Instrumentation for Pharmaceutical Analysis

Instrumentation for Pharmaceutical Analysis

Anton Paar s Instrument Guide to Pharmaceutical Analysis Anton Paar has been developing, producing and distributing high-precision measuring and analytical instrumentation for laboratory and process applications since 1922. You can count on solutions from Anton Paar realized with a passion for precision, a love of science, a shared enthusiasm in the entire chain of production, every step of the way. In the pharmaceutical sector in particular, where quality and traceability count above all else, analysis of parameters with Anton Paar s instruments is used to guarantee a consistently high quality of pharmaceutical products. 1

1-2 Introduction and Content 7 3-4 Technologies for Physical and Physico-chemical Analysis Service Programs 8-21 5-6 Pharmaceutical Qualification and Validation Instruments for Pharmaceutical Analysis 22-23 About Anton Paar 2

Technologies for Physical and Physico-chemical Analysis Anton Paar s instruments embody decades of technical know-how. This continuously growing knowledge at the cutting edge of technological developments forms the basis for robust and reliable analytical instruments. Anton Paar s deep understanding of each analytical method results in precise instruments with excellent performance and reproducibility. Openness towards customer requirements and attention to new market trends are the source of new ideas which meet the needs of customers. You want to raw materials, intermediates, excipients, active pharmaceutical ingredients (APIs), proteins, infusion solutions, ointments and many other kinds of formulations. 3

Ensuring Pharmaceutical Quality In Quality Control & Production Performing first identifications Testing the quality Checking the purity Assessing conformity with the specifications Evaluating the stability Detecting impurities Defining new analytical quality assurance methods In Research & Development Defining and screening new medical entities Developing and optimizing methods in the early stages Determining the homogeneous size distribution of formulations Providing structural information on size, shape aggregation behavior, crystal structure and molecular weight Investigating drug delivery behavior and kinetics Investigating the phase transition and its influence on the properties of formulations or medical substances Investigating temperature- and humidityinduced changes 4

Pharmaceutical Qualification and Validation Anton Paar understands your need for completely traceable results and supports you with a qualification and validation package following the 4Q model which complies with pharmaceutical regulations: GMP, 21 CFR part 11, GAMP-5, USP<1058>. This package aids you in achieving and maintaining the qualified status of your instrument. For the pharmaceutical, biotechnological, cosmetics and food industries. For defined instruments Anton Paar offers an instrumentspecific qualification and validation package to meet the strict pharmaceutical regulations. This package covers all steps to perform a complete instrument qualification: DQ, IQ, OQ and PQ Risk Analysis 21 CFR Part 11 checklist List of deviations Traceability list Certified Anton Paar representatives assist in the whole process if required. For all industry segments. After Anton Paar s documented qualified instrument installation, your in-house qualification officer can easily integrate the instrument into your process and create the complete qualification and validation documentation. For all industry segments. Delivery and installation of the instrument. Anton Paar s instruments are thoroughly tested and calibrated according to official guidelines, such as ASTM, TÜV, CE, etc. Embedded into Anton Paar s ISO system are the guidelines for preparing an instrument-specific pharma qualification and validation package. 5

Anton Paar s Certified Service provides the right service level for you: AllInclusive StandardPlus Standard

Instrument Qualification and Instrument Re-qualification To achieve and to further maintain the qualified status of your instrument, Anton Paar supports you with a Pharma Qualification and Validation Package for defined instruments. This shortens the time until the instrument can be used in your production process and saves you money and time during the implementation process. The 4Q Model DQ Design Qualification Design and quality criteria are defined. A qualification plan and risk analysis are the start of a risk-based qualification instruction and procedure. IQ Installation Qualification This ensures that the instrument fits the specifications. Defined test points assure the correct and quick installation and availability of the instrument. OQ Operational Qualification This ensures that the instrument operates as specified. OQ covers all the defined operational test points, including: Adjustment Calibration Standard sample measurement 21 CFR Part 11 checklist User SOP These points make sure that the instrument works as specified in the defined environment. PQ Performance Qualification This ensures that the instrument works under routine conditions within the defined specification. With Anton Paar s Pharma Qualification and Validation Package you are prepared for inspections. It is the correct and approved procedure for a validated instrument used in the production cycle. Anton Paar offers: A range of instruments which provide complete conformity and traceability via: A complete user management system Audit trail functionality GMP-compliant printouts and reports 21 CFR Part 11 compliance Standard materials for all instruments 6

Service and Support Anton Paar accompanies you with certified service throughout the whole life cycle of your instrument. Depending on your needs choose from Anton Paar s specially designed service programs: To keep your results on-spec To ensure the instrument s long working life To profit from trained and qualified Anton Paar service engineers To ensure use of certified test equipment for the highest level of accuracy Comprehensive Service for Lifelong Reliable Operation Anton Paar s certified service provides: Preventive maintenance Regular maintenance Unplanned maintenance in emergency situations Depending on the service level agreement, you benefit from: Calibration and adjustment checks Electrical safety checks according to standards Electrical and mechanical alignments Firmware and software upgrades Spare parts service Depot repair service Loaner instruments Additionally Anton Paar supports you during the qualification and validation process, during requalification of the instrument and during the retrospective qualification if an older instrument needs to be qualified. Anton Paar s documented service proves that your instrument has been checked to the highest standards. This meets your need for monitored quality for inspections and audits. For repair and emergency cases Anton Paar provides phone support and clearly specified short reaction times. For detailed information on Anton Paar s Certified Service, refer to www.anton-paar.com or email info@anton-paar.com 7

Density & Concentration Measurement Density measurement is used to characterize binary mixtures and provide density and concentration results. A combined density and sound velocity meter accurately determines the concentration of tertiary mixtures. Due to their robust design, Anton Paar density meters are very popular at manufacturing sites, R&D and quality control laboratories. They provide quick and accurate measurement results to ensure the right density and concentration values of solved pharmaceutical material during production and in the final product. Portable and benchtop density meters for concentration measurements The first-ever digital density meter was launched by Anton Paar. These DMA density meters have been continuously developed, resulting in highly reliable, repeatable and accurate density instruments with the following benefits: Measurement of liquid samples of any viscosity Investigation in the lab or quick checks directly at the sampling location Small sample volume of approx. 1 ml Non-destructive measurements Drift-compensated measurement at different temperatures Fast viscosity correction across the samples' entire range Filling errors detected automatically to guarantee reliable results and save time Only one adjustment at one temperature required Automatic sample changer for up to 96 samples 8 Anton Paar s density and concentration meters: DMA 35 portable density meter DMA 4100 M, 4500 M and 5000 M density meters DMA 500 density meters DSA 5000 M density and sound velocity meter

Temperature Measurements Almost all measurement parameters are in some way influenced by temperature. To guarantee complete quality assurance, Anton Paar provides certified test equipment for temperature checks, the calibration of other instruments and high-precision temperature measurements. Exceptional accuracy measurement uncertainties in the Millikelvin range The benefits of Anton Paar s temperature measuring instrument are: Ensures and maintains continuous quality of the products Monitoring of quality-relevant instruments can be proven to auditors Traceable to national standards and can be ordered with officially accredited sensors Compliant to ITS-90 and IEC 751 Two channels make the MKT 50 perfectly suitable for comparison calibration Measurement uncertainty of 400 µohm (equal 1 mk (0.001 C)) with an ideal Pt 100 sensor Portable instrument less weight (< 2 kg) and operation up to 10 hours without batteries Digital interfaces for flexible use Anton Paar s temperature measuring instrument: MKT 50 millikelvin thermometer 9

Polarimetry Determination of optical rotation is the method of choice to ensure use of the correct and optically pure pharmaceutical substances in all areas of pharmaceutical production, quality control and R&D. This is important for chiral drugs, for example, as some enantiomers can be inactive or even toxic. The optical rotation is a measure of the concentration of optically active substances and therefore directly proportional to the sample concentration and path length of the used sample tube. Laboratory and online measurement of optically active substances The benefits of Anton Paar s polarimeters are: Multi-wavelength option meets the requirements of pharmacopoeia Automatic detection of the sample cell ensures complete traceability Automatic transfer of calibration and adjustment data from the quartz control plate ensures error-free calibration and adjustment Use of certified calibration standards Automated checks and adjustment procedures Measurement of light and strongly colored samples with the same quality via selfadjusting light intensity Built-in Peltier temperature control Wide range of sample cells Numerous communication ports 10 Anton Paar s polarimeters: MCP 200 MCP 300 MCP 500 Propol automatic process polarimeter

Refractometry The Refractive Index (RI) is a physical property and is therefore characteristic for every substance. The RI of liquid and solid substances is quickly and easily measured using a refractometer. This measurement is the appropriate method for purity control and for checking the quality of pharmaceutical samples. The RI exactly correlates to the concentration of dissolved substances and can also be used for concentration measurements. From stand-alone to modular a refractometer for every task The benefits of Anton Paar s refractometers are: For all kinds of samples, including turbid, colored and opaque samples Sample volume in the microliter range No sample preparation required Predefined standard methods and scales Also for samples with high or low RI For determining dispersion and measuring RI at different wavelengths For use in harsh environments Anton Paar s refractometer series: Abbemat 300, Abbemat 500, Abbemat 350, Abbemat 550 Abbemat HP (high-precision model) Abbemat HT (high-temperature model) Abbemat MW (multi-wavelength model) Abbemat WR (wide range model) 11

Viscometry Viscosity determination is an established technique to define the optimal flow behavior and appropriate stability range for liquid formulations and excipients. Viscosity measurement is used to detect, for example, a protein s ability to crystallize and denaturate. It is therefore a suitable tool for checking the quality of pharmaceutical formulations. Viscosity results for research or quality control The benefits of Anton Paar s viscometers are: Extremely small sample volume Highly precise measurements from low sample volume High degree of modularity with other Anton Paar instruments Calculation of intrinsic, relative and dilute solution viscosity Precise thermostatting from +5 C to +100 C Closed measuring system to avoid evaporation or contamination High degree of automation 12 Anton Paar s viscometer: Lovis 2000 M

Rheometry Rheology is the appropriate method for describing the viscous and viscoelastic behavior of substances which influences the processability of, for example, formulations, coatings and the consistency of the final product during application. It is the method of choice for quality control during the production process and on the final product. In research and development, rheometry is used to characterize the correct used composition of final pharmaceutical formulations in consideration of their storage and application conditions. From quick single-point checks to complex rheological investigations The benefits of Anton Paar s rheometers are: Toolmaster - automatic recognition and configuration of measuring systems for errorfree setup TruGap technology for continuous control of the measuring gap to ensure correct measurement conditions Drift stability and low torque capabilities due to unmatched air bearing technology Modular temperature control system from -150 C to 1000 C with high thermal stability Automatic temperature calibration sensor A wide range of accessories for applications ranging from ointments to sprays and bone cements Wide range of parallel-plate, cone-plate and concentric-cylinder Rotational and oscillatory test modes Software package with predefined test modes Fully automated rheological measurements and analysis Anton Paar s rheometer series: MCR 502, MCR 302, MCR 102, MCR 52 RheolabQC Fully automated HTR high-throughput rheometer 13

Microwave-assisted Sample Preparation Trace element impurities influence shelf life, stability, and safe use of the final product. Regulations require pharmaceutical manufacturers to determine impurities at (ultra-) trace levels (i.e. USP <232>, <233>). Anton Paar s microwave-assisted sample preparation instruments provide complete digestion for the analysis of impurities (i.e. heavy metals) in APIs, formulation agents, and solvents, regardless of their formulation or chemical structure. A clear solution for your analytical task digestion and extraction The benefits of Anton Paar s sample preparation equipment are: Up to 300 C for complete acid digestion Minimized reagent consumption Closed vessel system no loss of analytes or cross-contamination Low blanks in quartz and TFM vessels Microwave-induced Oxygen Combustion (MIC) set - an efficient accessory for tough organic compounds Decomposition of up to 48 samples simultaneously Integrated cooling system Significant reduction in cycle times Certified to high safety standards (TÜV) Comprehensive method library Anton Paar also offers complementary methods such as microwave-assisted solvent extraction (MAE), UV digestion and acid evaporation. 14 Anton Paar s sample preparation instruments: Multiwave 3000 High Pressure Asher HPA-S

Microwave-assisted Synthesis Microwave-assisted synthesis is a time-saving and powerful method for developing and synthesizing new pharmaceutical compounds. This technology is suitable for scale-up processing from milligram to kilogram amounts. Microwave-assisted synthesis makes pharmaceutical compounds available quickly for screening and production purposes. From milligram to kilogram benchtop synthesis reactors The benefits of Anton Paar s synthesis instruments are: Simple method transfer for seamless scale-up up to the kilogram range Reduced time required for drug discovery and development Cost-efficient preparation of pharmaceutical compounds and APIs needed in small quantities Accurate internal temperature sensors for sophisticated reaction monitoring Rapid and uniform heating in any applicable scale Temperature homogeneity ensures full conversion of substrates Efficient reaction screening Parallel method optimization and synthesis Silicon carbide technology for efficient heating of even low-absorbing mixtures Anton Paar s synthesis instruments: Monowave 300 Synthos 3000 Masterwave BTR 15

X-ray Structure Analysis X-ray structure analysis provides structural information about active pharmaceutical ingredients and final dosage forms and helps to understand their behavior in the context of the used formulation and under physiological conditions. Anton Paar offers a small-angle X-ray scattering (SAXS) system as well as sample stages for non-ambient X-ray diffraction (XRD). Investigations into the solid or liquid state Non-ambient XRD measurements are non-destructive and are used for phase analysis based on the specific powder diffraction patterns resulting from different phases and polymorphs. Phase changes depend on different environmental conditions (e.g. temperature, humidity) that can influence the drug s properties, such as its stability during transport and storage. Non-ambient XRD is the method of choice for the determination of crystalline structure and crystalline impurities in drugs. Both have a strong impact on the morphology and physical properties of the ingredients and can influence the processability and the properties of the final drug. The benefits of Anton Paar s non-ambient X-ray diffraction sample stages are: In-situ characterization of the crystal structure Determination of changes in the chemical composition Determination of temperature- and humidity-induced changes of active pharmaceuticals and pharmaceutical formulations Measurements can be performed in vacuum, air, controlled humidity or inert gas Temperature-dependent diffraction studies in the range from -193 C to 450 C 16 Anton Paar s instruments for non-ambient XRD measurements: Cryo- and Humidity Chamber CHC plus + Low Temperature Chamber TTK 450

Small-angle X-ray scattering allows the non-destructive investigation of the structural behavior of various materials, such as active pharmaceutical ingredients, proteins, emulsions and dispersions, in the nanometer range from 1 nm to 100 nm. SAXS is used to obtain relevant information from pharmaceuticals in the solid and in the liquid state, during production and in the final dosage form. This includes shape and aggregation state of for example proteins in solution, particle size of emulsions and dispersions, size distribution, molecular weight and inner structure. These structural parameters can influence the thermal stability, solubility, dissolution times and the compactness, which can influence the shelf life of pharmaceuticals during storage and transport. The measurement from small to wide scattering angles provides complete information on the structure and the phase state of the pharmaceutical. The benefits of Anton Paar s small-angle X-ray scattering system are: Compact design and short measuring times Unique X-ray optics guarantee very low background scattering, i.e. for weakly scattering materials such as protein solutions Temperature-controlled sample holders for solids and liquids down to the µl range Autosampler with cooling option for high-throughput screening of samples TrueSWAXS simultaneous and continuous measurement from small to wide scattering angles in one run for complete information on the structure and the phase state of a drug Consistently high resolution over the entire measurement range Excellent data quality Powerful software for data acquisition, data processing and evaluation Anton Paar s system for SAXS/WAXS measurements: SAXSess mc 2 17

Zeta Potential Analysis Anton Paar s SurPASS for zeta potential determination is a suitable analyzer for characterizing the surface behavior of various solid materials for pharmaceutical applications. The zeta potential determination based on the streaming potential or streaming current method supports the investigation of materials such as polymers, glass or metal surfaces which are used in medical devices such as medical drip tubes or hemodialysis membranes, or as containers for drugs. It is important to determine whether components, such as APIs, additives and proteins, adsorb on the material s surface. Unsurpassed possibilities with a wide range of sophisticated accessories The benefits of Anton Paar s zeta potential analyzer are: Applicable for almost all kinds of solid surfaces Various measuring cells for a wide range of different materials Determination of the zeta potential of porous and swelling materials Fully automated measurements of ph and additive dependencies Integrated titration unit provides high-resolution dispensing of liquids Excellent measuring sensitivity due to continuous control of volume flow rate, differential pressure and cell resistance together with precise measurement of streaming potential and streaming current Intuitive control and evaluation software 18 Anton Paar s zeta potential analyzer: SurPASS

Modular Systems As an alternative to using a number of single instruments, Anton Paar provides systems for measuring a series of parameters in one cycle. As pharmaceutical materials can be very expensive, it is useful to measure a defined series of parameters on one single sample to monitor and characterize the material and formulation. Parameters which can be measured with Anton Paar s modular systems include density, refractive index, optical rotation, ph, turbidity and sound velocity. Define which parameters to measure and the modular system is configured accordingly Equip your laboratory to suit your individual needs and benefit from Anton Paar's wide range of instruments and accessories to automate your measurement routines. The benefits of Anton Paar s modular systems are: Non-stop operation increases productivity One sample for all routine parameters Non-destructive measurements enable reuse of samples and minimized waste One combined system saves lab space Automation minimizes errors and saves time Easy to use and clean Error-free sample handling ensures full repeatability Audit trail provides full data security and traceability Used methods comply with pharma-relevant regulations and pharmacopoeias Anton Paar s modular systems are available as two solutions: Simple Plug and Play modular systems: for combination of density and concentration measurement with refractometry, turbidity, ph, sound velocity and a wide range of autosamplers PC-based modular systems: for all above-mentioned parameters in combination with measurement of optical rotation and/or color 19

Online Process Instruments The analysis of process-sensitive parameters provides insight into the real-life conditions of products in the pipeline. Controlling the production process at every stage contributes to optimizing the production and output, which subsequently results in efficient use of raw materials, excipients and APIs as well as environmental resources. Anton Paar provides process instrumentation for density and concentration measurements and a unique solution for determining optical rotation. Using lab and process instruments based on the same technologies allows direct comparison of results The benefits of Anton Paar s process instruments are: Sensor has no influence on the process Robust and durable sensors for continuous operation Low maintenance Easy integration into the process (in-line or bypass) High resolution and repeatability A variety of wetted parts, materials and process connections are available to suit each application. Anton Paar s process instruments: Density and concentration measurement: DPRn, L-Dens, SPRn, DSRn Evaluation units: mpds 5 available in combination with the DAVIS 5 evaluation software Optical rotation measurement: Propol automatic process polarimeter 20

For details on Anton Paar s instruments refer to www.anton-paar.com or email info@anton-paar.com 21

90 Years of Innovation Measurement solutions from Anton Paar are developed and produced entirely in-house. In the fields of density and concentration measurement, rheometry and CO 2 measurement, Anton Paar is a global market leader. From the first hint of an opportunity to the final touches before shipping, over 1300 people with diverse talents, skills and mindsets join forces to provide you with results of relevance. Investing 20 % of its turnover into Research & Development, and closely cooperating with external scientific partners, Anton Paar continuously strives to find new solutions and to further improve existing ones to meet your present and future needs. A company s responsibility Producing solutions for your applications, Anton Paar is aware of its responsibility to guarantee you lasting success. This responsibility goes hand in hand with another: Every company s social responsibility for its employees and society in general. At Anton Paar, this is a tangible reality a promise made measurable. The Santner Foundation Anton Paar GmbH is owned by the Santner Foundation, a non-profit organization exclusively and directly aimed at charitable work and serving the public good. Its proceeds are targeted at financing research in the fields of natural science and technology, as well as addiction prevention and rehabilitation. 22

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Anton Paar GmbH Anton-Paar-Str. 20, A-8054 Graz Austria - Europe Tel.: +43 (0)316 257-0 Fax: +43 (0)316 257-257 E-mail: info@anton-paar.com Web: www.anton-paar.com Specifications subject to change without notice. 05/11 XDIP005EN-A