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Streamline Your Sample Preparation

Fri, 11/21/2014 - 10:15am
Joanne Ratcliff, PhD, Communications Project Manager, Laboratory Weighing Group, Mettler-Toledo AG

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In gravimetric sample preparation, both solids and solvents are weighed to prepare specific, precise concentrations, which helps to minimize out-of-specification errors. In nearly every case, this revolutionary method also enables productivity gains and substantial reductions in sample and solvent usage, resulting in monetary savings.

Joanne Ratcliff, Ph.D.Out-of-specification (OOS) results can have a significant impact on the profitability, and even reputation, of a pharmaceutical company. Take, for example, the much-referenced Barr Labs case in 1993, which caused the U.S. Food and Drug Administration (FDA) to revise their guidelines on handling OOS laboratory investigations.

Since that groundbreaking court case, the FDA has issued hundreds of observations concerning poor handling of OOS investigations. These observations indicate that not only are these types of errors more common than they should be, but also that labs have a hard time showing they understand what caused the error. Without systematic changes, they may also have a hard time proving that the error won’t happen again.

Why do labs have such difficultly getting a handle on the source of OOS results? Part of the answer can be attributed to the still-common practice of manual volumetric sample preparation. Workflows to prepare samples manually using volumetric flasks have not changed significantly in nearly 100 years. During this time, however, the substances have become more refined, more potent and, in many cases, more hazardous to handle— like the risk of airborne and surface contamination.

The time has come for a revolution in the way solid and solvent components of solutions are handled and measured. Dosing and balance technology has evolved to such a degree that gravimetric weighing— even for very small quantities— can promote greater accuracy, safety and cost-effective sample preparation on an ongoing basis than even the most consistent human operator using volumetric methods.

Where do errors come from?

Based on widely-publicized and widely-accepted surveys of lab practices, the largest single source of lab errors in an analytical workflow are human and sample-processing errors. There are many aspects of manual volumetric sample preparation that are subject to variability or uncertainty and can lead to imprecise concentrations and results. These include:

  • Glassware failure. A 2005 paper published by Coleman and Harris from NIST said the failure of new glassware to meet Class A specifications has been found to be as high as 50 percent.
  • Temperature. Volumetric flasks are typically calibrated for use at 20 C. Any significant temperature change of the solution can cause errors. Causes can include endo- or exothermic reactions in the flask or sonication steps. If care is not taken to return the flask to proper temperature before filling to the line, errors can result.
  • Contamination. Qualification of washing systems is difficult, which makes pre- and post-rinsing of flasks critical. If this step is missed, errors can be introduced here as well.
  • Revalidation. Volumetric glassware should be calibrated at least once every 10 years. In a high-volume lab, the cost of this process in terms of time and energy can be enormous. It can almost seem easier to replace existing stock in spite of the waste and expense.
  • Tolerance. NIST publish tolerances (relative percentage errors) associated with each size of volumetric glassware in use today. As the size of the glassware decreases, error-risk increases. This is not ideal when working in pharmaceutical development or other situations where sample sizes tend to be small.
  • Labeling. OOS results can arise from labeling mix-ups during manual processes. These types of errors are usually caught during audit. (Permanent marker labels must also be removed before beakers are sent out for cleaning or calibration.)

Confidence in the accuracy of gravimetric preparation

Quantos, a gravimetric sample preparation system from METTLER TOLEDO.Now, there is a new technique: gravimetric sample preparation, as described in United States Pharmacopeia (USP) 1251, which involves weighing both the solid and the solvent into a vial or container on the balance. The gravimetric method eliminates the potential error sources associated with volumetric flasks, listed previously. The end result is more accurate, consistent dosing.

The technology available to facilitate gravimetric sample preparation varies. However, in general, powders and liquids are both delivered into small, disposable target vials positioned on an analytical or semi-micro balance to achieve a concentration specified by the user. Spatulas are not needed and cross-contamination risk is eliminated by use of an individual dosing head for each powder storage container.

The safety benefits for the operator are also significant. With the powders contained inside the dosing head, there is little chance for them to become airborne and exposure risk is subsequently minimized.

Gravimetric sample preparation makes diluent addition an easier task. If the dosing of a specific amount of powder is overshot (either manually or automatically), the amount of diluent is automatically increased to keep the concentration consistent. The problem is solved without wasting valuable substances or additional rework time.

Reduced sample volume and savings

In addition to reducing waste and rework, preparing samples gravimetrically presents the opportunity for a substantial reduction of sample volume leading to significant materials savings.

Gravimetric addition of the diluent also means the amount of solution prepared is not dictated by the sizes of volumetric flask that the operator has to hand. Concentrations don't need to be prepared at discrete intervals, such as 20, 50 or 100 ml. Instead, just the amount of solution required can be made up. This factor, combined with the lower minimum weight achievable for automated gravimetric dosing, means that smaller amounts of sample can be used, smaller solution volumes prepared, and less material disposed of or wasted.

A matter of time

Improved accuracy of results, supported by the ease and security of recording weighing data, offer significant improvements compared to volumetric sample preparation.

Couple these advantages with enhanced operator safety, the reduced environmental impact of smaller sample volumes and valuable time, resource and monetary savings— and the benefits of gravimetric preparation become quite difficult to overlook.

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