Impurity Identification and Characterization
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 the experts in analyzing impurities 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, forced degradation/stability studies, to assessing genotoxic impurity load in a product. Our team will serve as your partners to deliver customized method development and validation by the FDA, ICH, EMA, and other global regulatory bodies.
There are three types of impurities
Organic impurities typically arise during drug manufacturing or storage
Inorganic impurities typically arise during drug manufacturing and include things like reagents, catalysts, heavy metals, or inorganic salts
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:
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-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.
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.
Drug or pharmaceutical formulation development involves combining the drug’s active pharmaceutical ingredient (API) with other inactive components (excipients) to generate a final drug product. Formulation development and subsequent analytical testing are among the most critical aspects of a drug’s clinical development pipeline.
Synthesis of Impurities and Degradants
Once tentatively identified, de novo synthesis for an impurity is required to confirm the structural assignments made, as well as qualify the impurity. Qualification of impurities for safety and interference are key for a drug development program and its eventual approval.
Analytical methods using liquid chromatography tandem MS (LC-MS/MS) and gas chromatography electron impact (triple quadrupole, QqQ) were developed to detect both thermally stable and unstable nitrosamines. According to the ICH M7 Guideline, nitrosamines are classified as probable human carcinogens.
Why regulatory agencies are concerned about impurities?
The two major concerns surrounding drug impurities are:
- That they may cause a drug substance to degrade (thereby reducing its efficacy or safety)
- 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.
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.