Isolation and Characterization of Trace Impurities in Pharmaceutical Products
The most important concern in the drug development process is safety of a drug and its impurities. The presence of impurities in trace quantities in a drug substance or drug products is inevitable. Therefore, the level of impurities in drug substances and drug products should be controlled and monitored.
Impure substances present in pharmaceutical products have to be identified to make sure no mutagenic or toxic substances will be administered to patients. Impurity profiling of pharmaceutical products needs to be established to guide stable formulation development and provide suitable drug shelf life assessment. Hence, impurity profiling of pharmaceuticals, i.e., the identification, isolation, characterization and purification of these impurities is required. Their limits and threshold values should be within the limits that are specified by the applicable regulatory agencies such as the International Conference on Harmonization (ICH), U.S. Food and Drug Administration (FDA), Health Canada, United States Pharmacopoeia (USP), European Pharmacopoeia (EP), British Pharmacopoeia (BP) and Japanese Pharmacopoeia (JP).
According to ICH guidelines on impurities in new drug substances and drug products, identification of impurities below a 0.1% level is not require unless the potential impurities are expected to be high potent or toxic. In accordance to ICH, the maximum daily dose threshold is ≤ 2g/day 0.1% or 1 mg/day intake ≥ 2g/day 0.05%.
Since impurity profiling is becoming increasingly of interest and under scrutiny by regulatory agencies, different pharmacopoeias have started to introduce limits of impurities present in Active Pharmaceutical Ingredients (API) and drug product formulations.
On August 29, 2005, FDA published a revised draft guidance for industry titled “ANDA's: Impurities in Drug Products” that was originally issued in December 1998.
The final guidance was issued for the following reasons:
To update information on listing of degradation products
Setting acceptance criteria
Qualifying degradation products (thresholds and procedures) in Abbreviated New Drug Applications (ANDA’s) in conformance with the revised guidance for industry on Q3B(R) Impurities in new drug Products; and
To remove those sections of the 1998 draft guidance containing recommendations that were no longer needed because they were addressed in the more recent Q3B(R)
The ICH Q3B(R) guidance was developed to provide guidance on impurities in drug products for New Drug Applications (NDA's). However, the Agency believes that many of the recommendations provided on impurities in drug products also apply to ANDA’s.
The primary criteria of analytical methodologies are to differentiate the compounds of interest and their related degradation products. A wide variety of highly sophisticated equipment is available for characterizing impurities. Such methods include spectroscopic methods, chromatographic methods and their combinations. The traditional approach in impurity identification involves isolation and purification by semi-preparative HPLC, followed by characterization using NMR spectroscopy, accurate MS or LC-MS/MS methods. Whichever approach is chosen, the qualification of impurities is important to confirming the safety of a drug product and that these impurities are controlled and monitored.