QA-QC Flashcards by Em A

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

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QC: Quality Control

Product testing - checks the identity, strength, purity, stability to BP specification

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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

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Quality Control is part of GMP: it includes..

– Sampling
– Specifications
– Testing
– Record keeping – Product release

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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

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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

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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

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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

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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

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Repeatability

precision obtained under same operating conditions over short time interval (intra- assay precision)

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Intermediate precision

within laboratory variation

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Reproducibility

between laboratories

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Compound random errors

– Systematic errors can be eliminated

– True random errors can not completely

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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?

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Analytical blank

– All materials apart from analyte (which may be drug)

– Follows exact same procedure

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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 ```