Pharmaceutical analysis

Quality assurance of pharmaceuticals 02

Metrohm...

• is the global market leader in titration • is the only company to offer a complete range of ion analysis equipment – titration, voltammetry, and ion chromatography • is a Swiss company and manufactures exclusively in Switzerland • grants a 3­year instrument warranty and a 10­year warranty on chemical suppressors for ion chromatography • provides you with unparalleled application expertise • offers you more than 1300 applications free of charge • supports you with expert service through local representatives and regional support centers • is not listed on the stock exchange, but is owned by a foundation • gives the interest of customers and employees priority over maximizing profit Metrohm − customized analysis for the pharmaceutical industry

The regulatory authorities set high standards You can count on our support With regard to the quality and safety of drugs, authori­ As a leading manufacturer of instruments for chemical 03 ties worldwide set high standards for the pharmaceutical analysis, we are aware of these challenges. For this rea­ industry. These are documented in pharmacopoeias in son, Metrohm offers you not only the latest instruments, the form of official collections of recognized pharmaceu­ but complete solutions for very specific analytical issues. tical rules. As legal tools of consumer protection, they Your Metrohm contacts are competent specialists, who ensure that drugs are used safely. It is only the measuring will develop customized applications and provide you and test procedures used within the framework of drug with professional support in all matters of regulatory testing that identify a drug and determine whether it is compliance. approved or not. Discover on the following pages what solutions Metrohm To ensure these high quality and safety standards, reliable is able to offer the pharmaceutical sector in general and instruments and methods are needed. you in particular, to ensure the quality and safety of your products. Challenge us! Chemical pharmaceutical analysis

The history of pharmacy Determination of active ingredients, excipients, 04 The search for remedies is as old as humanity itself. There and impurities is evidence that the first advanced civilizations (China, Pharmaceutical analysis provides information on the India, Mesopotamia, Egypt) were already using drugs of identity, purity, content, and stability of starting materi­ plant, mineral, and animal origin for medicinal purposes. als, excipients, and active pharmaceutical ingredients Systematic descriptions of remedies have been handed (APIs). A distinction is made between analysis of the pure down to us from Greek antiquity (Hippocrates, Theo­ active ingredients used to cure, alleviate, prevent, or phras­­­­tus) and from the Roman Empire (Dioscorides, identify illnesses and diseases (active ingredient analysis) Galen). This knowledge was adopted by Arabian scholars and analysis of medicinal preparations. The latter can (e.g., Avicenna) and was developed further. It served for exist in various forms (ointments, tinctures, pills, lotions, a long time as an important basis of medicine. It was not suppo­s­­itories, infusions, drops, etc.) and consists of the until the 16th century that this began to detach itself pharmaceutically active substance and at least one phar­ from the ancient models. A typical representative of the maceutical excipient. Impurities usually stem from the new direction was Paracelsus, who, in 1537, coined the synthesis of the active ingredient; they are usually moni­ famous phrase: «Only the dose makes the poison» tored according to the guidelines of the ICH (International («dosis sola facit venenum»). Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) and The way to organic synthetic drugs the pharmacopoeias. The emergence of organic chemistry at the start of the 19th century brought progress, the importance of which Pharmacopoeias to ensure the safety of drugs can hardly be overestimated. Whereas previously treat­ Specifications and test methods for the commonly used ment with drugs had been restricted largely to natural active ingredients and excipients are monographed in substances and inorganic chemicals, people now started detail in national pharmacopoeias in more than 38 states specifically to produce organic synthetic drugs, using according to the World Health Organization (WHO). They substances isolated from medicinal plants as the basis. include the United States Pharmacopeia (USP), the An unprecedented advance in pharmaceutical synthesis European Pharmacopoeia (Ph.Eur.), which emerged from led within a very short time to a vast number of synthe­ the harmonization of the regulations of a number of sized active ingredients. In this context, researchers in­ individual states, and the Japanese Pharmacopoeia (JP), crea­­singly succeeded in establishing a relationship be- to name but a few. The pharmacopoeias are official com­ t­ween the action of these substances and their chemical pendia and contain the statutory requirements regarding structure. the identity, content, quality, purity, packaging, storage, and labeling for active pharmaceutical ingredients and other products used for therapeutic purposes, and are essential for anyone who wants to produce, test, or mar­ ket medicinal products. 05

Selected test methods and USP-NF monographs

Metrohm is the competent contact for all matters con­ and monographs of the USP. The National Formulary (NF) cerning chemical-pharmaceutical analysis and the valida­ is the official compendium of standards for excipients tion of analytical methods. Apart from complying with and plant-based drugs. numerous official guidelines, Metrohm instruments and applications satisfy the test methods for quality control Structure of the USP-NF and product release that are listed in the most important Apart from the description of numerous analytical meth­ pharmacopoeias. ods in the general section of the USP-NF, the main section contains generally applicable standards for active ingredi­ In accordance with the harmonization efforts of the Phar­ ents (USP) and excipients (NF) in the form of monographs. ­­­macopoeial Discussion Group (PDG), the present bro­ More recent texts (since 1997) also contain a list of pos­ chure, taking the place of the pharmacopeias not men­ sible impurities (transparency list) that can be determined tioned here, relates primarily to selected test methods with the test methods described.

Test methods referenced in USP-NF monographs (USP 32-NF 27)

Parameter USP monograph Number of citations in the monographs Test method Page In 1328 USP monographs pH value USP<791> pH measurement 6 In 68 NF monographs Conductivity USP<645> Ultrapure water for pharmaceutical use Conductivity measurement 6 Various active ingredients In 127 USP monographs USP<541> Titration 7-9 Various excipients In 51 NF monographs USP<921> In 616 USP monographs Water content Karl Fischer Titration 10-11 Method I In 98 NF monographs Various active ingredients In 27 USP monographs USP<621>/USP<1065> Ion chromatography 16-17 Various excipients In 3 NF monographs Various active ingredients USP<801> In 8 USP monographs Polarography 18-19 Determination of Thimerosal USP<341> Polarography 19 antimicrobiotics pH value, conductivity, and parameters that can be Process-dependent Various Process analysis 20-21 determined by titration specifications and voltammetry 06

Water for pharmaceutical use (water for injection)

pH value Conductivity measuring cell (stainless steel) with The 867 pH Module provides all that is needed for meas­ Pt 1000 uring the pH value according to USP<791>. With 900 This measuring cell was developed especially for measure­ Touch Control, or tiamoTM full, intelligent sensors, and ment in waters with very low conductivity. The robust five-point calibration it meets the requirements of FDA and easy-to-clean stainless steel construction is ideally regulation 21 CFR Part 11. In conjunction with 900 Touch suited for conductivity values <300 μS/cm, and thus for Control it is possible to carry out an electrode test. measuring water for pharmaceutical use. Conductivity and pH value can be measured in the same . vessel if the 856 Conductivity Module is combined with the 867 pH Module.

Conductivity Particularly strict rules apply to the measurement of the conductivity of water for pharmaceutical use (water for injection) according to USP<645>. Apart from the highest level of precision, all the requirements of the U.S. FDA’s regulation 21 CFR Part 11 must be satisfied. The 856 Con­­ductivity Module, together with the 900 Touch Control, or tiamoTM full, guarantees this. PharmPAC – application know-how from experts

Because of the simplicity and the accuracy of the proce­ Some older USP methods are still frequently based on dure, a large proportion of the content determinations high sample weights, which require a titrant consump­ 07 described in the monographs are carried out using titra­ tion of up to 50 mL. Following Ph.Eur., Metrohm has tion methods, for example, according to USP<541>. re­­duced the sample weights considerably and thus cut Taking into account the latest methodological knowl­ titrant consumption to at most 10 mL. edge, Metrohm has developed hundreds of titration methods with Metrosensors based on the U.S. Phar­­ma­ All the methods have been worked out in such a way copeia (USP) and European Pharmacopoeia (Ph.Eur.). that you can adopt them as SOPs (Standard Operating Procedures) in your titration laboratory.

Titrations with bases or acids Aqueous acid-base titrations Indirect titrations (back-titrations) Alkaline titrants In ethanol with the addition of HCl In dimethylformamide (DMF) In acetone In pyridine In ethanol or methanol In special solvents Non-aqueous acid-base titrations Acidic titrants

In glacial acetic acid, with HClO4

In glacial acetic acid/acetic anhydride, with HClO4

In glacial acetic acid plus mercury acetate, with HClO4

In glacial acetic acid/methyl ethyl ketone, with HClO4 In formic acid/glacial acetic acid or acetic anhydride,

with HClO4 In other solvents or solvent mixtures Iodine/thiosulfate (Iodometry) Iodine/arsenite (Iodometry)

Diazotization with NaNO2 Cer(IV) (cerimetry) Redox titrations KBrO3 (bromatometry)

KMnO4 (permanganometry)

KIO3 Reducing sugars AgNO (argentometry) Precipitation titrations 3 Surfactant titrations Photometric EDTA titrations Photometric titrations (chelatometry/complexometry) Acid number and free fatty acids (FFA) Hydroxyl number Characteristic fat and oil values Iodine value Peroxide value Saponification value The Titrando – the intelligent titrator without reliability gaps

Thanks to its modular concept, the Titrando system can 08 easily be adapted to any application. It meets the require­ ments of FDA regulation 21 CFR Part 11, irrespective of its use as stand-alone titrator in combination with 900 Touch Control, or tiamoTM.

Brainy dosing elements with certification Metrohm dosing elements set new standards with regard to reliability. An inconspicuous data chip contains all the data that the Titrando needs to carry out the titration properly, i.e. serial number, cylinder number, type of rea­ gent, titer, last titer determination, shelf-life data, and much more. In addition, the Titrando compares the data it has obtained with those of the selected method. If they do not agree, a clear error message appears. Flexibility – from the individual instrument to the fully automated system The iTrodes – intelligent electrodes Increasing sample numbers, time-consuming sample The electrode used for the titration is the most important preparation steps, and unattended overnight operation component of any titration system. The Titrando with are good reasons for using sample changers. Together iConnect and iTrodes ensures complete traceability of the with the 814 USB Sample Processor and 815 Robotic USB analysis result to any component involved in the analysis. Sample Processor XL the Titrando offers a high degree of The built-in memory chip allows the storage of such automation at low investment costs. The 855 Robotic important sensor data as article and serial numbers, cali­ Sample Processor combines a top-class Robotic Sample bration data, calibration history, and calibration intervals. Processor with a Titrando and takes up minimum space. All the sensor data are read in automatically when the iTrode is connected to the Titrando. If the type of elec­ Sample preparation at the touch of a button trode is not the same as that defined in the method then Metrohm instruments not only cope with the analysis the user is informed. itself, but also, as the example of the 815 Robotic Soli­ prep shows, perform the most frequent sample prepara­ STAT titration with tandem dosing tion steps. The determination of enzyme activity (lipase, trypsin, etc.) or the release kinetics of antacid tablets requires a ­• Homogenizing titrator that rapidly adjusts to a preset pH value and The Polytron® PT 1300D made by Kinematica ensures keeps it constant for a long period. Tandem dosing is a reproducible particle size reduction and homogeniza­ feature that prevents dosing interruptions when the tion of all samples. buret is refilled during the titration – a second buret im­ ­• Filtering mediately takes over. In this way rapid reactions with a Commercially available syringe filters with standard high reagent consumption can be monitored with maxi­ Luer connector can be used directly with the Robotic mum accuracy. Soliprep. ­• Liquid handling From dilution series to sample transfer into a sealed vessel, liquid handling with Metrohm automation knows almost no limits. 09

tiamoTM – titration and more

tiamoTM is the leading control and database software for • Data export titrators and dosing devices as well as for complete labo­ tiamoTM offers you different export formats, including ratory automation up to a client-server system. This is the modern XML format. Your data are available to all why the name tiamoTM stands for «titration and more» conceivable Office applications, databases, and long- – tiamoTM can do much more than just titrate. tiamoTM term archiving programs. is a titration network (NTDS = Networked Titration Data • Determination reprocessing System). Wrong sample weight? No problem. With the reproc­ essing function you do not have to worry about your • tiamoTM guarantees data security documentation. tiamoTM automatically records all alter­ It does not matter whether the need is to satisfy the ­­ations and thereby gives you a complete overview. GMP or GLP rules, regulations on the security of elec­ • Report generator tronic data, or the requirement for the traceability of The unique report generator allows you to arrange results in accordance with the FDA’s regulation 21 CFR your analytical report layout as you want. You can Part 11 – tiamoTM has been developed from the very adapt one of the many report templates to suit your start to meet all these requirements and thus sets new particular requirements and then send the report com­ standards. fortably by e-mail. • Signatures • Data security Digital signatures can be added to determinations. tiamoTM supports you in safeguarding your data. Acti­ tiamoTM offers two signature levels. As soon as a level- vate the automatic backup function; tiamoTM will then 2 signature is appended to a determination, the data automatically make complete copies of all determina­ are protected from any further changes. tions and configurations. • User administration • Client-server functionality Arrange the access rights of each user according to In the simplest case you just install the databases on your company’s security policy. tiamoTM sets no limits, your local computer. tiamoTM will grow together with but will convince you with its unique flexibility. your requirements. As soon as data security and cen­ • Complete audit trail tral data management make it necessary, you can con­ Each action performed by a user is stored automati­ figure tiamoTM as client/server. cally in the audit trail. Data for an audit can be pre- • Plug and play pa­red by pressing a button. Our modern USB devices ensure that all connected • Traceability devices appear in the devices window. Monitoring op- Be absolutely certain and place your confidence in the t­ions rule out the use of system components that are traceability of Metrohm software and hardware for wrong or have expired. your titrations. Each data record contains all the raw • Parallel titration data necessary to ensure traceability. tiamoTM and the Titrando form a powerful team. Par­­­ al­lel titrations − if necessary, carried out by different users − increase efficiency. Water determination according to Karl Fischer

The quality, effectiveness, and shelf life of pharmaceuti­ 10 cal products depends to a very large extent on their water content. For this reason a great deal of importance is attached to water determination in pharmaceutical ana­lysis. Thanks to the specific and selective reaction with water, Karl Fischer titration (KFT) is one of the most accurate and most reproducible water determination methods. That is why, for many years, it has been pre­ scribed in numerous pharmacopoeias as a standard method for fast and automatable water determination.

If the test substance is completely soluble in the Karl Fischer reagent and does not enter into any secondary reactions with the solvent, the sample can be put directly into the titration cell and the water content determined directly using volumetry or coulometry. 901 Titrando with 900 Touch Control Not all substances dissolve completely in methanol. This is, however, an important requirement for the correct determination of the sample`s water content. Some tech­ niques for improving the solubility of samples are set out below. These techniques can also be combined with one another.

Solubilizers Depending on the test substance, solubilizers can be added. In the case of samples containing fat or oil, for example, ointments or creams, the KF reagent is treated with chloroform, to ensure that the sample dissolves completely.

High-frequency homogenizers Tablets must be comminuted prior to titration. This can be done either manually with a mortar or, more conven­ iently and above all more reproducibly, with the help of a high-frequency homogenizer directly in the closed titra­ tion cell. In this way one prevents the water content of 901 Titrando with 803 Ti Stand and Polytron PT 1300D the sample from changing during preparation. In addi­ tion, in some cases, it is possible to dispense with the use of toxic solubilizers.

Higher temperature in the titration cell Another possibility is titration of the water at a higher temperature (e.g., at 50 °C).

Titration cell 11

Karl Fischer oven method Many substances release their water only very slowly or only at high temperatures. Some react with KF reagents, forming water or consuming iodine, so the determined water content is incorrect. Such samples are unsuitable for direct Karl Fischer titration. For such substances both the U.S. Pharmacopeia and the European Pharmacopoeia stipulate determination of the loss on drying in the drying oven or desiccator. However, this method suffers from the drawback that it determines not only the water con­ tent, but also other volatile constituents in the sample. The 874 Oven Sample Processor with 852 Titrando

In the KF oven method, the test substance is heated in a tightly sealed vessel in an oven. The water driven off from the sample is transported into the titration cell with the help of a stream of dry carrier gas; there it is deter­ mined, usually by means of coulometric Karl Fischer titra­ tion. Because the sample itself remains in the vessel and only the water enters the titration cell, secondary reac­ tions and matrix effects can be ruled out.

860 KF Thermoprep with 870 KF Titrino plus and 803 Ti Stand Laboratory automation

The entire range of automatic sample 12 preparation from one supplier Normally, accurate pipetting and dilution of the sample is enough to determine liquid forms of drugs (tinctures, infusions, drops, etc.). Metrohm offers you a wide range of products with which the preparation of liquid samples can be automated precisely and with time savings.

If, however, solid or semisolid samples are involved, for example, tablets, suppositories, and ointments, the sample preparation is more demanding. As a specialist in the field of laboratory automation, we offer you a wide range of so­­lutions for the preparation of solid samples – customized to your needs, if necessary.

Automation = time savings and higher accuracy Fully automatic sample preparation and analysis of tablets: After In pharmacopoeia analysis, apart from direct titration, the addition of solvent the Polytron high-frequency homogenizer grinds the tablets directly in the sample beaker. Each sample is the reliance is mainly on chromatographic methods such treated exactly in the same way. as IC, HPLC, and GC. These techniques require that the sample is present in a liquid and filtered form before it can be injected onto the column. The preceding sample preparation steps, still often carried out manually, such as

• grinding/homogenizing • filtering • pipetting/diluting

are laborious and time-consuming. Furthermore, manual sample preparation bears the risk of erroneous results. Especially where high sample volumes are involved and when several persons work on the samples, it is hardly possible to ensure consistent quality in sample prepara­ tion.

The 815 Robotic Filtration Soliprep Robotic Soliprep – automatic sample preparation tailored to your needs 13 With instruments of the Robotic Soliprep family, neither deviant results nor time-consuming manual routines are an issue. The solid substance is simply weighed out and placed in the sample rack – all the rest is done fully auto­ matically. Depending on the model selected, different steps can be combined – including the direct connection to a chromatograph or the titration of the homogenized sample.

Robotic Robotic Robotic Robotic Titration Filtration Flexible Soliprep Soliprep Soliprep Soliprep for LC Homogenization + + + + Fully automatic filtration: The 815 Robotic Filtration Soliprep Titration + filters remaining solids out of the homogenized sample. What Filtration + + + remains is a clear filtrate, that can either be injected directly Transfer to + into the analyzer or diluted further. HPLC/GC vials Connection to + an LC system Oxidation stability

Ointments, lotions, cosmetics 14 Natural fats and oils have a limited shelf life, because The method is used to monitor natural fats and oils they slowly become oxidized by atmospheric oxygen. which are used in the manufacture of fat-containing The oxidation stability of fats and oils has been a stand­ phar­­maceutical products such as ointments, creams, and ard parameter in quality assurance for many years. To lotions. In many cases it is, however, also possible to exam­­ determine oxidation stability with the Rancimat method, ­ine the oxidation stability of the finished formulations. air is passed through the test sample at a high tempera­ The requirement here is that the proportion of fat in the ture to cause artificial aging. During this process the fatty sample is significantly higher than the proportion of water. acids are oxidized by oxygen, forming volatile organic compounds and other products. These are driven off by 743 Rancimat the stream of air, absorbed in water, and detected there The 743 Rancimat enables the oxidation stability of by means of conductivity measurement. The time until natural fats and oils to be determined easily and reliably these degradation products form is known as induction in up to eight samples. The instrument is controlled time and characterizes the resistance of the sample to by PC; the PC software plots the measurement curves, oxidative aging processes, i.e. the oxidation stability. eva­l­uates them automatically, and calculates the result. 15

Rancimat control: up to eight samples can be analyzed for their oxidation stability at the same time Ion chromatography

Ion chromatography (IC) is the method of choice to de­ The intelligent ion chromatographs, automation devices, 16 term­­ine active ingredients, excipients, and traces of and peripheral equipment are controlled by the user- impurities and metabolites in the form of organic and friendly software MagIC NetTM. Complete documentation in­­organic ions or polar substances in a number of phar­ on the state of the analyzers and user activities pro­­vides maceuticals, pharmaceutical solutions, or even body flu­ complete traceability of the analysis results. MagIC NetTM ids. Ion chromatography can determine chemically simi­ fully supports FDA regulation 21 CFR Part 11 and offers lar substances within a very short time in a single analy­ a large number of tools for compliance with the GLP sis. The concentration of the analytes can vary from ng/L guidelines. up to the percent range. Another advantage is the large selection of separation columns and elution systems Pharmaceutical solutions available. Interfering matrix effects can be avoided by The term pharmaceutical solutions denotes isotonic solu­ using a suitable inline sample preparation method or tions, hemodialysis solutions, or infusion solutions. They through the choice of the detection method: contain anions, cations, carbohydrates, and organic acids, the concentrations of which frequently differ from one • conductivity detection with and without suppression another by several orders of magnitude. Within the con­ • electrochemical detection text of production monitoring and final quality control • spectrophotometric detection with and without these ingredients need to be determined easily, quickly, post-column derivatization (UV/VIS) and with a high degree of precision. Ion chromatogra­ • coupled detection methods such as IC-MS and phy, with its intelligent analytical procedure and auto­ IC-ICP/MS. matic inline sample preparation, fully accomplishes this task.

Analysis of a solution of Ringer’s lactate; column: Metrosep C

4 - 100/4.0 (6.1050.410); eluent: 1.7 mmol/L HNO3, 0.7 mmol/L dipicolinic acid, 0.9 mL/min; sample volume: 10 μL; 1:20 (v/v) inline dilution

850 Professional IC with 858 Professional Sample Processor: an intelligent ion chromatography system for parallel determination of anions and cations in pharmaceutical products 17

Active pharmaceutical ingredients Impurities in pharmaceuticals Active pharmaceutical ingredients in tablets such as ­gen-­­ Apart from active ingredient analysis, it is also possible to tamicin, neomycin, cefadroxil, or bethanechol chloride determine impurities in pharmaceutical products by can be determined by ion chromatography in accordance means of ion chromatography. Even small concentrations with the regulations of the U.S. Pharma­ ­­copeia and of an impurity can cause significant side effects. The azide European Pharmacopoeia. The requirements regarding used in the synthesis of antihypertensive Irbesartan can precision, separation, and recovery of the analytes are be detected in traces as an impurity in the product. described in detail in the pharmacopoeias. The U.S. Pharmacopeia recommends ion chromatogra­ phic azide determination after direct injection according to USP<621>. Azide determination is more selective, more sensitive, and, above all, quicker with the use of inline matrix elimination, where the interfering pharma­ ceutical matrix is separated from the target analyte in the course of sample preparation.

IC determination of the antibiotic gentamicin by means of pulsed amperometric detection using the 871 Advanced Bioscan; column: Polymer Laboratories RP-S; eluent: 60 g/L

Na2SO4, 1.75 g/L sodium octane sulfonate, 1.34 g/L NaH2PO4,

8 mL/L THF (pH = 3, H3PO4), 1.0 mL/min; column temperature: 55 °C; sample volume: 20 μL; post-column addition: 300 mmol/L NaOH (0.4 mL/min)

Irbesartan sample spiked with 5...80 μg/L azide; column: Metrosep A Supp 10 - 250/4.0 (6.1020.030); eluent: 5 mmol/L

Na2CO3, 5 mmol/L NaHCO3, 1.0 mL/min; column temperature: 60 °C; sample volume: 1000 μL; inline matrix elimination with 70:30 (v/v) methanol/water

Precision and recovery of the azide Peak area Mean value RSD Recovery [µS·s/cm] [%] [%] 5 µg/L spike 0.4223 1.96 101.71 30 µg/L spike 2.5754 0.14 103.38 n = 3 measurements Voltammetry

Voltammetric trace analysis determines electrochemically addition, unlike the spectroscopic methods, voltammetry 18 active substances. In many cases these are traces of can distinguish between different oxidation states of heavy metals. Voltammetry is frequently employed to metal ions as well as between free and bound metal ions. complement and validate spectroscopic methods. Its This is referred to as speciation analysis. Voltammetric features are: compact equipment, relatively low invest­ results provide important information regarding the bio­ ment and running costs, simple sample preparation, availability and toxicity of heavy metals. short analysis times, and high accuracy and sensitivity. In

Detection limits (1 ppt = 1 ng/kg)

Element Detection limit Element Detection limit [ppt] [ppt] Antimony SbIII/SbV 200 Molybdenum MoIV/MoVI 50 Arsenic AsIII/AsV 100 Nickel Ni 50 Bismuth Bi 500 Platinum Pt 0.1 Cadmium Cd 50 Rhodium Rh 0.1 Chromium CrIII/CrVI 25 Selenium SeIV/SeVI 300 Cobalt Co 50 Thallium Tl 50 Copper Cu 50 Tungsten W 200 Iron FeII/FeIII 50 Uranium U 25 Lead Pb 50 Zinc Zn 50 Mercury Hg 100

Voltammetry also enables organic compounds to be de­ 797 VA Computrace ter­mined with a high degree of sensitivity. This makes it The 797 VA Computrace is a modern measuring stand possible to analyze many active pharmaceutical ingredi­ that allows voltammetric and polarographic determina­ ents according to USP<801>. tions to be performed. By adding Dosinos and a sample changer to the stand, analysis can easily be automated. Voltammetry is especially suitable for laboratories in which only a few parameters have to be monitored with a moderate sample throughput. It is frequently used for special applications which cannot be performed with other techniques or, if they can, require a lot of work. 19

Application examples Thimerosal in eye or nose drops, vaccines, and Fe(II) in iron sucrose injection solution cleaning solutions for contact lenses according to according to USP-NF USP-NF Polarography makes it possible to determine, directly and Mercury-containing thimerosal (or thiomersal) is used as selectively, the proportion of iron(II) within the total con­ a preservative for pharmaceuticals and cosmetics, to centration of iron in the preparation. No prior sample protect them from microbial contamination. Examples of preparation and chemical separation of the iron species the use of thiomersal are: cleaning and storage solutions is required. During determination the separate signals of for contact lenses, eye, nose and ear drops, and tattoo the iron(II) and iron(III) complex are measured. The iron(II) inks. Injectable medicinal products − for example, immu­ content is derived from the signal ratio. noglobulins or many vaccines (flu, hepatitis B, etc.) – can also be preserved with thimerosal.

In many cases direct determination in the finished prepa­ ration is possible.

Heavy metal impurities in pharmaceutical products Besides the main constituents, inorganic impurities, espe­ cially heavy metals, can also be determined. For this, the pharmaceutical preparation is digested and the relevant metal ions are then determined by means of stripping voltammetry.

Other active ingredients that can be determined by polarography according to USP-NF Electrochemically reducible and oxidizable active pharma­ ­­­­ceutical ingredients, for example, azathioprine, cefaman­ dole, cyst­­­eine hydrochloride, diclofenamide, iodine, or procarba­zine, can be determined directly with the help of Polarographic determination of iron(II) content po­­la­ro­graphy in accordance with USP<801>. Atline process analysis

PAT and QbD 20 Medicinal products are produced according to very strict ProcessLab features a modular design and it is configured guidelines and must satisfy the highest standards with according to analytical requirements and can be ideally regard to quality, effectiveness, and safety. During the integrated into the process communication system via production of the various active ingredients and excipi­ inputs/outputs (typically 4...20 mA). Through the use of ents every step of the process is closely monitored. In a barcode reader, sample identification can be made addition, there are extensive release analyses at the end even easier. Just a few minutes after sampling, the rele­ of the production process, which often lead to the situa­ vant process information is available to a LIMS or the tion where pharmaceutical producers spend more time master display. The process conditions can be rapidly and on final checks than on production. Furthermore, strict efficiently altered according to the preset conditions. regulatory requirements make optimization of the phar­ ProcessLab is therefore ideally suited for rapid and inde­ maceutical production processes more difficult. With the pendent process monitoring in an industrial environment. PAT (Process Analytical Technology) and QbD (Quality by Design) initiatives, the FDA aims to bring about an in­ A ProcessLab analysis system consists of a TFT operating crease in efficiency in pharmaceutical production, in­­clud­ panel and a customized analysis module. For even easier ing a trend away from final checks towards real-time and more comfortable operation, the operating panel is process analysis and control. also available with a touch-sensitive screen. With its splash-proof housings (protection class IP54), ProcessLab Fast process monitoring is ideally suited for use in the production environment. ProcessLab, a robust and easy-to-use system that is installed directly within the process, makes it possible to carry out not only the release analyses, but also the analysis of intermediate products. The sample is brought to the ProcessLab and the analysis is started with a single push of a button. ProcessLab is based on the proven Titrando system, which, combined with the tiamoTM soft­ ware, meets the requirements of FDA regulation 21 CFR Part 11.

ProcessLab analysis system with touch monitor and analysis module 21

Determination of acidic and basic components Determination of redox-sensitive components Numerous pharmaceutical intermediate and end prod­ Oxidizable and reducible components and active ingre- ucts contain acidic and basic components. These are dients are determined with redox titrations. Methods 2- determined by means of an appropriate acid-base titra­ frequently used include iodometry (I2/S2O4 ), cerimetry tion. Depending on the sample matrix, either aqueous or (Ce(IV)), bromatometry (KBr03), and permanganometry nonaqueous titrations are carried out. The latter are done (KMnO4). The modular structure of ProcessLab enables with a titrant and solvent suitable for the particular appli­ easy adaptation to the specific requirements of the appli­ cation, for example, with perchloric acid in glacial acetic cation. Because of its closeness to the process, the relevant acid or with tetrabutylammonium hydroxide (TBAH) in analytical values are available within just a few minutes. acetone. 22

Metrohm Quality Service

Security of results – for the lifetime of the analyzer Particularly in the pharmaceutical industry, measurement Analyzers used in laboratories must satisfy the latest re­ errors can have serious consequences and must there­ quirements of FDA regulations, GLP/GMP standards and fore be avoided at all costs. Throughout the world the the GAMP guidelines. This is achieved through instru­­ name Metrohm stands for high-quality laboratory ana- ment qualification and system validation. Metrohm offers lyzers in ion analysis. They are designed to deliver high- qualification and validation documents as well as ser- pre­cision results. Leading international pharmaceutical vices, which meet the requirements of the FDA and other com­­panies also value Metrohm for its comprehensive regulatory authorities. services, which ensure that the responsible people in the laboratories can absolutely rely on their results through­ These include: out the lifetime of their analyzers. • competent assistance with Design Qualification (DQ) • documented installation and fast professional setup of Regulatory Compliance new instruments with Installation Qualification (IQ) With the Metrohm Compliance Service, Metrohm guar­ • Operational Qualification (OQ), guaranteeing that antees compliance with statutory requirements for phar­ Metrohm instruments meet the stated equipment maceutical companies. Owing to the large number of speci­­fication. This ensures full performance capability. different laboratory instruments and analyzers, that has • all qualification and validation work, which is per- become very complicated. As an experienced and trusted for­med only by professionally trained and certified partner, Metrohm makes its regulatory expertise available service technicians to its customers. • user training taught by experts • efficient audit processes • competent requalification and revalidation Metrohm Quality Service The worldwide Metrohm Quality Service, especially the ween different types of service contracts. A full service 23 scheduled and preventive maintenance, extends the contract, for example, offers you optimum security for trouble-free life and operating time of your analysis sys­ work without any worries, whilst giving you complete tems. Qualified service technicians with proof of training control of costs and providing fully compliant documen­ carry out the maintenance work. You can choose bet­ tation.

Metrohm Quality Service at a glance

Our services Customer benefits Application support by means of our vast selection of Application Bulletins, Application Notes, monographs, Fast and professional solution to all arising application validation brochures, technical posters and articles issues and complex analytical challenges Personal advice from our specialists by e-mail or telephone Training courses Competent users contribute substantially to results Accurate results

Certified calibrations, e.g. of dosing and exchange units Documentary evidence to comply with regulations

and for efficient audits Remote maintenance Fast resolution of software issues Back-up support High data security Short response time and thus rapid resolution of Emergency services, e.g. express repairs on-site problems and minimization of downtimes Spare parts, made in Switzerland by Metrohm and Sustainable repair success, short delivery times, available worldwide, with guarantee of availability of minimization of downtimes spare parts ten years after the end of production Regional repair workshops available worldwide and Instruments soon available for use again a central workshop in Switzerland

Thanks to Metrohm Quality Service you can rely on your results for the lifetime of the analytical instrument. Ordering information

pH and conductivity measurement 24 pH measurement 2.867.0110 867 pH Module with Touch Control 2.867.0210 867 pH Module with tiamoTM light

Conductivity measurement 2.856.0110 856 Conductivity Module with Touch Control 2.856.0210 856 Conductivity Module with tiamoTM light 6.0916.040 Conductivity measuring cell c = 0.1 cm–1 with Pt 1000

Titration 2.907.1020 Pharm Titrando 2.902.0010 902 Stat Titrando 6.6056.2X2 tiamoTM 2.X full

Water determination according to Karl Fischer Coulometric KF titration 2.851.0010 851 Titrando with generator cell with diaphragm 2.851.0110 851 Titrando with generator cell without diaphragm 2.852.0050 852 Titrando with generator cell with diaphragm and volumetric titration cell 2.852.0150 852 Titrando with generator cell without diaphragm and volumetric titration cell

Volumetric KF titration 2.890.0110 890 Titrando with Touch Control 2.890.0210 890 Titrando with tiamoTM light 2.901.0010 901 Titrando including titration cell

KF oven 2.860.0010 860 KF Thermoprep 2.874.0010 874 Oven Sample Processor

Automation 2.815.1110 815 Robotic Titration Soliprep 2.815.2110 815 Robotic Flexible Soliprep 2.815.3110 815 Robotic Filtration Soliprep 2.815.4110 815 Robotic Soliprep for LC

Oxidation stability 2.743.0014 743 Rancimat (230 V) including software and accessories 2.743.0015 743 Rancimat (115 V) including software and accessories 25

Ion chromatography 2.850.3030 850 Professional IC AnCat – MCS for anion and cation determination 2.850.2150 850 Professional IC – MCS – Prep 2 for the determination of anions after inline matrix elimination 2.871.0010 871 Advanced Bioscan for pulsed amperometric detection

2.858.0020 858 Professional Sample Processor for the automation of determinations

6.5331.010 Equipment set for Au flow cell

6.1050.410 Metrosep C 4 - 100/4.0 for cation determination 6.1020.030 Metrosep A Supp 10 - 250/4.0 for anion determination

Voltammetry 2.797.0010 797 VA Computrace for manual operation MVA-2 VA Computrace system with automatic standard addition consisting of 797 VA Computrace with two 800 Dosinos. MVA-3 Fully automated VA Computrace system consisting of 797 VA Computrace with 863 Compact VA Autosampler and two 800 Dosinos for automatic addition of auxiliary solutions. Allows the automatic processing of up to 18 samples. This system is the optimum solution for automatic analysis of small sample series.

Process analysis 2.875.0010 875 ProcessLab Base Unit, left-hinged door 2.875.0020 875 ProcessLab Base Unit, right-hinged door 2.875.0510 875 ProcessLab Base Unit with TFT operating panel incl. touch function, left-hinged door 2.875.0520 875 ProcessLab Base Unit with TFT operating panel incl. touch function, right-hinged door 2.875.0210 875 ProcessLab Base Unit VA with TFT operating panel incl. touch function, right-hinged door 26 27 Subject to change Layout by Ecknauer+Schoch ASW, printed by Metrohm AG, CH-9101 Herisau, Switzerland 8.000.5014EN – 2011-09 pharma.metrohm.com