June 15, 2016 - Greifensee, Switzerland

With QbD-Quality by Design-weighing processes help ensure excellent consistency in final products

By Tobias Woelfing, marketing specialist, industrial weighing solutions, Mettler-Toledo

In nearly any industry, bad batches equal wasted production time, resources, labor and money. But in the pharmaceutical industry in particular, bad batches have the distinct ability to risk human health. Avoiding bad batches can help companies ensure that their products are safe and their reputation is preserved, helping to eliminate the risk bad batches can pose to profit margins.

Quality by Design (QbD) can help. QbD is a risk-based approach that allows proactive steps to be taken to ensure safety in medications and certain food products by identifying potential process errors early. A key goal of the framework is to assess risks and monitor process parameters/material attributes that influence final product quality. In essence, QbD builds quality into each step of the manufacturing process to help prevent bad batches.

QbD has been increasingly embraced by pharmaceutical manufacturers, where stakes for poor-quality product are high. The U.S. Food and Drug Administration (FDA) in particular is encouraging adoption because QbD focuses production processes on consumer safety from the beginning. Some food manufacturers are following suit and implementing QbD in their processes as well-particularly those that manufacture sensitive products such as baby formula and additives.

Weighing processes in quality critical production steps such as batching, formulating and filling can impact final product quality and should be considered when implementing a comprehensive QbD concept.

CHOOSING WEIGHING EQUIPMENT

Choosing the right equipment is an important first step in designing a weighing process according to QbD principles. Depending on the application, different aspects of weighing can play an important role in maintaining an accurate, reliable and traceable process to ensure consistent final product quality.

For batching and filling, rapid, accurate transfer of results to controller and I/O devices is essential. When formulating, preventing the use of wrong amounts of material or even wrong materials is critical to guarantee accurate formulations. Weighing solutions in these instances provide comprehensive monitoring and control of the manufacturing process, enabling real-time corrections of tolerance deviations.

It is also important to note that the narrower the process tolerance as defined by risk analysis benchmarks, the higher the requirements for a qualified weighing instrument. Aspects such as the speed and precision of data transfer will also significantly influence a particular model’s suitability. Data integration and storage, required to enable continuous monitoring of the manufacturing process, must also be addressed.

Furthermore, weighing stations provide important material ID points. Apart from recording a material’s weight value, a broad range of additional information can be captured, such as material ID, batch number, and responsible operator, helping to ensure traceability.

ASSESSING ACCURACY

When selecting a balance or scale, readability or display resolution is often mistaken for instrument accuracy. However, readability is just one contributor to measurement uncertainty (the scientific expression of instrument accuracy). Any measuring device, whether it is a scale, a speedometer or a ruler, is associated with some measurement uncertainty.

The measurement uncertainty of a weighing system is a combination of many factors. The readability, sensitivity, repeatability, non-linearity and eccentricity of the scale are all factors affecting measurement uncertainty and are associated with the scale design. The scale manufacturer can calculate the uncertainty of the weighing system associated with these factors.

However, the environment in which the scale is used also impacts uncertainty. This aspect is unique to every scale installation and cannot be calculated at the time of manufacture. Significant environmental impacts on weighing uncertainty can be attributed to issues such as wind, dirt or dust; temperature fluctuations; vibrations; and operator errors. The only way to calculate measurement uncertainty associated with these environment factors is to test the installed scale using appropriate tools and methods.

Whether or not defined measurement uncertainty matters is based on process risk. For example, at 10,000 grams (10 kilograms), a scale accurate to plus or minus 1 gram will have an uncertainty of one hundredth of one percent (0.01%) of the weight. In many situations, that uncertainty is small enough that it will not affect quality. However, if someone were to weigh a 10-gram sample on this scale, the uncertainty represents a full 10% of the reported weight. The actual sample may be 10% larger or 10% smaller than what this scale is reporting, simply due to uncertainty. Ten percent is almost always too big a risk in the pharmaceutical industry. Selecting the right balance for the job is of utmost importance.

ELIMINATING ERROR

While less-than-optimal selection can clearly pose a threat to accuracy, a significant source of weighing issues can also be traced to operator error. Automating the entire process can significantly reduce the risk of human mistakes. Working with QbD principles, such an approach would provide a fully monitored and controlled process resulting in consistent product quality.

However, particularly for pharmaceutical manufacturing, relevant process steps, such as the weighing of formulation components, involve manual tasks that are not easily automated. As such, pharmaceutical manufacturers face the challenge of ensuring process safety and product quality during manual weighing processes.

Both weighing equipment usability and quality of user guidance contributes to a secure manual weighing process. For example, one option is to show in distinct color when weighing results exceed or fall below defined limits, which helps to prevent incorrect weighing. A system might only allow the next process step if the weight is within those defined tolerances.

In addition, all batch-relevant information can be automatically documented-even in a manual process-to prevent possible errors. Process details can be captured using a database. Electronic signatures can be given if required to comply with regulations such as the FDA's Good Manufacturing Practice (GMP) regulation 21 CFR Part 11.

MAINTAINING ACCURACY

Getting the design and operational specifications right and selecting the proper equipment for the process are essential steps to achieve quality results. But quality also depends on precise calibration and maintenance of the weighing equipment, both at the point of installation and on an ongoing basis.

FDA’s GMP regulation 21 CFR Part 211 states that "automatic, mechanical or electronic equipment … shall be routinely calibrated, inspected or checked according to a written program designed to assure proper performance. Written records of those inspections shall be maintained." In essence, a manufacturer needs to demonstrate that it understands what is being measured and provide evidence that the weighing instrument works correctly.

Calibration of the weighing equipment must be conducted according to globally recognized standards, such as OIML and EA 10/18, and needs to account for both metrology and equipment construction. High risk coupled with a narrow process tolerance may call for frequent instrument accuracy verification. Even under a more frequent testing schedule, regulators determine an instrument’s uncertainty principle based on an assumption that proper installation and calibration actions have been performed. This means eccentricity, linearity and repeatability of the device are tested to evaluate if the device performs within the range of allowable errors.

Finally, protocols and validation methods are required to ensure process reproducibility and safe software data management when it comes to actions such as formulation or batching. Competent weighing equipment manufacturers will help specify the right equipment for an intended purpose, as well as provide knowledgeable service professionals to conduct initial commissioning and confirm satisfactory installation, set up and testing.

At the end of the day, appropriate installation and commissioning are not enough; the entire lifecycle of weighing equipment must be managed. After all, at any point when equipment is not working at optimum potential, it can produce bad batches that can cost companies in financial and reputational terms, as well as potentially impact human health. Maintaining ongoing serviceability through timely calibration and routine testing of any precision measurement instrument is key.

ENSURING RELIABLE PERFORMANCE

Because effective weighing requires assessing scale performance under real operating conditions, METTLER TOLEDO offers GWP® (Good Weighing Practice) Verification®. This systematic approach to your weighing process proves that the equipment runs within permitted tolerances and delivers the kind of reproducible measurements that lead to consistent product quality, increased productivity and regulatory compliance. If a scale or balance is performing poorly, GWP® Verification also recommends immediate measures to recover its accuracy.

Furthermore, GWP® Verification provides all necessary information for lifetime calibration and testing. This includes test methods, test intervals, test weights, test tolerances and standard operating procedures (SOPs) fine-tuned to your weighing process. GWP® Verification includes a complete set of audit-proof documentation that assures full compliance with regulatory requirements, and it is available any piece of non-automatic weighing equipment, regardless of brand or model.