Laboratory related Deviations occuring in Lab related to System Suitability.

1. Laboratory Deviations
related to HPLC Analysis &
How to Avoid them
Deepak
Mishra
(Quality)

2. Contents Covered
• What is deviation....????
• Types of Deviation
• Regulatory requirements
• System Suitability in USP
• Parameters of System Suitability
• Reasons of Deviation
• How to minimize Deviations

3. What is Deviation…????
• An activity performed or occurred in
different way from the specified procedure
or a Departure from the Written procedure
or a departure from an approved
instruction or established standard (PIC/S
Guide to GMP PE009-8, Pt II and USP
<1078>) or departure from cGMP.

4. Types of Deviation
Deviation
Planned
Deviation
Unplanned
Deviation

5. Types of Deviation
• Planned Deviation : Any deviation from
the documented procedure opted
deliberately for temporary period to
manage unavoidable situation without
affecting the Quality & safety of the drug
substance or drug product.
• Unplanned Deviation : Any deviation
occurred in an unplanned manner due to
system failure or equipment breakdown or
manual error.

6. Types of Deviation
• Unplanned Deviation :
• Unplanned deviations also called as
incident.
• Incident can be defined as unplanned or
uncontrolled event in the form of non-compliance
from the designed systems or
procedures at any stage of manufacturing,
packaging, testing, holding and storage of
drug product due to system failure or
equipment breakdown or manual error.

7. Regulatory Requirements
• Commission Directive 2003/94EC
• (replaces 91/356/EEC)
• – “…All process deviations and product
defects shall be documented and
thoroughly investigated…” (Article 10,
Production)

8. Regulatory Requirements
• 21 CFR 211.192 and Multiple Other
Provisions within 211
• – “Any unexplained discrepancy…shall
be thoroughly investigated…The
investigation shall extend to other
batches …that can have been associated
with the specific failure or discrepancy.
• A written record of the investigation shall
be made and shall include the conclusions
and follow-up.”

9. Regulatory Requirements
• ICHQ7A, GMPs for Active Pharmaceutical
Ingredients
• – “Any deviation from established procedures
should be documented and explained.
• Critical deviations should be investigated,
and the investigation and its conclusions
should be documented.”
• – “All deviation, investigation and OOS
reports should be reviewed as part of the
batch record review before the batch is
released.”

10. Regulatory Requirements
• EC Guide to Good Manufacturing
• Practice, Chapter 5 (5.15)
• – “Any deviations from instructions or
procedures should be avoided as far as
possible. If a deviation occurs, it should be
approved in writing by a competent
person…”

11. System Suitability in USP
Chapter <621> Chromatography :
“System suitability tests are an integral part
of gas and liquid chromatographic methods.
They are used to verify that the
chromatographic system is adequate for the
intended analysis. 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.”

12. System Suitability & Deviations
• “No sample analysis is acceptable unless the
requirements of system suitability have been
met.’’
• System suitability should test the entire
chromatographic system, not individual
modules
• system-suitability requirements to be set so
that they can be met easily if the method is
working right but will fail if there is a method
problem.

13. System Suitability & Deviations
• Analytical results should not be generated
until the system suitability test results have
been shown to pass.
• Deviations resulting from failures
associated with system suitability testing
for HPLC analysis should be investigated.

14. System Suitability & Deviations
• Desirable to minimize the occurrence of
system suitability failures because each
failure represents wasted time spent on
analysis and additional time spent
conducting an investigation into the failure.

16. System Suitability in USP

17. System Suitability & Deviations
• Most common reasons of System FAILURE :
• Degradation of the HPLC column,
• Poor Competence or Training of the analyst,
and
• Poor Maintenance or Calibration failure of the
HPLC system.

18. Degradation of the HPLC
column
• Affect Resolution, Theoretical plates & Tailing
.
• An evaluation of Column ageing necessary to
monitor the column failure with time.
• Set system suitability criteria which relate
specifically to the method in use. A column
degradation study will identify the parameters
of resolution, tailing and efficiency which
indicate that a new column should be used.

19. Poor Competence or Training of
the analyst
• Analyst’s competency on Instrumentation
also necessary to avoid deviations.
• HPLC operators to have suitable training
and familiar with the method in use, and in
particular, the robustness issues relating to
the method.
Mobile
Phase Affects Capacity
Factor
Retention
time
Resolution

20. Poor Competence or Training of
the analyst
Solution
Preparation Affects Accuracy Precision
HPLC
System
Setting
Affects Peak
Broadening
Noisy
Baseline

21. Poor Maintenance or
Calibration failure of the HPLC
Worn Injector part lead to Repeatability
failure
Temperature compartment fluctuations
lead to unstable Retention time
Aged lamp in detector lead to Baseline
noise & Quantitation of low level contents
Pump Parts lead to Retention problems

22. Poor Maintenance or
Calibration failure of the HPLC
• system suitability test not a substitute for
the performance qualification of the HPLC
instrument because it is method-based
rather than instrument-based.
• Implement a regular maintenance and
performance verification procedure for
HPLC systems.

23. • References:
• United States Pharmacopeia (USP),
Chromatography <621>.
• Reviewer Guidance: Validation of
Chromatographic Methods, US Food and
Drug Administration, 1994

24. THANKS