QA-QC Flashcards
QA: Quality Assurance
- QA provides evidence needed to establish quality in work.
- Activities requiring good quality are performed effectively.
- Covers all activities from design, development, production, installation, servicing and documentation.
To ensure that the product is safe, effective and of good quality to GMP standards
QC: Quality Control
Product testing - checks the identity, strength, purity, stability to BP specification
Quality Assurance
GMP is part of the QA process and includes the following:
• Processes • Facilities (premises and staff) • Equipment • Materials • Procedures • Storage and transport • Training • Record keeping • Distribution • Product recall • Complaints
Quality Control is part of GMP: it includes..
– Sampling
– Specifications
– Testing
– Record keeping – Product release
Questions in Pharmaceutical analysis
• Right drug? %-age correct?
• Impurities: – Present?
• Concentrations? safe?
• Stability–shelf-life
• Release rate of drug from formulation (bioavailability)
• Does it meet specification? (identity & purity)
– Drug & Excipient
• Biology: concentration of drug in tissue / body fluid
• pKa, partition coefficient, solubility & stability of drug under development
QC of Analytical Methods
Assay: measurement incl. all preparations
Control of errors: precision and accuracy
Validation of analytical procedures:
i. Reference standard
ii. Preparation procedures
iii. Reagents, solvents: quality & preparation
iv. Equipment: procedures & settings
v. Methodology: calibration, pre-processing of sample
Common Causes of Errors
- Incorrect weighing & transfer (analytes, standards)
- Inefficient extraction of analyte
- Volume measurement: incorrect choice & use of pipettes, burettes, glassware
- Improperly calibrated equipment
- Failure to use analytical blank
- Assay conditions degrade analyte
- Interference by excipients
Validation:
Identification tests, impurities: quantitative & limit tests, quantitative test of active moiety
Procedure: exact description of analysis
i. Quality & source of reference standard
ii. Procedure for preparation of solutions of reference
iii. Quality of chemicals & method of preparation
iv. Procedures & settings for equipment
v. Method for calibration & processing of sample prior to analysis
Precision:
“…closeness of agreement between a series of measurements obtained from multiple sampling of the same homogeneous sample under the prescribed conditions usually expressed as the variance, standard deviation or coefficient of variation of a series of measurements”
• Generally: < ± 1.0% desirable
(note: does not refer to actual formulation to be tested)
• Depends on nature of sample
• 5 sample aliquots, 5 measurements from each
25 measurements
Repeatability
precision obtained under same operating conditions over short time interval (intra- assay precision)
Intermediate precision
within laboratory variation
Reproducibility
between laboratories
Compound random errors
– Systematic errors can be eliminated
– True random errors can not completely
System suitability: the 4 Qs
– Design Qualification: Fit for purpose?
– Installation Q: Manufacturer claims correct?
– Operational Q: Does it work for analyst application?
– Performance Q: Continue to perform to standard?
Analytical blank
– All materials apart from analyte (which may be drug)
– Follows exact same procedure
Calibration
– Pre-set standard values under strict conditions
– Standard, precisely defined calibration samples
Limit of detection
– Smallest amount that can be detected reliably
– x- xB = 3 sB
(B: analytical blank)
Limit of quantification
– Smallest amount that can be quantified reliably
– x- xB = 10 sB
Range
Limit between which acceptable precision & accuracy
Linearity
– Measurement concentration or quantity
– E.g. B-L law application in your Stage 1 labs: A = ε x c x l
– Correlation coefficient: R2 > 0.99
Robustness
– Resistance of precision & accuracy against small variations
– E.g. stability of solutions, length of extraction time, pH of HPLC mobile phase, changing GC column, T, flow rate
Selectivity
– Measure analyte in presence of other compounds
– Selective techniques often less robust (complexity)
Sensitivity
– Response to small change in [analyte]
Out of Specification Preparations
• Impurity sources:
– Starting materials – Residual intermediates, side-reactions – Reagents, solvents, catalysts – Particulate from atmosphere, machines, devices, containers – Impurities in excipients – Cross-contamination through multi-use equipment – Microbial – Drug reacts with excipients – Impurities from packaging
Out of Specification Preparations: Processes
– Incomplete mixing prior to compression
tablets or filling capsules
– Physical instability of dosage form (tablet disintegration, creams or suspensions separate, over-/under-compression deviation in weight
– Chemical breakdown of drug (air, H2O, light, excipients, packaging)
– Partitioning drugs into packaging materials
UV/VIS Spectroscopy advantages and disadvantages
+ Easy to use, cheap & robust
+ Good precision for quantification
+ Routine method for important physico-chemical properties of drugs
+ Derivative spectra help
- Moderately selective
- Not good for mixtures
Applications of UV/VIS Spectroscopy
Applications include: pKa, quantitative drug, partition coefficient, solubility, drug release studies
Absorptivity
Symbol: a
How much of a specific wavelength under specific conditions does a specific amount of a molecule absorb?
≠A=absorbance
How much does an actual sample absorb
A= a x l x c with c in g/L and l in cm.
a is a pharmacy-specific standard replacing the ε used in chemistry.
a x MR = ε so using ε involves the molar mass
Note the units for the concentration: g / L → a in units of cm-1 g-1 L
A(1%, 1cm)
Pharmacopoeial definition – used in pharmacy and defined as standard rather than using ε
Hypothetical value
Defined as the ABSORBANCE (not absorptivity!) that a 1% solution would have if measured in a 1cm cell.
Since a 1% solution is g / mL this is equivalent to g / L
Beers Law
From Beers Law:
A(1%, 1cm) = a x 10 x (conc. in g/L) x 1 cm
Where a = absorptivity; 1 cm = path length of cell Therefore: a = A(1%, 1cm) / 10
Vibrational Spectroscopy: IR, NIR
• IR: – Qualitative fingerprint – Preliminary identity check – CO group? – (semi-) solid – Films coatings, packaging – Polymorphs
• NIR: combinations & overtones of X-H stretches
– Quantitative mixtures
– Fingerprint check
– Multivariate analysis – Easy sampling
Near-IR
• 1000–2500nm(mid-IR:400–4000cm-1)
• Determine physico-chemical properties: – Drugs
– Excipients
• Physical: e.g. blend uniformity, particle size
+ NIR penetration into material – easy sampling + Rapid analysis of multi-component samples
- Extensive computerised method development – MVA
- Expensive instruments
Atomic Spectrophotometry: metals
• Emission (AES): atoms excited detect emitted light – Quantification
– Impurities
– Robust, cheap, selective
– Only alkali & some alkaline earth metals
• Absorption (AAS): volatilise metals, measure absorbance of narrow band of specific radiation. Identify metal if match. – Residues – Sensitive – Lamp for each element more specific but also more “hassle”
Fluorescence Spectroscopy
- Excite by UV/Vis - measure emission at longer λ
- Low dose fluorescent drugs if non-fluorescent excipients
- Limit tests if impurity is (made) fluorescent
- Binding of drugs in complex formulations
- Bioanalysis: small amounts, drug-protein binding
\+ Selective \+ Quantitative \+ Changes in complex molecules, e.g. proteins - Not all molecules fluoresce - Interference possible: - Other molecules - Heavy ions - Temperature
