ic12 quality assurance

Question 1

5 key components of GMP

Answer 1

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.

Question 2

who overlooks the quality for medicines

Answer 2

intl conference on harmonisation of technical requirements for registration of pharmaceuticals for human use (ICH)

• standardise requirements for medicine regulation throughout the world

Question 3

what does the ICH standardise

Answer 3

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.

Question 4

sources of impurities

Answer 4

1) raw materials
2) method of manufacture
3) atmospheric contaminants
4) manufacturing hazards
5) inadequate storage

Question 5

how can method of manufacture lead to impurities?

Answer 5

• reagents employed in the process
• reagents added to remove other impurities
• solvents
• reaction vessel (unit designed for use in chemical reactions)

Question 6

how can manufacturing hazards lead to impurities?

Answer 6

• 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.

Question 7

how can inadequate storage lead to impurities?

Answer 7

• filth
• reaction with container materials
• chemical instability
• physical changes
• temperature effects

Question 8

what are limit tests

Answer 8

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)

Question 9

what are the types of limit tests

Answer 9

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

Question 10

WHAT IS
infrared absorption test for identification

Answer 10

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)

Question 11

WHAT IS
UV absorption test for identification

Answer 11

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

Question 12

WHAT IS
TLC test for identification

Answer 12

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

Question 13

advantages of titrimetric analysis for pharmaceuticals

Answer 13

a) capable of high degree of precision and accuracy
b) generally robust methods
c) analyses can be automated + cheap to perform

Question 14

limitations of titrimetric analysis for pharmaceuticals

Answer 14

a) methods may not be selective
b) time consuming
c) require large amounts of sample and reagents

Question 15

what are primary standards?

Answer 15

stable chemical compounds
high purity
used to standardise the standard solutions used in titration

= used to determine correction factor (f)

Question 16

compare primary standards to their uses

Answer 16

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

Question 17

what is back titration used for

Answer 17

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)

Question 18

what is blank titration used for in back- titration

Answer 18

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

Question 19

what is argentometric titration (direct)?

Answer 19

quantitative precipitation (as long as the point where precipitation is complete can be determined).

used for volumetric determinations

Question 20

determination of 0.1N = xxx

Answer 20

refer to the slide
to learn!
note 1N means 1g equivalent of solute weight in 1000ml of solution

Question 21

HPLC analysis for quantitative analysis of drugs in formualitons

what are the methods

Answer 21

1) calibration w an external standard
- known pure sample

2) single point calibration

3) calibration w an internal standard

calibration curve: AOC over concentration

Question 22

limitations and assumptions of single point calibration

Answer 22

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

Question 23

requirements for internal standard

Answer 23

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

Question 24

general formula for calibration with an external standard

Answer 24

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

Question 25

general formula for calibration with an internal standard

Answer 25

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

Question 26

when to use internal vs external standard

Answer 26

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.