Qualification is the process of establishing the biological safety of a product in the presence of a degradation compound or impurity above specified levels.
A reasoned approach should be used to establish acceptable impurity criteria and should include the safety criteria considered. The interpretation of the regulation is very important to define a course of actions regarding the "qualification" of impurities or related compounds.
The fundamental question posed by the action of qualifying an impurity is to answer the question: Does the compound represent a health risk to the consumer?
A compound will be considered qualified when the level of any degradation product present in a new pharmaceutical substance or drug has been adequately tested by one of the following types of studies:
- Clinical Studies
- In vivo studies
- In vitro studies
- In silico studies.
According to the ICH Q3A and Q3B guidelines, a level above the Qualification Treshold for an impurity may be established based on an analysis of the actual amount of impurities administered in previous relevant safety studies.
To carry out the qualification of an impurity, an in silico study can be performed , by means of which risk criteria can be established that are sufficiently reliable to indicate a new specification percentage in accordance with the aforementioned guidelines.
In silico studies are mentioned in several guidelines and documents that are taken as a reference for the treatment of degradation compounds and impurities around the world, the most recent and updated document is the Manual of Policies and Procedures (MAPP) 5017.2, which states the following:
"...to be confident that the product works as designed, it is necessary to establish acceptance criteria for impurities. Currently, the establishment of acceptance criteria for drug impurities can be supported by clinical or non-clinical data (e.g., in silico, in vitro and animal study data), comparative impurity analysis of the proposed product with FDA-approved drugs (those found in the reference drug list)[1], a process called Potential Degradation Products Phase, in order to make a prediction of possible degradation products. Subsequently, a calculation of relevant physicochemical properties and a chromatographic time simulation is performed in order to identify compounds that can be eluded in the retention time of the degradation product. Finally, a toxicological evaluation is performed by means of a TOXscreen study.
For some drugs or medications, higher or lower impurity qualification thresholds may be appropriate, depending on scientific justification and level of concern, including drug family effects and clinical experience.
Qualification may be especially important when there is evidence that such impurities in certain drugs have previously been associated with adverse reactions in patients. In these cases, a lower qualification threshold may be appropriate. Conversely, a higher qualification threshold may be appropriate of higher qualification when the level of safety concern is lower than usual, based on similar considerations (e.g., patient population, drug class effects, clinical considerations). Alternative threshold proposals would be considered on a case-by-case basis.
One of the most important advantages for the pharmaceutical industry is that in addition to ensuring that the degradation compounds generated in the drugs during stability testing have low toxicological risk potentials at the concentrations found, this same information can be used as a powerful tool to avoid the step of reformulating a drug that has exceeded the qualification limits established for it. In addition, if reformulation is ultimately necessary, relevant information on the reliable levels of the presence of a degradation compound will be available.
QSAR Analytics is the Mexican company with more experience in the treatment of impurities and degradation compounds. If you have problems with this type of compounds, we invite you to join the community that already enjoys having successfully solved their problems and has been able to register their products and save unnecessary costs by reformulating.
[1] "To provide assurance that a product performs as is intended, there is a need to establish impurity acceptance criteria. Currently, the establishment of a drug substance and drug product impurity acceptance criterion can be supported by clinical data, nonclinical data (e.g., in silico, in vitro, and animal data), comparative impurity analysis of the proposed drug product with an FDA approved drug product (listed drug or reference listed drug (RLD))..." (CDER, 2018)