Applications

Norms and Standards 21 CFR Part 11 is the FDA rule relating to the use of electronic records and electronic signatures.Recognizing the increasing impact of electronic media on critical data in regulated environments, the FDA met with members of the pharmaceutical industry in the early 1990s. The pharmaceutical industry and the FDA were interested in how they could accommodate paperless record systems and ensure the reliability, trustworthiness, and integrity of electronic records.

Chemometrics is a powerful tool widely used for method development in the pharmaceutical industry. This whitepaper describes the lifecycle of multivariate models and summarizes the workflow of the development of chemometrical models according to the new USP chapter <1039>.

This white paper summarizes the steps involved in converting an existing manual titration procedure to semi-automated or automated titration procedures. It discusses topics such as selecting the right electrode and titration mode. For a better understanding, the discussion topics are illustrated with three examples.

The objective of validation of an analytical procedure is to demonstrate that it is suitable for its intended purpose. Recommendations for the validation of analytical methods can be found in ICH Guidance Q2(R1) Validation of Analytical Procedures: Text and Methodology and in USP General Chapter <1225> Validation of Compendial Procedures. The goal of this white paper is to provide some recommendations for the validation of titration methods.

A high throughput automated system was developed to determine pH of culture media using a pH module equipped with an external flow cell. A custom septum-piercing, vented needle was developed to accommodate the shape and size of the customer sample vials. For this application, both accurate and precise pH measurements were required. The data presented in this document was collected by a customer as a part of their validation process and was provided for use with their consent.

Raman spectroscopy is an advantageous analytical tool that allows for the measurement of molecular structure and identifying chemical composition of materials based on the rotational and vibrational modes of a molecule. With advanced technology and an optimized optical design, the B&W Tek BAC102 series E-grade probe can access lower frequency modes down to 65 cm-1, providing key information for applications in protein characterization, polymorph detection, and identification, along with material phase and structure determination.

Handheld Raman is used for raw material testing of different sample types and forms. The use of optimized sampling accessories enhances the utility of handheld Raman without compromising data quality or complicating testing.

The raw materials whey, sorbitol, stearic acid, and calcium phosphate dihydrate dibasic all show very distinctive, unique Raman signatures, which indicates that Raman spectroscopy is the ideal technology for identification of these materials. The PCA model-based method provides reliable specificity to successfully identify these nondestructively in plastc samples bags using the NanoRam.

The NanoRam handheld Raman, with a TE-cooled spectrometer, and patented CleanLaze technology packaged in a small, touch-screen operating unit, delivers high quality raw material testing capabilities for pharmaceutical manufacturers.

The combination of Raman spectroscopy and vapor sorption techniques provides a comprehensive understanding of vapor-solid interactions of pharmaceutical materials as it relates to the structural properties.This paper investigates the in-situ monitoring of a moisture-induced polymorphic transformation (D-mannitol from delta to beta form) using a combined Raman-vapor sorption technique.

Botanicals are derived from plant materials and used for their medicinal and therapeutic properties in the nutraceuticals market. They are not as heavily regulated by the U.S. Food and Drug Administration (FDA) like the pharmaceuticals drug market, but they are required to follow Good Manufacturing Practice (GMP Requirements).The NanoRam®-1064 is an asset for pharmaceutical identity testing, minimizing fluorescence generated by typical handheld Raman systems with 785 nm lasers. As such, the NanoRam®-1064 is used here to identify botanicals that would normally fluoresce with a 785 nm laser.

Raman spectroscopy’s use for process analytics in the pharmaceutical and chemical industries continues to grow due to its nondestructive measurements, fast analysis times, and ability to do both qualitative and quantitative analysis. Spectral preprocessing algorithms are routinely applied to quantitative spectroscopic data in order to enhance spectral features while minimizing variability unrelated to the analyte in question. In this technical note we discuss the main preprocessing options pertinent to Raman spectroscopy with real applications examples, and to review the algorithms available in B&W Tek and Metrohm software so that the reader becomes comfortable applying them to build Raman quantitative models.

Ezetimibe is a cholesterol-reducing drug. It reduces the cholesterol resorption in the small intestine. The molecule holds two fluorophenyl groups. Applying Combustion IC the amount of fluorine in the drug is determined. To avoid an excessive introduction of fluoride into the system, Ezetimibe is dissolved in ethanol prior to the combustion.

The quantification of residual moisture in lyophilized pharmaceutical peptides is an important measure for quality control in the pharmaceutical industry. For development purposes, such measurements are necessary and routinely performed during stability studies and to optimize the freeze-drying process (lyophilization). Currently, Karl Fischer titration is widely used for moisture determination in routine analysis. However, this method is time consuming and destroys the sample during analysis. This Application Note shows that near-infrared spectroscopy (NIRS) is a fast, reagentless, non-destructive method to determine moisture content in lyophilized pharmaceutical products.

Material verification models with complex algorithms such as Principal Component Analysis (PCA), quasi-infinite parameters, and preprocessing options can be incredibly complex. Each model must be rigorously built, evaluated, and validated before it can be put into routine use. Mira P simplifies material verification for all. With a short, defined user workflow, straightforward results, and a foolproof Operating Procedure-based design, Mira P is already one of the simplest RMID tools available. ModelExpert, in Mira Cal P, does a chemometrician’s work. ModelExpert automatically determines the best model parameters for robust method development. With Mira P and ModelExpert, even non-technical users can achieve better results in a fraction of the time.

This application shows how to seamlessly transition from Metrohm’s NanoRam 785 to the newer MIRA P system, ensuring continuity in raw material identification (RMID).

Potassium bitartrate for pharmaceutical use must comply with USP requirements. The actual monograph (USP 42) uses a colorimetric method for the determination of ammonium impurities. Ion chromatography allows the measurement in a single determination under the same conditions used for the potassium assay (see AN-C-181). In the course of the USP monograph modernization, this ion chromatographic approach makes this type of analysis even easier.

2-amino-N-(2,2,2-trifluoroethyl)-acetamide is a organic building block for synthesis of pharmaceutical products. Its purity is crucial for the success of the respective synthesis step. 2,2,2-trifluoroethylamine, glycine, and inorganic cations are of interest. Their total peak area is required to be < 2 % of the peak area of all peaks above the reporting level. Separation and quantification is achieved on a Metrosep C 4 - 250/4.0 cation column.

Karl Fischer titration can be used to determine the water content in N-acetyl-L-cysteine. Special solvent mixtures can be used to prevent unwanted side reactions in the Karl Fischer titration. The water content of N-acetyl-L-cysteine can thus be determined quickly and accurately, as is shown in this Application Note.

Determination of sulfate in gentamicin sulfate using anion chromatography with conductivity detection after chemical suppression.

Dental care products often contain sodium fluoride as an active ingredient. Manufacturers use the United States Pharmacopeia and National Formulary (USP-NF) Monograph «Sodium Fluoride» to quantify sodium fluoride and its anionic contaminants chloride and acetate in these products. The validated USP method proposes ion chromatography (IC) with suppressed conductivity detection to carry out the fluoride assay as well as the impurity determination in a single chromatogram.

Ion chromatography (IC) with suppressed conductivity detection has been approved by the U.S. Pharmacopeia (USP) as a validated method to quantify the monofluorophosphate (MFP) content in sodium monofluorophosphate. This Application Note shows that all acceptance criteria for the USP Monograph «Sodium Monofluorophosphate» are fulfilled and the procedure was approved as a validated USP method.

Accurate determination of Fe(II) and Fe(III) in water is crucial for many industries. Cathodic sweeping voltammetry (CSV) offers a robust, cost-effective solution.

This Application Note shows the automatic pH adjustment of a mixture of acetonitrile, water and amine using a Metrohm titrator.

This White Paper will walk you through the selection process of ion chromatography as the best analytical tool in the product development of a cell-based gene therapy.

The NanoRam is able to test material through multiple layers of transparent plastic bags. Postive identification of material on PE bags from 1 to 9 layers were obtained, demonstrating minimum interference from the PE bags on the material identification result.

A new Raman system design is presented that expands the applicability of Raman to See Through diffusely scattering media such as opaque packaging materials, as well as to measure the Raman spectrum and identify thermolabile, photolabile, or heterogeneous samples.

The RVM method requires only a few spectra to make a model and can be quickly developed on the NanoRam-1064. Multivariate analysis of the Raman spectra on handheld Raman instruments provides more robust methodologies for identifying samples.

Although the process of building, validating and using a method is well-defined through software, the robustness of the method is dependent on proper practice of sampling, validation, and method maintenance. In this document, we will detail the recommended practices for using the multivariate method with NanoRam-1064. These practices are recommended for end users who are in the pharmaceutical environment, and can expand to other industries as well. This document aims to serve as a general reference for NanoRam-1064 users who would like to build an SOP for method development, validation and implementation.

This Application Note shows how, with the help of Vis-NIR spectroscopy and a special plant library, 46 different medicinal and aromatic plants, e.g., Organicum majoricum and Tilia cordata, can be conveniently identified on the basis of their spectrum. In comparison with alternative methods for the determination of plants, which are elaborate and require experienced scientists for their performance, the Vis-NIR method permits rapid and uncomplicated identification.

Eltrombopag is a pharmaceutical agent used in certain conditions of thrombocytopenia. As such it is an orphan drug. The molecule of Eltrombopag is a protonated aromatic carboxyl compound. Under ion chromatography condition (alkaline eluent), it can be deprotonated and can thus block ion exchanger sites on the column. This results in decreasing retention times over time. To avoid this, Inline Matrix Elimination is applied, where the protonated Eltrombopag is washed off the preconcentration column before injection. Nitrite is then analyzed with conductivity detection after sequential suppression.

In severe cases of cyanide poisoning, sodium nitrite is used along with sodium thiosulfate for treatment. This Application Note describes the nitrite ion chromatography assay with the Metrosep A Supp 4 column and suppressed conductivity detection. This column equivalency study was in cooperation with the USP according to the USP General Chapter <621>.

Raman spectroscopy is used for material characterization by analyzing molecular or crystal symmetrical vibrations and rotations that are excited by a laser, and exhibit vibrations specific to the molecular bonds and crystal arrangements in the molecules. Raman technology is a valuable tool in distinguishing different polymorphs. Examples of portable Raman spectroscopy for identification of polymorphs and in monitoring the polymorphic transiton of citric acid and its hydrated form are presented.

This Application Note shows the rapid, non-destructive identification of isopropyl alcohol from two manufacturers using Raman spectroscopy following the creation of a suitable library. The measurements with the hand-held Raman spectrometer Mira M-1 require no sample preparation and provide immediate results that identify the samples unambiguously.

Vitamin C, also known as ascorbic acid or L-ascorbic acid, is an essential nutrient involved in the repair of tissues and the enzymatic production of certain neurotransmitters. It is required for the functioning of several enzymes and immune performance, and is also an important antioxidant. This nutrient is found in many foods and is often used as a dietary supplement.USP general chapter <580> describes a titration technique to determine the assay of Vitamin C as ascorbic acid, sodium ascorbate, and calcium ascorbate dehydrate, or their mixture in finished dosage forms as capsules, tablets, and oral suspensions. This Application Note demonstrates the Vitamin C determination in water-soluble vitamin tablets. The methodology can also be applied for oil-soluble vitamin or mineral tablets, as well as oil- and water-soluble vitamin or mineral capsules.

The pharmaceutical industry is very likely more comprehensively regulated that any other branch of industry. It therefore requires analytic methods that meet the requirements of regulations while at the same time being practical. This applies in particular for large sample quantities, such as are encountered with incoming goods inspections, for example. It is here that particularly rapid and simple analysis methods are called for which make routine analyses simpler and more efficient. This White Paper describes some of the most important regulations in the pharmaceutical analysis and shows how Vis-NIR spectroscopy can solve analytic problems in the pharmaceutical industry in accordance with regulations.

Ion chromatography is a flexible technique with a large selection of intended uses in the pharmaceutical industry. – A few development trends and the latest advances are displayed here.

Ion measurement can be conducted in several different ways, e.g., ion chromatography (IC), inductively coupled plasma optical emission spectrometry (ICP-OES), or atom absorption spectroscopy (AAS). Each of these are well-established, widely used methods in analytical laboratories. However, the initial costs are relatively high. In contrast, ion measurement by the use of an ion-selective electrode (ISE) is a promising alternative to these costly techniques. This White Paper explains the challenges which may be encountered when applying standard addition or direct measurement, and how to overcome them in order for analysts to gain more confidence with this type of analysis.

This Metrohm White Paper shows the requirements demanded of the pharmaceutical industry by the FDA with respect to software products. Implementation examples of the regulations formulated by the FDA in 21 CFR Part 11 are presented using Vision Air Pharma Software.Key words: electronic signatures, audit trails, user management, documentation

Analytical Instrument Qualification (AIQ) according to the United States Pharmacopeia (USP) ensures that instruments perform as intended and users may have confidence in data quality. As the Pharma industry adopts handheld Raman instruments for incoming materials identification and verification, producers of such systems must provide suitable calibration and validation routines. Upon completion of these tests, end users are assured that all measurements are in accordance with agreed standards at Metrohm Raman, we have sophisticated AIQ routines in place to confirm the quality of your results.

This white paper differentiates between methods for identification of unknowns and verification of known materials. The goal of this publication is, ultimately, to inform the user of the capabilities of the handheld Metrohm Raman Mira P system. Best practices for building robust training sets for materials verification with Mira P can also be found here.

With Hydranal™ NEXTGEN FA reagents, the water content in ketones can be determined quickly and reliably. Compared to other existing KF reagents for ketones on the market, the side reactions are measurably better suppressed.

The USP and FDA started to modernize several monographs and General Chapters. In many cases, IC-focused methods have replaced older, wet chemistry procedures. Learn more about the USP modernization initiative and the advantages of ion chromatography in this white paper.

OMNIS Client/Server boosts business performance with scalable server management, cutting costs by reducing hardware, energy use, and maintenance across locations.

Pharmaceutical analysis guarantees drug safety by providing information on the identity, content, quality, purity, and stability of pharmaceutical products using analytical chemistry. Ion chromatography (IC) offers a broad range of pharmacopeia-compliant applications for quality control, monitoring, and improving drug manufacturing.As a very accurate and versatile technique, IC meets the requirements of many pharmaceutical applications. IC is a USP-accepted standard method for the determination of active pharmaceutical ingredients (APIs), excipients, impurities,pharmaceutical solutions as well as pharmaceutical starting materials, finished pharmaceutical products (FPPs) and even body fluids.This poster describes some typical examples.

The analytical challenge treated by the present work consists in detecting sub-ppb concentrations of low-molecular-weight amines in the presence of strongly retained cationic drugs by using ion chromatography (IC) with upstream inline coupled-column matrix elimination (CCME). In contrast to direct-injection IC, where the late elution of strongly retained drugs requires eluents with added acetonitrile, the CCME technique uses two preconcentration columns in series. In an «inverse matrix elimination step, cationic drug and target amines are trapped on a high-capacity and a very-high-capacity preconcentration column, respectively. During amine determination, a rinsing solution flushes the drug to waste. This significantly shortens the analysis time and improves sensitivity as well as selectivity. Besides the determination of monomethylamine in Nebivolol hydrochloride discussed here, the CCME technique is a promising tool for detecting further low-molecular-weight amines in a wide range of drugs.

The poster describes the water determination in pharmaceuticals using the Karl Fischer oven technique.

Moisture in cannabis impacts potency and must be accurately determined. Loss on drying (LOD) is the most popular method for determining moisture in cannabis. Unfortunately, this technique is not specific to moisture and the loss of any volatile components, such as terpenes, will be incorrectly classified as moisture. Karl Fischer (KF) titration is the only chemically specific test for moisture. This poster describes the instrument used to determine moisture content by Karl Fischer titration and compares the results of this data to loss on drying.

The NanoRam is a state-of-the-art, handheld Raman spectrometer for the rapid identification of chemicals used in the pharmaceutical manufacturing process. It has been specifically designed for these applications and is fully compliant with all the major global regulatory, safety, and commercial testing agencies applicable to the pharmaceutical industry.

Today’s Raman instrumentation is faster, more rugged, and less expensive than previous instrumentation.The design of high performance, portable and handheld devices has introduced the technology to new application areas that were previously not possible with older, more cumbersome instruments. Handheld Raman instruments such as the NanoRam® from B&W Tek are well-suited for pharmaceutical applications such as the testing of raw materials, verification of final products and the identification of counterfeit drugs due to the technique’s extremely high molecular selectivity.