Mass Measurement Precision of Small Objects in Pharmaceutical Production

July 25, 2016
Unlocking the regulations-related advantages when using the new generation of contactless measurement systems

Traditional methods of weight measurement are based on comparison with standards accepted in designated areas. Over the past 200 years, a kilogram became such a standard and a metric base unit [1]. In the International System of Units (SI), it is defined as a mass standard and is used as a base for weight measurements worldwide.

Nowadays, with using the standard kilogram, it is expected it yields the same reading of high-precision weighing devices all over the world. As long as single measurements under laboratory conditions are at stake, using a standard mass in calibration procedures on state-of-the-art load cells is sufficiently precise as they allow for achieving highly repeatable and precise measurements.

However, load cells maintenance and calibration become a disadvantage when fast, precise and accurate measurements of single milligrams and micrograms are applied in-process production. It is a known fact, that under such conditions, scales have their limitations and correct adherence to regulations and production targets might not be ensured at the same time.

At first, scales with load cells require adjustment to the geographical location, otherwise the measured weight yields an error dependent on the actual location. In fact, scales do not measure mass but weight which is then translated into mass taking into account the locational gravity force.

Mass-reading error is caused by variation in the gravitational acceleration and the resulting gravity force (weight) that are not constant around the world.

The mass-reading error is caused by variation in the gravitational acceleration and the resulting gravity force (weight) that are not constant around the world. For an object of a given constant mass, its actual weight depends on both latitude and altitude of the actual location of the balance used for the measurement. Diagram 1 shows the variation in the gravitational acceleration around the world, at a constant altitude of 100 meters.

The gravitational acceleration at the Equator amounts to approximately 9.78 [m/s2], while at the poles it is approximately 9.832 [m/s2], resulting in discrepancy of 0.052 [m/s2], i.e. 0.53%.

Additionally, gravitational acceleration is affected by local altitude, tilt of Earth’s rotational axis, precession, equatorial bulge, etc. [2]. Gravity-related effects apply when, e.g. calibrating weight measurement devices to a mass standard, hence the more accurate and precise the measurement is required, the more time and effort are required both for calibration and the actual measurement. Furthermore, measurement precision and accuracy of scales and load cells changes with time from the last calibration, as they depend on elastic properties of materials in load cells, environmental conditions, and other components of a weighing system [4, 5]. 

This discrepancy implicates variation in weight readings when an object of a given mass is measured at various latitudes and altitudes. Scales compensate this significant error by providing reference masses for pre-calibration. Evidentially, this calibration becomes critical when fast measuring small masses, e.g. in milligrams range; leading to more frequent calibration to ensure reliable measurement in line with regulations.

When now moving away from the perfect laboratory environment to the real production environment, more factors influence the weight measurement of small masses. Machines vibrate which cause slow measurements and/or potentially incorrect readings; potent products require contained handling inside RABS or isolators which require constant ventilation; products may vary in water content during processing whereas the dry weight is in focus, etc. Accumulation of these influencing factors limits the useable range of accuracy of load cells or even does not permit determining small masses accurately, precisely and quickly.

Furthermore, closed processes add and/or mix substances in a way that does not permit to monitor the correct execution of adding or mixing, because the process is closed or continuous. Such applications may not allow the use of load cells but only offline sampling or indirect estimation of weight. In particular, for continuous manufacturing, the offline monitoring of small weights is not an option – because it represents a time delay. In case of frequent sampling, “offline” is described as “inline” though it is not “online.”

Removing gravity and ambience from the equation

A solution to the above described discrepancies is a highly time-stable, gravity-independent measurement system, capable of measuring the mass of objects online, i.e. the amount of substance instead of weight of fast-moving objects, e.g. capsules, tablets or powder. Such measurements would be identical around the world and independent of the influencing factors, allowing not only for tight and online monitoring of substances but also direct data comparison.

Over the past years, we have developed such a novel system [3] and successfully installed it in a number of factories around the world. The system uses sensors emitting a local energy field directly interacting with the substance passing through the field and this way, alternating its output signal. As a result of such a field-substance interaction, the initial (empty sensor) signal changes adequately, creating an output signal. Such modified signal is equivalent to the amount of the substance passing through the measurement system. Once measured, the signal can be instantly converted to mass or the local weight. Knowing exactly the quantity of the substance dosed, i.e. mass of an object, the whole dosing-measuring system is automatically calibrated to the weight measurable in any region (location) where it is destined, without a need for overdosing or a risk of underdosing.

As only the substance change the output signal, the signal is ambience-independent, allowing for online, positive process control. As sensor signal data processing is fast enough, it allows for closed loop control.

A new industrial application

An industrial version of such a system has been built and verified with a variety of small objects, including capsules in 4 to 00 size range, tablets as well as with micro-dosing of powder from 1mg to 500mg into vials and syringes. The system requires just a single push-button calibration that once done at a location, does not need any further recalibration services. The system has proven stable precision and accuracy within one sigma ranging from 0.25% to 3%, the dispersion depending mainly on materials structure and morphology.

Most important for production environments, the proposed system ensures quick, precise and accurate mass measurement of a very wide range of objects, with no need for major system adjustment, special environmental conditions, leveling, isolation from vibration and ventilation or prolonged measuring time. The system has no moving or flexing elements hence it is free from disadvantages associated with common weight measurement systems.

With already initiated transition of the pharmaceutical industry from batch production to continuous manufacturing, such a system is an important and highly anticipated tool for reliable monitoring quantities of smallest ingredients and finite products.

There are well-known shortcomings of customary, online weight measurements systems, especially for industrial applications in the pharmaceutical industry. However, alternative system for online, precise and accurate measurement of small masses are available.

The gravity-independent and highly effective mass measurement system facilitates compliance with existing drug quality regulations as well as with the industry safety directives and guidelines for cGMP, QbD and PAT. It does provide the capability to reduce cost but most importantly, it enables extension of products serialization down to formulation and components level and streamlines industrialization processes.


  1. Kilogram – the base unit of mass, Wikipedia
  2. Earth’s rotation, Wikipedia
  3. Patent application GB2512026A
  4. Pharmacopeia USP General Chapter 41 and 1251
  5. European directive 2009/23/EC
About the Author

Arek Druzdzel and Arne Wieneke | Aiger Group AG