QC Flashcards
How would you approach cleaning validation?
Product knowledge- Solubility/Toxicity
Effectiveness of cleaning solutions
Validation of analytical method
-LOD, LOQ, Accuracy, Specificity
Non specific methods- Conductivity
Surface material of construction
Surface area
Surface proximity
Visibly clean
Rinse samples
Swab samples
Efficiency studies of rinse/swab
Clear criteria for specification
When can you release material if an OOS has unassignable cause?
No manufacturing cause
Robust product history
Retest results within known variability
95% Ci in spec
All other results consistent with re-test
What rules are there for averaging QC data in OOS investigation?
Can’t average certain data (mass)
Outlier test
If not outlier then include in average- average must be within 95% CI
Define Method validation, method verification and method transfer
Method validation- demonstrate new method suitable for use (ICHQ2)
Method verification- Demonstrate pharmacopoeial method is suitable for use (Chapter 6 QC)
Method transfer- Documented protocol for transferring method between labs (Tech transfer WHO annex 7)
Method validation characteristics
Accuracy
Precision (intermediate, repeatability)
Specificity
LOD
LOQ
Linearity
Range
What process/maths would you expect to see in method validation?
Accuracy- 9 results in triplicate (80, 100, 120%), Mean, SD
Precision- Repeatability, one analyst prep triplicate 80, 100, 120%. Compare data sets- TOST, Confidence interval
Precision- Intermediate. Two analysts, different days, different kit. Triplicate for each (18 data points), dixons outlier, TOST, CI, P value 0.05.
Specificity- Spike impurity into analyte and demonstrate separation.
Linearity- minimum of 5 concentrations, Linear regression, r value >0.999
Y intercept
Define specificity
Ability of method to unequivocally identify analyte of interest in presence of other material expected in sample (imps, matrix)
Define precision
Closeness in agreement (scatter) between samples taken from the same homogenous stock expressed as SD
Define accuracy
Closeness in agreement between value known as true value and the value found
What is source data for specifications?
Pharm Dev, Toxicology, Stability, process variability, Pharmacopoeia
What do you know about UV analysis?
Absorption based
Structurally dependent
Compound must be chromophore
Beer lambert law- concentration proportional to absorbance
Usual detector in HPLC
What do you know about Gas Chromatography?
Used for volatile compounds and some packaging components
Sample injected and mobile phase is helium gas.
Oven is in main chamber at 250 degrees
Stationary phase is column inside oven coiled.
Detector is flame ionisation
What do you know about IR?
Infrared analysis
Vibration of bonds within compound- structural groups
Presented in oil and KBR discs
What do you know about atomic absorption?
Elemental impurities
Energy emission post flame
ICP + Mass spec
High temp
All metals in PT
What do you know about HPLC?
Chromatographic method- separation (size/charge)
Mobile phase of liquid (solvent)
Stationary phase of column
Injection site for prepped sample +diluent
Pump to move sample and mobile phase through stationary phase
Sample results based on retention time in column
UV detector
Gradient - change in composition of mobile phase across the method
Describe an OOS procedure
MHRA published standard
Phase 1a- Obvious error (calculations, wrong solvent, incorrect glassware, power failure of equipment, SST failure)
Phase 1b- Supervisor + analyst investigation. Check calculations, dilutions, method steps- determine any assignable cause and re-measure reagents.
Phase 2- Parallel manufacturing investigation and hypothesis testing in QC lab. Approved protocol for re-testing by QA. Retest results either support or do not support initial result. Min 5 and max 7 resamples.
If support initial result, confirmed OOS- manufacturing investigation to determine cause + reject material.
If retest does not support initial result, perform dixons outlier test on results. Include/exclude point and if they are accepted as not outlier- average all results and determine if mean is within 95% ci
What method do you use for biotech purity analysis?
ELISA- Enzyme linked immuno absorbant assay
Specific ligands (antigens) for antibody target present in well plates.
Analyte added which specifically binds.
Secondary antibody added- linked to enzyme substrate producing colour effect based on potency of analyte.
What stability requirements do new DS and DPs have to meet?
ICHQ1
25/60- 1 year Long term
30/65- 6M- Intermediate
40/75- 6M - Accelerated
Cold store
2-8- 1 year long term
25/60- 6M accelerated
Frozen
-20 +-5-12M
Year 1- batch set down every 3M
Year 2- Batch set down every 6M
Year 3+- Annual set down
What guidance is available for Impurities?
ICHQ3
A- DS (Rel subs)
B-DP
C- Residual Solvents
D- Elemental impurities
E- Extractable and Leachable
What would you find in an analytical method?
Principle/ Scope
Apparatus
Parameters
Standards/ reagents
Prep of sample
Reagent prep
Method
SST
Calculations
Data
What are the universal Specifications for DS, bio and DP? Where do you find them?
ICHQ6a- Chemical
ICHQ6b- Biologic
Chemical DS/DP;
Appearance
ID
Assay
Impurities
Biological;
Appearance
Quantity
Potency
Purity/Impurities
What are the ISO Standards for sampling by attribute?
Sampling by Variable?
Attribute- ISO 2859
Variable- ISO3951
What is Composite sampling?
Pool all samples together
Test once
Homogeneity is critical
Must be justified approach
What is a reference sample?
What is a retained sample?
Reference- Kept to perform 2x full analytical testing if the need arises.
Retention sample- Kept as in tact finished product to aid complaint and market recall investigations if required.
What is contained in an analytical procedure?
Principle/scope
Equipment
Operating parameters
Protocol of work
Laboratory standards
Equipment SST
Standard prep
Reagent prep
Sample prep
Calculations
Conclusion
Do OOS investigations apply to IPCs?
If the IPC is used as release determination requirement then typical OOS will apply.
What are typical biological methods?
ELIZA- Enzyme linked immuno absorbent assay
FFA- Florescent Foci Assay. Assay and quantitative test.
Biosafety tests- Cells used to determine effect of impurities of adventitious agents (Measles etc).
What is contained in the latest update of ICHQ2?
Development data can now be used as validation data
Definitions amended- aligned now with biological and non linear methods (working range vs linear)
Table for guidance on selecting correct validated test.
Examples inclusive of biotech included
Close link with ICH Q14- Analytical procedure development.
What is contained in the new ICHQ14 guidance?
Close link with ICHQ2
Scientific principles and risk based approach to develop suitable methods
Analytical target profile link with performance criteria
What validation parameters would you perform for an ID test?
Specificity
What validation parameters would you perform for an Quantitative impurity test?
Accuracy
Precision
Specificity
LOD
LOQ
Range (upper and lower)
What validation parameters would you perform for an impurity limit test?
Specificity
LOD
What validation parameters would you perform for an Assay test?
Accuracy
Precision
Specificity
LOQ
Range
What are the reportable ranges in ICHQ2 for;
Assay
Potency
Content uniformity
Dissolution
Impurity
Purity
Assay- 80-120%
Potency- -20% to +20%
Content uniformity- 70%-130%
Dissolution- 45%- 140%
Impurity- Reporting threshold- 120%
Purity 80-100%
What is an SST? What are criteria?
Integral part of analytical procedure- test system as a whole on each analysis to give confidence in final results.
Criteria
Retention time
Relative retention time
Qualitative curve comparison
Resolution
Tailing factor
What is LOD? LOQ? What are the Signal/noise ratios in ICHQ2?
LOD- lowest level of analyte at which can be detected. 3:1 signal/noise ratio
LOQ- Lowest level of analyte which can be quantified with suitable precision and accuracy. 10:1 Signal/noise ratio.
What are stability testing timepoints and allowable deviations? Can you use release data for stability data at time 0?
3,6,9,12,18,24,36Months
3 days from date due for sample
30 day allowance to perform analysis when out of chamber
Yes- if all tests and specifications are the same.
What is in a method transfer protocol?
Confirmation method complies with MA prior to transfer
Method- testing required
Materials- samples and standards to be tested
Environment- storage of samples and standards
Measurement- Acceptance criteria versus ICH
People- training for
Deviation review
WHO Annex 7 stats;
- TOST
- SD and P value
- F2 test for dissolution
