QA-QC

Question 1

QA: Quality Assurance

Answer 1

• 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

Question 2

QC: Quality Control

Answer 2

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

Question 3

Quality Assurance

GMP is part of the QA process and includes the following:

Answer 3

• Processes
• Facilities (premises
and staff)
• Equipment
• Materials
• Procedures
• Storage and transport
• Training
• Record keeping
• Distribution
• Product recall
• Complaints

Question 4

Quality Control is part of GMP: it includes..

Answer 4

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

Question 5

Questions in Pharmaceutical analysis

Answer 5

• 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

Question 6

QC of Analytical Methods

Answer 6

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

Question 7

Common Causes of Errors

Answer 7

• 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

Question 8

Validation:

Answer 8

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

Question 9

Precision:

Answer 9

“…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

Question 10

Repeatability

Answer 10

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

Question 11

Intermediate precision

Answer 11

within laboratory variation

Question 12

Reproducibility

Answer 12

between laboratories

Question 13

Compound random errors

Answer 13

– Systematic errors can be eliminated

– True random errors can not completely

Question 14

System suitability: the 4 Qs

Answer 14

– 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?

Question 15

Analytical blank

Answer 15

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

– Follows exact same procedure

Question 16

Calibration

Answer 16

– Pre-set standard values under strict conditions

– Standard, precisely defined calibration samples

Question 17

Limit of detection

Answer 17

– Smallest amount that can be detected reliably
– x- xB = 3 sB
(B: analytical blank)

Question 18

Limit of quantification

Answer 18

– Smallest amount that can be quantified reliably

– x- xB = 10 sB

Question 19

Range

Answer 19

Limit between which acceptable precision & accuracy

Question 20

Linearity

Answer 20

– 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

Question 21

Robustness

Answer 21

– 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

Question 22

Selectivity

Answer 22

– Measure analyte in presence of other compounds

– Selective techniques often less robust (complexity)

Question 23

Sensitivity

Answer 23

– Response to small change in [analyte]

Question 24

Out of Specification Preparations

• Impurity sources:

Answer 24

– 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

Question 25

Out of Specification Preparations: Processes

Answer 25

– 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

Question 26

UV/VIS Spectroscopy advantages and disadvantages

Answer 26

+ 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

Question 27

Applications of UV/VIS Spectroscopy

Answer 27

Applications include: pKa, quantitative drug, partition coefficient, solubility, drug release studies

Question 28

Absorptivity

Answer 28

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

Question 29

A(1%, 1cm)

Answer 29

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

Question 30

Beers Law

Answer 30

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

Question 31

Vibrational Spectroscopy: IR, NIR

Answer 31

• 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

Question 32

Near-IR

Answer 32

• 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

Question 33

Atomic Spectrophotometry: metals

Answer 33

• 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”

Question 34

Fluorescence Spectroscopy

Answer 34

• 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