Forced Degradation in the drug products

[aruna sharma]

I am confuse about the forced degradation in the drug products.

We are doing the Force degradation during the time of the Method development (stability indicating) by using the pratical conditions i.e Thermal,humidity and the photodegradation . for the indentification of degradents.

I want to know that alkali and H2O2 degradtion is must for the drug product or not . In my view these are not the practical conditions?

It is necessary to do the forced degradation in the Method validation as we are doing it during the method development. is it correct or not ?

as i mention that practical condition should be included in the forced degradation for the drug products (Formulation) or not?

Please clear my doubts

[Rob Burgess]

What do you mean by alkali? 0.1 M NaOH I presume. I agree it is not a practical condition that any drug formulation should ever encounter, but it does act as worse case scenario. In that way your can be sure to cover every possible degradation peak that is likely to occur (same goes for acid hydrolysis).

The same goes for oxidation potential using H2O2; it probably is a bit too severe. I believe we have tried to change our departmental protocols for degradation studies to try something else for oxidation degradation i.e. bubbling oxygen through a solution of drug product.

Any other views out there?

[Mattias]

I don't think one should view the forced degradation study as something that the drug will actually be exposed to in real life. It is just a way to explore the different degradation mechanisms of your drug (without having to wait for years).

It is thus a valuable aid in the development of a stability indicating analysis method, when you know what impurities that you possibly can expect in e.g. a stability study.

One thing that I find a little bit blurry is how far one should go to achieve degradation. The guidelines suggest conditions that create 10-30% degradation. As you mention, 0.1M NaOH is quite tough and to increase the NaOH concentration further feels beyond the point of relevance.

Do people settle with that, or do they turn up the degradation parameters further??

[Consumer Products Guy]

I, too, have always found the forced degradation parts of validation a very "gray region", but lots of the validation parameters are similarly "gray". For example, forced degradation at higher or lower pH: our products would be out of specification at those pH levels, so would be deemed OOS regardless of whatever the active level actually was.

[pawan ratra]

The best approach for proving that the method is stability indicating is to analyze the expired sample (e.g. after 2 years). But practically it is not feasible. The other approach is to analyze accelerated study sample but for that also a sample should be exposed to specific condition for 3 months.
Thus to prove that analytical method is stability indicating during method development/validation, it is required to demonstrate that under the worst case scenerio of exposure to various conditions, the analytical method is capable of separating all the degradants from the main component.
Also acid, alkali, H2O2, thermal, Humidity and Photolytic degradation give the idea about the probable degradation route/product which may further be helpful in product development including packaging.
I don't know whether any guidelines suggest to achieve 10-30% degradation but it is industrial practice to achieve that much degaradtion and if possible to identify major degradation products.

[John G]

First, forced degradation studies should be done as part of your method validation. The purpose is to show that your method is capable of separating and accurately quantitating ANY possible impurities. We stress API samples and drug product in method validation under numerous conditions, thermal wet and dry, UV-VIS wet and dry, 0.1 N HCl, 0.1NaOH, and H2O2. We adust the conditions, lenght of exposure, temperature, concentration of H2O2 etc. to give us 5-10% degradation. These conditions are developed in method development then repeated in the method validation. The method validation is the proof of your method, this is where forced degration studies belong, if your method is for stability indication you need to show and document that it can quantitate potential impurities. The last thing you want is a method failing 6 months into a stability study.

In most cases the highest amount of degradation you will see in a drug product in stability studies is around %5, so why would you degrade 5 times that amount. The concern here is secondary degradation products. If you degrade to 30% you will see secondary degradations products. In most cases this should be avoided as it is not nesscessary and simply makes for a very messy chromatogram.

Hope this helps
John

[gtma]

I agree with all of you. My experience is that you conduct forced degradation to obtain stress samples for stability indicating method development. Generally proposed stress conditions are : 0.1N HCl, 0.1N NaOH, 0.3% peroxide, AIBN, purged with Oxygen, metals (e.g. copper, iron), 2-3X ICH conformation photostability, heat/humidity (e.g. 70-80C). The drug is usually exposed to these conditions for a certain time period to obtain 5-20% degradation. If you cannot achieve a certain amount of degradation products within the specified time period, then you simply stop the stress testing rather than continuing with more harsher conditions. The reason is that it is unlikely that the drug will experience harsher conditions.

Especially for API methods, one should also look at the chemical synthesis to ensure that some of the above conditions are consistent with what the API are exposed to (e.g. metals, acid). Also, some of the above conditions may give you a worst case seniaro indication of how the drug behave under physiological conditions.

In general, the more degradation you have, the more difficult to separate them from each other during method development and the longer it takes to develop a method. Therefore, I personally would not want to use stress samples with more than 5% degradation. Unless you believe your drug specification will have total related substances greater than 5% then it make sense to use stress samples with greater than 5% degradation.

I strongly recommend you use the acid/base or photostability samples during method development rather than later on in the validation because you may be in for a surprise to find you have specificity issues which may lead you to redevelop the method.

Lastly, I challenge the regulatory bodies to address this issue.

[pawan ratra]

The reason is that it is unlikely that the drug will experience harsher conditions.

In one of the case I know:
During packaging of soft gelatin capsules the temperature for sealing goes upto 170C resulting in degaradtion of active at the time of packaging. Thus unexpected condtions should be taken into account at the time of degradation studies.