Impurity Analysis

Impurity Identification and Characterization

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Impurity Identification and Characterization

Characterization, quantitation, and control of impurities are key activities for any pharmaceutical discovery and development program. At Emery Pharma, we are experts in analyzing impurities, metabolites, and active pharmaceutical ingredients (APIs) at low levels in drug substances and products across various drug modalities (small molecules, peptides, biologics, etc.).

Our services range from residual solvent analysis, process-related impurities, extractables/leachables, and forced degradation/stability studies, to assessing and managing the risk of nitrosamine formation in your drug product.

Our team will serve as your partner to deliver customized method development and validation in accordance with FDA, ICH, EMA, and other global regulatory bodies.

There are three types of impurities

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Organic impurities

Organic impurities typically arise during drug manufacturing or storage

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Inorganic impurities

Inorganic impurities typically arise during drug manufacturing and include things like reagents, catalysts, heavy metals, or inorganic salts

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Residual solvents

Residual solvents are typically introduced during the preparation of the drug substance

Impurities Testing for Pharmaceutical APIs and Drug Products

Emery Pharma offers comprehensive support in identifying and characterizing impurities in drug substances and drug products. We can perform stability testing, followed by method development, and method validation for quantitation of the impurity. We have extensive experience analyzing various formulations such as oral, topical, IV, rectal products, etc.

Since 2018, several impurities have been highlighted by the FDA as an area of concern. These include:

Nitrosamine Impurities

Benzene Contamination

Our Solutions

Liquid Chromatography-Mass Spectrometry (LCMS)

LC-MS is a powerful analytical chemistry tool used in the pharmaceutical, biotechnological, and environmental industries.  This equipment combines the separation capabilities of high-pressure liquid chromatography (HPLC) and the mass analysis capabilities of mass spectrometry to provide very sensitive and specific detection of a wide range of molecules.

High/ultrahigh-performance liquid chromatography (HPLC/UPLC) and LC-MS

HPLC/UPLC assays are the usually the analysis of choice for evaluating impurity profiles, as well as quantitating impurities for most active pharmaceutical ingredients (APIs) and drug products, irrespective of the modality.

Nuclear Magnetic Resonance (1D, 2D, qNMR)

Unknown impurities are inherently challenging to characterize. Nuclear Magnetic Resonance (NMR) spectroscopy is perhaps the most powerful tool in a Chemist’s arsenal for structural elucidation of unknown organic impurities. 

High-Resolution Mass Spectrometry

High-resolution mass spectrometry offers an orthogonal perspective to structure elucidation data (as compared to NMR) related to unknown impurity characterization. HRMS provides accurate mass data that are highly resolved, allowing for computation of the molecular composition for an unknown entity.

Preparative HPLC Isolation of Impurities

For successful structural elucidation of unknown impurities, preparative HPLC-based isolation of the target impurity must be accomplished prior to NMR analysis. Prep-LC and flash chromatography is used to isolate desired compounds or impurities for subsequent evaluation and/or structural determination. 

Residual Solvents by Gas Chromatography (GC-MS/GC-FID)

Gas Chromatography (GC)-based assays, usually in tandem with a headspace autosampler (HS-GC) is exclusively used to evaluate residual solvent burden of an API or drug product. Most commonly GC with flame ionization detection (GC-FID) are used, however, in certain scenarios, mass spectrometry (GC-MS) may also be used.

Stability Studies

Studies that evaluate the stability of the drug substance and product are critical for any new drug development program.  At Emery Pharma we employ a range of stability/environmental chambers to evaluate the stability of drug substances and products, under conditions prescribed in ICH Q1A (R2), as well as custom conditions for temperature, humidity, pH (acidic/basic), photosensitivity, oxidative stress, etc. 

Excipient Analysis

Once their formation is established, de novo synthesis of an impurity or degradate is required to confirm the structure and qualify the impurity/degradant. Qualification of impurities, degradants, and metabolites, as well as biological safety, are critical for a drug development program and its eventual approval. Recent guidance (Ref. 2) sets out to assure the absence of NDSRIs in all new NDA approvals. We can provide a small quantity of your NDSRI with a known retention time in a specific LC-MS method early in the development process.

Benzene Contamination

Quantitation of benzene can be done using Headspace Gas Chromatography with Mass Spectrometry (HS-GC/MS). Benzene is a known human carcinogen. The FDA has drawn recent attention to Benzene contamination in consumer products such as sunscreens, hand sanitizers, and deodorants.

Nitrosamine Risk in Drug Products (NDSRIs)

Given the ubiquitous presence of nitrite ion in common pharmaceutical excipients (Ref. 1), the nitrosation of a drug's secondary amine (or a secondary amine impurity, both called NDSRI's) and tert. amine during drug product manufacture and storage is now a regulatory concern (Ref. 2). Emery Pharma's experts can help assess the risk associated with nitrosamine formation during the chemical process, API formation, and excipients used. They can also provide a small quantity of the NDSRI of concern for spiking/confirmatory testing in clients' drug products. The risk of significant secondary amine degradates (of a tertiary amine or tertiary amide API) can be determined.

Synthesis of Impurities, Degradants, and NDSRI’s

Once their formation is established, de novo synthesis of an impurity or degradant is required to confirm the structure and qualify the impurity/degradant. Qualification of impurities, degradants, and metabolites, as well as biological safety, are critical for a drug development program and its eventual approval. Recent guidance (Ref. 2) sets out to assure the absence of NDSRIs in all new NDA approvals. We can provide a small quantity of your NDSRI with a known retention time in a specific LC-MS method early in the development process.

Why regulatory agencies are concerned about impurities?

The two major concerns surrounding drug impurities are:

  1. That they may cause a drug substance to degrade (thereby reducing its efficacy or safety)
  2. The impurities (or their effects on the drug substance) may be harmful to patients. This was seen in the cases of NDMA and Benzene contamination in consumer products.

FDA Guidelines

The FDA requires that all starting materials and final drug products be evaluated for “identity, strength, quality, and purity.” The FDA has implemented the ICH Q3C guideline which outlines guidelines for residual solvents.