Stability of analytical solutions

[Lrv]

Where can I find something resembling a protocol for testing the stability of standard and sample solutions used in an analytical method? I am not working with drugs, but an FDA procedure on how to design the test (although overkill) would even be OK-I'm just having a little trouble finding something.
Help anyone??

[dorota]

I think you will not find such a procedure, look at the answer No.4 here:
http://www.fda.gov/Drugs/GuidanceCompli ... 4787.htm#4

For in-house prepared solutions, such as mobile phases or other non-quantitative solutions, FDA would expect that an assessment be conducted (again, literature review may be acceptable) to determine an appropriate expiry period. However, for in-house prepared solutions used for quantitative analysis, such as sample or standard solutions used in assay or impurity testing or titration solutions, FDA requires that formal stability studies be conducted to determine an appropriate expiry. As mentioned in Guidance for Industry: Q2B Validation of Analytical Procedures: Methodology, the stability of analytical solutions is a typical method variation that should be evaluated during robustness testing during method validation. Method validation is a CGMP requirement at 211.160(b).

[lynzjm]

I used to be a validation and stability study director for a pharma company.

Our basic stability protocols involved testing the samples first of all for the actual drug formulation stability, e.g. making a mock pot of the full preparation (sampling it if a suspension is obviously not acceptable, only solutions can you aliquot). At time 0 we would take a sample of the drug formulation and dilute it down to the working concentration of the method and assess it for duplicate injections for content etc. We would then store the drug formulation for the required number of days sampling on designated timepoints as before.

We would alongside this test the analytical solution stability where would would on day 0 take the mock formulation pot and sample it and dilute to the working concentration of the method (as for the formulation stability this can be the same day 0 samples save you doing it twice). We would then store aliquots of the analytical working solutions alongside the formulation pot and test these as well thus allowing us to have results for our formulation pots and our analytical working solutions.

The timepoints you use are fully up to you depending on what you're testing. The matrix effects (specificity etc) would be part of our validations as well.

hope thats of use!

lynz x

[Consumer Products Guy]

As mentioned in Guidance for Industry: Q2B Validation of Analytical Procedures: Methodology, the stability of analytical solutions is a typical method variation that should be evaluated during robustness testing during method validation.

On a theoretical basis, I agree that stability of analytical solutions realistically belongs in Robustness studies.

However, on a practical basis, I've calculated that a study for 90-day stability of analytical solutions takes......90 days. So we go back after and evaluate the stability of analytical solutions. If I took 90 days to evaluate stability of the solutions in a validation, the heads of R&D and Marketing would have fits !!!

Any guideline for how much agreement of Area/concentration over time is enough to say that the analytical solution is "stable" ?

[lynzjm]

for solutions we typically gave guidelines of 90-110% recovery and <5% RSD between replicate injections, and for suspensions we gave 85-115% recovry and again <5% RSD. This was for drug formulation stability in our case.

We would typically test no longer than 10 days as a max for our solution/suspension stability of analytical solutions - we'd er-prepare these after this time. THe actual drug formulations however we'd give longer expirys and often run the stability study alongside the main study as like the previous poster said, a 90day stability study isnt practible to delay a main study alongside this! We'd typically stgger the starts and start our stability a few days before the main study and that way if we had any fails you have a few days warning for the main study expiry. Standards also although I believe you can use the same "validated" standards throughout your stability study according to the regs we did not as what if your standards pass the criteria (e.g. 90% recovery after 7 days) and then you test against them when they are down at 90% - you're getting artificially high results for your samples. Standards were always prepared fresh in our stability study department.

lynz x

[Consumer Products Guy]

Standards were always prepared fresh in our stability study department.
lynz x

Thanks. What is a "stability study department" ?

Don't tell me that you also have a Method Development Department and a Validations Department....

[lynzjm]

We had a validations and stability section as we had a large number of studies being conducted for on site internal "clients" and for off-site clients. Every new fomulation for every study needed formulation analysis testing, a new HPLC/MS or UV detection method developed, validated and a full stability study done before we would then go on to do the actual study and the subsequent quality control sample testing. So yup method development&stability section was our official title! Thats a big company for you not willing to out-source anything!

lynz x

[Alex Buske]

for solutions we typically gave guidelines of 90-110% recovery and <5% RSD between replicate injections, and for suspensions we gave 85-115% recovry and again <5% RSD. This was for drug formulation stability in our case.
lynz x

Whats that? If you have a drug product release specification 95-105 % and your standard solution is already degraded by 10 % or evaporated up to 110% relese testing becomes a gamble.
We usually test standard and sample solutions for three days in an autosampler. the must differ from Start NMT 2.0%.

90 days testing of standard stock solution is also possible. In that cases we do that alongside with drug product testing. you will have to write two validation reports one for the ich stuff, one for the solution stability.

Alex

[lynzjm]

Whats that?

that would be the pass guidelines for drug formulations for subsequent dosing samples. What was being dosed was assessed for "quality control" of the drug formulations to ensure the dosing mg/kg was what it said it was so as to minimise harmful effects and ensure high doses and low doses were correct. We had samples shipped to us and results sent back prior to dosing.

Standards were always prepared fresh in our stability study department.

for exactly that reason to minimise and stop degradation becoming an issue when comparing the standard to the samples. We did standard solution/suspension stability also to assess the hourly stability and the degradation rate, obviously the criteria for our standards were much tighter than for the samples. The criteria for the samples was set and approved by the MHRA as being appropriate for the intended use.

If storing your samples in an autosampler same as above poster make sure you are using amber vials, as (depending on what you're testing!) stability should be assessed protected from light as well as a constant temperature.

lynz x