Pharmaceutical Quality Control Services

Titration analysis of active ingredients, excipients and preservatives in raw materials and finished pharmaceutical products. Commonly employed techniques are liquid chromatography, gas chromatography -both coupled with various detectors-, titrations of various types, spectrophotometric analysis, gravimetric analysis and elemental analysis.

Analysis of impurities and degradation products that are chemically related to the drug substance. This includes identifying and quantifying process-related impurities, degradation products, and by-products that may form during manufacturing or storage. High-performance liquid chromatography (HPLC) is commonly used for this purpose, ensuring the safety and efficacy of the pharmaceutical product.

Elemental impurities are a potential hazard in drug products: it is necessary to monitor their presence and their limits must be contained under acceptable concentrations. Pharmacopeias set binding limits for metal residues in pharmaceutical products and developed methods for their control, too.

Detects and quantifies residual solvents used in the manufacturing process that could remain in the final product. Techniques like gas chromatography (GC) are commonly used. The analysis ensures that residual solvents are within acceptable limits set by regulatory guidelines (e.g., ICH Q3C).s

Identifies and quantifies impurities that could cause genetic mutations or cancer. Techniques such as liquid chromatography-mass spectrometry (LC-MS) are used due to the high sensitivity requested. Regulatory guidelines (e.g., ICH M7) set acceptable limits for these impurities to ensure the safety of pharmaceutical products.

Mérieux NutriSciences | Pharma and Healthcare has already developed and/or validated high sensitive methods suitable for more than 70 NDRSIs (Nitrosamine Drug Substance-Related Impurities) and small nitrosamines. Most of our methods have been checked to be robust relative to the in situ nitrosamine formation thanks to our in-house protocol for the Analytical Procedure Nitrosation Stability verification applied since 2022 to all analytical methods developed by our R&D lab for NDRSIs determination.

Measures the rate and extent to which the active pharmaceutical ingredient (API) dissolves in a specified solvent, simulating the process of drug release in the gastrointestinal tract. It’s crucial for understanding bioavailability and ensuring consistent therapeutic effects.

In vitro in-house validated model mimicking in vivo condition during GI digestion and intestinal absorption is available as well.p

Determines the time it takes for a tablet or capsule to break down into smaller fragments in a specified medium. This test ensures that the drug will dissolve properly in the body, making the active ingredient available for absorption.

Evaluates the size distribution of particles in a drug formulation. Particle size affects drug solubility, dissolution rate, bioavailability, and stability. Techniques used include sieve granulometry, laser diffraction, dynamic light scattering (DLS), and microscopy.

Utilizes various spectroscopic methods to identify and quantify the molecular composition of a substance. The techniques applied include UV-Vis spectroscopy, FT-infrared (FT-IR) spectroscopy and mass spectrometry (MS). These analyses provide information on molecular structure, purity, and concentration.

Examines the different crystalline forms (polymorphs) of a drug substance using X-ray diffraction. Polymorphism can impact the drug’s solubility, stability, and bioavailability. XRD helps in identifying and characterizing these polymorphic forms.

Measures the presence and concentration of particulate matter in drug formulations. Visible particles are detected using visual inspection or optical microscopy, while sub-visible particles (typically ranging from 2 to 100 micrometers) are counted using techniques such as light obscuration and flow imaging. This test ensures product safety and compliance with regulatory standards.

Specific test for detecting amino acids, peptides, and proteins, which react with ninhydrin to produce a colored compound. This test is often used in the analysis of drug substances that contain or might be contaminated with these compounds. It is particularly useful in the quality control of pharmaceuticals derived from biological sources.

Encompasses a broad range of tests to detect and quantify various unwanted hazardous substances that might be present in pharmaceutical products thanks to the multi-decade experience in residual analyses. Ensuring these residues are within acceptable limits is critical for product safety and regulatory compliance.

The Total Aerobic Microbial Count (TAMC) measures the overall number of aerobic bacteria in a sample, providing an indication of the microbial load and helping to ensure the product meets safety standards. The Total Yeast and Mold Count (TYMC) measures the total yeast and mold content in a sample to ensure the product is free from fungal contamination, which could affect stability and safety. Microbial load counts (TAMC and TYMC) are also conducted on surfaces and environments through environmental sampling. In addition to these, other methods are used for the detection and determination of specific microorganisms.a

Assesses whether a pharmaceutical product is free from viable contaminating microorganisms. This test is critical for products intended for sterile applications, such as injectable. The procedure involves incubating the product in specific media under controlled conditions to detect microbial growth.

Bioburden test determines and quantifies the total microbial count present in a product and/or in a sterile barrier system. This type of test is applied to:

• Validate and requalify sterilization processes
• Monitor production processes
• Control raw materials, components, or packaging
• Evaluate the effectiveness of cleaning processes

Evaluates the preservative systems’ effectiveness in pharmaceutical products. This involves inoculating the sample with a known concentration of standardized microbial strains (bacteria, yeasts, and molds) and subsequently assessing the change in microbial count for each microorganism at defined time intervals. This test confirms product stability by verifying microbial load reduction within a specified timeframe, following the acceptability criteria defined by compendial methods.

Quantifies the potency of antibiotic substances using microbial growth inhibition techniques. This involves comparing the growth of a test micro-organism in the presence of the antibiotic with a standard reference, ensuring the efficacy of the antibiotic.

The Limulus Amebocyte Lysate (LAL) test for bacterial endotoxins (BET) detects or quantifies endotoxins from Gram-negative bacteria in injectable pharmaceuticals, water, biological products, and medical devices. This test is essential to ensure pyrogen-free products, thereby avoiding febrile reactions in patients using injectable or implantable products. Three techniques are applied:

• Gel-clot limit test: detects endotoxins via clot formation
• Kinetic Turbidimetric method: quantifies endotoxins based on turbidity formation
• Kinetic Chromogenic method: quantifies endotoxins based on color formation

This test is an alternative to animal-based methods and allows the detection of both endotoxic and non-endotoxic pyrogens. By incubating monocytes with the test sample, it mimics the human immune reaction by testing for the possible release of pro-inflammatory cytokines in response to pyrogens. If pyrogens are present, monocytes are activated and produce inflammatory molecules, cytokines, responsible for the febrile reaction.

Microorganisms are identified through MALDI-TOF (Matrix-Assisted Laser Desorption Ionization-Time of Flight), a fast and accurate technique for identifying bacteria, yeasts, and molds. The MALDI-TOF technique is preferred for its speed, accuracy, and capability to identify a wide range of microorganisms from clinical and environmental samples. Mérieux NutriSciences | Pharma & HealthCare uses two MALDI-TOF systems:

• Bruker Daltonics-Biotyper Software
• Vitek-MS (Biomerieux)-Saramis Software

When MALDI-TOF identification is inconclusive, alternative molecular methods are applied:

• 16S DNA sequencing for bacteria: targets the highly conserved 16S rRNA gene with hypervariable regions specific to bacterial species.
• D2LSU sequencing for yeasts and molds: targets the D2 domain of the rRNA large subunit gene, useful for differentiating yeast and mold species.

These molecular methods, 16S rDNA for bacteria and D2LSU for fungi, provide high-resolution identification and are especially useful when traditional methods (including MALDI-TOF) are insufficient or when dealing with new or poorly characterized microorganisms.

The detection and counting of particles are crucial to ensure the quality of liquid pharmaceutical products, whether injectable, non-injectable, ophthalmic, or for medical devices. Subvisible particles are counted and measured using techniques such as Light Obscuration (LO) and Membrane Microscopy (MM), while visible particles are detected with the naked eye using a light station with specific brightness requirements.

Optical microscopy testing is performed to demonstrate the purity of specific matrices, active ingredients, or excipients that may be part of a pharmaceutical product. The tests conducted include:

• Crystallinity: verifies the correct crystalline conformity of a material
• Starch identification: checks the purity and proper conformity of a specific starch type, whether from potato, wheat, or other sources
• Particle counting and measurement: quantifies and measures particles present in a product, primarily antibiotics

The integrity of pharmaceutical packaging is critical to ensure product quality. The hermetic seal of rubber closures for containers of aqueous parenteral preparations, powders, and lyophilized powders is tested by applying vacuum stress.

Evaluates the antimicrobial activity of water-miscible antiseptic medicinal products intended for direct contact with skin or mucous membranes. The procedure involves adding standardized microbial suspensions to the antiseptic product and determining its ability to reduce the microbial load. The method is validated to verify its capacity to detect the required reduction in viable microorganism count using appropriate experimental controls. The antimicrobial activity of the product is expressed as the logarithmic difference between the viable microorganism count in the controls and that observed in the test.

Assesses the bactericidal, fungicidal, yeasticidal, and sporicidal activity of a disinfectant on surfaces inoculated with microbial suspensions. This method is applied to products intended for the chemical disinfection of surfaces in clean rooms and other manufacturing areas in the pharmaceutical industry. The method is conducted under defined test conditions that can reflect practical usage parameters, including conditions that may influence the product’s effectiveness. The procedure is validated to verify its ability to demonstrate the required reduction in viable microorganism count using appropriate experimental controls. The microbial load reduction attributed to the product’s action is calculated as the logarithmic difference between the viable microorganism count in the experimental control conditions and the test