Stability Indicating Methods(SIM)

According to FDA guidelines, a SIM is defined as a validated analytical procedure that accurately and precisely measures active ingredients (drug substance or drug product) free from potential interferences like degradation products, process impurities, excipients, or other potential impurities.

A SIM is a quantitative analytical procedure used to detect a decrease in the amount of the active pharmaceutical ingredient (API) present due to degradation.

A degradation product is a molecule resulting from a change in the active ingredient brought about over time as a result of processing or storage (e.g. oxidation, hydrolysis). Compounds that are formed from a reaction of the active ingredient with an excipient or container closure component are also considered degradation products.

Stability Indicating methods are mandatory as FDA's Current Good Manufacturing Practice Regulations (cGMP) are published as Parts 210 and 211 of the Code of Federal Regulations (21CFR) with Section 211.166 specifically addressing stability testing.

The regulation asking a formal written stability testing program whose results are used to establish storage conditions and expiration dates of drug products and further mandates the use of “reliable, meaningful, and specific test methods.”

The stability indicating methods should be applied to the analysis of stability samples of drug substances or drug products. The data generated with these methods can be used to establish retest date for drug substance and expiration dating for drug products.

Typical Stability Assessment for Drug Substance

It is necessary to demonstrate the specificity of the analytical methods. Specificity is the ability to assess unequivocally the analyte in the presence of components which may be expected to be present. Typically these might include impurities, degradants, matrix, etc.(ICH). So as per the definition of the specificity the analytical methods being used should be able to to separate the response of the active ingredient from the potential process impurities including starting materials, intermediates and by-products as well as degradative impurities is of critical importance.

Peak purity analysis play a significant role in demonstrating the specificity of the analytical method. This analysis can be done with Photodiode Array detectors or Mass detectors in HPLC. Peak Purity Analysis will provide an assessment of an analyte peak to check for potential coelution (The process whereby two or more chemical compounds elute from a chromatographic column at the same time, making separation and identification difficult.). The peak purity analysis should be conducted for both active material as well as impurities and the acceptable levels of purity should be 99.999%. Modern chromatographs are with software which can do the purity analysis.

Spiking studies are likely the definitive technique for the demonstration of specificity.Authentic samples of the active ingredient and the various potential impurities/degradants may be introduced to the analytical system at the appropriate levels. The resulting output provides excellent information on the ability of the methods to separate the impurities in the drug substance from the active ingredient and each other.In these studies Resolution between the closest eluting peaks is the criteria in establishing the specificity.

The analytical methods usually require a validated LOQ for process impurities and degradants at a level that is equal to or better than the International Conference on Harmonization (ICH) Identification Threshold (0.05%-0.10% depending on maximum daily dose). The Identification Threshold may be lowered for impurities that may be exceptionally toxic.

The LOD is usually expected to be at least as sensitive as the ICH Reporting Threshold (0.03% or 0.05%). Linearity and spiking studies are normally used for this type of documentation.

The analytical methods should be employed in a stress testing study to demonstrate their appropriateness as well as to help elucidate intrinsic stability characteristics of the drug substance being tested. Such stress stability testing employs conditions far more severe than accelerated stability testing although for far lesser periods of time (hours or days as opposed to months).

Stress tests include extreme conditions of temperature, hydrolytic potential (both acidic and alkaline), ultraviolet radiation exposure and oxidative potential (exposure to peroxide or entrained oxygen). If the degradation pathway is not well-known or a unified procedure is being used, the active ingredient response should be free of interference under all of these conditions.

A stress degradant that co-elutes with the active ingredient would be acceptable if that particular compound does not form under accelerated stability conditions or if it is controlled with a separate validated method. The ability of the analytical method to separate and accurately quantitate stress degradants is only necessary for those compounds that actually form above the ICH Identification Threshold in accelerated stability studies.

The validated stability indicating analytical procedures are finally applied to formal accelerated and long-term stability studies. If no significant degradation is detected in the accelerated or longterm studies, the limit for individual degradants is appropriately set at less than the Identification Threshold and a LOQ solution is recommended to be employed in the System Suitability parameters as a check on the method sensitivity during routine use.

If meaningful (i.e. above the Identification Threshold) degradation is detected during the accelerated studies, it is necessary for the compounds to be subjected to further analysis to have their structure elucidated and for the method to be validated for the ability to quantitate them accurately.

Relative Response Factors need to be determined to provide a reasonable mass balance between the active ingredient and the degradants. Further intermediate condition and label condition stability studies would be appropriate as necessary to justify regulatory limits for the individual degradants and establish the retest or expiration dating period.

Article Contributed by
Mr.Srikanth Nagabiru
M.Sc., DAC