Impurity Profiling and Characterization for Generic Project Submission to USFDA

Impurity profiling is the process of identifying, quantifying, and characterizing unwanted chemicals—known as impurities—in a pharmaceutical product. These can arise from the drug synthesis process, raw materials, degradation over time, or storage conditions. For generic drug projects, impurity profiling is essential because the U.S. FDA mandates that generic drugs must match the quality, safety, and efficacy of the reference listed drug (RLD). Proper impurity profiling ensures that the generic formulation does not introduce harmful substances, meets regulatory limits, and qualifies for market approval. Without comprehensive impurity data, USFDA approval is likely to be delayed or denied.

Impurities in pharmaceutical products fall into several main categories:
Organic Impurities: These are related to the drug synthesis process, such as unreacted starting materials, intermediates, or degradation products.
Inorganic Impurities: These include reagents, catalysts, and metal residues.
Residual Solvents: Organic solvents that remain from the manufacturing process.
Degradation Products: Compounds that result from the breakdown of the active pharmaceutical ingredient (API) during storage or formulation.
All these types must be detected, quantified, and evaluated for safety, especially if they exceed regulatory thresholds set by the ICH Q3A/B guidelines and USFDA standards.

The USFDA follows ICH (International Council for Harmonisation) guidelines for impurity profiling. For generic drugs, the most relevant are ICH Q3A(R2) for drug substances and ICH Q3B(R2) for drug products. These outline three key thresholds:
Reporting Threshold: Impurities must be reported if they exceed a certain percentage (e.g., 0.1% for APIs).
Identification Threshold: If an impurity exceeds this level, it must be structurally identified.
Qualification Threshold: Impurities above this level must be assessed for safety using toxicological data.
Resolving these thresholds ensures that a generic drug meets all regulatory expectations and avoids issues during FDA review.

At ResolveMass Laboratories, we follow a systematic, science-driven approach to impurity profiling:
Method Development & Validation: We tailor analytical methods specific to your API or formulation.
Routine Testing: We conduct batch testing to detect and monitor impurity levels over time.
Advanced Instrumentation: Our lab is equipped with LC-MS/MS, GC-MS, NMR, FTIR, and HPLC for high-precision analysis.
Structural Elucidation: Unknown impurities are isolated and structurally identified using state-of-the-art spectroscopy.
Regulatory Support: We provide full documentation, including ICH-compliant validation protocols and impurity reports for FDA submissions.
Our experience with numerous generic filings positions us as a reliable CRO partner for impurity characterization projects.

We utilize a variety of highly sensitive and specific techniques, including:
High-Performance Liquid Chromatography (HPLC): For separating and quantifying organic impurities.
Gas Chromatography (GC): Especially for residual solvents.
Mass Spectrometry (LC-MS/MS and GC-MS): For molecular weight determination and impurity identification.
Nuclear Magnetic Resonance (NMR): For structural analysis of unknown impurities.
Fourier-Transform Infrared Spectroscopy (FTIR): For functional group identification.
By combining these techniques—often called hyphenated techniques—we provide a holistic impurity profile with high accuracy and compliance.

While impurity profiling focuses on identifying and quantifying impurities at any given point, stability testing monitors the formation of new impurities over time under different storage conditions (e.g., temperature, humidity). Stability testing helps ensure that the drug:
Remains safe and effective until its expiration date
Meets the regulatory requirement for shelf-life
Avoids formation of harmful degradation products
At ResolveMass, we integrate both impurity profiling and long-term stability studies to deliver a comprehensive picture of a product’s quality lifecycle.

Yes. Even trace-level impurities can impact drug approval if they exceed the reporting, identification, or qualification thresholds. Moreover, genotoxic impurities, even in very small amounts, can pose serious safety risks and require detailed toxicological evaluation. The FDA demands scientific justification and safety data for any impurity exceeding these limits. At ResolveMass Laboratories, we employ ultra-sensitive techniques capable of detecting impurities at parts per billion (ppb) levels to ensure full compliance and minimize regulatory risk.

While bioequivalence (BE) primarily compares the pharmacokinetics of a generic drug with its reference product, impurity profiling supports the chemical equivalence and safety of the formulation. A similar impurity profile helps establish that:
No new impurities are introduced in the generic formulation
The manufacturing process is well controlled
The drug meets the same safety standards as the innovator product
This is especially crucial for ANDA (Abbreviated New Drug Application) submissions where the goal is to match the reference listed drug (RLD) as closely as possible.

Timelines vary based on project complexity, but our standard turnaround includes:
Method Development and Validation: 2–3 weeks
Routine Impurity Profiling: 5–10 business days
Structural Elucidation of Unknowns: 2–4 weeks
Regulatory Documentation: Concurrent with testing or within 1 week post-analysis
ResolveMass offers expedited services for urgent filings and projects with tight regulatory deadlines. Our streamlined workflow and expert team ensure fast and accurate results.

Starting a project with us is simple:
Visit our Impurity Profiling Service Page
Fill out the contact form or directly reach out via Contact Page
Our technical team will arrange a consultation call to understand your formulation, timeline, and regulatory needs
You’ll receive a custom proposal, including pricing, scope, and project plan
Once approved, our scientists initiate your project with full confidentiality and quality assurance
With ResolveMass Laboratories, you’re partnering with a trusted name in pharmaceutical analytics backed by years of expertise in impurity profiling and regulatory support.