Flashcards in Analysis & Testing Deck (22):
What are the principles of GCLP? (WHO)
1. Management and infrasturcutre:
Organisation and management
Control of documentation
Data processing equipment
Equipment, instruments and other devices
2. Materials and set up of equipment, instruments and other devices
Calibration, validation and verification of equipment, instruments and other devices
3, Working procedures
Evaluation of test results
4. Safety in pharmaceutical control lab
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
Reagent, ligands, and catalysts
Inorganic impurities: MFG process + norm known and ID
Reagents, ligands and catalysts
Heavy metals or other residual metals
other: i.e. filter
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
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
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
Include other attributes i.e. micro, physicalchemical
Release and shelf life limit justified
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)
25 deg + 60 RH or 30 deg + 65RH (12 Months)
30 deg + 65RH (6 months)
40 deg + 75RH (6 months)
Long term at 25 deg: significant change at accelerated - then additional point at intermediate
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
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?
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
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
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.
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
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.
Reproducibility expresses the precision between laboratories (collaborative studies, usually applied to standardization of methodology)
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
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.
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
Approaches for Detection limit
6.1. Based on Visual Evaluation
Visual evaluation may be used for non-instrumental methods but may also be used with instrumental methods.
The detection limit is determined by the analysis of samples with known concentrations of analyte and by establishing the minimum level at which the analyte can be reliably detected.
6.2. Based on Signal-to-Noise
This approach can only be applied to analytical procedures which exhibit baseline noise.
Determination of the signal-to-noise ratio is performed by comparing measured signals from samples with known low concentrations of analyte with those of blank samples and establishing the minimum concentration at which the analyte can be reliably detected. A signal-to-noise ratio between 3 or 2:1 is generally considered acceptable for estimating the detection limit.
6.3 Based on the Standard Deviation of the Response and the Slope
6.4 Recommended Data
Approaches for Quantitation limit
Several approaches for determining the quantitation limit are possible, depending on whether the procedure is a non-instrumental or instrumental. Approaches other than those listed below may be acceptable.
7.1. Based on Visual Evaluation
Visual evaluation may be used for non-instrumental methods but may also be used with instrumental methods.
The quantitation limit is generally determined by the analysis of samples with known concentrations of analyte and by establishing the minimum level at which the analyte can be quantified with acceptable accuracy and precision.
7.2. Based on Signal-to-Noise Approach
This approach can only be applied to analytical procedures that exhibit baseline noise.
Determination of the signal-to-noise ratio is performed by comparing measured signals from samples with known low concentrations of analyte with those of blank samples and by establishing the minimum concentration at which the analyte can be reliably quantified. A typical signal-to-noise ratio is 10:1.
7.3. Based on the Standard Deviation of the Response and the Slope
The quantitation limit (QL) may be expressed as:
where σ = the standard deviation of the response
S = the slope of the calibration curve
The slope S may be estimated from the calibration curve of the analyte. The estimate of σ may be carried out in a variety of ways for example:
7.3.1 Based on Standard Deviation of the Blank
Measurement of the magnitude of analytical background response is performed by analyzing an appropriate number of blank samples and calculating the standard deviation of these responses.
7.3.2 Based on the Calibration Curve
A specific calibration curve should be studied using samples, containing an analyte in the range of QL. The residual standard deviation of a regression line or the standard deviation of y-intercepts of regression lines may be used as the standard deviation
7.4 Recommended Data
The quantitation limit and the method used for determining the quantitation limit should be presented.
The limit should be subsequently validated by the analysis of a suitable number of samples known to be near or prepared at the quantitation limit.
Tell me about SYSTEM SUITABILITY TESTING
System suitability testing is an integral part of many analytical procedures. The tests are based on the concept that the equipment, electronics, analytical operations and samples to be analyzed constitute an integral system that can be evaluated as such. System suitability test parameters to be established for a particular procedure depend on the type of procedure being validated. See Pharmacopoeias for additional information.
Describe a typical HPLC system i.e. solvent systems, detectors etc
Describe a typical dissolution test
See Ph Eur 2.9.3 Dissolution test for sold doses
For types of apparatus
Apparatus 1 (Basket apparatus).
Apparatus 2 (Paddle apparatus).
Apparatus 3 (Reciprocating cylinder).
Apparatus 4 (Flow-through cell).
How do you establish impurities level in product development?
Through Method validation and through control of the raw material.