To ensure the quality of APIs and finished drug products, impurities must be monitored carefully during process development, optimization, and process changeover. The isolation, characterization, and control of impurities in pharmaceutical substances are being reviewed with greater attention based on national regulatory and international guidelines. In Part I of this article, the authors examine the different types and sources of impurities with specific examples.
Definition and sources of impurities
An impure substance may be defined as a substance of interest mixed or impregnated with an extraneous or usually inferior substance. The greatest financial impact on the cost of a drug substance often is found in the final preparation process. Product yield, physical characteristics, and chemical purity are important considerations in the manufacture of the active ingredient, the formulation of the dosage form, and the manufacture of the finished drug product. Processes to control the preparation of the drug substance and drug product must be disclosed to FDA as part of a new drug application. If production batches do not meet the purity and impurity specifications required, the manufacturer must attempt to upgrade materials by rework procedures, which are costly because they consume drug substance and resources and prevent the preparation of other batches of drug substance. The sources and types of impurities can be illustrated by considering a general flow scheme for manufacturing drugs. The formation of impurities is interconnected with each stage as shown in Figure 1.
In short, any material that can affect the purity of an API or finished drug product is considered an impurity. Impurities arise from various sources, which commonly include starting material(s), intermediates, penultimate intermediates, byproducts, transformation products, interaction products, related products, degradation products, and tautomers.
Figure 1: Schematic representation of impurity-formation pathways for APIs and finished drug products. DMF is drug master file.
Impurity control in starting materials used to manufacture APIs has long been expected by regulatory agencies (1). An API starting material is a raw material, intermediate, or API that is used in the production of an API and that is incorporated as a significant structural element into the API. API starting materials normally have defined chemical properties and structure (2). An FDA draft guidance, Drug Substance: Chemistry and Manufacturing Controls Information, reflects the concern that starting materials should be selected and controlled such that any potential future changes to the quality of the starting material would have an insignificant impact on the safety, identity, purity, or quality of the drug substance (3). Based upon the principles outlined in this FDA draft guidance and ICH guidelines for process understanding and control over potential adverse effects on the quality of the produced drug substance, the following framework has been offered for the selection of starting materials:
- Appropriate, discriminating methodology is used to determine the quality of the starting material.
- Specifications are appropriate to ensure quality of the API.
- The impact of the starting material quality on API quality is understood and controlled.
- The starting material is available commercially and is incorporated into the new drug substance as an important structural element.
- The starting material is characterized, and stability is well understood.
- The starting material is a compound whose name, chemical structure, chemical and physical characteristics and properties, and impurity profile are well defined in the chemical literature (4).
Because of the starting materials' potential impact on the quality of an API, stricter requirements for a starting material arise based on the proximity in the API synthesis of the starting material to the final API. For example, fluoronitrobenzene is a key starting material for the API olanzapine. If the 2-4-difluoronitrobenzene impurity is present in the key starting material, the same will be converted under reported conditions to 8-fluoro-olanzapine, a nonpharmacopeial impurity (US Pharmacopeia [USP] method, relative retention time [rrt] 1.07). The 2,4-difluoronitrobenzene is carried forward along with the fluoronitrobenzene, resulting in analogous compounds up to the final stage.
In another example, N-[6-(4-phenylbutoxy)hexyl)] benzenemethanamine (see Figure 2) is a drug master file (DMF) starting material for the selective long-acting -2-adrenoreceptor agonist salmeterol. The drug is used clinically as an inhaled bronchodilator for treating asthma and chronic bronchitis (5, 6).
Figure 2: Reaction scheme of salmeterol and impurities. EP is the European Pharmacopoeia. NaH is sodium hydride. TBAB is tetra-n-butylammonium bromide DMSO is dimethyl sulfoxide. NABH4 is sodium borohydride. Pd/C is palladium on carbon.
In the case of salmeterol, 4-phenyl butanol reacts with 1,6-dibromohexane to give Intermediate 1, which in turn reacts with benzylamine in the presence of dimethyl sulfoxide and triethylamine to yield N-[6-(4-phenyl butoxy)hexyl)] benzenemethanamine, a DMF starting material for salmeterol (see Figure 2). The compound 4-phenyl butanol is commercially available and prepared from benzene with succinic anhydride (7–11). If the benzene has a trace amount of toluene, the toluene is converted to 4-(4-methylphenyl)-1-butanol. The compound 4-(4-methylphenyl)-1-butanol is present in 4-phenyl butanol as a starting material impurity, which undergoes further reaction, similar to 4-phenyl butanol, to afford the methyl salmeterol impurity (see Figure 2). Similarly, the presence of 2-phenylethanol, 3-phenyl-1-hydroxypropane, and 4-phenyl-2-hydroxybutane in the 4-phenyl butanol will yield known salmeterol Impurities B, C, and E, respectively.
Similarly, 6-hydroxy and dichloro impurities, if present in the DMF starting material of ciprofloxacin, will be converted to European Pharmacopoeia impurity F and nonpharmacopeial impurity (chloro ciprofloxacin) at 2.1 RRT.