Page 13 - CuttingEdge April 2023

Key Changes in USP <621>
Key Changes in USP <621>
- Future Expectations

Product Test Sensitivity Check solution Suitability requirement
Fondaparinux Sodium Free Sulfate Sensitivity check solution (2.0 µg/mL): Dilute Signal-to-noise ratio : NLT 10, Sensitivity check
Injection Determination 1.0 mL of Standard solution 2 with water to 5.0 solution
mL.
Fondaparinux Sodium Organic 0.01 mg/mL of USP Fondaparinux Sodium for Signal-to-noise ratio : NLT 10 for the
Injection Impurities Assay RS in water from the Standard solution fondaparinux peak in the chromatogram of
the Sensitivity check solution
Doxycycline Organic 0.001 mg/mL of USP Doxycycline Monohydrate Signal-to-noise ratio : NLT 10, Sensitivity
Impurities RS in Diluent solution
Amiloride Hydrochloride Organic 0.001 mg/mL of USP Amiloride Hydrochloride Signal-to-noise ratio : NLT 10, Sensitivity
Tablets Impurities RS in Diluent, from the Standard solution solution
Argatroban Injection Organic 2.0 µg/mL of USP Argatroban RS from Signal-to-noise ratio : NLT 10 for Argatroban (R-
Impurities the Standard solution diluted with Solution A isomer) and Argatroban (S-isomer),Sensitivity
solution
Chlordiazepoxide Organic 0.025 μg /mL each of USP Chlordiazepoxide Signal-to-noise ratio: NLT 10 each for
Hydrochloride Capsules Impurities Hydrochloride RS and USP 2-Amino-5- chlordiazepoxide and 2-amino-5-
chlorobenzophenone RS in Diluent chlorobenzophenone, Sensitivity solution
Etravirine Tablets Organic 0.05 µg/mL of USP Etravirine RS from Signal-to-noise ratio : NLT 10, Sensitivity
Impurities the Standard solution in Diluent solution
Table 4 Sensitivity Check Solutions - Significance
Table 4: Sensitivity Check Solutions - Significance

In General, OEM of LC instruments warrants the D2 lamp to ignite and pass start up diagnostic test for 2000 hours or one year from the date of
purchase, whichever comes first. Against the statement, USFDA regulatory inspector cited 483 observations as ‘For all High-performance Liquid
7. Significance of hours of their UV detectors …’. It the lamp itself can also have an
Chromatography systems (HPLC), the firm failed to monitor the lamp hours of their UV detectors …’. It was observed that after exceeding the
Introduction of 'System was observed that after exceeding impact. The lower the wavelength,
deuterium lamp hours (2000 h for Waters) the firm has proceeded for quantification analysis of related substances without lamp replacement.
Sensitivity' the deuterium lamp hours (2000 the more degradation in output
h) the firm has proceeded for can be expected. This may mean
The signal-to-noise ratio is used to quantification analysis of related that an aging lamp that works
define the system sensitivity. The substances test without lamp almost perfectly at 340 nm and is
Page 17 of 17
limit of quantitation (corresponding replacement. acceptable at 280 nm could be next
to a signal-to-noise ratio of 10) is to useless at 210 nm. Of course,
equal to or less than the reporting In such scenario, in the absence if the signal from the analyte
threshold. In general, during the of sensitivity check solution is sufficiently large, then the
quality control analysis of Related (reporting threshold concentration) substandard energy output from the
substances / Organic impurities it is very difficult to assure the lamp may not be a problem. Lamp
by HPLC during the System accurate quantification of all energy becomes important if the
suitability run there are many impurities/degradation products. signal is small. If the signal-to-noise
cases wherein, the test procedure An experienced analyst will ratio is low, then the greater impact
does not mandate the injection of recognize the signs that a lamp of the baseline noise may alter the
'System sensitivity check solution'. might not be performing perfectly, detectability of trace analytes due
But in recent updated/published including baselines that feature to the compromised output from
USP monographs are specified irregular, high, or periodic noise. the lamp.
to meet the ‘System sensitivity’ There are several reasons why
as part of the test method system this may be the case, but, if other To address the above stated
suitability requirement. Few of factors - including air bubbles in problem in a Scientific manner,
them are depicted in Table 4. introduction of Sensitivity check
the system, temperature swings or solution (typically reporting
In General, one of the OEM of pump pulses, a contaminated flow threshold or LOQ concentration)
LC instruments warrants the D2 cell, or if immiscible solvents are during the SST run is strongly
lamp to ignite and pass start up being used- then an aging lamp recommended. To comply with the
diagnostic test for 2000 h or one may be the cause. Another indicator new USP<621> Chromatography
year from the date of purchase, is that the peak response is lower requirement of System sensitivity,
which ever is earlier. Against the than expected. Again, the flow cell it is recommended for all the
statement, USFDA regulatory might have been contaminated, generic manufacturers supplying
inspector cited 483 observations as or the injection volume might be medicines to US to ensure all the
‘For all High-performance Liquid insufficient; but it may also be test methods (related substances/
Chromatography systems (HPLC), indicative of the lamp’s diminishing organic impurities by HPLC/
the firm failed to monitor the lamp performance. Characteristics of UPLC/GC etc.) to initiate the

Spinco Biotech 13
April 2023