In the pharmaceutical industry, bad batches equal wasted production time, resources, labor and money. But most importantly, bad batches may pose a risk to human health. By avoiding bad batches in the first place, businesses can ensure product safety and protect their profits and reputation; QbD principles can help businesses accomplish this.
BUILDING PROCESS QUALITY
Quality by Design (QbD) is a risk-based approach that identifies potential process errors early so that proactive steps can be taken to ensure safety and efficacy of medications and certain food products. A key aspect of the QbD framework is the assessment of risks and monitoring of process parameters and material attributes that influence finished product quality. In a nutshell, QbD builds quality into each step of the manufacturing process and prevents bad batches in the first place. Quality by Design has been increasingly implemented in pharmaceutical manufacturing, as the stakes are high when there is a chance products of poor quality might get into consumers’ hands. It is strongly supported by regulatory authorities, including the U.S. Food and Drug Administration (FDA), because it focuses the manufacturing process on consumer safety — from the beginning. Some food manufacturers are taking a cue from the pharmaceutical industry and are implementing QbD in their processes as well. We are seeing this with food companies that manufacture particularly sensitive products, including baby formula, dairy products and additives.
A comprehensive QbD framework needs to consider the risks that an inadequate weighing process may pose to final product quality. Depending on the application, different aspects of weighing can play an important role in maintaining an accurate and reliable process. Weighing processes, such as batching, formulating and filling, can critically influence product quality and should be considered in a comprehensive QbD concept. Inaccurate weighments can negatively impact the consistency of the blend of ingredients or the correct potency of the final product.
THE RIGHT STUFF
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 and reliable process and ensuring consistent product quality.
In batching and filling, the accurate and fast transfer of results to controller and I/O devices is essential. In formulation, it is critical to prevent the use of wrong amounts of material or even wrong materials to guarantee accurate formulations. Checkweighing, X-ray and metal detection systems as well as in-process control solutions help fulfill regulatory requirements and ensure consistent product quality. Weighing solutions can provide comprehensive monitoring and control of the manufacturing process, enabling real-time corrections of manufacturing tolerance deviations and fulfilling required regulatory requirements.
It is also important to note that the benchmarks depend on each product’s tolerance and a risk analysis defined in the manufacturing process. The narrower the process tolerance, the higher the requirements for a qualified weighing instrument, which will drive the selection of the scale. Furthermore, a calibration program and a selection of test standards are required to ensure compliance to process tolerances over time.
In addition to the accuracy and reliability of the actual weighing equipment, factors such as the speed and precision of data transfer, can significantly influence the accuracy of the measured result. Other aspects, such as data integration and storage, are required to enable continuous monitoring of the manufacturing process and real-time adjustments. Furthermore, weighing stations are important material ID points. Apart from the weight value, a broad range of information such as raw materials, batch number, responsible operator, and much more can be captured and tracked.
EQUIPMENT ACCURACY AND RELIABILITY
Readability (or display resolution) of a balance or scale is often mistaken for accuracy. In fact, readability is just one contributor to the measurement uncertainty, which is the scientific expression of an instrument’s accuracy. Any measuring device, whether it is a ruler, a speedometer or a scale, is associated with some measurement uncertainty. Uncertainty means that no measurement is perfect; it is always distorted by random, environmental and unknown systematic errors.
For example, suppose one has a scale that is accurate to plus or minus 1 gram. At 10,000 grams (10 kilograms), this uncertainty represents one hundredth of one percent (0.01%) of the weight. In many situations, that uncertainty is small enough that it won’t affect quality. Now suppose someone is weighing a 10-gram sample on this scale with an uncertainty ± 1 gram. Now 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 just due to the 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.
The environment in which the scale is used also impacts the uncertainty of the weighing system. The environment is unique to every scale installation and cannot be calculated at the time the scale is manufactured. Significant impacts from the environment on weighing uncertainty can be attributed to wind, dirt or dust; temperature fluctuations; vibrations; and operator errors, among other factors. The only way to calculate the measurement uncertainty associated with the environment is to test the scale installed in the environment using the appropriate tools and methods.
ELIMINATING USER ERROR
Operating errors are a main reason for out-of-specification batches and product recalls due to quality issues. Obviously, the risk of human mistakes in a manufacturing process can be significantly reduced by automating the entire process. In line with QbD principles, such an approach would provide a fully monitored and controlled process, ensuring consistent product quality. However, in pharmaceutical manufacturing, relevant process steps, such as the weighing of formulation components, involve manual tasks that cannot easily be automated. The challenge in ensuring process safety and product quality is to eliminate the risk of operating errors during manual weighing processes as far as possible. Both the usability of the weighing equipment as well as user guidance contributes to secure handling of the weighing process by operating personnel. For example, weighing results that exceed or fall below defined limits can be immediately shown to the operator in distinct colors, helping prevent incorrect weighing. The system can even be set up to only allow the next process step and log the component weight if the actual weight is within defined tolerances. A number of advanced features can help improve usability of the weighing equipment for the operator.
In addition, it is possible to automatically document all batch-relevant information to prevent possible errors during manual or paper-based documentation. All process steps can be filed in detail in the database, and electronic signatures can be given if required to comply with regulations such as FDA’s Good Manufacturing Practice (GMP) regulation 21 CFR Part 11.
Getting the design and operational specifications right and selecting the proper equipment for the specified process are essential steps to achieve quality results. But quality also depends on precise installation, setup, calibration and maintenance of the weighing equipment. According to the FDA’s GMP regulation 21 CFR Part 211, “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, this means that evidence that the weighing instrument works correctly needs to be provided, and it needs to be demonstrated that the manufacturer understands what is measured.
High risk and 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.
Calibration of the weighing equipment must be conducted according to globally recognized standards, such as OIML and EA 10/18, and need to account for metrology as well as equipment construction. During calibration, eccentricity, linearity and repeatability of the device need to be tested in order to evaluate if the device performs within the range of allowable errors. Finally, validation methods and protocols are required to ensure process reproducibility and safe data management when it comes to software, such as formulation or batching applications. Competent suppliers of weighing equipment not only help specify the right equipment for the intended purpose, but also have knowledgeable service professionals to confirm satisfactory installation of new weighing systems and conduct initial commissioning, set up and testing.
At the end of the day, it is essential operationally to manage the entire lifecycle of weighing equipment. After all, when this equipment is not working up to its optimum potential, or if it needs repair or recalibration, it can produce bad batches that will not only cost companies in financial terms, but cost them in terms of reputational damage, as well as the very real threat of human costs associated with health risks from quality compromised products.