Lecture 4
Reference Standards
Definition
• Reference standards are every well characterized
materials which can be used for calibration of
measuring systems.
• It may be a device, a specific system or a substance
for which definite numerical values can be related to
specific characteristics, such as:
• Reference methods.
• Reference data (e.g. specific absorption)
• Reference spectra.
• Calibrated weights and thermometers.
• Reference solutions e.g. normal solutions.
• Reference substances e.g. primary standards.
Types of standards
1- A reference standard (i.e., primary standard) may
be obtained from the USP/NF or other official
sources.
• When there is no official source, a reference
standard should be of the highest possible purity
and be fully characterized.
2- A working standard (i.e. secondary standard) is a
standard that is qualified against and used instead of
the reference standard.
Certificate of analysis
• A certificate of analysis (COA):
- For reference standard from non official
sources should be submitted in the section of
the application on analytical procedures and
controls.
- For standards from official sources, the user
should ensure the suitability of the reference
standard.
- The standard should be stored correctly and
used within the established use interval.
Characterization of Reference Standards
• Reference standards from USP/NF and other
official sources do not require further
characterization.
• A reference standard that is from non official
source should be of the highest purity and it
should be thoroughly characterized to ensure its
identity, strength, quality, purity and potency.
Generally this characterization information should
include:
• Brief description of the manufacture of the
reference standard if the manufacturing process
differs from that of the drug substance. Any
additional purification procedures used in the
preparation of the reference standard should be
described.
• Legible reproductions of the relevant spectra
chromatograms, thin layer chromatogram (TLC)
photographs and other appropriate instrumental
recording.
• Data establishing purity:
The data should be obtained by using appropriate
tests, such as TLC gas chromatography (GC), high
pressure liquid chromatography (HPLC), phase
solubility analysis, appropriate thermometric
analysis.
• Appropriate chemical information such as:
Structural formula, empirical formula, and molecular
weight, analytical tests, such as elemental analysis,
IR Spectrophotometry, UV - Spectrophotometry,
NMR and Mass Spectrometry, as well as applicable
functional group analysis.
• Detailed interpretation of the test data in support
of the claimed structure should be provided.
• A physical description of the material including its
color and physical form.
• Appropriate physical constants such as melting
range, boiling range, refractive index, dissociation
constants (pK values) and optical rotation.
