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(Not so) quick thought about GC method development

Updated: Aug 10, 2023

Let me think out loud about how to develop the perfect GC method for QC purposes.

In pharma, there may be a lot of different GC-methods for different reagents, solvents, possibly regulatory starting materials you purchase. This is alright I guess, since the impurity profile is king: you want to apply the best stationary phase to resolve your impurities as well as possible.

However, what about the methods for residual solvents? There shouldn't be that much of a variety in those methods, should they?

First steps - column and mobile phase

Most of the time the best choice to choose a columns is to apply either 624 or wax (I prefer 624, but this is only my taste :) ).

How about the mobile phase? In the 21st century, you want to choose hydrogen above all, for two reasons:

  • you can achieve the best resolution under the shortest time

  • hydrogen is much cheaper than helium

Some theoretical planning

There are some modeling tools on the internet, but I found this is a very good tool to establish a good draft method that you can finetune later in reality.

What thumbrules can you apply to develop your theoretical method?

  • choose all possible solvents to resolve in your test, adding all possible degradation products of the above (like benzaldehyde next to benzyl-alcohol, or ethyl acetate next to ethanol)

  • be greedy: choose the smallest column possible - the quicker method you have, the less energy and gas comsuption you will realize when you implement your method

  • choose the highest starting temperature possible - to be able to start the next injection as soon as possible

  • when you succeed to resolve the most volatile components, go for the sky with the temperature ramp! - of course, considering your GC's specification on the maximum heating ramp (sadly the tool mentioned above is not capable to mimic pressure ramp)

If you succeed to establish your method in this tool, you are ready to finetune it on your real-life GC.

First injection(s)

So let's have our first trial! The best scenario is if you have an ALS to develop your GC part of your HS-GC method, just to focus on the resolutions.

Start from the method developed in the modelling tool, with a mixture that contains all components to determine. Try to recreate the method you established theoretically, and then try and 'squeeze' your method even more with applying pressure ramp. Don't forget: you want to have a really quick method to have your result as prompt as possible, with the minimal energy and gas consumption.

HS part 1: heating time

There are some thumbrules for establishing the ideal HS parameters, let me not go into those withing this post. However, let me highlight one (for the sake of QC): the incubation time. You want to make sure that all components are well recovered from your products when performing the test. So what to do: start from - IDK, maybe from 10 minutes? Inject a sample solution after 10 minutes. Then after 15 minutes. Then after 20 minutes. See when you can extract the most from your sample, and stop there, not a minute later.

HS part 2: s/n vs. column saturation

The next step is to define the amount of analyte to inject to the column. You can use either static HS or CTC, you want to make sure you are in the ideal range for injecting the sample later.

This is the point where you need to be aware of your products: choose the smallest (perhaps 0,5 ppm of benzene) and the highest (perhaps 120% of 5000 ppm of a Class 3 solvent) amount to determine - what? two things:

  • Injection volume - even in case of static HS you can choose from some scenarios - for example 1 or 3 ml loops

  • Split ratio - this will be the key to determine the best amount of sample: you want to have at least s/n = 3 for the smallest amount, considering also to avoid the oversaturation of the column


OK, we have all our HS-GC parameters, how can we choose the best system suitability test?

If we want to go with an external standard evaluation (inject reference solution, calibrate from it, then the sample solution result quantitated from the calibration curves), we want to go for the bottleneck of the mehod. But what can that be?

If you did your job well, your bottleneck will be the resolution value between the two nearest peaks on your chromatogram. You don't need anything else - you paid a lot of money to exclude the lack of roboustness derived from your GC and HS - these instruments are built up to be as accurate and precise as possible.


Before starting the validation of the method, you want to be really sure your method is not only an artistic R&D piece, but also fits to be a good QC method. How can you make sure of that? Just like with LC: apply a ton of injections to check any adverse trends on the peak areas, shapes or anything not adding up.

If your method survives this bossfight - you really have a method in your hands to validate!


ICH Q2 tells us almost everything what you need to go ahead and validate your HS-GC method. But what to focus on?

First, you need to define your range. From Limit of Detection, to 120% of your specification.

Then you need to selectivity - on every solvent, on specification level.

Next steps: linearity and precision. What kind of precision you ask? Of course, system precision is out of the question (because you can inject one analyte only once), you need to stay with method precision and intermediate precision.

And finally, a key point: recovery. You need to demonstrate that you are able to extract all solvents from your sample, response factor is not really a solution here.


When you are done with the above, you can celebrate you own the most efficient method for residual solvents' determination - just wait till Regulatory affairs allows you to implement it.

However, it shouldn't take too much time: as an example, in EU, the update of QC-method of API residual solvents is usually a Type Ib :).

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