid is incorporated (encapsidated) into the
buffer. Sometimes a solvent is used and just viral capsid. (See also capsid)
referred to as the eluent. encapsulation To enclose in a capsule,
elution Washing out; removing adsorbed usually one made of a biodegradable
material with a solvent or buffering agent. polymer.
elution profile A graph made to show how endogenous Growing or developing from
much material is being carried out of the col- a cell or organism, or arising from causes
umn by the eluent in column chromatography within the organism.
over time. The graph will show a number of endonuclease A restriction enzyme that
different peaks; each peak represents a differ- breaks up nucleic acid molecules at specific
ent separated material from the original mixed sites along their length. Such enzymes are
substance. Also called a chromatogram. naturally produced by microorganisms as a
defense against foreign nucleic acids. viables and non-viables via standardized
endoplasmic reticulum A highly sampling methods performed at established
specialized and complex network of branch- time intervals.
ing, interconnecting tubules (surrounded enzymes Proteins that catalyze bio-
by membranes) found in the cytoplasm chemical reactions by causing or speeding
of most animal and plant cells. The rough up reactions without being changed in the
endoplasmic reticulum is where ribosomes process themselves.
make proteins. It appears rough because epithelium (epithelial) The layer(s) of
it is covered with ribosomes. The smooth cells between an organism or its tissues or
endoplasmic reticulum is the site for organs and their surrounding environment
synthesis and metabolism of lipids, and it (skin cells, inner linings of lungs or digestive
is involved in detoxifying chemicals such as organs, outer linings of kidneys, and so on).
drugs and pesticides. epitope A molecular region on the
endotoxin A poison in the form of a fat/ surface of an antigen that elicits an
sugar complex (lipopolysaccharide) that immune response and can combine with
forms a part of the cell wall of some types the specific antibody produced by such a
of bacteria. It is released only when the cell response; also called a determinant or an
is ruptured and can cause septic shock and antigenic determinant.
tissue damage. Pharmaceuticals are tested equivalence Two lots of product are
routinely for endotoxins. equivalent if, within experimental error,
engineering batch A batch run at the they are essentially equal in purity/impu-
defined cGMP production scale for the pur- rity, potency, identity, and safety. A more
pose of evaluating the performance of any or stringent requirement than comparability.
all of the unit operations prior to initiating (See comparable)
cGMP manufacturing. It is not intended to be Escherichia coli Bacteria normally
released as a fully compliant cGMP batch. An found in the intestinal tract and widely
engineering batch may be executed using a used in biochemical and genetic studies and
batch record, but need not comply with all genetic engineering. E. coli is often used as
instructions and requirements. a vehicle for combining a segment of DNA
enthalpy Heat content; enthalpy change with an unrelated segment, creating con-
of a chemical reaction equals the difference tinuous DNA that does not occur naturally
between the heat put into breaking bonds (recombinant DNA).
and the heat released by new bond forma- eukaryotes Complex organisms, often
tion. multicellular, whose cells contain nuclei.
environmental monitoring A docu- exception A deviation from approved
mented series of sampling and testing GMP procedure; an out-of-specifications
performed on controlled environments to result or unexpected or out of trend result;
assure compliance with room classifications. a customer complaint. Exceptions must be
Testing typically includes monitoring of detected, investigated, and managed using
quality systems such as CAPA (corrective (such as the medicinally active components
and preventive action). of plant or animal tissue) by a physical
excipient A type of raw material that or chemical process. 2. Materials that
is present in the drug product and thus are actually removed from a container or
has direct patient contact; includes inert closure by a given formulation or product.
materials such as bulking agents, stabiliz- (See leachables)
ing agents, preservatives, salts, solvents, extraction Liquid-liquid extraction is
or waters. An excipient must be evaluated a process in which a solute is removed
for safety in animals, unless it has been ap- from a liquid by transferring the solute
proved as GRAS or is on a list of approved into a second liquid phase. The two liquid
excipients. phases must be insoluble with each other.
exclusion limit In size-exclusion (or gel Separation is based on different solu-
filtration) chromatography, the smallest size bilities of the solute in the two phases.
or dimension of molecule that is too large to Extraction is gentle and suitable for
enter the pores on gel particles. unstable molecules.
excretion The elimination of substances extrusion A process of forming rods,
from the body. In rare cases, some drugs tubes, or other continuously formed
irreversibly accumulate in body tissue. pieces by pushing hot or cold semisoft
exogenous Developing from outside, solid material through a die; also any
originating externally. Exogenous factors process of pushing a substance through
can be external factors such as food and holes or a tube.
light that affect an organism.
express To translate a cells genetic
information, stored in its DNA (gene), into a F
specific protein. Fab Antigen-binding fragment of an
expression system A host organism immunoglobulin. An IgG Fab is prepared by
combined with a genetic vector (such as a enzymatic cleavage of the intact tetrameric
virus or circular DNA molecule called a plas- IgG, and reduction of the inter-chain disul-
mid) that is loaded with a gene of interest. fide links, and binds one mole of antigen per
The expression system provides the genetic mole. [See F(ab)2]
context in which a gene will function in the F(ab)2 Dimeric antigen-binding frag-
cellthat is, the gene will be expressed as ment of an immunoglobulin. An IgG F(ab)2
a protein. is prepared by enzymatic digestion of the
expression vector A virus, plasmid, intact IgG, which removes the Fc portion of
cosmid, or artificial chromosome that the molecule. F(ab)2 binds two moles of
delivers foreign genes to a host, creating a antigen per mole. (See Fab)
recombinant organism that will express the FAb Antibodies are Y-shaped molecules.
desired protein. The arms of each Y are the FAb regions
extractables 1. Substances withdrawn (fragment antigen binding sites) that bind
scopic liquid used to denature nucleic radiation: How much is absorbed at each
acids and as a solvent, softener, or chemi- wavelength indicates the types of chemical
cal intermediate. bonds present in the molecules of the
formic acid The simplest carboxylic sample. The Fourier-transformation is a
acid, miscible with water and most polar mathematical method used to interpret the
organic solvents, and somewhat soluble vibrations of functional molecular groups
in hydrocarbons. It is used in laboratories and highly polar bonds. FT-IR produces a
as a solvent modifier for HPLC separations fingerprint illustrating the vibrational
of proteins and peptides, especially when features of all sample components.
the sample is being prepared for mass functional genomics A method of se-
spectrometry analysis. lecting among the thousands of drug leads
formulation The method and process that can come out of discovery efforts.
of selecting the components of a mixture; Whereas genomics studies the genetic
the product of such a process; the form in basis of organisms and their diseases,
which a drug is given to patients (tablets functional genomics challenges drug lead
or injections, for example); developed in candidates derived from genomic studies
concert with a drug delivery system and with early development-style assays to
targeting mechanism needed to get the build as much information as possible
active ingredient to its site of action. about the potential drug into the discovery
fraction A separate portion of a mix- process.
ture, often used to describe the part that fusion partner When making a small
contains a particular molecular species. protein or peptide in E. coli, it is often
fractionation range The range of necessary to produce the protein fused
molecular sizes that can fit (or diffuse) to a larger protein to get high levels of
into the pores of a gel filtration chroma- stable expression. The resulting fusion
tography medium particle. protein must be cleaved (chemically or
free radicals Short-lived, highly reactive enzymatically) to yield the desired protein
molecular fragments that are often capable or peptide. The non-product fusion partner
of initiating/continuing chemical reactions is left over and usually thrown away.
by means of a chain reaction mechanism. fusion protein A protein containing
They are usually formed by the splitting amino acid sequences from each of two
of molecular bonds, which requires energy distinct proteins. It is formed by expres-
input. Free radicals act as initiators or sion of a recombinant gene in which
intermediates in oxidation, combustion, two coding sequences have been joined
polymerization, and photolysis. together. Typically, this is accomplished by
FT-IR Fourier transform infrared cloning a cDNA into an expression vector
spectroscopy; an analytical method that in frame with an existing gene.
measures the ability of a sample to
absorb different wavelengths of infrared
G
gas chromatography Analytical method
gene therapy, the parents egg and sperm
cells are changed with the goal of passing
on the changes to their offspring.
in which a volatile substance to be separated genetic engineering Altering the
is introduced into a stream of nonreactive genetic structure of an organism (adding
gas or other stationary phase. For example, foreign genes, removing native genes, or
in capillary gas chromatography, the gas both) through technological means rather
mixture moves through a tube coated with than traditional breeding.
liquid, and how fast it moves through the genetic polymorphisms Gene altera-
tube depends on the degree to which it stays tions, additions, omissions, or deletions that
in the nonreactive gas or dissolves in the alter biologic functioning or changes in drug
liquid (partitioning). metabolism.
GCP Good clinical practice; according genome The collection of all the genes
to 21 CFR Parts 56, 312, and 314, the for an organism.
regulations that govern the actions and genomics Study of the genetic make-up
environment of those working in clinical of organisms, including sequencing and
testing of drugs and medical devices on mapping of their DNA. The Human Genome
human beings. These regulations include Project was a government-coordinated
rules for obtaining informed consent and effort of many genomics researchers who
data integrity requirements. sequenced and mapped the entire human
gene The unit of inheritance consisting genome.
of a sequence of DNA occupying a specific genotoxicity Ability of a substance to
position within the genome. Three types of damage the genome.
genes have been identified: structural genes genotoxin A substance that causes dam-
encoding particular proteins; regulatory age to an organisms DNA.
genes controlling the expression of the genotype The genetic composition
other genes; and genes for transfer RNA or of an organism (including expressed and
ribosomal RNA instead of proteins. non-expressed genes), which may not be
gene therapy Treats, cures, or prevents readily apparent. Compare to phenotype,
disease by changing the expression of a the outward characteristics that result from
persons genes or inserting genes into the gene expression.
genome. In its infancy, current gene therapy germ cell The sex cells in higher
is primarily experimental, with most human animals and plants that carry only half of
clinical trials only in the research stages. the organisms genetic material and can
Gene therapy can target somatic (body) combine to develop into offspring.
or germ (egg and sperm) cells. In somatic glass state The amorphous solid that,
gene therapy, the recipients genome is for example, contains the therapeutic protein
changed, but the change is not passed in lyophilization; any material that takes
along to the next generation. In germ-line the shape of its container and is formed
tory level up from a Points to Consider Waters MS Technology that couples high-
(PTC) document (and below official Code of efficiency ion mobility separations (IMS)
Federal Regulations law). with time-of-flight (TOF) mass analysis.
GXP All-inclusive term for GCPs, GLPs, HDMS provides an additional dimension
and GMPs. of information for separations, providing
additional details on glycopeptide, protein,
gene is inactivated (knocked out), leaving Leachables are potential extractables, and
other genes unaffected; provides the best may be evaluated by USP standard tests.
way to delineate the function of a gene. lead 1. A molecule that modulates the
LAL assay Limulus amebocyte lysate activity of a receptor or other target protein.
assay; detects pyrogenic endotoxins using a Successful lead compounds become candi-
reagent that was discovered in the blood of dates for drug development. 2. Pb, a toxic
Limulus horseshoe crabs. heavy metal.
laminar flow clean air device A clean legacy system Old hardware and
bench, clean workstation, and wall or ceiling software applications in which a company
modules or other devices that incorporate a has already invested considerable time
filter and motor blower for supplying clean and money, and which is no longer state-
air in one direction for a controlled work of-the-art or compliant with regulatory
space; more correctly referred to as unidi- requirements.
rectional airflow, which is air flow having Leu Leucine; one of more than 20 natu-
generally parallel streams operating in a rally occurring amino acids.
single direction and with uniform velocity ligands Molecules or ions that chemically
over its cross section. bind to certain other molecules or ions. In
LC/MS systems Liquid chromatography/ a binding action, usually the smaller of the
mass spectrometry systems; laboratory two molecules is considered the ligand.
instruments that combine two popular ana- ligase An enzyme that causes molecular
lytical methods into one piece of equipment. fragments (such as DNA, RNA, or peptides) to
LC/IMS/MS systems Liquid chromatog- link together; DNA ligase is used with restric-
raphy/ion mobility/mass spectrometry sys- tion enzymes to create recombinant DNA.
tems; laboratory instruments that combine light-scattering analysis Analytical
three popular analytical methods into one method that gives information about the size
piece of equipment. and shape of molecules based on how they
LC/MS/MS Liquid chromatography disperse ultraviolet and visible light.
with tandem mass spectrometry detec- LIMS Laboratory information manage-
tion; a highly selective method using an ment system; computers and software that
atmospheric-pressure ionization tandem handle all the data produced by laboratory
mass spectrometer to measure the differ- research and analytical methods.
ence in the mass-to-charge ratio of ionized liquid chromatography Analytical
molecules and fragments. method used to separate mixtures of sub-
leachable Chemical entity that has the stances based on the differential distribution
potential to be extracted from a container of the substances between a stationary
or closure when exposed to certain condi- phase (material such as silica gel or silicic
tions of solutions. Examples of common acid, usually contained in a column, tube,
leachables seen in pharmaceuticals include or capillary) and a liquid mobile phase (a
plasticizers, metals, accelerating agents. medium that carries the sample through
the stationary phase). This very effective cellular membrane of cells by chemical,
technique can separate substances that are enzymatic, or mechanical means. A solution
nearly identical. containing the contents of lysed cells is
liquid fractionation Any of several called a lysate.
precipitation or phase-separation methods lysosomes Cell organelles containing
used to determine the molecular weight dis- enzymes, responsible for degrading proteins
tribution of polymers, based on the tendency and other materials ingested by the cell.
of polymers of high molecular weight to be
less soluble than those of low weight.
lot A GMP-defined word used to refer to M
an entire batch of product. MAb Monoclonal antibody; a highly
lot release testing Samples from each specific, purified antibody that recognizes
drug lot (batch) manufactured for clinical only a single epitope.
trials or (later on) for sale are tested to prove MAC Mammalian artificial chromosome;
that the batch meets specifications for con- a vector used to clone DNA fragments larger
tent and purity before it is released for use. than 100,000 base-pairs long. As sug-
luciferase In luminiscent organisms gested by the name, MACs are constructed
(fireflies, some bacteria, and certain from mammalian cell DNA.
marine organisms), luciferase is an enzyme macrokinetics Movement of whole cells
that acts on species-specific light-emitting and their media within a bioreactor.
substances known as luciferins. Chemi- macromolecules Very large molecules
luminescent assay systems using firefly (proteins, carbohydrates, nucleic acids),
luciferinluciferase have detected small often formed by two or more identi-
amounts of ATP, the energy-storage com- cal molecules in a chain configuration
pound of a cell. Such systems may serve (polymers).
as alternatives to radioimmunoassays and MALDI-TOF Matrix-assisted laser
fluorescence methods. desorption ionizationtime of flight; mass
lymphocytes White blood cells that spectrometry technique for determin-
produce antibodies. ing molecular weight. Electrons become
lyophilization Freeze-drying; a proce- excited after laser irradiation, transfer-
dure by which a liquid solution is frozen to a ring energy into the mixture and causing
glassy state (primary drying), then slightly molecules and ions to be ejected from its
heated to remove the unfrozen water by surface. Commonly used in proteomic and
sublimation. peptide analyses.
Lys Lysine; one of more than 20 natu- mannitol A sugar alcohol (found
rally occurring amino acids. naturally in many plants, algae, and fungi)
lysed-cell slurry A mixture of the debris that is obtained by reducing mannose and
formed by disintegrating or breaking cells. used as a pharmaceutical excipient and in
lysis Disruption or breaking of the diagnostic tests of kidney function.
mannose A sugar (an aldohexose) often use. (See working cell bank)
used as an excipient in drug formulations. media Plural form of medium, a (usually
mass spectrometry Mass spectrometry sterile) preparation made for the growth,
(MS) is an analytical technique that mea- storage, maintenance, or transport of micro-
sures the mass-to-charge ratio of charged organisms or other cells.
particles. It is used for determining masses Met Methionine; one of more than 20
of particles, for determining the elemental naturally occurring amino acids.
composition of a sample or molecule, and metered dose inhaler (MDI) A device
for elucidating the chemical structures used to deliver a fixed volume or dose of an
of molecules, such as peptides and other aerosol form of an active drug substance to
chemical compounds. The MS principle the lungs and/or bronchi.
consists of ionizing chemical compounds metabolism Drug metabolism is the
to generate charged molecules or molecule biochemical modification of pharmaceutical
fragments and measuring their mass-to- substances by living organisms, usually
charge ratios. through specialized enzymatic systems. This
master batch record The template that is a form of xenobiotic metabolism. Drug
describes the step by step procedures to be metabolism often converts lipophilic chemi-
followed during manufacturing, with spaces cal compounds into more readily excreted
to record actual data. The master batch polar products. Its rate is an important
record is uniquely identified, under change determinant of the duration and intensity of
control, pre-approved by quality assurance, the pharmacological action of drugs.
and used to generate each individual batch metabolites Chemical products of me-
record that is issued when a given batch is to tabolism, the chemical process of life.
be manufactured. micelle A spherical arrangement (bub-
master cell banks A master cell bank is ble) formed by a group of lipid molecules
prepared by culturing a homogeneous popu- in an aqueous environment; hydrophobic
lation of cells, such as an established, cloned ends of the molecules are turned inward and
cell line, under defined conditions and then hydrophilic ends are turned outward. A mo-
distributed into containers in a single opera- lecular aggregate that constitutes a colloidal
tion, processed together to ensure uniformity, particle (a substance consisting of particles
and stored to ensure stability. Each vial is dispersed throughout another substance with
presumed to have comparable properties, particles too small for resolution with an
and thus the bank may be characterized by ordinary light microscope, but that can pass
testing a representative number of individual through a semipermeable membrane).
vials. Cell cultures derived from the master microassays Assays usually run on very
cell bank are used to prepare working cell small samples, often using microplates,
banks for manufacturing of a biopharmaceu- and often automated. Microplates can have
tical. Both master and working cell banks are room for 96, 384, or even 1,536 tiny
extensively tested and characterized before samples. Microassays measure small quanti-
ties of components even when the sample from only some of the molecules. The
size is large. purified product is then a mixture of a
microbial fermentation Processes protein with the native sequence and a
involving the use of microorganisms, such protein with the native sequence plus the
as E. coli, to produce a protein or other extra amino acid.
substance. microinjection Manually using tiny
microbial testing Analytical methods needles to inject microscopic material (such
required by regulations to ensure steril- as DNA) directly into cells or cell nuclei;
ity and to measure bioburden or identify video screens provide a magnified view.
microorganisms in controlled, classified micron See micrometer. The preferred
environments. term is micrometer.
microbiology The study of microscopic micrometer One millionth of a meters
life such as bacteria, viruses, yeast, and length. Abbreviated as m.
protozoa. microorganism A microbe; a free-living
microcarrier A microscopic particle (of- organism too small to be seen by the
ten a 200 m polymer bead) that supports naked eye.
cell attachment and growth in suspension microspheres Tiny polymer spheres
culture; alternative to microencapsulation. (usually biodegradable) measured in
Cells anchor into tiny pores on the beads for micrometers.
protection. miRNA A single-stranded RNA molecule
microencapsulation In cell culture, trap- of about 21 to 23 nucleotides in length,
ping cells inside a thin protective membrane which regulates gene expression.
to provide anchorage and protect them from mitochondria Animal-cell organelles
harsh conditions. Microspheres are often that reproduce using their own DNA. They
biodegradable. metabolize nutrients to provide the cell with
microfiltration A method of sterile energy and are believed to have once been
filtration, clarification, or cell harvest- symbiotic bacteria. Chloroplasts are their
ing that removes particles in the 0.1 to plant-cell equivalents.
10.0 m range. MOBCAL Software that calculates mobili-
microheterogeneity In biopharma- ties. MOBCAL is an open-source software
ceuticals, usually small differences in and is command-line driven (www.indiana.
the amino acid sequence or structure edu/nano/software.html).
of a polypeptide chain. For example, to moiety One of the portions into which
produce a recombinant protein in E. coli, something is divided; a component, part,
a Met must be added to one end of the or fraction. In chemistry, a specific section
protein sequence to act as a signal that of a molecule, usually complex, that has a
initiates protein synthesis. In most cases, characteristic chemical effect or property.
that Met is removed once the protein is mole The amount of a substance that
made. Sometimes the Met is removed contains the same number of elements (such
as atoms, molecules, or ions) as there are analysis to obtain both MS and MS/MS data.
atoms of carbon in 12 grams of carbon-12; Data acquired in MSEE mode can be mined at
one mole contains Avogadros number of a later date for different information.
molecules (6.02 x 1023). multicellular Referring to organisms
monomer A simple molecule that may composed of more than one celloften bil-
combine with others to form polymers. lions of themarranged in various organs,
monosaccharide (see carbohydrate) tissues, and systems.
mRNA Messenger RNA; which serves as multimer Any small polymer; in biophar-
a template for protein synthesis. It is made maceuticals, usually a protein made up of
as a complement to a DNA sequence and more than one polypeptide chain.
then transported from the cell nucleus to the multimer formation Association of pep-
ribosomes. tide or protein molecules to produce dimers
MSDS Material safety data sheets; docu- (two linked identical molecules), trimers
mentation (including data describing physical (three linked identical molecules), and so on
characteristics, toxicity, health effects, first depending on how many identical molecules
aid, reactivity, storage, disposal, protective link up together
equipment, and spill/leak procedures) that mutagen An agent (chemicals, radiation)
provides workers and emergency personnel that reacts with DNA to produce mutations.
with the proper procedures for handling or mutagenicity The degree to which a
working with a particular substance. substance can cause a change in an organ-
MSEE The simultaneous acquisition of ex- isms DNA.
act mass data using alternating collision cell mutation A permanent change in DNA
energies. This technique is unique to Waters sequence or chromosomal structure.
mass spectrometers, which can perform this MW molecular weight; refers to the mass
simultaneous data capture at UPLC speed of a molecule, usually stated in Daltons.
(see also UPLC). The MSEE approach, when mycoplasma Parasitic microorganisms
used to acquire precursor and product ion that infect mammalian cells, possessing
information, has the additional benefits of some characteristics of both bacteria and
obtaining both types of data in one analyti- viruses. Prokaryotic microorganisms, fam-
cal run. Both the precursor and product ion ily Mycoplasmataceae, with no cell walls
data are acquired in accurate mass mode (therefore resistant to many antibiotics) and
so that elemental composition information needing sterols for maintenance and growth.
can be generated from both sets of data. Potential contaminants of mammalian cell
Another advantage of MSEE is that neutral cultures, they may grow attached or close
loss information from a comparison of the to cell surfaces in the cytoplasm, subtly
two alternating collision energy scans can be altering properties of the cells, but escaping
obtained, eliminating the need for any further detection unless specifically monitored. In
experimentation. The mode of operation also cell culture of biopharmaceuticals, each lot
removes the need for time-consuming re- must be tested at the end of cell culture for
nitrogen-rich base, phosphoric acid, and a to laboratory error, operator error, or process
sugar. The bases can be adenine (A), cyto- error; and a judgment made whether the
sine (C), guanine (G), thymine (T), or uracil result itself is valid (accurate estimate of the
(U). These molecules comprise the basic true value of the analyte) or invalid. Usually,
structural units of RNA and DNA. confirming an OOS result as valid results in
nucleus The largest organelle, a affected lot(s) of product being rejected.
membrane-bounded compartment found in OOT Out of tolerance; 1. refers to
eukaryotes that contains most of the cells equipment or instrument which, when
genetic material and a nucleolus that builds its calibration is checked, is outside of a
ribosomes. defined range and requires adjustment or
repair. 2. Out of trend; a test result that is
injection; subcutaneous, intra-muscular, and elution fraction). The sharp rise in the line
intravenous delivery are most common. Drug graph of a chromatogram that represents
must be sterile. this phenomenon.
particle filtration Particle filtration is PEG Polyethylene glycol; a polymer
used to filter macro particles, which are vis- that usually consists of a size distribution
ible to the naked eye and range in size from of various molecular weight compounds.
50 m to 1000 m. Examples of particles Physical and chemical properties vary with
in this size range include beach sand, the molecular weight (liquid to solid, viscos-
granular activated carbon, human hair, mist, ity, etc.). PEGs are used as surfactants in
pollen, milled flour, and precipitates formed industry (for foods, cosmetics, and pharma-
during bioprocessing. ceuticals); and in biomedicine as dispersing
passage number When cells are cul- agents, solvents, ointment and suppository
tured, the passage number is a theoreti- bases, vehicles, and excipients.
cal number of cell generations, or how PEGylation Covalent attachment
many times the cells have been pas- of polyethylene glycol molecule(s) to
saged in vitro. a protein molecule via selected amino
PAS Pre-approval supplement; a regula- acid side groups, for example free amino
tory submission to FDA used for biologics or sulfhydryl groups. May be done to
and biopharmaceuticals when major changes decrease toxicity or improve its solubility
to the process, facility, or quality control and circulating half-life in the body.
system are desired. The sponsor must wait peptide bioanalysis The use of analyti-
for full FDA review and approval before cal techniques to quantitatively measure
any product manufactured may be placed peptide drugs and their metabolites in
in distribution. Often, a PAS or a CBE-30 biological systems. Formerly performed
may be part of a comparability protocol, and using ligand-binding assays such as radioim-
the type of submission required for a given munoassay and ELISAs, LC/MS/MS is now
package of changes is negotiated with FDA being applied to peptide bioanalysis for its
by RA personnel. higher accuracy levels. A successful, highly
PAT See process analytical technology. sensitive method for the analysis of peptides
PCR Polymerase chain reaction; a process relies upon a combination of high-perfor-
that exponentially amplifies (reproduces) mance chromatography, mass spectrometry,
a short piece of DNA having a specific and sample preparation.
nucleotide sequence, making possible many peptide bond The carbon-nitrogen
research and clinical applications involving covalent bond (link) between an amino
that DNA (used extensively in forensics). PCR group of one amino acid and a carboxyl
may be qualitative or quantitative (qPCR). group of another, formed by removing water
peak An individual component of a and resulting in the group RCO-NH. This
mixture that is washed out of the chro- linkage does not allow free rotation, and it
matography column during elution (the is the important bond that connects amino
acid monomers to form the polymer known identify and describe the critical quality at-
as a polypeptide. tributes and critical process parameters that
peptide mapping Bioanalytical method influence product quality and performance.
in which proteins are selectively cleaved by pharmacodynamics Study of the reac-
enzymes to create a characteristic pattern tions between drugs and living structures,
of peptides that is elucidated through chro- including the processes of bodily re-
matographic separations and spectroscopic sponses to pharmacological, biochemical,
or spectrometric detection. physiological, and therapeutic effects. A
peptides Short polymers formed from PD study seeks to determine where a drug
the linking, in a defined order, of amino ac- penetrates in the body and by means of
ids. The link between one amino acid residue what mechanisms.
and the next is known as an amide bond or a pharmacokinetics Sometimes abbrevi-
peptide bond. ated as PK, (from Ancient Greek pharmakon
perfusion Sometimes perfusion propaga- drug and kinetikos to do with motion;
tion; a cell culture or fermentation process see chemical kinetics) is a branch of phar-
commonly used in antibody production, in macology dedicated to the determination of
which high concentrations of mammalian the fate of substances administered exter-
cells inside a chamber have fresh growth nally to a living organism. The substances
media continually circulated around them for of interest include pharmaceutical agents,
continuous addition of nutrients and removal hormones, nutrients, and toxins. (See also
of waste products. ADME.)
permeate Also called filtrate, the part of Phe Phenylalanine; one of more than 20
a mixture that passes through a filter. naturally occurring amino acids.
pH Power of hydrogen or the log of the phenotype The observable characteristic
concentration of H+ ion in a solution. Mea- that results from the action of an organisms
surement of the relative alkalinity or acidity of genes. Phenotype varies depending on which
a solution. Pure water is pH neutral (7), acidic In pharmaceutical development, analysts
solutions have pH values between 0 and 7, generate information-rich and reliable an-
alytical methods to support IND and NDA
and alkaline or basic solutions have pH values submissions for innovative medicines.
between 7 and 14. Often a critical control
parameter in biopharmaceutical processes.
phage A virus-like parasite that infects
bacteria; also bacteriophage.
pharmaceutical development Col-
lected information from development stud-
ies conducted to establish that the dosage
form, formulation, manufacturing process,
and quality attributes are appropriate for the
product. The development process should
alleles of each gene are present. and self-replicating and found (naturally in
phosphoramidite or nucleoside phos- bacteria and some yeasts) in the cytoplasm
phoramidites The individual base building of cells. They can be used as vectors for
blocks that are used to synthesize short introducing up to 10,000 base-pairs of
nucleic acid chains also known as oligo- foreign DNA into recipient cells.
nucleotides. polar solvent A solvent for molecules
phosphorylation Addition of a phosphate that have permanent electric dipoles.
(PO4) group to a molecule, usually enzymati- polishing The final purification step(s) in
cally done by transferring a phosphate group a biopharmaceutical manufacturing process,
from ATP (adenosine triphosphate). usually involving an affinity or other refined
physical state The form that matter chromatography method. Often this step
takes, whether solid, liquid, gas, or plasma. uses the most expensive technique in the
pI Isoelectric point; the pH at which a process because it handles the smallest
substance has no net charge, above which a amount of material.
substance acts as a base and below which polyacrylamide A high molecular-
it acts as an acid. A solution of proteins or weight polymer of acrylamide (a neurotoxin)
amino acids has its minimum conductivity used as a support and separations matrix in
and viscosity at the isoelectric point. electrophoresis and gel chromatography.
pichia pastoris An alternative yeast polymer A large molecule formed by the
species proposed as a recombinant expres- combination of at least five (and sometimes
sion system. It performs post-translational as many as 1,000) identical smaller mol-
modifications that are more similar to human ecules (monomers).
protein modifications than those performed polymerase An enzyme that catalyzes
by other yeasts used in fermentation. the production of nucleic acid molecules.
pilot plant A medium-scale biopro- polymerize To undergo or subject to
cessing facility used as an intermediate in polymerization, a chemical reaction in which
scaling up processes from the laboratory to two or more molecules combine to form
commercial production. larger molecules that contain repeating
placebo A fake treatment (usually the structural units.
same formulation used for the real product, polymorphism A single mutation in a
but without the active ingredient) adminis- gene at one nucleotide locus that potentially
tered to the control group in a controlled changes gene expression with a modified
clinical trial so that the specific and nonspe- protein that may possess different proper-
cific effects of the experimental treatment ties, for example, the activity of an enzyme
can be distinguished. The experimental with a drug.
treatment must produce better results than polysaccharide A kind of complex
the placebo to be considered effective. carbohydrate (macromolecule composed
plasmid Hereditary material that is not of long chains of simple sugars). Several
part of a chromosome. Plasmids are circular polysaccharides from microorganisms have
development, involving studies designed called TSEs. (Term originally derived from
to determine the compatibility of initial proteinaceous infectious particle.)
excipients with the active substance for a Pro Proline; an imino acid often grouped
biopharmaceutical; physicochemical and with the 20 naturally occurring amino acids.
bioanalytical investigation in support of process analytical technology (PAT)
promising experimental formulations. A system for designing, analyzing, and
preparative chromatography Chroma- controlling manufacturing through timely
tography methods used in manufacturing measurements (i.e., during processing) of
rather than analytical applications, larger in critical quality and performance attributes of
scale and intended to purify a product; also raw and in-process materials and processes
called process chromatography. Chromato- with the goal of ensuring final product qual-
graphic methods were first used in analytical ity. [From ICH Q8]
laboratories, and only later in the 20th process control 1. The means by which
century were they adapted to industrial a process is monitored and operated, and
separations use. (Contrast with small-scale is designed to maintain critical parameters
analytical chromatography.) within set ranges determined to be safe. 2.
preservative A chemical additive that A consistent process that follows predictable
prevents spoilage by killing or inactivating statistical trends and is monitored using
microorganisms; also stabilizes molecules control charts is said to be in a state of
such as when using antioxidants or sulfhy- statistical control.
dyls to stabilize proteins. (Contrast with bac- process development The step in the
teriostatic agent, which prevents microbes life cycle of a product that starts with
from multiplying but does not kill them). information from research, and deliv-
primary recovery The early steps in ers a scalable process to manufacturing
separation and purification of a biophar- plants that can be validated, operated
maceutical, in which a complex biological under cGMP controls, and be commercially
solution containing the protein of interest is viable. During process development,
concentrated and clarified, usually by means preclinical and clinical trials supplies of
of filtration, centrifugation, or extraction the product are manufactured.
(precipitation); and the protein of interest process knowledge A compilation of all
is isolated from residual debris, cells, and facts about a manufacturing process from
other macromolecular materials. development through full-scale manufacture.
primary structure The amino acid process-related impurities Impurities
sequence of a biomolecule. that are derived from the manufacturing
prion Believed to be the smallest, process. They may be derived from cell
simplest infectious particle consisting of a substrates (e.g., host cell proteins, host cell
hydrophobic protein (no nucleic acid, DNA, or DNA), cell culture (e.g., inducers, antibiotics,
RNA), suggested as a possible model for the or media components), or downstream pro-
causal agent of scrapie and related diseases, cessing (e.g., processing reagents of column
leachables). [From ICH Q6B] rable to the desired product and are not
process robustness Ability of a process to considered impurities. [From ICH Q6B]
tolerate variability of materials and changes product specification A list of tests and
of the process and equipment without nega- acceptance criteria (limits) that are used to
tive impact on quality. [From ICH Q8] define the quality of a drug substance or
process understanding Comprehension drug product. The specification is often listed
of process knowledge such that all critical on the Certificate of Analysis along with
sources of variability are identified and results for a specific batch or lot.
explained; variability is managed by the product variant A molecule that is
process; and product quality attributes can related to the product but differs from it
be accurately and reliably predicted over the chemically, such as a degradation product,
design space established for the materials intermediate, or different configuration of
and process. Through process understanding, the protein of interest due to deamidation or
process performance and product attributes other chemical reactions. A product variant
can be explained logically and scientifically is form (charge isoform, n- or c- terminal
as a function of process parameters, inputs, form, eglycoform, etc.) that is considered
and input material attributes. part of the product definition.
product lifecycle All phases in the life prokaryotes Simple organisms, such as
of the product, from the initial development bacteria, with no cell nuclei and only a few
through marketing until the products discon- cell organelles.
tinuation. [From ICH Q9] protease An enzyme that cleaves the
prodrug A modified version or precursor peptide bonds linking amino acids in protein
of a parent compound designed to enhance molecules, classified according to the most
delivery properties and be converted to the prominent functional molecular group (such
parent compound in the body. as serine or cysteine) at the active site; also
product-related impurities Molecu- called proteinase.
lar variants of the desired product (e.g., proteinase K A serine protease (used
precursors, aggregates, certain degrada- in molecular cloning and DNA sequenc-
tion product arising during manufacture ing, nucleic acid research, and protein and
and/or storage) that do not have properties peptide structural analysis) with broad
comparable to those of the desired product specificity toward aliphatic, aromatic, and
with respect to activity, efficacy, and other hydrophobic amino acids, cleaving
safety. [From ICH Q6B] their peptide bonds.
product-related substances Molecular protein conformation The characteristic
variants of the desired product formed three-dimensional shape of a protein, includ-
during manufacture and/or storage that are ing the secondary, tertiary, and quaternary
active and have no deleterious effect on structure of the peptide chain.
the safety and efficacy of the drug product. protein folding A rapid biochemi-
These variants possess properties compa- cal reaction involved in the formation of
proteins. It begins even before a protein proteomics Study of protein function and
has been completely synthesized and structure.
proceeds through discrete intermediates protocols Documentation (submitted to
(primary, secondary, and tertiary struc- FDA or other agency in support of regulatory
tures) before the final structure (quater- filings) that directs the work performed in an
nary structure) is developed. FDA-regulated company. Protocols tell who
protein truncation Shortening a directs which activities, who approves what,
polymeric chain of amino acids; the protein and who is allowed to sign off on materials
truncation test developed by Dutch research- and products, even where to find specific
ers screens proteins to identify abnormally files and documentsall tying together
short molecules that suggest the location of numerous SOPs.
genetic mutations. PTC Points to Consider; PTC documents
protein variants Proteins with the same are not regulations with the force of law, but
amino acid sequences but different folds or are instead guidelines on issues that FDA
different carbohydrate residues. They must believes should be considered by regulated
be separated from the therapeutic proteins. industry. These documents are not definitive
proteins Complex organic macromol- or all-inclusive. In fact, they are presented
ecules whose structures are coded in an as drafts subject to further modification,
organisms DNA. Each is a chain of more and readers are invited to submit com-
than 40 amino acids in peptide linkages ments. They acknowledge that processes
that folds back upon itself in a particular and associated knowledge change with time.
way. Proteins are the principal constituent They suggest and recommend procedures
of all cell protoplasms (the entire contents that manufacturers should consider during
of a live cell). Each protein has a unique, ge- development of new drugs and biologics.
netically defined amino acid sequence that purification A central part of down-
determines its specific shape and function stream processing that takes a crude
(as enzymes, structural elements, hormones, fermentation supernatant or cell homog-
and immunoglobulins, involved in oxygen enate (a chaotic slurry of tissues and cells)
transport, muscle contraction, or electron and isolates the product from it in a fairly
transport, for instance). pure form.
proteolysis Separation (cleavage) of pyrogen Any fever-inducing (pyrogenic)
peptide bonds in proteins by proteases substance; more specifically, a lipopolysac-
(enzymes that recognize and cut specific charide (the major constituents of the cell
peptide bonds) or other means. walls of Gram-negative bacteria). The major
proteolytic Capable of lysing (denatur- endogenous pyrogen in mammals is prob-
ing, or breaking down) proteins. ably interleukin-1, production of which is
proteome The complete listing and stimulated by lipopolysaccharide.
description of all the proteins and their func- pyrogenic endotoxins Components
tions for an organism. of bacteria (such as lipopolysaccharides)
that induce a feverish immune response in trometry. It consists of four circular rods,
higher organisms. set perfectly parallel to each other. Ions
are separated in a quadrupole based on
product lifecycle. [From ICH Q9] material from another organism. Genetically
quality system A series of processes altered microorganisms are usually referred
that are linked together and controlled to as recombinant, whereas plants and
centrally to increase assurance of product or animals so modified are called transgenic.
manufacturing process quality. Term used by (See also transgenics)
FDA, ICH, and ISO to define those systems recovery Purifying a molecule of interest
that are created and maintained by QA to from the mix of biological components pro-
support GMP operations. Examples include duced by a biotech manufacturing fermenta-
documentation, facility, equipment, packag- tion or cell culture process.
ing, and labeling. redox Equilibrium reaction of oxida-
quaternary protein structure The tion/reduction, for example, thioldisulfide
defined organization of two or more exchange, a step used during refolding
macromolecules with tertiary structure of recombinant proteins that contain Cys
such as a protein that are held together by residues, in order to form correct pairing
hydrogen bonds and van der Waals and of sulfhydryl groups (SH) and form stable
coulombic forces. disulfide (SS) bonds.
radiolabeled Covalently labeled with a reducing agent A molecule that donates
radioactive isotope or substance. an electron in an oxidation-reduction reac-
R&D Research and development; dis- tion, which is a chemical change in which
covering and developing new products; the one species is oxidized (loses electrons) and
department within a company that does so. another species is reduced (gains electrons).
raw material Term with differing Reducing agents such as active metals
definitions in different documents; com- (sodium, magnesium, aluminum, and zinc)
monly means all materials that are used can be used to take the place of proteins and
to manufacture a drug substance or drug keep them from being oxidized.
product, and regulated by 21 CFR 84. (See regeneration (of a column) The act of
also components, starting materials). stripping and cleaning a chromatographic
reanneal The process of renaturing resin of any bound product or contaminants,
complementary single-stranded DNA mol- then stabilizing the surrounding environ-
ecules to yield duplex molecules. ment in preparation for reuse, usually done
recall Product recall; the act of locating by a sequence of various solvents or buffers.
all units of a given lot of product that have regulatory affairs Drug companies
been placed in the distribution chain for must show that their products consistently
human use and recalling them, for cause. meet standards set by government agen-
Recalls are classified based on a risk assess- cies and that manufacturing stays within
ment. (See also withdrawal) approved boundaries defined in the license
recombinant Refers to DNA (or the pro- application. Regulatory affairs departments
tein resulting from such DNA) that has been document those activities, submit propos-
genetically engineered to contain genetic als, and follow those proposals through
risk The combination of the probability severity of that harm. [From ICH Q9]
of occurrence of harm and the severity of risk review Review or monitoring of out-
that harm. [From ICH Q9; see also ISO/IEC put/results of the risk management process
Guide 51] considering (if appropriate) new knowledge
risk acceptance The decision to accept and experience about the risk. [From ICH Q9]
risk. [From ICH Q9; see also ISO Guide 73] robust Strongly formed or constructed,
risk analysis The estimation of the sturdy; a product or process that doesnt
risk associated with the identified hazards. break easily or remains stable and (for a
[From ICH Q9] process) reproducible despite physical and
risk assessment A systematic process chemical stress or varying conditions.
of organizing information to support a risk roller bottle A container with large
decision to be made within a risk manage- growth surfaces in which adherent cells
ment process. It consists of the identification can be grown in a confluent monolayer.
of hazards and the analysis and evaluation The bottles are rotated or agitated to keep
of risks associated with exposure to those cells in contact with growth media, but
hazards. [From ICH Q9] they require extensive handling, labor, and
risk communication The sharing of media. In large-scale vaccine produc-
information about risk and risk manage- tion, roller bottles have been replaced by
ment between the decision maker and other microcarrier culture systems that offer
stakeholders. [From ICH Q9]. the advantage of scale-up, minimizing
risk control Actions implementing risk contamination.
management decisions. [From ICH Q9; see R subgroup (or side chain) The group
also ISO Guide 73] of atoms that differs among different
risk evaluation The comparison of amino acid molecules and thus deter-
the estimated risk to given risk criteria mines their diverse chemical properties;
using a quantitative or qualitative scale for example, the R subgroup on a Gly
to determine the significance of the risk. molecule is simply a hydrogen atom, on an
[From ICH Q9] Ala it is a methyl complex (a carbon atom
risk identification The systematic use of and three hydrogens), and on Glu it is a
information to identify potential sources of combination of carbon, oxygen, nitrogen,
harm (hazards) referring to the risk question and hydrogen atoms.
or problem description. [From ICH Q9]
risk management The systematic ap-
plication of quality management policies, S
procedures, and practices to the tasks of Saccharomyces cerevisiae Brewers
assessing, controlling, communicating, and yeast, familiar to cooks as the yeast used
reviewing risk. [From ICH Q9] to leaven bread, was the first and is still
risk reduction Actions taken to lessen the most widely used yeast species in
the probability of occurrence of harm and the biotechnology. Certain strains are used in
the manufacture of alcoholic beverages and aiding in their separation. Analytical separa-
fermented foodsand also for expression tion technique, often used to characterize
of genes. Biologically active interferons, proteins or mixtures, that uses a charged gel
for example, have been produced in it and it environment through which molecules of
can be used in the manufacture of biologics. varying sizes and electric charges migrate
Commonly abbreviated: S. cerevisiae. from one pole to the other. Unlike gel-filtra-
scale-down To model a biopharmaceuti- tion chromatography, larger molecules move
cal manufacturing process (or section of that more slowly than smaller molecules because
process) at the laboratory scale, usually for migration rate is not dependent on diffusion
validation or other study purposes. Scale- into and out of particles.
down requires holding the critical param- SEC Size-exclusion chromatography, gel-
eters constant, and may be confounded by filtration or gel-permeation chromatography.
differences in equipment dead volumes, An analytical method that uses porous
performance, or materials of construction. particles to separate molecules of different
scale-up To transfer a biopharmaceutical sizes. Molecules that are smaller than the
manufacturing process from the laboratory pore size can enter the particles and there-
scale to a manufacturing scale while holding fore have a longer path and longer transit
critical parameters constant. time than larger molecules that cannot enter
Schizosaccharomyces pombe The sec- the particles. SEC can separate biological
ond most commonly used yeast species in molecules and help scientists determine the
biotechnology, originally used in east Africa molecular weights and molecular weight
to brew millet beer, but which is typically distributions of polymers.
unsuitable for other types of fermentation SNP Single-nucleotide polymorphism (See
because of the large amount of sulfurous DNA fingerprinting).
compounds it emits. secondary structure In proteins,
SDMS Scientific Data Management the folding, twisting, coiled, sometimes
System; an automated, electronic repository spring-like chain that results when hydrogen
that stores and manages all types of scien- bonds form between the adjacent parts of a
tific data to a centralized database, offering molecule, as in an alpha helix or beta sheet.
integration with a multitude of research seed stock The initial inoculum or the
applications. cells placed in growth medium from which
SDS Sodium dodecyl sulfate; an ionic other cells will grow.
detergent that binds to and denatures sequence The precise order of bases in a
proteins, and binds in rough proportion to nucleic acid or amino acids in a protein.
the size of the protein; used to aid analyti- Ser Serine; one of more than 20 natu-
cal separations. rally occurring amino acids.
SDS-PAGE Sodium dodecyl sulfate- serum The watery portion of an animal
polyacrylamide gel electrophoresis; the SDS or plant fluid (such as blood) remaining after
detergent denatures and binds to proteins, coagulation.
shear Tearing force (to cells), such as that sodium hydroxide A highly caustic,
caused by blending or stirring. alkaline chemical (NaOH) used to neutralize
shelf life The period of time during which acids and destroy soft body tissues (with
a drug can be stored without decreasing in potassium hydroxide, the most widely used
quality, safety, or efficacy. caustic agent in industry).
sialylated oligosaccharides Oli- solubility The degree to which a solute
gosaccharides that contain sialic acid can be dissolved in a defined solvent
(N-acetyl) neuramic acid are sialylated). (sometimes describes the opposite of
Sialic acid is often found as a terminal hydrophobicity).
residue of oligosaccharide chains of solute A substance that is dissolved
glycoproteins. Sialic acid imparts negative in a solvent; the part of a solution that is
charge to glycoproteins, because its car- uniformly dispersed in another substance.
boxyl group tends to dissociate a proton at somatic cell In higher organisms, a
physiological pH. cell that (unlike germ cells) carries the full
silica Silicon dioxide, SiO2, occurring genetic make-up of an organism.
naturally in crystalline, microcrystalline, and SOPs Standard operating procedures;
amorphous form; used to make glass and detailed (step-by-step), instructions to
ceramics, and used in pharmaceuticals. Silica achieve uniformity in the performance of a
gel is a jelly-like form of silicon dioxide specific process or piece of equipment, which
that is widely used as a solid medium, as a are approved by the quality control unit and
dehumidifying and dehydrating agent, and in used for GMP operations.
many chemical processes. Southwestern blot Analytical blotting
SIP Steam-in-place; using steam to clean technique for studying DNA-protein interac-
and sterilize equipment or systems without tions using labeled DNA to detect proteins
removing them from their installed location. transferred to membrane filters.
(See CIP) sparge To spray. A sparger is the
siRNA Small interfering RNA, short component of a fermentor that sprays air
interfering RNA, or silencing RNA; a class of into the broth.
20 to 25 nucleotide-long double-stranded species In chemistry, a particular kind of
RNA molecules that play a variety of roles in atomic nucleus, atom, molecule, or ion.
biology. Most notably, siRNA is involved in specifications Tests, analytical proce-
the RNA interference (RNAi) pathway, where dures, and appropriate acceptance criteria
it interferes with the expression of a specific that are numerical limits or ranges that
gene. (See RNAi) establish a set of criteria to which a raw
skid Common term for a complete chro- material, drug substance, or drug product
matography system on wheels. must conform to be considered acceptable
SMB Simulated moving bed; a method in for its intended use.
liquid chromatography of making separa- specificity The degree to which a
tions constant rather than in a batch process. substance exerts a definitive and distinctive
influence on a particular part of the body acteristic of a given product; stability profile
and on the course of a particular disease. means the types of chemical degradations,
spectrometry Spectroscopy methods rates, and expected shelf life that character-
related to measurements of mass. ize a product.
spectroscopy Study of the molecular stabilizer A chemical additive that
absorption of light using optics. Different helps maintain solution stability or drug
wavelengths and types of light can tell dif- product stability.
ferent things about the molecules identity staining A procedure of labeling tissues,
and condition. Proteins are often studied organisms, or molecules (such as DNA or
using fluorescence and infrared (see FT-IR) proteins) with colored or fluorescent dyes
spectroscopy. Fluorescence spectroscopy to allow visualization by microscopic or
induces molecules to emit light by the ap- macroscopic techniques.
plication of laser energy. starting material European term
spike Adding a known amount of analyte meaning raw materials used in cGMP
from a laboratory standard, sometimes manufacturing, but excluding components.
with something highly reactive (such as a (See component, active starting material,
radioactive or fluorescent dye) to act as a raw material)
tracer. Used to check a method for recovery statistical process control Monitoring
or accuracy. and controlling a process using statistical
sponsor Organization that takes primary analysis with the aim of managing variabil-
ownership and responsibility for a product, ity at critical process control steps.
and usually will be the license holder. A stereoisomer Any of a group of isomers
sponsor may outsource testing, clinical tri- in which atoms are linked in the same order
als, or manufacturing to other entities (CLO, but differ in their spatial arrangement.
CRO, CMO) but retains oversight of the pro- sterile Absolutely free of any microbio-
gram. The exact division of roles is specified logical contamination; an absolute state that
in contracts and in the quality agreement, a cannot be proven unless all of a material
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 dis- contaminated. (See USP Sterility Test)
persed 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
and storage (shelf) time. 2. A defined char- assumed basic structure) but differs in the
a molecule unravels to something that more drugs to test for sterility. By itself, this test
closely resembles a basic chain of amino does not prove a given lot is sterile; rather,
acids. taken together with all other validation, GMP
unicellular A single-cell organism. controls, and product/process testing, it
unit operation A distinct chemical or increases confidence that a given lot is safe.
physical step in a downstream process, (See sterility)
such as ultrafiltration, centrifugation, or UV-vis Ultraviolet-visible spectroscopy;
chromatography. an analytical method that measures the
UPLC Technology The use of a high- absorption of light in the 200 to 750 nm
effiency LC system holistically designed range of the electromagnetic spectrum. It is
by Waters Corporation to accommodate used in determining protein concentration
sub-2 m particles and very high operating and is often applied to HPLC detection.
pressure is termed UltraPerformance Liquid
Chromatography. The major benefits of this
technology are significant improvements
in resolution over HPLC, and/or faster run VZ
times, while maintaining the resolution seen vaccines Preparations that elicit an im-
in an existing HPLC separation. mune response (production of antibodies) to
USP or USP-NF The United States Phar- protect a person or animal from a disease-
macopeial Convention, Inc.; establishes and causing agent.
disseminates officially recognized standards vacuolation In cell and tissue culture, ex-
of quality and authoritative information for cess fluid, debris (aggregates), or gas (from
the use in the manufacture and testing of sparging) can form inside a cell vacuole, a
drugs, excipients, and raw materials. Also cavity within the cell that can be relatively
called one of the compendia. Other compen- clear and fluid filled, gas filled (as in a
dia include, for example, Ph.Eur (Pharmaco- number of blue-green algae), or food filled
peia Europa), JP (Japanese Pharmacopeia). (as in protozoa).
The USP, which defined specifications for val Valine; one of more than 20 naturally
approved drugs as well as general methods occurring amino acids.
and guidances, merged with the NF, National validation 1. Documented evidence
Formulary, which focused on specifications that shows that an assay or process, when
for raw materials and excipients. General operated within specified ranges of critical
chapters are not legally binding, but specific parameters, has a high probability of meeting
chapters are considered to be binding, and specifications. 2. The process of determin-
defined USP methods are accepted by the ing the degree of validity; the procedures
FDA as an appropriate standard. involved in checking data for correctness,
USP sterility test A method defined compliance with standards, and conformance
in the USP and Ph.Eur, and considered with the requirement specifications. A series
acceptable for per-lot testing of parenteral of experiments performed using a pre-ap-
proved protocol that will generate adequate viral clearance step Process step which
documented evidence to support a claim of a separates a given class of virus, if any are
validated state. present, from the desired product. A clear-
vCJD Variant Creutzfeld-Jakob disease; ance factor may be estimated by performing
a fatal neurological disease in humans, scaled-down experiments using a model
believed to be caused by infection with a virus, to determine process capability.
prion that also causes bovine spongiform en- viral inactivation step Process step,
cephalopathy (BSE) or mad cow disease in which inactivates the activity of a given class
cattle. CJD, or classical CJD, is not caused by of virus to provide assurance of safety. An
the BSE agent, and its etiology is unknown. inactivation factor may be estimated by
vector The plasmid, virus, or other performing scaled-down experiments using a
vehicle used to carry recombinant DNA into model virus, to determine process capability.
the cell of another species. virus The simplest form of life: RNA or
venture capital Also risk capital; money DNA wrapped in a shell of protein, some-
invested in a small, young, or start-up times with a means of injecting that genetic
company that is perceived to have excellent material into a host organism (infection).
growth prospects but without other access Viruses cannot reproduce on their own, but
to capital markets. Venture capitalists gener- require the aid of a host (bacteria, plant, or
ally supply capital in return for substantial animal). The host cells synthesis is often
equity and/or a seat on the board of direc- inhibited by the infecting virus, which may
tors. Sometimes, they provide management or may not result in disease (more than
and other financial support to their investee 200 viruses are known to produce human
companies. disease). An individual virus particle is
Vero An established cell line derived from called a virion, and virions vary in structure,
the kidney of the African green monkey. complexity, and size (ranging from 20 to
vessel jacket A temperature control 25 nm or less to 2,000 nm or more). Six
method consisting of a double wall outside classes of virus are defined by whether they
the main vessel wall. Liquid or steam flows are single or double stranded, DNA or RNA,
through the jacket to heat (or cool) the fluid or positive or negative.
in the vessel. Because biopharmaceuti- virus-like particles Also RVLP (retrovi-
cal products are so sensitive and vessel rus-like particles); particles that resemble
jackets can cause uneven heating (hot or retroviruses, yet lack infectivity, and usually
cold spots), shell-and-tube or plate-and- are found in established lines of mammalian
frame heat exchangers are more common in cells. Cell bank characterization seeks to
biopharmaceutical production systems. determine whether viral activity is present,
viability The extent to which cells and as a means of assessing risk. Not present in
tissues are living. Cells can be metaboli- nonmammalian cells or cell lines.
cally viable even if they are not reproduc- viscosity Thickness of a liquid; deter-
tively viable. mines its internal resistance to shear forces.
warning letter The most serious FDA is usually made from a single vial of the
post-audit (after inspection) letter, notify- master cell bank, in which each vial has
ing a manufacturer of adverse inspection comparable contents and is expected to
findings and giving it 15 days to reply with perform consistently when introduced into a
a concrete plan for remediation. May or may process or assay. Both master and work-
not be associated with other actions, such ing cell banks are extensively tested and
as injunction, consent decree, or product characterized before use. Manufacturing
seizure. usually starts when a vial of working cell
washing (of a column) Flushing a bank is thawed and added to a reactor. (See
column with a large volume of a solvent or master cell bank)
buffering agent before selective elution of xenobiotic A chemical found in an organ-
the desired analyte. ism but which is not normally produced or
well-characterized A chemical entity expected to be present in it. It can also cover
whose identity, purity, impurities, potency, substances which are present in much higher
and quantity can be determined and con- concentrations than are usual. Specifically,
trolled; most well-characterized biologics drugs such as antibiotics are xenobiotics in
are recombinant DNA-derived proteins or humans because the human body does not
monoclonal antibodies. produce them itself, nor are they part of a
Western blot An immunochemical normal diet.
method for identifying proteins in a complex xenotransplantation Implantation of
mixture, proteins separated by electropho- living cells, tissues, or solid organs from
resis are transferred (blotted) from the gel one species into another, used when human
medium to a protein-binding nitrocellulose donors are unavailable or when a temporary
or polymeric membrane; the transferred or bridge organ is needed; a controversial
proteins are then detected by their relative practice given concerns about potential
binding to labeled antibodies. (See blotting) viral transmission and strong immuological
WFI Water for injection; very pure water reactions.
that meets specifications defined by the USP YAC Yeast artificial chromosome; a vector
or other compendia; suitable for parenteral used to clone DNA fragments up to 100,000
uses. base-pairs long. YACs are constructed from
withdrawal Product withdrawal; a recall the telomeric, centromeric, and replication
of a lot of product that is done voluntarily by sequences of yeast cells.
a firm, when there is concern about product yeast A single-celled fungus (eukary-
quality that is not proven. A recall may be ote).
mandated by FDA or regulatory bodies. (See
also recall) Waters, UltraPerformance Liquid Chromatography, and
WHO The World Health Organization; a UPLC are registered trademarks of Waters Corporation.
BiopharmaLynx, HDMS, High Definition Mass Spectrom-
United Nations organization. etry, MassLynx, SYNAPT, and The Science of Whats Pos-
working cell bank A cell bank that sible are trademarks of Waters Corporation.
suggested resources
If you are looking for additional information (or terms not included
in our glossary), here are some places to begin your search.
www.biotechinstitute.org users.path.ox.ac.uk/~scobbold/tig/new1/
The Biotechnology Institute mabth.html
A Hundred Years of Antibody Therapy
www.online-medical-dictionary.org
www.mtdesk.com
The Online Medical Dictionary
Alphabetical index of terminology: new drugs,
whatis.techtarget.com equipment, and procedures
TechTargets glossary of IT-related words www.ncbi.nlm.nih.gov
NCBIs PubMed
www.nationalhealthmuseum.org
The National Health Museum online www.genome.gov
Glossary of Genetic Terms from the National
www.biospace.com Human Genome Research Institutes division of
BioSpace intramural research
www.bioworld.com www.ornl.gov/TechResources/Human_
BioWorld Online Genome/glossary
Human Genome Projects genome glossary
www.chem.vt.edu/chem-ed/ac-meths.html www.pharma-lexicon.com/index.php
Encyclopedia of Analytical Instrumentation from MediLexicon
the Virginia Techs Chemistry Hypermedia Project
www.ncbi.nlm.nih.gov
www.emea.europa.eu National Center for Biotechnology Information
European Medicines Agency
www.pdr.net
www.geneed.com/glossary/index.html PDR.Net
GeneEds biotechnology glossary www.expasy.org
www.genomicglossaries.com Swiss Institute of Bioinformatics
Genomics Glossary by Cambridge Healthtech www.webmd.com
Institute Web MD
ifpma.org www.whybiotech.com
International Federation of Pharmaceutical Council for Biotechnology Information
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