Analysis & Testing Flashcards
What are the principles of GCLP? (WHO)
1. Management and infrasturcutre: Organisation and management Quality system Control of documentation Records Data processing equipment Personnel Premises Equipment, instruments and other devices 2. Materials and set up of equipment, instruments and other devices Sepcification archive reagnets Reference materials Calibration, validation and verification of equipment, instruments and other devices Traceability 3, Working procedures Incomping sample Analytical worksheet Testing Evaluation of test results Retained samples 4. Safety in pharmaceutical control lab General rules
What is ICH Q3A? What are the outlines of the guideline?
Impurities in new drug substances Classification: organic / inorganic / residual solvents Organic impurities: MFG process or storage + ID or un-ID, volatile or non-volatile Starting materials By-products Intermediates Degradation products Reagent, ligands, and catalysts Inorganic impurities: MFG process + norm known and ID Reagents, ligands and catalysts Heavy metals or other residual metals Inorganic salts other: i.e. filter Reporting threshold: Less than - more than 2g / day: Reporting threshold: 0.05 - 0.03% ID threshold: 0.10%- 0.05% Qualification threshold: 0.15%- 0.05% Qualification = establishes the biological safety of an individual impurity Genotoxicity studies General tox studies: one species, 14-90 days
What is ICH Q3B? What are the outlines of the guideline?
Impurities in new drug product
Degradation product reporting:
Below 1%: applicable reporting threshold
Above 1%: one dc
What is ICH Q1 series? What are the outlines of the guideline?
Stability testing of new drug product and substances
Batch selection
Substances: 3 primary batches - min to pilot scale + same synthetic route
Product: 3 primary batches - same formulation & packaging + 2 / 3 pilot scale - 3rd can be smaller if justified + use diff batch of API
Container closure: same as proposed product
Specification:
Include other attributes i.e. micro, physicalchemical
Release and shelf life limit justified
Testing frequency:
Long term (at least 12/12): every 3/12 first year + 6/12 second year + 12/12 after
Accelerated: min of 3 points (0, 3, 6) + may need a fourth
Intemediate (sig change at accelerated): 4 poins (0, 3, 6, 9, 12)
Storage conditions:
Long term:
25 deg + 60 RH or 30 deg + 65RH (12 Months)
Intermediate:
30 deg + 65RH (6 months)
Accelerated:
40 deg + 75RH (6 months)
Long term at 25 deg: significant change at accelerated - then additional point at intermediate
Significant change:
5% change in assay or failure to meet the acceptance criteria for potency
Any degradation product exceeding limit
Failure to meet appearance, physical attributes and functiaonality test
Falure to meet pH limit
Falure to meet dissolution for 12 units
Also water loss
What would you expect to see in a OOS investigation?
SOP + 3 step investigation
Describe Karl fischer titration (used for water content determination)
Three basic forms of the Karl Fischer titration:
Volumetric titration using one-component reagents
Volumetric titration using two-component reagents
Coulometric titration
Karl Fischer volumetry is used for samples with high water content, i.e. 1-100 mg per sample. An iodine-containing solution serves as titrating agent. The water content of the sample is calculated using titration volume and titer of the titrating agent. One-component reagents conveniently contain all reactants (iodine, sulfur dioxide and a base) dissolved in a suitable alcohol in one solution, whereas two-component reagents contain all necessary reactants separated in two different solutions to enhance the rapidity of the Karl Fischer reaction and the titer stability of the titrating agent.
Karl Fischer coulometry is a micro-method and is particularly suitable for samples with low water content, from 10 µg up to 10 mg. Here, the required iodine is generated electrochemically in the titration vessel by anodic oxidation from iodide contained in the coulometric reagents. The amount of consumed electric charge is used to calculate the consumption of iodine and therefore the amount of water in the sample.
How would you work out LOD and LOQ?
DETECTION LIMIT
The detection limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be detected but not necessarily quantitated as an exact value.
6. QUANTITATION LIMIT
The quantitation limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be quantitatively determined with suitable precision and accuracy. The quantitation limit is a parameter of quantitative assays for low levels of compounds in sample matrices, and is used particularly for the determination of impurities and/or degradation products.
What criteria would you use to validate an anlytical method?
Per ICH Q2
Accuracy+specificity+linearity+precision+repeatability(inter)+robustness
Define Specificity
components which may be expected to be present. Typically these might include impurities, degradants, matrix, etc.
Lack of specificity of an individual analytical procedure may be compensated by other supporting analytical procedure(s).
This definition has the following implications:
Identification: to ensure the identity of an analyte.
Purity Tests: to ensure that all the analytical procedures performed allow an accurate statement of the content of impurities of an analyte, i.e. related substances test, heavy metals, residual solvents content, etc.
Assay (content or potency):
to provide an exact result which allows an accurate statement on the content or potency of the analyte in a sample
Define Accuracy
The accuracy of an analytical procedure expresses the closeness of agreement between the value which is accepted either as a conventional true value or an accepted reference value and the value found.
This is sometimes termed trueness.
Define Precision
The precision of an analytical procedure expresses the closeness of agreement (degree of scatter) between a series of measurements obtained from multiple sampling of the same homogeneous sample under the prescribed conditions. Precision may be considered at three levels: repeatability, intermediate precision and reproducibility.
Precision should be investigated using homogeneous, authentic samples. However, if it is not possible to obtain a homogeneous sample it may be investigated using artificially prepared samples or a sample solution.
The precision of an analytical procedure is usually expressed as the variance, standard deviation or coefficient of variation of a series of measurements
What are the three types of precision
4.1. Repeatability
Repeatability expresses the precision under the same operating conditions over a short interval of time. Repeatability is also termed intra-assay precision .
4.2. Intermediate precision
Intermediate precision expresses within-laboratories variations: different days, different analysts, different equipment, etc.
4.3. Reproducibility
Reproducibility expresses the precision between laboratories (collaborative studies, usually applied to standardization of methodology)
Define Linearity
The linearity of an analytical procedure is its ability (within a given range) to obtain test results which are directly proportional to the concentration (amount) of analyte in the sample
Define Range
The range of an analytical procedure is the interval between the upper and lower concentration (amounts) of analyte in the sample (including these concentrations) for which it has been demonstrated that the analytical procedure has a suitable level of precision, accuracy and linearity.
Define robustness
The robustness of an analytical procedure is a measure of its capacity to remain unaffected by small, but deliberate variations in method parameters and provides an indication of its reliability during normal usage
