ic12 quality assurance and pharmacopeial assays Flashcards
compare between quality assurance (QA) and quality check (QC)
QA
i) proactive
ii) process oriented and focuses on preventing quality issues from arising
iii) controls overall methods and procedures at system level
iv) activities is a road map for creating high quality products
v) involves entire team
vi) processes incl documentation, audits, supplier management, personnel training, change control, investigation procedures
*comprises of good manufacturing practice (GMP)
QC:
i) reactive (to correct quality issues that was uncovered from testing)
ii) product oriented and focuses on quality of manufactured products
iii) controls manufacturing processes
iv) involves verification of products post manufacture stage
v) by dedicated personnel
vi) processes incl batch inspection, product sampling, validation testing, lab testing, software testing
what are the key components of GMP
- raw or starting materials used must be pure (based on specifications in pharmacopiea)
- premises and equipment used for manufacturing must be maintained for operational readiness
- people involved in the manufacturing process must be trained to competent level
- the manufacturing procedures must use the latest technology and science
- processes must be documented to show compliance
what is the ICH and their role
ICH is the international conference on harmonisation of technical requirements for registration of pharmaceuticals for human use
ICH is the organisation that standardises requirements for medicines regulation throughout the world
ICH standardises the validation of analytical procedures and indicates that validation is req for:
i) identification tests
ii) quantitative tests for impurities
iii) limits tests for the control of impurities
iv) quantitative tests of the API, drug products and selected components in the drug products
what are the possible sources of impurities
i) raw materials
ii) method of manufacturing (reagent employed, reagent added, solvents, reaction vessels)
iii) atmospheric contaminants
iv) manufacturing hazards (particulate contamination, process errors, cross contamination, microbial contamination, packing errors)
v) inadequate storage (filth, chemical instability, reaction w container materials, physical changes, temp effects)
what are “limit tests” and what are the types of limit tests
limit tests are quantitative or semiquantitative tests designed to identify and control small quantities of impurity which may be present in the drug substance
i) quantitative: to test and determine the exact amt of API/ product
ii) semi quantitative: to compare to a standard and if < than standard then means that product have < of that impurity
limit tests can be done by comparison method or by quantitative determinations
COMPARISON METHOD
i) standard containing a definite amount of impurities is set up under the same conditions and at the same time as the test experiment
ii) extent of reaction in the experiment is determined by comparison of the test solution and the standard solution
*limits for sulphates, chlorides, iron and heavy metals are based on this principle
QUANTITATIVE DETERMINATION
types of tests incl
i) limits of insoluble matter
ii) limits of soluble matter
iii) limits of moisture, volatile matter, residual solvents
iv) limits of non volatile matter
v) loss on ignition (limits of residue on ignition, ash values)
vi) precipitation methods
what is the total ash method and what is it for
total ash method is one of the types of tests for quantitative determination for limits testing of impurities
total ash method involves measuring the total ash remaining after incineration
i) high ash value is an indication of contamination, substitution or carelessness in preparing the crude drugs for marketing
ii) potential constituents of residues are inorganic salts of carbonates, phosphates or silicates of Na, K, Ca, Mg
what are the types of identification tests
infrared absorption test, UV absorption test and TLC test are identification tests
INFRARED ABSORPTION TEST
rationale: molecules absorb IR energy resulting in vibration and bonds bending and stretching
i) reactions to IR absorption will be shown as peaks in the IR spectrum
ii) IR absorption relates to the stretching and bending of bonds in the diff func groups
iii) thus IR absorption test good at identifying the func groups present in the molecule
iv) look at fingerprint region (600-1400cm-1) of the IR spectrum (bc this region normally shows many bands)
v) compare the IR spectrum of the test sample to the USP reference to seek evidence for identity
UV ABSORPTION TEST
i) UV absorption measured for a test solution and a standard solution using a 1cm cell over 200-400nm
ii) compare the UV spectra between the test and standard solutions to determine the absorptivities (eg. A(1%,1cm)) and/or absorbance ratios as indicated in monograph
iii) req is met if the UV spectra of the test and standard solution have the same maxima and minima at the same wavelength, and the absorptivities and/or absorbance ratios are within specified limits
THIN LAYER CHROMATOGRAPHY (TLC) TEST
i) using a silica gel chromatographic plate impregnated with a suitable fluorescing substance
ii) apply 10µL of test solution and 10µL of standard solution prepared using USP ref standard
iii) use TLC developing solvent system consisting of chloroform, methanol, water in parts 180:15:1 (unless otherwise stated in monograph)
iv) if Rf value of principle spot obtained from test solution corresponds to that obtained from standard solution then it indicates a pos identity to the standard ref
v) Rf values are comparable bc pharmacopoiea stipulates the req of the tests being run
vi) TLC can separate compounds incl impurities (although depending on how much there are) based on the spots that appear
vii) not as sensitive as HPLC but not all labs have HPLC and HPLC able to identify and quantify the amount of each component
what is a type of quantitative test and what is the rationale behind it and its applications (elaborate on the subtypes, advantages, limitations also)
titrimetric analysis is a type of quantitative test
types incl:
i) direct acid base in aq phase
ii) indirect in aq phase
iii) argentometric
iv) complexometric
v) redox
vi) non aq
vii) potentiometric
rationale: amount of standard reagent of a precisely known conc is used to react chemically w an analyte such that the amount of standard reagent used can be used to estimate the purity of the analyte
application: determine the purity of API, content of API in a dosage form, purity of raw materials for medicinal product preparation
advantages:
i) capable of high degree of precision and accuracy
ii) methods are generally robust
iii) analyses can be automated and cheap to perform
disadvantages:
i) method may not be selective
ii) time consuming
iii) req large amounts of sample and reagents
what are “primary standards”, list eg. of primary standards and its uses
primary standards are stable chemical compounds that are available in high purity and that can be used to standardise standard solutions that are used in titrations
primary standards also used to determine correction factor (f)
eg. of primary standards and their uses:
i) potassium hydrogen phthalate: for standardisation of NaOH and acetous perchloric acid
ii) potassium iodide: sodium thiosulphate solution through the generation of iodine
iii) anhydrous sodium carbonate: HCl
iv) Zn metal: EDTA
what is “correction factor” and what is it used for
correction factor (f) is
i) usually used in volumetric analysis to simplify calculations
ii) calculated as a ratio of (actual conc)/(desired/nominal conc)
iii) tells us how much the given solution differs from the nominal (true) conc
if f < 1 = prepared solution is of lower conc than what was desired
if f > 1 = prepared solution is of higher conc than what was desired
if f = 1 = prepared solution is prepared precisely to the desired conc
how is “equivalence” derived
using acetic acid irrigation USP
CH3COOH + NaOH -> CH3COO-Na+ + H2O
1000mL 1N of NaOH ≡ H+ ≡ 60.05g of CH3COOH (where 60.05g is MW of acetic acid)
1mL 1N NaOH ≡ 0.06005g CH3COOH
hence 1mL 0.1N NaOH = 0.006005g CH3COOH ≡ 6.005mg CH3COOH
what is “indirect titration” and what might be req for this type of titration
indirect titration is essentially back titration
it involves adding (usually from a pipette) an excess of volumetric solution (VS) to a weight amount of the analyte f/b determining the excess unreacted VS
*back titration with blank titration is necessary for some indirect titrations
uses:
i) volatile substances (eg. ammonia, volatile oil - add reagent in first then stopper to let it react with substance first then titrate)
ii) insoluble substances bc will take time to dissolve
iii) substances for which a quantitative reaction will only proceed rapidly when there is excess reagent (eg. lactic acid)
iv) substances that req heating with a volumetric reagent during the determination in which decomposition or loss of the reactants or products would occur in the process (eg. aspirin - weigh out amt of aspirin then add known vol of NaOH using bulb pipette to be accurate then NaOH introduced to aspirin then boil or heat for x mins then titrate afterwards for unreacted NaOH)
what is “blank titration” and why might it be necessary for some indirect titrations
blank titration involves conducting the titration without adding the active ingredient (blank determination)
req bc eg. titrations that involve heating a liquid containing excess of standard alkali, cooling and back titrating the excess, the heating and cooling processes may cause apparent changes in the strength of the excess reagent thus the blank titration will standardise the conditions in both the blank and the sample determination
key things to note about the assay of aspirin
CALCULATING EQUIVALENCE
i) aspirin req two reactive species thus 2000mL of NaOH is used
ii) 1mL of 0.5N NaOH is used for equivalence bc 0.5M of NaOH reacts with 1M of aspirin
CALCULATING PURITY
i) (for this expt) the titration involves use of 0.5N H2SO4 as titrant to determine the unreacted 0.5N NaOH (each mole of H2SO4 produces 2H+ to neutralise 2M of NaOH thus 1mL 0.5N (0.25M) H2SO4 can neutralise 1mL 0.5N (0.5M) NaOH
ii) equivalence is such that 1mL 0.5N H2SO4 ≡ 1mL 0.5N NaOH ≡ 45.05mg aspirin
iii) from titrant volume determined, calc the amount of aspirin using equivalence
(titre of H2SO4 in blank) - (titre of H2SO4 in analyte expt) x f of H2SO4 x 45.05mg aspirin (f here is for H2SO4 bc H2SO4 is used for titration in burette)
iv) since blank expt done then take the diff between blank and analyte expt to determine how much NaOH reacted w aspirin
what is normality vs what is mole
normality (N) tells you the number of reactive species
eg. 1000mL NaOH ≡ 1N
1000mL H2SO4 ≡ 2N
mole (M) refers to molarity which indicates the number of mols in 1L of solution
*during paper work out mole ratio first then determine N!!
