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METTLER TOLEDO supports the pharma industry The pharmaceutical industry is facing substantial challenges: R&D productivity is decreasing due to the costly development and time-consuming nature of new blockbusters and industry legal requirements are becoming more demanding. It is important to collaborate with a competent partner for laboratory equipment in order to overcome these challenges. METTLER TOLEDO has the superb knowledge and understanding of the pharmaceutical industry necessary for such a partnership.
Difficult times for pharma Pharmaceutical companies have been under considerable pressure during the last few years. The rush of merger in the industry has not brought the flood of novel drugs they were hoping for. Only 20% or 30% of the drugs launched in recent years were first or second in their class. Producing a truly innovative drug requires more money and resources than previously. Legal requirements force pharmaceutical companies to constantly inspect their quality management procedures and also protect employees from harmful substances. Stringent rules are applied to the pharmaceutical production and quality control in particular. As a result, manufacturing and quality control departments are often subject to audits by the FDA or other regulatory bodies.
Competent partners As an important aspect of one of our segment initiatives, METTLER TOLEDO investigated the specific requirements of the pharmaceutical industry. It is our aim to maintain understanding and to be a competent partner providing the best solutions. Some of our products are especially tailored to the highly regulated pharmaceutical industry. They help pharma companies to comply with regulations such as GMP and GLP. Some examples are ● A balance that allows one to set a minimum weight as specified in the USP regulation ● Customizable printouts to guarantee that all weighing results are documented and traceable ● A fully automatic titrator permits better and faster sample analysis in the quality control.
Successful and forward-looking pharmaceutical and biotechnology companies contact METTLER TOLEDO. Our sales force are enthusiastic to demonstrate our products and are capable of finding the right solution for your specific application and need. X www.mt.com/pharma
Contents PharmaNews 1 METTLER TOLEDO supports the pharma industry
Automatic weighing data capture: the busy day of a LabX system Would you like to collect your weighing data electronically yet keep
Automatic weighing data capture: the busy day of a LabX system The new Excellence Plus XP analytical balance Thermal analysis used for pharmaceutical screening – Part 1
using a balance as simple as it is today? This article demonstrates how data may be collected independent of any PC with the METTLER TOLEDO LabX system. Data is stored in an industry-standard database, readily available for subsequent viewing, reporting, signing, exporting or printing from any of your lab or office PCs. LabX helps to avoid costly errors thanks to powerful instrument management functionality. Rely on LabX to fully administer your installed balance base and enhance process security within your lab.
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Imprint Publisher Mettler Toledo GmbH Laboratory & Weighing Technologies Im Langacher CH-8606 Greifensee Switzerland Production Laboratory Marketing Support Switzerland Technical Articles Mettler Toledo GmbH – Laboratory & Weighing Technologies – Analytical Instruments
Subject to technical changes. © 2005 Mettler-Toledo GmbH Printed in Switzerland.
Benefit from easy data capture Gisela is a new lab assistant in the process development lab of a large pharma company. She began her job last week.
log into LabX via the balance display; a 21CFR Part 11 requirement . The system gives the calibration weight and guides Gisela through the calibration procedure.
“I got a quick introduction to LabX balThe second job is a mass uniformity ance from one of the lab technicians. That check of 20 capsules. Gisela weighs the was very easy for me because I knew the filled capsules and pauses the job, then LabX titration software washes and dries the from my former position capsules. Finally, she as lab assistant in the proresumes the job by duction facility across the weighing the 20 empty river. Just change “titracapsules. The system tion method” into weighcalculates the weight ing “job template”, that’s difference between the it. In practice, with AX 2 sample series. She User Name and password are entered from the and XP balances, you do promptly accesses the balance display. not have to touch a comjob report from the lab puter to weigh your computer. All points are samples. As you can see on nicely distributed the balance display, I have around the target value 3 jobs waiting in the XP job with none falling queue”. outside the specified limits. Tom, the lab The first job waiting in manager, will evaluate Easy data transfer in only one touch. the XP job queue is the the report from his daily balance check. Gisela selects this job office PC before noon, sign it electronically from the balance’s touch screen display. and report to his customer accordingly. She enters her user name and password to
Gisela’s final job on the list is HPLC standards preparation. The balance prompt here is slightly different. This time, Gisela enters solvents names in addition to the sample identification. In the background, both identifications are exported, together with weight value, time stamp and user identification, into the LIMS. This information is then transferable to the HPLC system. Improve data reliability Dee, a metrology specialist, relies on LabX to administer the 20 most critical balances on site. She has just learnt that the AX205 in the Analytics Lab did not pass the daily check this morning. From her office PC, she notices the last daily check marked as unsuccessful in the calibration history. The numerous FACT records (automatic adjustments of the balance) indicate an unusual instability for the last 3 days. Two weeks ago, the repeatability check still fell within the most stringent tolerances. “Maybe some changes in the air conditioning? Let’s call the lab technician. This level of data traceability was unreachable without LabX! Imagine, it happened to me
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twice to find FACT tickets in the trash bin! Additionally, weighing data is more reliable. The balance is automatically locked for critical weighing tasks until the daily check is successfully executed. That could be worth to add some more instrument licences into the system to connect the 5 balances of the Toxicology Lab.” Thanks to the external test administration, Dee has the overview.
If you would like to learn more about our LabX systems and how they can connect all lab balances and titrators in order to ensure data security please visit our web site: X www.mt.com/labx
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The new Excellence Plus XP analytical balance Accurate results are crucial within daily workings of the pharmaceutical industry. Increasing productivity is key throughout any company, while stringent regulations must be fulfilled simultaneously. Analytical balances must support the requirements of today and be ready for the future. METTLER TOLEDO has innovated ‘MinWeigh’, which warns the user when a minimum weight value is violated. As this function is essential for pharmaceutical companies, it has now been further developed for the XP analytical balance.
Hands-free operation with SmartSens Dealing with hazardous or expensive substances are daily tasks when weighing in a pharma lab. The built-in ‘SmartSens’ sensors enable you to focus on the safe handling of those valuable substances to avoid spillage and minimize the risk of contamination. Both sensors can be set for different tasks, enabling the user to tare, print and open the draft shield without touching the balance at all. Secure and fast results The XP Series provides unparalleled weighing performance and ergonomics. The unique ‘SmartGrid’ weighing pan, in combination with the high resolution weighing cell and the adjustable inner draft shield, offer fast and highly reproducible weighing results day after day. This assures that you can weigh in even the smallest sample sizes according to your regulations and increases the yield of expensive substances. ‘Ergoclips’ are a further contribution to efficient weighing that can be connected to the grid, enabling the possibility
to place any tare container safely and securely onto the weighing pan. Seamless documentation Besides weighing, sample documentation is another important pharma industry requirement . Up to four identifications per sample can be easily entered using the keypad. Printouts are freely definable to fulfil all compliance demands. The XP analytical balance is equipped with fully automatic internal adjustment (proFACT), stored in a history file, which secures its performance. This provides the highest level of accuracy with automatic linearization and temperature compensation.
MinWeigh for certain minimum weights The function MinWeigh provides outstanding support for the pharma industry where guidelines of a quality assurance system, such as GLP or GMP, apply. Since balances are integrated into the company’s quality management system, measurement uncertainty cannot be left to LevelControl sends a shrill warning signal, and shows you, right in the display, exactly what you need to do to level the balance.
chance and must lie within defined limits. How large must the minimum weight be in order to stay inside the tolerances of the quality management system? The basic settings, which depend on the location of the balance, are entered by a METTLER TOLEDO service technician. The technician performs all necessary measurements, according to the specifications of your quality assurance system, and determines the allowed minimum weight with the best possible settings and the typically used tare weights.
Weighing can begin immediately without checking the balance level as the function LevelControl automatically warns when the balance is not levelled. It then displays easy-to-follow instructions how to adjust the balance. If the results fall below the allowed minimum sample weight MinWeigh warns with the results displayed in red.
The XP analytical balance offers unprecedented data security and user safety.
The advantages of MinWeigh
If the weight falls below the allowed minimum sample weight according to the regulation applied, MinWeigh automatically warns the user, with results displayed in red and an asterisk beside the weight value on the printout. The XP has the unique capability of storing up to three different minimum weight values (e.g. one minimum weight determined according to USP, another according to the internal SOP) which can be activated when needed.
• The balance warns if the weight falls below the minimum value. • The balance settings cannot be changed. • Weighing results that are too low are marked on the printout. • The weighing results meet the specifications of the certificate and, therefore, the guidelines of your QA system. • Up to three MinWeighs with associated minimum weighing values may be entered. • Switchover between three different taring ranges is automatic. • Information about parameters and tare weights is shown on the display of the balance terminal.
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• A warning is displayed if MinWeigh has expired and needs to be renewed.
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Thermal analysis used for pharmaceutical screening – Part 1 Polymorphism and pseudo-polymorphism are important fields of study
USP standards require the dissolved ion content (conductivity) to be mea-
for the thermal analyst. Pharmaceutical organizations need to be aware
sured. The measurement of the conductivity depends on several factors
of the possible occurrence of polymorphic behavior of active ingredi-
such as the dissolved ion content, the temperature and the dissolved gases
ents in order to optimize production and storage conditions so that
(usually CO2) and therefore not specific to a single dissolved specimen. Specialists have finally come to an agreement on two specimens of low conductivity (Cl- and NH4+) in order to determine thresholds (1.33 mM or 1.66 mM) as a function of temperature (see table below).
only the desired form is present. Thermal analysis techniques are widely used for screening, crystallization and storage optimization. The measurements provide companies with valuable information of great benefit to the drug development process. Part 1 of this topic focuses on polymorphism where the key issues are identified and a case example is given using thermal analysis techniques. Polymorphism and DSC Polymorphism is the term used to describe the ability of a pharmaceutical substance to exist in several different crystalline forms. It is important to understand the
erties of polymorphic forms, such as melting point, heat of fusion, solubility behavior and bio-availability, can vary considerably. Polymorphism is particularly important in the pharmaceutical industry where safety and reliability are of paramount importance. Differential scanning calorimetry (DSC) is a technique widely used to detect
Sulfapyridine Analysis A good example of this is the analysis of a sample of sulfapyridine after shock-cooling from the melt. The transitions that occur on heating can be particularly well observed using thermomicroscopy in the transmission mode with polarized light. Spherolites are produced through cold crystallization from the originally amorphous material. This metastable form then melts and immediately crystallizes to the stable rhombic modification, which in turn melts at about 190 °C. The corresponding DSC heating curve shows the fusion and recrystallization of the different modifications. Microscopy images were taken at 110 °C and 180 °C, allowing visual interpretation of the results to be made. X www.mt.com/ta
properties of active pharmaceutical ingredients so that crystalline forms can be developed that provide the desired drug delivery rate. Even though the chemical composition is the same, the physical prop-
and investigate polymorphism in substances. Thermal microscopy can be used to visualize and interpret the different crystal modifications and transitions between polymorphic forms.
USP and EP “Water is the most widely used substance, raw material, or ingredient in the production, processing and formulation of compendial articles.” Chapter 1231 of the United States Pharmacopoeia (USP) begins with these words in the article “Water for pharmaceutical purposes” which are repeated in the European Pharmacopoeia (EP). The preparation of drinking water, purified water, distilled water and sterilized water for injecting, rinsing or inhalation preparations, or the determination of the total organic carbon (TOC) or ionic content (conductimetry) are all codified by the USP and the EP. Overall, the European Pharmacopoeia remains more demanding, more precise and, above all, requires measurements to be carried out at 20°C, which precludes on-line analyses. Harmonization is currently underway. METTLER TOLEDO monitors these evolutions closely and offers you the material support necessary with the “SevenMulti” in view of this harmonization. Temperature in °C
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On-line Analysis or spot laboratory analysis The USP proceeds in 3 steps which allows all users to implement this method :
tivity. The water meets the USP directives if the measured values comply with those given in the table. X www.mt.com/ph
Step 1: Measures the conductivity without contact with atmospheric gases (CO2) as well as the real temperature without any temperature compensation. It then compares this measurement with the value given in table 1 at the same temperature. If it is lower than the value given in the table the analysis is complete. Step 2: Pollution by atmospheric gases cannot be avoided. A sample of at least 100 ml is agitated at 25+/-1°C in an open recipient until the variation in conductivity stabilizes out at less than 0.1 µS/cm for 5 minutes. If the resulting value is less than 2.1 µS/cm the sample is “in specification” and the analysis is complete. Step 3: When the measurement is “out-of-specification” one has to add (within 5 minutes of the end of step 2, under agitation and at the same temperature) a saturated KCl solution (0.3 ml/100 ml) and then measure the pH and the conduc10
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Role of the SevenMulti™ The SevenMulti has numerous advantages making it the ideal choice for the USP: • Most measurements are satisfied at step 1. In USP mode, the SevenMulti deactivates the temperature compensation, integrates the table into its memory and indicates directly whether the sample is in specification or not. Its sensitivity is 10 times that required by the USP. • The SevenMulti offers the possibility of carrying out measurements at regular intervals (step 2). • The SevenMulti produces and memorizes a complete report in compliance with the BPL/BPF. • METTLER TOLEDO ensures regular software updating, as a function of modifications to the USP, and offers installation and operational qualification protocols (IQ/OQ) as well as periodic certifications of the SevenMulti. The InLab740® electrode makes it an indispensable tool.
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Conductivity limit in µS/cm 0.6 0.8 0.9 1.0 1.1 1.3 1.4 1.5 1.7 1.8 1.9 2.1 2.2 2.4 2.5 2.7 2.7 2.7 2.7 2.9
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We share our knowledge Learn from what we have learned. Our knowledge and experience are at your disposal - in print, on the web, and also increasingly available on CD-ROM. Each document can be used as a reference book, glossary, or guide to inform you of the manner by which METTLER TOLEDO applications laboratories are developing and constantly refining methods for a wide ranging variety of purposes.
Application booklets for the pharma industry Titration:
– Applications in the pharmaceutical industry: “METTLER TOLEDO Titration”
Thermal analysis:
– Pharmaceuticals: “Collected Applications Thermal Analysis”
itration www.mt.com/t a www.mt.com/t
Product literature 1 2 3 4
Excellence Plus XP analytical balance Excellence Plus XP precision balance LabX instrument control software Analytical instruments by Seven 1
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Technical documents 5 Balances in Quality Management – an aid to model selection 6 Quality Management – the permanent assurance of quality 7 Quality factor MinWeigh 8 Basics of titration
Mettler-Toledo GmbH Laboratory & Weighing Technologies Im Langacher CH-8606 Greifensee Switzerland
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Mettler-Toledo GmbH Analytical Instruments Sonnenbergstrasse 74 CH-8603 Schwerzenbach Switzerland
