Potential Impurities in Drug Substance & Drug Products

Forced-degradation for drug products -Regulatory-Considerations
Forced Degradation Studies for Drug Substances and Drug Products- A Regulatory Considerations
June 27, 2020
scientific-consideration
Forced Degradation Studies for Drug Substances & Drug Products- Scientific Considerations
July 1, 2020
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potential impurities

Potential impurities are the substance which are formed during the reaction or already present in the form of starting materials, by-products, or intermediate products. Potential Impurities have no therapeutic value and are potentially harmful.  Therefore, they need to be controlled.

Potential impurities may be arising due to:

  • The residue of the starting material
  • The residue of the intermediate
  • Impurities in the starting material
  • Reagents
  • Solvents
  • Catalysts
  • Reaction by-products
  • Degradation products
  • Excipient-API interactions
  • Drug substance/product manufacturing process
  • Container closer interactions

As per ICH Q3A defines potential impurities as those “that theoretically can arise during manufacture or storage.” Understanding how the potential degradation products form via specific degradation pathways or mechanisms. This provides a basis for minimizing or eliminating degradation e.g. through processing conditions, formulation, storage condition, or packing.

Based on the knowledge about the manufacturing process, intrinsic characteristics of the API, official monographs, forced degradation studies and, possibly, literature references, the API manufacturer should determine which are the potential impurities.

Genotoxins must be considered carefully due to their toxicity at even very low levels. If you are looking for an impurity using a test method that cannot detect the impurity then the method is not capable to detect the low levels of impurities. Hence it is important that analytical methods demonstrated specificity and appropriate LOD/LOQs levels, especially for genotoxins. Analytical detection and quantification are often challenging and requires sophisticated methods and/ or derivatization.

Potential degradation impurities in drug substances:

Normally, Potential degradants are chemical collapse compounds of the drug substance formed during storage. In rare cases, degradants are formed when the drug substance chemically interacts with other compounds or contaminants. In addition, degradants may also be formed by physical degradation, e.g. aggregates of proteinaceous material, dimers, trimers, and so forth, of synthetic compounds, polymorphs of synthetic compounds.

Potential Degradants

Potential degradation impurities in drug products:

Drug products contain both drug substances and excipients. The resultant biological, chemical and physical properties of the drug product are directly dependent on the excipients chosen, their concentration, and interactions with the drug substance. Excipients are sub-divided into various functional classifications, depending on the role that they are intended to play in the resultant formulation, e.g. fillers, disintegrants, binders, lubricants, color, flavors, and glidants. Also, the impact of the manufacturing process, conditions, packaging, and storage of finished dosage forms.

There is a tendency to skip the step-in discussion and just adopt pharmacopeial specifications if a monograph exists. Hence there is need to find out what are the expected potential impurities? What is the additional literature-based impurities? What are the other reported impurities? 

Consequently, for any drug registration, one of the principal requirements is to specify both identified and unidentified impurities in drug substance/drug product as per ICH guidelines Q3A(R), Q3B(R) and Q3C. Characterization of impurities is required, particularly when they are present at a level higher than the identification threshold to control their levels in the final API or drug product.

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