Modification of integration paramters in QCC Lab

[GT]

Dear All,
I would like to know your opinion regarding the following issue:
I work in QCC lab in high regulated enviroment (pharma) and I use for HPLC control a CDS full compliant with 21CFR11 (Agilent).
During last audit the inspector gave us a major deficiency because we don't discuss with supervisor any manual change of integration parameters (peak width, slope sensitivity, etc..) defined into SOP to obtain an accurate integration.
Do you agree with this? Is this a normal procedure in pharma QCC Lab? Do you discuss with your supervisor before any change in intergation parameters also during related substances analysis?
Thanks for reply

[HPLCaddict]

If integration parameters are defined in the SOP (bad chance ) then, yes, they should be discussed and the changes properly documented. So the question is, do they have to be defined in the SOP ?

[LC_labrat]

I am not sure if the issue is that there is not an SOP or that the integration changes are not verifed with the supervisor?

Peak integration needs to be defined in a procedure (major deficiency).

If the SOP is general as most procedures are such that the integration parameters used suitably integrate the peaks. Manual changing of parameters is required to integrate the peaks as there are slight differences between each HPLC run, hence the reason for system suitability. If the requirements for proper integration are met and the data was reviewed and found to be accurate, I do not see any value added to discuss minor integration changes with the supervisor (minor or no deficiency). If the reviewer disagrees with integration parameters used at that point a discussion is needed with analyst and/or supervisor.

[GT]

Dear All,
thanks for reply.
The situation is that each analytical SOP is very specific with a defined set of integration parameters, but obviusly it works for 10% or real analysis, the others 90% (release is different from stability, variability due to columns and so on..) must be adjusted to obtain an accurate integration and I think that it's routine analyst job.
The final results is then approved by my supervisor so, again, which is the sense of "discuss" with him if I would like to change peak width or others int. param. to optimize integration? And again how can I document this pre approval discussion?

I begin to think that this work is going to become impossibile!!

[Peter Apps]

If you have SOPs that do not work for 90% of your analyses then whether or not you discuss integrations with your supervisor is the least of your problems.

Peter

[GT]

Hi Peter,
thanks for your reply.
In your job, are you so clever and lucky that your integration parameters fit for 100% of all your samples analyzed on different HPLC with different HPLC columns?

[JMcK]

When I managed a GMP lab, our methods provided "suggested integration parameters", and we stated that these may need to be adjusted to obtain "suitable integration". We then had a separate general SOP for use of chromatographic systems that defined "suitable integration". It also explained in detail the use of integration software, calculations used for chromatography, etc. I think this SOP kept us out of a lot of trouble with regulatory auditors.

[Peter Apps]

Hi Peter,
thanks for your reply.
In your job, are you so clever and lucky that your integration parameters fit for 100% of all your samples analyzed on different HPLC with different HPLC columns?

Fortunately I no longer work in a laboratory where I have to follow SOPs. When I was working in such an environment the SOPs were written in such a way that they could be followed as written - i.e. without the operators having to adjust conditions and integration parameters as they went along. Usually this meant that for each analyte / matrix combination the sample prep, running conditions, column etc would be specified, and the integration parameters would be considered as part of the analytical method. All of these would be validated before any results could be issued.

If an analysis had to be run with different columns on different instruments its robustness to these changes would be validated, and any changes that were necessary for a particular instrument would be written into the method section of the SOP.

Our aim was always to have good enough chromatography for the automatic integration to be easily and repeatably able to find peaks and integrate them. A continual need to be adjusting parameters or integrating by hand was seen as a symptom of a method that needed to be improved.

If you are having to change integration parameters to get "accurate" integrations then how do your methods pass validation ? And how do you know that the integrations that you get after your manual adjustments are "accurate" - do you run a set of control samples and standards to check each time. Or do you use parameters that put the product composition where you expect it to be ?

Peter

[Consumer Products Guy]

Hi Peter,
thanks for your reply.
In your job, are you so clever and lucky that your integration parameters fit for 100% of all your samples analyzed on different HPLC with different HPLC columns?

I can't answer for Peter.

I can answer for myself: Yes.

[vickig]

I supervised in a QC lab for 20+ years. We never required that a change in integration parameters be discussed w/ a supervisor.
I suggest:
1. Make sure peak integration is adequately described in general in an SOP
2. Use the same method to integrate all the chroms in the run (first time through) and save all the original traces
3. For those injections where you need to modify the parameters, where it is not obvious why you needed to reintegrate, provide a concise explanation on the chromatogram. Then initial and date the reintegrated chrom and provide to the reviewer along with the original. Your audit trail can be used as a format for providing the explanation and signing, but if you don't have this option you will need to do it manually.

Remember that in a regulated environment it is all about traceability. As long as you state what your labs procedure is, then follow it, and make the trail clear to a reviewer, you should be OK.

[Peter Apps]

JMcK and vickig's posts show how audit driven quality control can lose its way - the aim should not be to generate a paper trail that keeps auditors happy, but to generate accurate results that are fit for purpose. Having ad hoc adjustments to methods generates results whose accuracy cannot be determined, because they are not covered by the validation of the method under its original conditions.

Also, compared to methods that are reliable and robust, having operators make adjustments as they go along is horribly inefficient in terms of re-work and operator-hours, it takes much longer for an operator to fiddle with the integrator settings and draw baselines by hand than it does for the software to do an automatic integration from a good separation using properly validated parameters that are applied uniformly across samples and standards. As soon as there is manual intervention the problem of human error (what metrologists call blunders) which is very difficult to handle statistically appears, and the potentially much more serious problem of deliberate bias and manipulation rears its ugly head.

Peter

[GT]

Thanks to All for your comments.
Only few comments:
JMcK and vickig: thanks for your ideas, we have a SOP for general integration, but I could use it better in case Audit
Peter: in my analytical job (cGMP lab FDA inspected) it's impossible to set an int . param. set to fit for all the analysis.
Have you already seen a related substances chrom for final drug or API after release and during its stability? The SOP is the same but the chroms are quite different (peaks on tail of main peak, double peaks to be splitted, impurity peaks which increase and so on..) and so there isn't ineficient into the reintegration step to produce accurate results.
You wrote "Fortunately I no longer work in a laboratory where I have to follow SOPs..." so I can immage that now you work without Customer Audit, QA self inspection, QA CAPA, SOP for all kind of activity, analytical deviations and OOS, QA periodical training with final written test, and so on ... Wow, can I send you my curriculum?

[Peter Apps]

Thanks to All for your comments.
Only few comments:
JMcK and vickig: thanks for your ideas, we have a SOP for general integration, but I could use it better in case Audit
Peter: in my analytical job (cGMP lab FDA inspected) it's impossible to set an int . param. set to fit for all the analysis.
Have you already seen a related substances chrom for final drug or API after release and during its stability? The SOP is the same but the chroms are quite different so why do you not have different SOPs for the different types of sample ? - I cannot see any way that you can have one SOP that applies to all analyses unless it is written in such general terms that ad hoc changes are inevitable, in which case it is no long a Standard operating procedure, it is just a vague general guideline that does very little to assure the quality of results(peaks on tail of main peak, double peaks to be splitted, impurity peaks which increase and so on..) and so there isn't ineficient into the reintegration step to produce accurate results I am still wondering how you know that the results of your manual integrations are accurate.
You wrote "Fortunately I no longer work in a laboratory where I have to follow SOPs..." so I can immage that now you work without Customer Audit, QA self inspection, QA CAPA, SOP for all kind of activity, analytical deviations and OOS, QA periodical training with final written test, and so on ... Wow, can I send you my curriculum? No

[paul_b]

I think that the integration issues are really secondary to the chromatographic ones here. I am not surprised that the auditor raised concerns. Co-elutions should be a real no-no in such an analysis (and would mean that your integrations would just work). How do you integrate the peak in the tail, tangent or baseline drop; have spiking experiments been performed to look at the LOD for such components?