Forced Degradation Conditions

[zheyin]

Can someone experienced tell me what conditions do you use or where can I find resources for forced degradation in the stress test for method validation?
UPDATE: AN EXAMPLE I FOUND
- 2 hrs direct sunlight (70-90 klux)
- 1 wk at 75C ambient humidity
- 1 wk at 75C 100% RH
- 24 hrs 3% H2O2, 1N HCl, 1N NaOH
But it does not say the volume for the 3 reagents.
Supposedly stress the drug product, NOT neat ref std, and the product is in solid form
when you put powder in a solution, you should indicate the vol.

ICH Q1B
For confirmatory studies, samples should be exposed to light providing an overall
illumination of not less than 1.2 million lux hours and an integrated near ultraviolet energy of
not less than 200 watt hours/square meter to allow direct comparisons to be made between the substance and product.
too confused!!!
Any ideas?

[DoryFish]

There's a superb paper by Alsante et al in Advanced Drug Delivery Reviews 59 (2007) 29-37 titled "the role of degradant profiling in active pharmaceutical ingredients and drug products" that gives you recommended ranges for the various stress tests.

[zheyin]

There's a superb paper by Alsante et al in Advanced Drug Delivery Reviews 59 (2007) 29-37 titled "the role of degradant profiling in active pharmaceutical ingredients and drug products" that gives you recommended ranges for the various stress tests.

Thank you very much!
Hope I can find this paper.

[Andy Alpert]

There's a recent paper about the exposure of the polypeptide pharmaceutical exenatide to all of these treatments:
X.-X. Zong, M. Zhu, J.-A. Liu, M.-X. Wang, and H.-Q. Zhao, J. Shenyang Pharmaceutical Univ. 28 (2011) 791. The paper is in Chinese, although the abstract and figure legends are in English.

[zheyin]

There's a recent paper about the exposure of the polypeptide pharmaceutical exenatide to all of these treatments:
X.-X. Zong, M. Zhu, J.-A. Liu, M.-X. Wang, and H.-Q. Zhao, J. Shenyang Pharmaceutical Univ. 28 (2011) 791. The paper is in Chinese, although the abstract and figure legends are in English.

Chinese reading is not a problem to me.
But I wouldn't trust any Chinese publications as my references.
Although pubs on international journals are different stories.

[Lusby43]

The accepted target is around 15% degradation of the original compound for chemical degradation (based on peak area of degradants).

The conditions required to acheive this depend entirely on the molecule you are investigating. I sugest some range finding experiments, and adjust until the desired level of degradation is acheived.

You also need to consider what you product is exposed to during storage and transport. If the product is an acidic salt, you may want to check stability in the presence of that acid, and if your product is packaged in light proof containers, light degradation may not be required.

The place to look for further info is the ICH guidelines, it is here that it is specified that light degradation requires the material to be exposed to light for a minimum of 1.6 million lux hours (as an example).

[zheyin]

The accepted target is around 15% degradation of the original compound for chemical degradation (based on peak area of degradants).

The conditions required to acheive this depend entirely on the molecule you are investigating. I sugest some range finding experiments, and adjust until the desired level of degradation is acheived.

You also need to consider what you product is exposed to during storage and transport. If the product is an acidic salt, you may want to check stability in the presence of that acid, and if your product is packaged in light proof containers, light degradation may not be required.

The place to look for further info is the ICH guidelines, it is here that it is specified that light degradation requires the material to be exposed to light for a minimum of 1.6 million lux hours (as an example).

Thank you very much for the ICH guidelines.
Seems to me upper management wants to do all stress conditions.
I read somewhere generally starting from 2 hr as the duration.

[zheyin]

The accepted target is around 15% degradation of the original compound for chemical degradation (based on peak area of degradants).

The conditions required to acheive this depend entirely on the molecule you are investigating. I sugest some range finding experiments, and adjust until the desired level of degradation is acheived.

You also need to consider what you product is exposed to during storage and transport. If the product is an acidic salt, you may want to check stability in the presence of that acid, and if your product is packaged in light proof containers, light degradation may not be required.

The place to look for further info is the ICH guidelines, it is here that it is specified that light degradation requires the material to be exposed to light for a minimum of 1.6 million lux hours (as an example).

I read somewhere to use 2 hrs direct sunlight (70-90 klux)
that is only 0.16 million lux hours, am I right?

I finally found an ICH Q1B, (not on FDA website), it is supposed to be 1.2 million lux hrs, NOT 1.6,
am I reading an older version or not?

[krickos]

Check www.ich.org for latest versions.

[prepcolumn]

Zheyin

1.2 million lux.h is correct. But please don't forget this value is for conformity. To get forced conditions you have to process your samples at least 2 times the ICH recommendation..

[zheyin]

Zheyin

1.2 million lux.h is correct. But please don't forget this value is for conformity. To get forced conditions you have to process your samples at least 2 times the ICH recommendation..

The QA director says just put the samples along the window for light stress.

[tom jupille]

The QA director says just put the samples along the window for light stress.

If that's your company's general attitude toward meeting regulatory requirements, remind me to *not* buy any of their products.

[KM-USA]

The QA director says just put the samples along the window for light stress.

Like I've said and read before: most folks interpret all this stuff differently....like I've never been able to get a decent answer on how much a matrix contribution (like from a fragrance peak) can be compared to the API. Sure, we'd all like it to be zero, but fragrances can be 100 components, some of those are mixtures, there can be seasonal changes, different vendors for the individual materials....

Any guidance Tom ? or others?

[qfiviera]

The accepted target is around 15% degradation of the original compound for chemical degradation (based on peak area of degradants).

The conditions required to acheive this depend entirely on the molecule you are investigating. I sugest some range finding experiments, and adjust until the desired level of degradation is acheived.

You also need to consider what you product is exposed to during storage and transport. If the product is an acidic salt, you may want to check stability in the presence of that acid, and if your product is packaged in light proof containers, light degradation may not be required.

The place to look for further info is the ICH guidelines, it is here that it is specified that light degradation requires the material to be exposed to light for a minimum of 1.6 million lux hours (as an example).

Totally agree.
But, if you want something fast, and you have no idea of the estability of your molecule, try this at first:
15 minutes reflux of:
Sodium bisulfite 3%
Hydrogen Peroxide 10%
30 minutes reflux of:
HCl 1N
NaOH 1N

This may gave you a first idea. Then you can dilute or concentrate, increase or decrease time. But try a placebo too.