ic12 quality assurance Flashcards
5 key components of GMP
1) MATERIALS
starting materials used in manufacturing must be pure
2) EQUIPMENT
premises and equipment used for manufacturing must be maintained for operational readiness
3) PEOPLE
people involved in manufacturing process must be trained to competent level
4) PROCESSES
manufacturing procedures must use the latest technology and science
5) DOCUMENTATION
processes must be documented to show compliance.
who overlooks the quality for medicines
intl conference on harmonisation of technical requirements for registration of pharmaceuticals for human use (ICH)
- standardise requirements for medicine regulation throughout the world
what does the ICH standardise
standardise validation of analytical procedures:
- identification tests
- quantitative tests for impurities
- limit tests for control of impurities
- quantitative tests of API, drug products, and selected components.
sources of impurities
1) raw materials
2) method of manufacture
3) atmospheric contaminants
4) manufacturing hazards
5) inadequate storage
how can method of manufacture lead to impurities?
- reagents employed in the process
- reagents added to remove other impurities
- solvents
- reaction vessel (unit designed for use in chemical reactions)
how can manufacturing hazards lead to impurities?
- particulate contamination
- microbial contaminations
- cross contaminations
- process errors
- packing errors
facility = rounded angles to facilitate cleaning.
= only manufacture one drug because of cross-contamination risk.
how can inadequate storage lead to impurities?
- filth
- reaction with container materials
- chemical instability
- physical changes
- temperature effects
what are limit tests
quantitative OR semi-quantitative tests to identify and control small qty of impurity present in the drug substance
comparison w a standard containing a definite amount of impurity (same time, same conditions)
what are the types of limit tests
limits of
- insoluble/soluble matter
- volatile/non-volatile matter
- residual solvents
- moisture
loss on ignition
- limit of residue on ignition
- ash value (high value= contamination, substitution, carelessness = inorganic salts of carbonates, phosphate or silicates of Na, K, Ca, Mg)
precipitation methods
WHAT IS
infrared absorption test for identification
compare
IR spectrum of the test sample
VS
USP reference standard
- IR spectrum = stretching and bending of bonds in different functional groups
- check the fingerprint region (600-1400cm-1) of the IR spectrum)
WHAT IS
UV absorption test for identification
measure with a standard solution using a 1cm cell, over 200-400nm (lambda).
compare UV spectra of test VS standard solution
- find the absorbance + plot grapth of absorbance vs lambda (nm)
requirements
- maxima and minima at same wavelength
- absorptivities/absorbance ratios are within specified limits
WHAT IS
TLC test for identification
TLC using silica gel chromatographic plate impregnated with suitable fluorescing substance
apply 10uL of test solution, 10uL of standard solution prepared from USP reference standard
solvent: chloroform, methanol, water (180:15:1)
Rf value should correspond to that obtained from the standard solution = positive identity
Rf = distance travelled by compound/distance travelled by solvent
advantages of titrimetric analysis for pharmaceuticals
a) capable of high degree of precision and accuracy
b) generally robust methods
c) analyses can be automated + cheap to perform
limitations of titrimetric analysis for pharmaceuticals
a) methods may not be selective
b) time consuming
c) require large amounts of sample and reagents
what are primary standards?
stable chemical compounds
high purity
used to standardise the standard solutions used in titration
= used to determine correction factor (f)
compare primary standards to their uses
potassium hydrogen phthalate = sodium hydroxide, acetous perchloric acid
potassium iodate = sodium thiosulphate solution (generation of iodine)
anhydrous sodium carbonate = hydrochloric acid
zinc metal = EDTA solution
what is back titration used for
1) volatile substances (ammonia, volatile oil)
2) insoluble substances (CaCO3)
3) substances for which quantitative reaction proceeds rapidly only in excess of reagent (lactic acid)
4) substances requiring heating w a volumetric regent during the determination in which a decomposition or loss of the reactants/products would occur in the process (aspirin)
what is blank titration used for in back- titration
blank determination in assay
- heating a liquid w/ excess standard alkali
= cooling - back titrate excess
used to standardise conditions
= used for aspirin back titration analysis
what is argentometric titration (direct)?
quantitative precipitation (as long as the point where precipitation is complete can be determined).
used for volumetric determinations
determination of 0.1N = xxx
refer to the slide
to learn!
note 1N means 1g equivalent of solute weight in 1000ml of solution
HPLC analysis for quantitative analysis of drugs in formualitons
what are the methods
1) calibration w an external standard
- known pure sample
2) single point calibration
3) calibration w an internal standard
calibration curve: AOC over concentration
limitations and assumptions of single point calibration
limitations:
- if AOC falls outside the calibration curve (ie too concentrated), it will not be accurate
= dilute sample
assumptions
- single point curve uses origin
= assue that zero conc = zero response
requirements for internal standard
1) should be closely related in structure to the analyte
- similar peak shape, retention time, and response.
2) should be stable
3) should be chromatographically resolved from the analyte and any excipients present in the chromatogram of the formulation extract
4) should eluate as close as possible to the analyte with the restrictions above
- for a given weight should produce a detector response similar to that produced by the analyte
- time to produce HPLC should be close to one another
general formula for calibration with an external standard
if area of external standard is x counts
where the concentration is y ppm
and the area of the test solution is m counts,
then the concentration of that test solution is
= y/x * m
or
conc/standard area x analyte area
general formula for calibration with an internal standard
COMPARE peak area ratio (of internal standard and standard sample OR analyte) vs concentration ratio (same)
ratio of standard to analyte
/
ratio of standard to sample
x
conc of sample
when to use internal vs external standard
external:
- when the experiment is relatively clean, ie not too many components
- commonly used in a pharmacopeial assay for determination of API or dosage form.
internal:
- for complex systems where cleaning up of the matrix is required
- commonly for biological fluids analysis eg blood sample TDM.
