Drug Testing

GMP pharmaceutical impurity testing, analysis, and identification to meet the ICH Q3A and Q3B guidelines criteria and services for drug process impurities, residual solvents, genotoxic impurities, elemental impurities, contaminants, extractables or leachables.

Pharmaceutical impurities can originate from a variety of sources, such as leachables, degradation products, reagents, catalysts, solvents, intermediates, and excipients, together with associated contaminants. These could be elemental, inorganic, or process- or drug-related organic contaminants.

Key examples at the moment are impurities related to nitrosamines, such as NDMA, which the US FDA has identified as a concern and which is assumed to be a byproduct of the production process.

In addition to offering analysis expertise for resolving extractables and leachables, elemental impurities testing, residual solvents (OVI or VOC) analysis, or process-related impurities, our scientists are skilled at method development and validation of appropriate analytical procedures. They routinely overcome the challenges of low detection levels and difficult matrices. Furthermore, we provide extremely sensitive and specialized method development and validation experience to handle genotoxic impurity control and determination, including nitrosamines.

Guideline for Elemental Impurities:

The guideline for elemental impurities in pharmaceuticals is provided by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH).

ICH Q3D provides recommendations on the control of elemental impurities in drug products to ensure their safety and quality. Elemental impurities can arise from various sources, such as raw materials, excipients, manufacturing processes, and packaging components.

The specific guideline is known as ICH Q3D, titled “Guideline for Elemental Impurities,” and provides an international standard for testing metals in the member regions of Europe, the USA, and Japan.

These guidelines for the determination of heavy metals have been integrated into the American Pharmacopeia (USP/NF) in chapters <232> and <233>. For the European Pharmacopeia (Ph.Eur.), these guidelines appear in chapters 5.20 “Elemental impurities” and 2.4.20 “Determination of elemental impurities.”

The previously used visual test from the corresponding pharmacopeias (e.g. USP <231>, Ph.Eur. 2.4.8) has thus been replaced by modern methods using instruments such as the ICP-MS and/or ICP-OES.

Concerns about nitrosamine contaminants, including N-Nitrosodimethylamine (NDMA), have been raised by the US FDA and other regulatory bodies. To ensure patient safety and regulatory compliance, it is imperative that pharmaceutical products undergo sensitive and accurate testing to identify and measure harmful contaminants. For the purpose of detecting traces of nitrosamines, taking the necessary action to lessen their presence, and preserving the integrity of pharmaceutical products, the accuracy of such testing is essential.

The discovery of the genotoxic contaminant N-Nitrosodimethylamine (NDMA) at low levels in a few medications caused the pharmaceutical industry great alarm. The EU reviews have identified a number of root causes leading to the presence of nitrosamines in medicines, all of which have in common a reaction of a secondary or tertiary amine with a nitrosating agent that leads to the formation of an N-nitrosamine. Frequently, the nitrosating agent was found to be sodium nitrite, often under acidic conditions during manufacture of the active pharmaceutical ingredient (API).

Although nitrosamine impurities have been discovered in only a few drug products, and batches of those products have been recalled due to unacceptable levels of these impurities, nitrosamine impurities may exist in other APIs and drug products as a result of the use of certain processes and materials that can produce nitrosamines.

Potential nitrosamine impurities have also been identified in terms of N-nitroso-dimethylamine (NDMA), N-nitroso-diethyl amine (NDEA), N-nitroso-N-methyl-4-aminobutanoic acid (NMBA), N-nitroso-iso-propyl ethyl amine (NIPEA), N-nitroso-di-isopropyl amine (NDIPA), N-nitroso-dibutyl amine (NDBA), N-ethyl-N-nitroso-2-propanamine (NEIPA), N-nitroso-di-n-propylamine (NDPA) N-nitroso-methyl-phenylamine (NMPA).

The FDA has been working closely with industry to ensure products entering the market do not contain these impurities in the future, while establishing suitable analytical methods to determine acceptable levels of these nitrosamine impurities and establish interim limits. In September 2019, the EMA began a review under Article 5(3) of Regulation (EC) No. 726/2004 to provide guidance to marketing authorization holders on how to avoid the presence of nitrosamine impurities in human medicines.

Our professionals have extensive experience offering analytical services in compliance with FDA GC-MS, GC-MS/MS, LC-MS/MS, and LC-HRMS methods. This includes carrying out the necessary method validations where the data is suitable for supporting regulatory submissions or API or drug product quality assessments.

Extractables and Leachables testing is a method used in a variety of sectors, most notably pharmaceuticals and packaging, to verify product safety and quality. Here’s the breakdown:

Extractables: Chemical substances that can be extracted from a material in a lab setting are known as extractables. The possibility for contaminants, additives, or degradation products to transfer from the material into the product it comes into contact with, can be found in them. In extractables testing, several extraction solvents and conditions are applied to the material in order to mimic real-world use and determine which components can potentially seep out.

Leachables: Materials that, under typical usage circumstances, migrate into the product or formulation they are brought into contact with. Leachables, in contrast to extractables, are assessed in real-world settings with respect to temperature, time, and pH. They may originate from plasticizers, dyes, metal catalysts, polymers and degradation products, among other substances. In the case of biopharmaceuticals in particular, these could accelerate the drug’s degradation while also potentially posing a toxicological concern. Leachable testing seeks to locate and measure any materials that might be dangerous for the product’s quality or safety for consumers.

Testing for extractables and leachables is essential for identifying and quantifying potentially hazardous leachable impurities that could leak out of pharmaceutical container closure systems and contaminate a drug, endanger patient safety, or result in serious quality problems.

Regulatory expectations for Extractables and Leachables Analysis:

Regulatory expectations vary depending on the industry and the specific product being evaluated. However, there are some common principles and guidelines that are generally followed:

• ICH Guidelines: The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) has provided guidelines for pharmaceuticals, including ICH Q3D for elemental impurities and ICH Q7 for Good Manufacturing Practice (GMP).
• FDA Guidance: The U.S. Food and Drug Administration (FDA) provides guidance documents for pharmaceuticals, medical devices, and other regulated products. For example, FDA Guidance for Industry on Bioanalytical Method Validation outlines expectations for validation of analytical methods used to assess the identity, strength, quality, purity, and potency of biological drug products.
• USP General Chapters: The United States Pharmacopeia (USP) publishes general chapters that provide standards for the pharmaceutical industry. USP <1663> and USP <1664> are specifically related to extractables and leachables testing.
• EU Directives: In the European Union, directives such as EU Directive 2009/48/EC on the safety of toys and EU Directive 2011/65/EU on the restriction of the use of certain hazardous substances in electrical and electronic equipment may apply to extractables and leachables analysis.
• ISO Standards: International Organization for Standardization (ISO) standards such as ISO 10993 for biological evaluation of medical devices and ISO 18562 for biocompatibility evaluation of breathing gas pathways in healthcare applications may also provide guidance.
• Industry Best Practices: Many industries have developed their own best practices and guidelines for extractable and leachable analysis. For example, the Parenteral Drug Association (PDA) publishes technical reports and guides related to pharmaceutical manufacturing and quality assurance.

Overall, compliance with relevant regulations and guidelines is essential to ensure the safety and efficacy of products and to meet regulatory requirements for market approval.

Eureka offers extractables and leachables testing services through our GMP-compliant laboratory located in Delhi/NCR with research support facilities as part of our commitment to total quality assurance. Different analytical techniques are employed in extractables and leachables analysis to identify and quantify substances that may leach into the product itself from packaging materials, medical devices, or other products. Among the often-used methods are nuclear magnetic resonance (NMR) spectroscopy, Fourier-transform infrared spectroscopy (FTIR), inductively coupled plasma mass spectrometry (ICP-MS), gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS).

Microbiology testing is critical to ensuring sterility of your product and to determine antimicrobial effectiveness, as well as identifying microorganisms and potential contamination.

Accurate analysis of contaminants and impurities in biotechnology products is necessary during product characterization in order to help you comply with ICH Q6B recommendations. Our range of services and methods includes the characterization of contaminants and impurities in products obtained from biotechnology.

Our solutions include:

• Sterility Testing: Pharmaceutical laboratories conduct sterility testing to ensure that products are free from viable microorganisms. This is particularly crucial for sterile products such as injectables, ophthalmic solutions and parenteral drugs. Sterility testing involves incubating the product in culture media for a specified period under appropriate conditions and examining for microbial growth.
• Microbial Limits Testing: Microbial Limits Testing determines the total viable aerobic microbial count present in pharmaceutical products. It ensures that products meet specified microbial limits and are free from excessive microbial contamination. This testing helps assess the cleanliness of manufacturing processes and the efficacy of preservation systems.
• Endotoxin Testing: Endotoxin testing is performed to detect and quantify endotoxins, which are components of the cell wall of Gram-negative bacteria. Endotoxins can cause fever, shock, and other adverse reactions in humans. Often, we use Limulus Amebocyte Lysate (LAL) assays to detect endotoxin contamination in products.
• Bioburden Testing: Bioburden testing measures the total number of viable microorganisms present on a product before sterilization. It helps assess the effectiveness of sterilization processes and is performed on raw materials, components, and in-process products.
• Environmental Monitoring: Pharmaceutical laboratories conduct environmental monitoring to detect and control microbial contamination in manufacturing facilities. Environmental monitoring helps identify potential sources of contamination and implement corrective actions.
• Microbial Identification: In cases where microbial contamination is detected, microbial identification techniques are used to identify the specific microorganisms present. Polymerase chain reaction (PCR) and sequencing are common methods used for microbial identification.
• Method Validation: It is essential to validate microbial testing methods to ensure their accuracy, precision, specificity, and robustness. Method validation involves testing the method’s performance characteristics using appropriate controls and acceptance criteria.
• Compliance with Regulatory Standards: Pharmaceutical laboratories must comply with regulatory standards such as those provided by the United States Pharmacopeia (USP), European Pharmacopeia (Ph. Eur.), and other regulatory agencies such as the FDA and EMA. Compliance ensures that microbial testing is conducted according to established guidelines and requirements.

A primary area of interest for us is doing pharmacopoeia-compliant testing on pharmaceuticals and medical devices. In addition, we provide testing services for all raw materials needed for production, including excipients, active substances and packaging components.

We provide an efficient, dependable and timely service. With our state-of-the-art instruments and years of expertise conducting analytical analyses, we can deliver complex and effective solutions at any time. These begin with the test sample’s preparation and analysis and ends with completion of requisite documentation.

Analysis includes:

• Active Ingredients and Excipients (Analytics in accordance with the methods of the relevant pharmacopoeia (Ph.Eur., USP, BP, JP, CP))
• Finished Products in the Field of Human and Veterinary Pharmaceuticals and Medical Devices (Testing according to Pharmacopoeia or Customer Method)
• Packaging Materials
• Implementation of Analytical Methods, including Transfer, Monitoring, and Reporting
• Semi-Finished Goods
• Small Scale Batches and Batches from Development (from Phase 1 to Market)

Our global analytical GXP laboratory network supports drug development by providing regulatory-driven and phase-appropriate methodology through pharmaceutical analytical method development and validation laboratory services.

Development and Validation of New Analytical Methods for:

• API’s and Raw Materials used for Pharmaceuticals
• Chemically Defined Substances
• Medical Devices

Development and Validation of Impurity Testing

• Degradation Products in Finished Formulations
• By-Products Resulting from Synthesis of Active Substances made for Pharmaceutics
• Trace Components and Detergents
• Forced degradation studies

Our highly qualified method development scientists have years of expertise working with a wide range of goods, technologies, and methods to ensure the method is “perfect for purpose” for APIs, raw ingredients, excipients, medicinal products, or packaging. We are skilled in working with a wide range of substances and formulations, such as liquids, solids, patches, gels, ointments, biologics, nanoparticles and inhaled goods.

Eureka Lab is equipped with advanced analytical technologies such as chromatography, mass spectrometry, elemental analysis and spectroscopy. Our team possesses expertise in sample preparation methods, encompassing steps for tracking analysis levels and strategies appropriate for the matrix’s physical and chemical characteristics as well as the dose form.