Enable a “Culture of Quality”€¦ · Data Integrity and Automation Enable a “Culture of...

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Pharma & Biotech

Analytical solutions in the laboratoryAugust 2014

Data Integrity and AutomationEnable a “Culture of Quality”

The QA management system at Novartis has clear objectives: efficiency, compliance and traceability with complete data integrity. Their ChemOps site in Brazil set the goal of ensuring data integrity and simplifying analytical processes. With the help of LabX® software validated for multiple instruments, their goal has been achieved.

Novartis is a well-known global leader in health care with their headquarters located in Basel, Switzerland. The com-pany has around 135,000 employees in 140 countries worldwide. In Brazil, Novartis has over 3,000 employees in 4 different locations. One of these oper-ations, ChemOps in Resende, produces a wide range of active pharmaceutical ingredients (API) and their intermedi-ates used in the production of therapeu-tic drugs. Intermediates of the Diovan® compound are the main product of the site today.

The “Culture of Quality” projectChemOps in Resende is part of the Novartis “Culture of Quality” project. The major objective of the project is to ensure data integrity, i.e. records of ana-

lytical results that cannot be manipulat-ed by the user. This project led to various actions in their analytical sector.

A wide selection of METTLER TOLEDO instruments are involved in quality control analysis at the Resende site with the latest installations being an MP90 melting point instrument and an RM40 refractometer. Both are fully validated in compliance with 21 CFR Part 11 through LabX, a software solution that controls most of the instruments, automates the analysis and manages the data. The key goal of this installation was to improve the reliability and tracking of analyti-cal results through enhanced automa-tion which, in turn, improves product quality.

Publisher Mettler-Toledo AG Laboratory Division Im Langacher CH-8606 Greifensee, Switzerland

Production LAB Division MarketingGlobal MarCom Switzerlandwww.mt.com/lab-segmentnews

Subject to technical changes. © Mettler-Toledo AG 08/14 Printed in Switzerland.

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Manager and operator satisfactionNovartis QC lab manager Silvio Toledo already feels the benefits of the LabX soft-ware system, “Thanks to integrating the MP90 and RM40 instruments with LabX, the reliability and traceability of analyt-ical results has increased significantly. The improved automation of the system has contributed to the increased qual-ity of our analytical results and reports. In 2012, ChemOps Resende achieved the largest number of batches analyzed by full time employees out of all the ChemOps Novartis sites.”

Several Novartis employees have now had hands-on experience with the validated LabX system. These operators are highly satisfied as, “The user interface is intui-tive and easy to use. There is an excellent

“task fields” tool where we can add rele-vant warnings if necessary. Another great feature is the option to make calibration compulsory if necessary. This greatly fa-cilitates the daily laboratory routine, re-duces paperwork and fulfills 21 CFR part 11. The practicality of an integrated sys-tem run by a single software is fantastic. It not only helps with our daily analyses but also when searching for results in the audit trail.”

Novartis Resende have now added to the instruments already managed by LabX and have connected a larger number of balances to this data-management sys-tem.

Thanks to METTLER TOLEDO’s LabX software system, ChemOps Resende gets

consistently high quality results with simplified workflows and increased ef-ficiency. Another positive step achieved towards Novartis’ “Culture of Quality”.

Text: Christoph JansenMarket Manager SBU AnaChem

www.mt.com/LabX

Left: OneClick™ to your desired methodRight: Melting Point sample capillaries

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Compatibility StudiesSupport Drug Formulation

The potential interactions between active ingredients and excipients can affect the chemical nature and stability of drugs. DSC delivers key insights into these interactions to develop optimal drug recipes.

In the pharmaceutical industry, the next step after developing an active ingredi-ent is to formulate a drug product. DSC is an important method at the pre-for-mulation stage for quickly obtaining in-formation concerning different formula-tion component interactions. Desirable interactions improve the solubility of an active pharmaceutical ingredient (API). In contrast, undesirable interactions may reduce the activity of the API.

Two substances are compatible if the melting behavior of an API in an excip-ient remains unchanged and if the en-thalpy of melting observed, corresponds to that expected from the concentration of the substance.

API-excipient compatibility experimentsThe experiment below displays the endo-thermic melting curves of pure irbesartan (top), pure lactose (middle) and a 50/50 mixture of irbesartan and lactose (bot-

tom). Pure irbesartan exhibits a melt-ing peak at about 185 °C and pure lac-tose monohydrate shows a peak at about 146 °C, which is related to the evapora-tion of water. Since there are no signifi-cant changes in the melting peak of the mixture, we can conclude that irbesartan is compatible with lactose monohydrate.

The second diagram shows the DSC heat-ing curves of pure acetyl-salicylic-acid and calcium-stearate together with a mix-ture of both substances in a one-to-one concentration. The curve of the mixture displays only one endothermic peak at a temperature much lower than the peaks of the two pure constituents. This demon-strates incompatibility due to strong inter-actions between the two substances.

Text: Matthias WagnerMaterials Characterization Product Manager

www.mt.com/dsc

Figure 2: Incompatibility of calcium stearate and acetylsalicylic acidFigure 1: Compatibility of Irbesartan and lactose

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Understand and Control Bioprocesses with Inline Analysis

Improving the yield, quality and batch-to-batch repeatability of bio-products is challenging. Scientists are under increasing product demands and are turning to inline Process Analytical Technology to address these issues.

As demand for bioproducts increases, so does the need for fast and accurate bio-process monitoring to ensure efficient process control and, in turn, maximize productivity and product purity. Tradi-tional inline bioreactor measurements, such as pH, temperature, dissolved oxy-gen, CO2 and agitation speed, etc., pro-vide some process data but do not offer in-depth understanding of the health, nutrient demand and metabolite pro-duction of the culture. Likewise, offline techniques are labor intensive and do not truly represent a process as it exists in re-al time. This culminates in delayed pro-cess control decisions and batch-to-batch variability.

Optimizing fermentationReactIR inline FTIR spectroscopy simul-taneously measures, in real time, the concentration of multiple growth medi-um components and metabolites during the course of a bioprocess, such as fer-mentation. It offers many advantages in-cluding eliminating the need for sam-pling and sample preparation (as data is acquired in situ), quantitative informa-tion through Multivariate Analysis (MV-DA) and utilizing ATR probes designed to withstand harsh and variable environ-ments.

ReactIR is a non-invasive and non-de-structive technology that allows re-searchers to gain insight into the bio-process enabling them to answer key questions about the reaction under inves-tigation.

Text: Vaso VlachosSegment Market Manager

www.mt.com/ReactIR

Broaden your knowledge of how in situ spectroscopy im-proves bioprocesses.

Download our whitepaper now

www.mt.com/wp-bioprocesses

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Modern Electronic Pipettesfor Compliance-Based Labs

GLP/GMP compliance and regulatory requirements have become more demanding in recent years. Functionalities in modern electronic pipettes help achieve seamless traceability and adherence to internal SOPs.

For many labs, an SOP requires pipettes to be calibrated on a specific frequency throughout the year. If the pipette is used outside of that calibration date, without an updated calibration record, the lab is liable to fail an audit. The new Rainin XLS+ pipettes are all equipped with RFID tags that support the routine monitoring of pipette calibration date requirements.

Control the end productMany compliance-based labs are look-ing to have all of their manual liquid handling work carried out using an elec-tronic pipette in the belief that there is greater end product control. However, the next hurdle in such an environment is to restrict the use of these pipettes to only performing specific tasks.

With most pipettes, the operator can make mistakes in minor programming adjustments on their pipette. The new Rainin E4 XLS+ features an admin mode setting, which permits Lab managers to remove unwanted modes or lock settings and this minimizes pipetting SOP devi-ations. This is the ideal solution in labs where only certain applications are per-mitted. E4 XLS+ also features password protection and onboard service data. The new features in electronic pipettes are key elements in achieving GMP / GLP com-pliance in regulated environments.

Text: Murray AndersonRainin Marketing Head

www.mt.com/e4-xlsplus

E4 XLS+

Save your Protocols!Store multiple custom protocols in the on-board memory. Simul-taneously review and select your protocols with a simple move-ment of the joystick. No more re-entering preferred protocols over and over again!

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Gravimetric Dilution a Leap in Concentration Accuracy

Preparing dilutions is a standard task in most pharmaceutical labo-ratories as it is used extensively to study drug properties. However, creating accurate solutions with concentrations as low as 1 ng/mL is challenging. The Quantos QA3 liquid dispensing system uses gravimet-ric methods to produce highly accurate and traceable concentrations.

Pharmaceutical solutions frequently con-tain a very low (down to 1ng/mL) con-centration. In order to prepare such solu-tions in the lab, single or serial dilutions are performed, i.e. a stepwise source so-lution dilution in solvent. Typically, a 1-step dilution is prepared by pipetting the source solution into a volumetric flask and filling it up with the solvent to yield the required dilution. Alternatively, both the source solution and the solvent may be pipetted.

Known dilution problems A 1-step dilution is a fast and simple method, but has certain risks attached when used in regulated environments. If the pipette or flask is not at the calibrated temperature a high degree of error may be introduced. Bubble inclusions can al-so affect the volume pipetted but there is no way of clearly identifying this. In ad-dition, transcription or calculation errors can also impact the final result. Serial dilutions, on the other hand, yield more accurate solutions but calculation errors are amplified across each subsequent dilution.

In a protein binding experiment, for ex-ample, samples taken from the reaction process need to be diluted by a factor of 10,000 from a concentration of around 0.01 mg/mL down to the detection limits of around 1 ng/mL. This can be achieved by diluting in the ratio 1:10 four times. At each dilution step any error becomes larger. After analyzing the diluted sam-ples, the analytical results are back-cal-culated using the assumed dilution fac-tor to determine the precise composition of the original samples. Clearly, if the as-sumed dilution factor is not correct, this will directly affect the final results.

All-in-one solution: XP analytical balance, Rainin pipette and Quantos gravimetric dosing system.


A gravimetric approachIn the gravimetric approach, the source solution is pipetted into a tared vial on either an analytical balance or a micro-balance. In order to produce accurate and repeatable results, it is recom mended that the initial amount of source solution should not be smaller than around 50 µL (~ 50 mg). Using a vial with a narrow neck minimizes errors caused by eva-poration.

The Quantos liquid dispensing module then automatically dispenses the sol-vent using a micro-valve directly into the same vial on the balance to obtain the desired concentration. The correct amount of solvent to be added is calcu-lated automatically and is based on its weight.

Process robustnessThe major advantage of this process is that all steps are carried out on the bal-ance and that the weight is recorded au-tomatically at each step: Vial tare weight,

source solution weight added to the vial and dispensed solvent weight. Full trace-ability of the process is assured. In addi-tion, bubble inclusions and temperature deviations do not affect the weighing re-sult and all calculations are carried out automatically. Operators simply select on the Quantos display to perform a di-lution based on a ratio, e.g. 1:15, or a tar-get concentration, e.g. from 12 mg/mL to 0.3 mg/mL and the rest is carried out automatically.

The Quantos gravimetric dilution pro-cess greatly improves results by pro-viding highly accurate concentrations whilst minimizing errors and assuring full traceability.

Text: Lars MüllerQuantos Product Manager

www.mt.com/quantos

Gravimetric Sample PreparationWatch the videos and webinars or read related white paper and brochures.

www.mt.com/q-gsp

Know

-How Don’t Let Electrostatic Charges

Influence Your Weighing Results

One of the most common problems experienced when weighing dry substances in a laboratory environment is the influence of electrostatic charges, leading to inaccurate weighing results. The new XPE analytical balance offers a unique technology to detect electrostatic forces, measure its influence in the weighing and eliminate them.

StaticDetect™

Built-in StaticDetect technology warns you when electrostatic charges affect the weighing results above your defined threshold.

ErgoClip™

The ErgoClip basket for plastic and glass tubes shields the weighing pan from electrostatic changes. Small tubes also reduce the risk of creating charges.


Download the ‘Electrostatic Charges in Weighing’ whitepaper

www.mt.com/lab-electrostatic-weighing

Antistatic Kit

Attach the Antistatic kit to the analytical balance and eliminate charges without causing turbu-lences in the weighing chamber.

FAQ Electrostatic Charges in Weighing

1. What are electrostatic charges?An electrical charge on the balance or vessel to be weighed causes electrostatic forces. Electrostatic forces can alter weighing results either increasing or diminishing the real weighing value.

2. How are electrostatic charges originated?Friction is the most common way that electrostatic charges are generated. However, under climate controlled environments, such as the typical analytical lab, charges are more easily generated and lead to greater source of error. Weighing a small quantity of dry sample into a large glass or polymer vessel will also significantly increase the error of the weighing result.

3. How do they influence weighing results?Electrostatic charges exert forces on the sample to be weighed and the weighing pan, thus causing significant falsification of measurement results. Inaccurate weighing results range from few milligrams up to 100 mg.


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www.mt.com/LR-universal www.mt.com/LR-LTS

No more ‘dead spots’ The entire tip surface is covered with a uniform field of highly repellent flu-orines. This improves pipetting accu-racy when using viscous and adherent sample solutions.

Pipette Proteins, Enzymes and DNAwith Low-Retention Tips

Conventional pipette tips exhibit low wettability with aqueous solutions due to the intrinsic hydrophobicity of polypropylene. However, this hydrophobic property hampers pipetting viscous or other problematic liquids and molecules, which can interact with the tip surface. METTLER TOLEDO has recently launched a new set of Rainin low-retention tips with improved repellent properties.

Prevent liquid retention The highly repellent tip surface guar-antees uniform fluid movement across the internal tip surface to ensure com-plete sample aspiration and discharge regardless of fluid composition.

Complete offering The new Rainin Low Retention tips are available in a comprehensive range of tip styles, sizes and packaging options to accommodate every application.


www.mt.com/synthesis-workstations

Enhanced reaction understandingBy incorporating inline probe tech-nology into synthesis workstations, re-searchers easily obtain in-depth reac-tion knowledge in real-time.

Complete More Researchwith EasyMax Advanced

R&D departments are continually striving to improve quality, reduce costs and increase development speed. EasyMax Advanced provides real-time, in-depth reaction information to speed up the investigation process thanks to 24h temperature control. By replac-ing traditional round bottom flasks and jacketedlab reactors with EasyMax Advanced, scientists can quickly develop new synthetic routes, eliminate non-viable candidates earlier and improve reac-tion optimization.

Volume flexibilityUtilize the smaller 100 mL volume re-actor for reaction screening and op-timization and the larger 400 mL for scale-up experiments and crystalliza-tion studies.

Data capture and analysis All experimental data is captured to provide enhanced control and under-standing of reactions. Complete data capture enables institutional knowl-edge building and sharing.

www.mt.comFor more information

www.mt.comFor more information

Mettler-Toledo AGLaboratory DivisionIm LangacherCH-8606 Greifensee, Switzerland

Local contact: www.mt.com/contacts

Broaden Your Lab Knowledgeat www.mt.com/lab-library

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