Special Features Help Avoid Fines and Audit Problems
For analytical scientists and quality assurance (QA) professionals working in highly regulated industries such as pharmaceuticals and health care, analytical balances are the heart of virtually every quantitative analysis. Keeping balances used in regulated environments calibrated—and not weighing with them when they are out of tolerance—is the essence of good science and safe manufacturing.
As any QA manager can tell you, accurate weighing is essential to many critical research and manufacturing steps, including preparing analytical reference standards, taking aliquots of samples for analysis, or preparing solutions and buffers. In all these sensitive processes, weighing errors—especially when working with active substances, where even minute inconsistencies can alter effectiveness—are best avoided.
Generally, to ensure accurate use, balances must be calibrated and meet defined requirements for repeatability and accuracy. For companies that need to comply with the United States Pharmacopeia (USP), risk-based testing protocols and scheduled calibrations must be carried out according to chapter 41, with advice given in general chapter 1251. For other companies around the world, and for other applications or in other segments, a risk-based approach to balance testing and calibration is still highly recommended.
Related Article: Maintenance Matters: Laboratory Balances
However, even knowing all three applicable USP chapters (41, Balances; 1251, Weighing on an Analytical Balance; and 1058, Analytical Instrument Qualification) and with careful lab protocols in place, many lab directors around the world are more than a bit nervous when their local inspector calls. That’s because audits and inspections can be comprehensive, with minute attention to detail, to say the least.
The U.S. Food and Drug Administration (FDA) is authorized to perform inspections under the Federal Food, Drug, and Cosmetic Act, Sec. 704, “Factory Inspection.” They use a Form 483, “Inspectional Observations,” to document and communicate any concerns discovered during these inspections. The FDA has jurisdiction only within the United States. However, the supply chain for pharmaceuticals often extends beyond its boundaries, so the FDA clearly has a strong interest in ensuring that any foreign operations involved in the U.S. supply chain also meet appropriate standards, even though they have no legal authority to do so. Nevertheless, the FDA does has the ability to restrict imports into the U.S. after performing foreign inspections, and it has exercised this right in some recent high-profile cases involving pharmaceutical manufacturing sites in India.
A general inspection outline
When beginning an investigation, inspectors typically start with an organization’s quality control system, assessing document control, training records, policies and procedures, and management protocols set in motion when deviations are suspected. The inspector will also check the lab against good manufacturing practice (GMP) regulations and specific industry requirements. Then, however, the inspector’s attention will be drawn to those critical instruments: any balances used along the supply, research, and production chains.
In general, to pass the inspection, balances used in pharmaceutical manufacturing must:
- be specified, installed, and qualified correctly against specification with appropriate qualification documentation;
- be calibrated at installation and at defined intervals thereafter (with records of results and any maintenance or service performed);
- have appropriate and regularly scheduled routine testing protocols;
- operate in a scientifically sound manner; and
- have proper logs that include all use and weight data.
Of course, these balances must also not be used during periods when they do not meet all of the aforementioned criteria.
Inspectors frequently do find occasion to issue citations when labs are falling short in their analytical balance compliance. Some relatively recent FDA warnings regarding weighing have been issued.
“Your response is inadequate, as you have not included a review of calibration status of all equipment and instrumentation used in the production or testing of API intended for the U.S. market.” (FDA warning letter, March 2012)
“Our investigator reviewed your previous annual calibration records … and found them to be outside of specified tolerances.” (FDA warning letter, September 2011)
“Your firm failed to properly calibrate the scale within the range of its intended use.” (FDA warning letter, April 2011)
“You fail to challenge the analytical balances for minimum weight, measurement uncertainty, and drift value.” (FDA warning letter, October 2010)
Needless to say, whether or not results achieved with the balances in question were accurate, these letters show that a lack of proof of calibration is enough to cast a shadow over the work of a laboratory. Being compliant is always easier and cheaper than having to correct mistakes. It is also the basis of sound science and good weighing practice.
Does your lab maintain inspection readiness? If an inspector walked into your facility today, would you pass an audit? If there is any question in your mind, you may want to consider the advantages of implementing balances that incorporate the latest state-of-the-art technology. This technology can enable you to ensure audit-passing operation, traceability, and accuracy of weighing measurements.
Assurance at a glance
Recent advances in balance technology are helping QA operators in a variety of industries, including pharmaceutical, approach audits and inspections with a greater degree of confidence and control. They know they can demonstrate compliance with regulations as well as their own internal procedures and that laboratory records are complete.
One example is the status light (StatusLight™) that appears on the latest Mettler Toledo balance models. This feature allows QA operators in a variety of industries to maintain confidence in their processes. The green, yellow, or red status lights, displayed around the edge of the balance terminal, indicate whether the balance should be used for weighing.
The principle behind this visual indicator is simple. Essentially, if the status light is green, you can safely go ahead and perform a weighing. If the light is yellow, you need to be careful; you may be operating in a grace period prior to recalibration or during a balance test. If the light is red, you should stop using the balance. This indicates that there is an error that will affect weighing results, which must be dealt with before accurate weighing can resume.
Of course, the technology behind such an indicator is complex. Ensuring at a manufacturing level that the balance can handle all aspects of readiness requires an intimate understanding of the weighing process. However, using a status light is one of the simplest ways pharmaceutical companies can help guarantee that their weighing results are accurate on an ongoing basis.
Staying on the level
A level balance is particularly critical when weighing small amounts of sample or reference standard. However, on typical balances, the spirit level that indicates whether or not a balance is level—a determination that can be particularly important after cleaning—is at the back of the balance. This makes the bubble difficult to see if space is restricted or the balance is located inside a fume hood. On the latest analytical balances, an out-of-level balance warning message is given (along with an audible beep). A graphical level bubble representing the spirit level appears on the screen, turning from red to yellow at the legal limit of leveling, and finally to green when the balance is optimally level and ready to weigh. The status light also indicates whether or not the balance is level.
As a further measure to protect weighing results, in many newer balance models sensors also detect when the balance pan is out of position. This is particularly important after cleaning or if different balance pan designs are used. The status light and a warning message will indicate that the balance pan needs to be repositioned. A green indicator shows the pan has been placed correctly.
Internal calibration advantages
Internal adjustment of an analytical balance, such as the kind used in fully automated calibration technology (FACT), can also help ensure accurate use. Internal weights calibrated at the factory to eliminate measurement drift caused by environmental fluctuations may also be used to run calibration checks. Before-and-after measurements show how much the instrument has been adjusted.
To pass an audit, however, users must be careful not to rely solely on these checks. The revised USP chapter 1251 describes a risk-based approach to balance testing, explaining that balances with internal adjustment weights may be tested less often with external weights. This saves significant routine testing time and enhances productivity. Good Weighing Practice™ (GWP) can determine the frequency of external calibration, which routine tests to perform, and how often they should be carried out. This recommendation is based on a full risk assessment of the companies’ processes. GWP can be applied to any laboratory balance or industrial scale, from any manufacturer.
Routine testing and SOPs
It is important to carry out routine testing operations at intervals predefined by the risk assessment, as well as to ensure that records that these tests have been performed are maintained and accessible. Balances now offer features such as TestManagerTM, which can provide added assurance. This feature provides step-bystep on-screen guidance to ensure that routine tests are performed at predefined intervals and that calibration standard operating procedures (SOPs) are followed. It allows an authorized user to register and define the weights to be used for external calibration. When a routine test is due, the status light turns yellow in order to inform the balance user immediately when the balance needs testing. If the test fails, the balance can be automatically blocked, which means that the status light turns immediately to red, and no weighing tasks can be carried out, pending review by quality management. Once the test procedure is complete and the test is passed, printouts can be signed and added to the lab notebook or analytical batch record, and the status light returns to green. This is a practical example of how balance technology can ensure that weighing performance is maintained at the highest level, and lab managers are protected from generating any out-of-specification or noncompliant weighing data.
In conclusion, weighing accuracy is enhanced by proper calibration and maintenance according to risk-based testing protocols, recommended by the USP. However, it is also critical to produce up-to-date, accurate records for the calibration, routine testing, and maintenance performed, in order to pass an audit or inspection. Detailed documentation relating to what should be done and proof of what has been done shows inspectors that you are in control of the process, and this is perhaps the best way to meet the challenge of trouble-free inspections in a highly regulated industry such as pharmaceuticals.
New technology based on sound weighing principles can go a long way toward establishing this essential control and ensuring the accuracy of analytical balances used in regulated laboratories.
For more information or to download the free white paper, go to www.mt.com/green-light