|  Technical
Glossary
Amorphous
material/ Glass: A rigid
material that lacks crystalline behaviour. Does not crystallise
upon freezing, but becomes rigid and forms a glass.
cGMP Current good manufacturing
process: A series of standards
determined by the appropriate authority, e.g. FDA, to which organisations
must comply in order to manufacture drugs for human use.
CMO
Contract manufacturing organisation: An
organisation that manufactures drugs on a contract basis.
Collapse:
If the temperature of the product exceeds
the Collapse Temperature (Tc), the material will soften and distort,
and will be unable to support itself. Consequently, it will collapse.
Collapse
Temperature: The temperature
at which a material undergoing sublimation is no longer able to
support its own weight, resulting in collapse at the drying front.
Differential
Scanning Calorimetry (DSC): DSC
is a thermoanalytical technique in which the difference in the
amount of heat required to increase the temperature of a sample
is measured as a function of temperature. In freeze-drying, DSC
is used to studying phase transitions, such as glass transitions.
These transitions involve energy changes or heat capacity changes
that can be detected by DSC with great sensitivity.
Design
Space: Design space is defined
by the International Conference on Harmonization as:
“The
multidimensional combination and interaction of input variables
and process parameters that have been demonstrated to provide
assurance of quality.” (ICH Q8 Annex – Pharmaceutical
Development).
Consequently,
design space provides a range of values, within which a suitable
output can be obtained. This experimental space is usually developed
by running multiple experiments with differing values for selected
variables. The products from these tests are analysed for compliance
with pre-determined selection criteria, enabling the user to define
the limits, beyond which the product is no longer suitable. These
product characteristics are called Critical Quality Attributes
(CQA), and are defined as “a physical, chemical, biological
or microbiological property or characteristics that should be
within an appropriate limit, range or distribution to ensure the
desired product quality” (ICH Q8 Annex), and should be defined
prior to commencement of design space development. Importantly,
work carried out within the design space is not considered to
be a change to approved processes (ICH Q8 Annex), while movement
out of the design space would normally require regulatory approval.
Drying
Front: During freeze-drying,
the boundary between dry and wet regions, which is actively undergoing
sublimation. A crucial region that must be maintained below the
collapse temperature.
Eutectic
Formulations: Formulations
containing only water and crystallising solutes, and no amorphous
components.
Eutectic
Point: For crystallising
solutes, the eutectic point is the lowest temperature at which
the residual liquid phase and solid phase are in equilibrium.
Excipient:
An ingredient that is intentionally
added to a drug for purposes other than the therapeutic or diagnostic
effect at the intended dosage. Excipients are added to formulations
to improve certain characteristics of the drug, e.g. facilitating
administration or stability. With regard to freeze-drying excipients
are added to formulations to improve thermal/physical characteristics,
making them more suitable for the freeze-drying process.
Formulation:
The solution to be freeze-dried and, ultimately, administered.
Usually contains the drug substance and excipients in an appropriately
buffered solution.
Freeze-drying:
A process to remove 97-99% of the water from a solution. Formulations
are cooled to turn the water into ice. A vacuum is then pulled
to sublime the ice directly to water vapour. Freeze-drying cycles
can vary in length from hours to days, depending on the formulation.
Freeze-drying
Microscopy: A process used
to identify the collapse temperature of a formulation. Samples
are placed between two glass coverslips, and placed into a chamber
that mimics the freeze-dryer. The sample is frozen and a vacuum
pulled. The temperature is ramped up, and the collapse temperature
observed.
Glass
Transition Temperature: The
temperature at which amorphous material in the glass state first
exhibits a change in viscosity. For liquid/frozen formulations,
this is referred to as the Tg’, while for dry structures
this is referred to as Tg.
Karl
Fischer Titration: This
method is FDA approved for analysis of moisture content of lyophilized
samples, and provides high sensitivity and selectivity. Based
on the reaction of water in the sample with free iodine in the
Karl Fischer medium, resulting in the production of hydrogen iodide.
The amount of water in the sample is then determined electronically,
as a consequence of free iodine. Can be affected by solutes which
can react with free iodine, e.g. reducing sugars/copper ions.
Skin:
A layer of dense material
at the surface of the solution. Impedes the escape of water vapour,
reducing the efficiency of sublimation.
SDS
PAGE: Sodium dodecyl sulfate
polyacrylamide gel electrophoresis. A method for resolving peptides
and proteins according to size. Allows analysis of protein integrity.
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