ROCKY MOUNTAIN INSTRUMENTAL LABORATORIES
FDA and ICH Guidelines require that pharmaceutical agents be tested to determine their stability over time and under various standard conditions. As a part of this effort, it is common practice to force the degradation of both the drug substances and the final product or device. This will then allow for the identification of those substances which may appear during the normal life of the drug, formulation or device.
ICH stability conditions (1) are intended to reproduce reasonably possible storage of pharmaceuticals. Therefore, stress testing or "forced degradation" is necessary (2, 3) to generate and identify degradants which might appear. These conditions are necessarily more severe than are the normal stability conditions. The drug substance, product, or device is subjected to extremes of acid, base, light, and oxidation. As with the ICH conditions for stability testing, it is necessary to construct a plan for the forced degradation experiments. Biotechnology products are subject to a different Guidance (4). There are multiple approaches available for the stressing of molecules. The information gathered from stress testing is needed for the development of valid, stability-indicating routine assays. The information also is essential for product development. For example, an API may be stable in the presence of one excipient, but not when exposed to other excipients. This is covered very well in Baertschi's book (3), but also requires a good knowledge of the organic chemistry of the excipients and the parent drug.
The stress testing plan will include a range of pH values, light stress with known light sources, and oxidation by several distinct oxidation sources (5).
For example, there are three distinct methods which are commonly used to oxidize actives and excipients. The results of those stress experiments may well be different from each other and provide valuable information for product development and likely storage conditions.
In general, identification of potential degradants and the methods used to create them often can tell the mechanisms by which the degradants are formed. This then can lead to the use of a better choice of excipients and preservatives for the drug or product.
At RML we can establish the stress testing protocol for a particular drug, drug product, or device. Using HPLC/MS/MS and other technologies, we can the identify the degradants formed. Note that this is not always routine or simple. Of particular interest is the use of our quadrupole - linear ion trap system (API-4000Q) which allows us to search for the various metabolites and degradants that have a major fragment in common. This greatly improves our ability to detect low levels of such related degradants, contaminants, and metabolites.
If additional information
on our services is needed, please contact either Dr. Patricia Sulik or
Dr. Robert Lantz.
1. Guidances for Industry (ICH). Many documents are available from FDA and ICH. Of particular interest are Q1A (R2) and Q3A on Stability Testing and Impurities.
2. Ahuja, S. and Scypinski, S. "Modern Handbook of Pharmaceutical Analysis" Academic Press (2001).
3. Baertschi, S., "Pharmaceutical Stress Testing" M. Dekker Publ. (2005). This is an excellent text, written by some of the foremost experts in the field of stability and stress testing.
4. Guidance for Industry (ICH) Q5C, Stability Testing of Biotechnological/Biological Products.
S. et al "Toward a Generic Approach for Stress Testing of Drug Substances
and Drug Products" Pharmaceutical Technology February
pp 48-66 (2005).
Rocky Mountain Instrumental
108 Coronado Ct.
Ft. Collins, CO 80525
970-266-8108 303-530-1169 (Denver Metro voice and FAX)
UPDATE: 16 APRIL 2012