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API Production: Building an Impurity Profile

Impurities and the ICH Limits for Impurities

Impurities are unwanted chemicals produced during normal manufacturing of Active Pharmaceutical Ingredients, or APIs. As you well know, impurities have no therapeutic value and therefore must be controlled. An impurity profile describes the identified and unidentified impurities a new drug contains.

Arising from many sources, the types of impurities include:

Organic

  • Starting materials or intermediate impurities
  • By-products
  • Degradation products
  • Synthesis-related

Inorganic

  • Reagents, ligands, catalysts
  • Heavy metals (which are further categorized into 3 classes, per ICH Q3D – Guideline for Elemental Impurities)
  • Other impurities, such as filter aids, charcoal, etc.

Enantiomeric

  • This is a compound with the same molecular formula as the drug, which has a different spatial arrangement of atoms within the molecule and is a mirror image that cannot be super-imposed.

Residual solvents, which are divided into the following 3 classes:

Class I Solvents to avoid Known human carcinogens, strongly suspected human carcinogens, and environmental hazards.
Class II Solvents to limit Non-genotoxic animal carcinogens or possible causative agents of other irreversible toxicity. Solvents suspected of other significant but reversible toxicities.
Class III Solvents with low toxic potential Low toxic potential for humans; no health-based exposure limit is needed.

In-process production impurities

  • Crystallization-related
  • Stereochemistry-related
  • Residual solvents: Class I, II and III
  • Synthetic intermediates and by-products
  • Impurities caused during storage

As you can see, impurities can arise virtually anywhere across the API development and manufacturing process.

ICH limits for impurities have long been established to minimize the risk posed by such contaminants. The ICH limits are:

Maximum Daily Dose Reporting Threshold Identification Threshold Qualification Threshold
≤2 g/day 0.05% 0.10% or 1.0 mg/day
(whichever is lower)
0.15% or 1.0 mg/day (whichever is lower)
˃2 g/day 0.03% 0.05% 0.05%

Methods for Isolating Impurities during API Production

A wide range of methods effectively isolate impurities, which allows us to understand where and how the impurities enter the API manufacturing process. With an understanding of the contaminant’s formation in hand, new methods or process modifications can be crafted to minimize and control them.

Here are some of the common methods used in API manufacturing to help control impurities:

  • Solid phase extraction, where compounds that are dissolved or suspended in a liquid mixture are separated from other compounds in the mixture.
  • Liquid-liquid extraction, in which a compound is transferred from solvent A to solvent B. Both solvents are liquids that form layers when added together, like oil and water.
  • Accelerated solvent extraction, a patented technique that uses common solvents at elevated temperatures and pressures to extract solid and semisolid sample matrices, is also sometimes employed. This method reduces extraction time from hours to minutes.
  • Supercritical fluid extraction – chemical compounds are extracted using supercritical carbon dioxide instead of an organic solvent.
  • Capillary electrophoresis – in which an applied voltage separates ions according to their electrophoretic mobility – determined by the molecule’s charge and viscosity, and the atom’s radius.
  • Numerous types of chromatographic methods have also been shown to be effective. In column chromatography, the mixture to be analyzed is placed inside a column containing stationary phase (usually silica gel/alumina or its derivatized form). The liquid is passed through the column by either gravity (known as gravity column chromatography) or by positive air pressure (known as flash chromatography), with molecules moving at different rates. The eluent (solvent) is collected in fractions and analyzed to gauge the success of the separation. The method used to analyze the fractions is generally thin-layer chromatography, where a sheet of glass, metal, or plastic is coated with a thin layer of adsorbent material, such as silica or alumina.
  • Gas chromatography – volatile components of a mixture are separated by drawing a small amount of the sample into a syringe. After being injected into a gas chromatograph, the gaseous components are pushed onto the column and separated.
  • High/ultra performance liquid chromatography – a reservoir holds the solvent. And in high-performance thin-layer chromatography, the capillary action of a solvent and stationary phase is used to separate compounds in a mixture.

At Neuland, we use a number of methods – including combinations of methods – to isolate contaminants. Which method(s) to use generally comes down to the characteristics of both the API and the contaminants present.

Characterization Methods

To control contaminants, it is critical to understand them. Isolated impurities are subject to a number of potential techniques designed to identify what they are – the first step towards developing methods to control their formation.

Several methods can be used to characterize compounds. In mass spectrometry, a mass spectrometer converts molecules to ions so they can be moved by external electric and magnetic fields. In nuclear magnetic resonance (NMR) spectroscopy, electron distribution leads to a chemical shift in the resonance frequency, making it possible to elucidate structure. Raman spectroscopy measures the wavelength and intensity of inelastic light scattered from molecules.

In liquid chromatography-mass spectrometry (LC-MS), an HPLC system separates chemicals on a column, and a mass detector scans the molecules and separates ions by mass. And in LC-MS-NMR, methods are linked, and peaks of interest are identified by NMR and MS.

Validating Impurity Methods
An impurity profile must be validated in order to ensure the integrity, accuracy and repeatability of the methods chosen. In order to validate impurity methods, the following protocol is used:

  • Specificity
  • Linearity/range
  • Accuracy
  • Repeatability/intermediate precision
  • Detection limit/quantitation limit
  • Robustness

While building an impurity profile is a complex process, knowing how to properly build such a profile is essential as drug safety continues to come under increasing scrutiny from both the media and consumers.

How much emphasis does your organization place on impurity profile design?

 

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