Controlling and monitoring impurities in APIs and finished drug products is a crucial issue in drug development and manufacturing.
Part I of this article, published in the February 2012 issue of Pharmaceutical Technology, discussed the various types of and sources of impurities with specific case studies (1). Part II, published in the March
2012 issue, examined chiral, polymorphic, and genotoxic impurities (2). In Part III, the authors examine various degradation
routes of APIs, impurities arising from API–excipient interaction during formulation, metabolite impurities, various analytical
methodologies to measure impurity levels, and ways to control impurities in pharmaceuticals.
Definition of impurity
The term impurity reflects unwanted chemicals that are present in APIs or that develop during formulation or upon aging of the API in the formulated
drug product. The presence of such unwanted material, even in small amounts, could affect the efficacy and safety of pharmaceutical
products. Several guidelines from the International Conference on Harmonization (ICH) address impurities in new drug substances,
drug products, and residual solvents (3–6). As per the ICH guidelines on impurities in new drug products, impurities present
below a 0.1% level do not need to be qualified unless the potential impurities are expected to be unusually potent or toxic
(5). In all other cases, impurities should be qualified. If the impurities exceed the threshold limits and data are not available
to qualify the proposed specification level, studies to obtain such data may be required. Several recent articles describe
a designed approach and guidelines for isolation and identification of process-related impurities and degradation products
using mass spectrometry, nuclear magnetic resonance (NMR) spectroscopy, high-performance liquid chromatography (HPLC), and
Fourier transform infrared (FTIR) spectroscopy for pharmaceutical substances (7–9).
Degradation products are compounds produced by decomposition of the material of interest or active ingredient. Several impurities
may result because of API degradation or other interaction on storage, so stability studies need to be conducted to ensure
drug product safety (10). Hydrochlorothiazide (see Figure 1) is a classical example of a degradation impurity. It has a known
degradation pathway through which it degrades to the starting material as disulfonamide in its synthesis.
Figure 1: Degradation of hydrochlorothiazide. (ALL FIGURES ARE COURTESY OF THE AUTHORS)
Degradation products could result from the synthesis itself, storage, formulation of the dosage form, and aging (11). These
degradation pathways are further discussed.
Impurities in a drug substance or a new chemical entity originate mainly during the synthetic process from raw materials,
solvents, intermediates, and byproducts. The raw materials are generally manufactured to much lower purity requirements than
a drug substance, and thus, it is easy to understand why they can contain a number of components that can in turn affect the
purity of the drug substance.
1-Methyl-3-phenyl piperazine (see Figure 2) is present as an unreacted starting material that competes in all the stages eventually
leading to the impurity keto-piperazine derivative of mirtazapine (see Impurity C, Figure 2).
Figure 2: Reaction scheme for mirtazapine impurity. Ph. Eur is the European Pharmacopoeia. DMF is dimethylformamide. EtOAc
is ethyl acetate.