System Suitability

[biochemist]

I'm wondering if anyone can explain the rationale for the system suitability requirement for precision from the FDA:

- Why 5 or 6 (why not 2, when repeatability has already been shown as part of validation)

- Why test repeatability for syst suit at all (when %RSD of true preparation replicates, for all stds and smpls, is a much more difficult criterion to pass, and is going to be checked anyway)

- Why only repeatability is tested for system suitability (and not other validation parameters, such as recovery, LOD, linearity, etc).

- How to derive the %RSD limit for syst suit, or preparation replicates (if it's more than 2%) from the product/impurity specifications? And from method validation data?

- Why not use the approach used by clinical labs, where a control sample is tested after every X samples, and has to be within a specified range (in addition to duplicate analysis and blank analysis)

Also, for resolution and tailing factor
- When is it checked - beginning? middle? end? every injection?

Thanks in advance to all the great people on this forum for helping me understand!

[krickos]

Hi

Large topic that could be discussed endlessly I think, my few cents on it:

1. General concept taken from Ph Eur, similar to USP but a bit clearer, especial last part:
The various components of the equipment employed must be qualified and be capable of achieving the performance required to conduct the test or assay.
The system suitability tests represent an integral part of the method and are used to ensure adequate performance of the chromatographic system.
Factors that may affect the chromatographic behaviour include:
— the composition, ionic strength, temperature and apparent pH of the mobile phase;
— flow rate, column dimensions, column temperature and pressure;
— stationary phase characteristics including type of chromatographic support (particle-based or monolithic), particle or macropore size, porosity, specific surface area;
— reversed-phase and other surface-modification of the stationary phases, the extent of chemical modification (as expressed by end-capping, carbon loading etc.).

Compliance with the system suitability criteria is required throughout the chromatographic procedure. Depending on various factors, such as the frequency of use of the procedure and experience with the chromatographic system, the analyst chooses an appropriate verification scheme to monitor this.

1. So validation data just shows that the chromatographic system was OK at validation, not each day when doing your analysis, hence we have SSTs as a verification that system is running OK on a daily basis.

2. RSD is not the only SST requirement used, Ph Eur in particular in chapter 2.2.46 list default ones apart from those in monographs. For related substances there is a default signal to noise requirement at the disregard limit for the monograph. Also if you use a calibration curve in your analytical procedure I would imagine that most would check the correlationcoefficient each time.

3. The rationale for certain SSTs or validation parameters are sometime consensus based like the signal to noise approach or statistcal (RSD) or science based.

4. When to test SSTs. Assays in general, standards for RSD are spread out over sequence. FDA requirement and also mentioned above in Ph Eur. Other SSTs no clear guidence, guess most test tailing factor etc in begining only.
Related substances/impurities, depending on if external calibration is used or internal normalisation is used there may be different considerations on whats the most critical to repeat in end of sequence.

[krickos]

Hi again

Realized that I could add some more comments.

Let me guess a bit, when you speak of FDA and also mention the "old" 2% limit for injection precision, I dare to say that you speaking of the quite old reviwer guidance from FDA from about 1994? Since then FDA has accepted ICH Q2 among other things which in turn refers to pharmacopieas for SSTs.
USP chapter 621 nowdays has same equation table for RSD requirements for assays based on specification limit as Ph Eur. Can be helpful, but I typically prefer and recommend not more than 1,0% as default limit, and that equation table becomes somewhat frustrating when you have a specification of 99,0-101,0 or perhaps even tighter.

[mukharir]

- Why 5 or 6
-> I think its about the power of the sample.

- Why test repeatability for syst suit at all
-> Repeatability is a measure of System precision, i.e. variation that depend on the (chromatographic) system alone. while replication is a measure of method precision, i.e. variation that depend all factor involved in the measurement that can causing variation.

- Why only repeatability is tested for system suitability
-> see above. it is System Suitability test
. that means, we should test whether the system is suitable for its intended purpose or not.

- How to derive the %RSD limit for syst suit, or preparation replicates (if it's more than 2%) from the product/impurity specifications? And from method validation data?
-> I don't know how to derive the limit, but i use AOAC approach for setting RSD limit for precision. you can review it from :http://www.aoac.org/vmeth/Validation_Guidelines.htm on the single laboratory validation part.
- Why not use the approach used by clinical labs, where a control sample is tested after every X samples, and has to be within a specified range (in addition to duplicate analysis and blank analysis)
-> it is a good approach for quality control test, if we analyze large amount of samples.

[unmgvar]

these days in most pharmas like for clinical testing, the standards are repeated during the work and RSDof area of them is also monitored.
if for 5 injections the RSD is 2.0 and many times even 1.0%, we set the RSD for all the injections during the work that can be a dozen and above, to an RSD of 2.5%
and as Krickos tried to explain to you repeatability is not the only issue that you monitor with your SST.
depending on the application you decide what to set but you must set other parameters like tailing, resolution, signal to noise,
these are application and mainly column dependent, and will allow you to monitor this very important par tof the system as well.
monitoring the area with area allows you to cover several aspects of the system and see if all is running well or not
first of course the precision of the sampler,
but also an imprecise flow rate will show up as changes of the area.

in statistics, in general the more numbers of individuals you have the more precise the results.
so if we do 5 injections for assays, where the conc. is always in an easy range of work, 5 injections allows you to be in range more easily
for impurities, where you can be in a very small AU response and precision is less then moving to 6 injections makes it statistically easier for you. also for impurities you can even have an application going to 10% RSD as the limit.

[phucto]

I have a question in need of your help. in one day, I using same HPLC system for analyzing two components in two different pharmaceutical products with different the column, mobile phase.....? Do I must run system suitability test in each running or only one in same day?

[Consumer Products Guy]

I have a question in need of your help. in one day, I using same HPLC system for analyzing two components in two different pharmaceutical products with different the column, mobile phase.....? Do I must run system suitability test in each running or only one in same day?

We would run system suitability on each assay, bracketing the samples as well. So I vote yes.