As GLPs expanded to include all instrument and non-instrument operations, in tox labs and beyond, other U.S. agencies, most notably the U.S. Environmental Protection Agency, adopted the idea. The original GLPs spawned regulatory and standards practices worldwide whose goals were to improve quality through best practices.
Quality in, quality out
GLPs’ inputs are best practices, and their output is data quality. A key component relates to 21 CFR Part 11, promulgated in 1997. Part 11 covers electronic records, signatures, and related computer systems. George Porter, product manager for titration at Metrohm USA (Riverview, FL), refers to the regulation as “the gold standard of compliance.” Adhering to it, he says, ensures compliance with most if not all U.S. regulatory bodies “because Part 11 is a very stringent standard.”
At one time, all recordkeeping and compliance recording were done by hand in paper notebooks and on forms. Today, even labs lacking a Lab Information Management System (LIMS) or an electronic lab notebook (ELN) are computerized.
“That’s why customers should look for systems with built-in traceability and compliance aids,” Porter says. Software and touch panel-controlled firmware can even assist with operations crucial to GLP compliance. “It goes well beyond electronic signatures. The software can tell if you’re using the right burette, electrode, reagents, even the right method. Many modern titrators have this ability built in.”
Metrohm embeds microchips into its components, peripherals, and systems to ensure that the right components are used with the right method. Parts identify themselves through unique serial numbers. Systems will not operate when components are incorrect or past their calibration dates. Users obtain the equivalent of a full system compliance audit every time they turn the titrator on. “In the past you had to keep track of and record this information on paper. Now the titrator does it for you,” Porter adds, “and a computer is not even required in order to be in compliance.”
To Robert Menegotto, president of MANTECH (Guelph, ON), GLP is a broad term that encompasses best practices followed in many industries that use titrators. “As long as you can demonstrate a year from now that you were following procedures that gave you the best chance for a correct answer, you are probably following GLPs.”
This means calibrating key components and maintaining a history of calibration and quality checks; for example, ensuring that burettes have been validated for dispensed volume within a timeframe specified by the protocol. And, importantly, demonstrating that all users have followed the manufacturer’s maintenance recommendations.
“As long as you save this information in a database or log and can prove down the line that the record has not been tampered with, you’ve likely covered your validation requirements,” Menegotto tells Lab Manager.
He advises potential purchasers to acquire software that handles most routine compliance tasks automatically. Users still need to make up and run standards, “but the software should remind operators and management to complete those tasks, and to keep track of burette calibration, titrant standardization, and electrode calibration. Operators should not have to worry about [these things].”
Compliance software should interface with LIMSs and ELNs in both workflow directions. A LIMS, for example, can generate worksheets containing automated quality check standards and collect and process data as each sample runs, not only when the batch is completed.
The critical ingredient for such automation, Menegotto says, is simplicity. Otherwise, the benefits of automated recordkeeping are squandered through human error and/or lack of compliance.
“Good compliance begins with good recordkeeping and good instrumentation,” says John D. MacFarlane, applications support specialist at JM Science (Grand Island, NY). The company is the exclusive importer and distributor of the AQUACOUNTER® titrator line manufactured by Hiranuma (Ibaraki, Japan). Kenichi Hiranuma, president, offers the following instrument-related tips to facilitate GLP compliance:
- Electrodes: Record electrode(s) type, starting date of use, and manufacturer data such as lot number. These data provide reference points for documenting subsequent maintenance and testing activities.
- Burette: Record the starting service date and total dispensed quantities. For reliability checks, fill burettes with pure lab water and dispense quantitatively into an appropriate tared weighing vessel. Confirm repeatability and accuracy by measuring dispensed weight. Hiranuma recommends following burette practices outlined in JIS K 0050:2011, General Rules for Chemical Analysis from the Japanese Industrial Standards Committee. Other official or unofficial standards are acceptable as well. Also, confirm operation of the burette sample changer.
- Calibration and error history: Saving past pH calibration data reveals the point in time when electrode malfunction began. Hiranuma advises labs to maintain a daily graph of calibration and error events.
Good compliance for titration is a matter of managing risk, which Mettler Toledo (Columbus, OH) recognizes through a trademarked initiative, Good Titration Practice™ (GTP®). Metrohm USA has a similar initiative, Titration Boot Camp, to instruct end users on proper use and regulatory compliance for its titration product line.
GTP consists of five steps: evaluation of current and future analytical needs, instrument selection, installation, qualification, and operation. The company website provides a GTP “risk check” guide covering:
- Temperature fluctuation: A 5°> temperature change can affect volumes of non-aqueous titrants by 0.5 percent, while pH is also temperature-sensitive.
- Installation mode: Least desirable is self-installation; most desirable is vendor installation.
- Titration mode: The more automated the better, to reduce human error and free operator time.
- Documentation: Forget handwritten results. Consider a system that provides automated GLP-compliant printouts or, even better, that stores results in a compliant database.
- Training: GLP regulations do not specify training requirements. However, operators should be trained in titrator operation as they would be for any other instrument.
- Performance verification: Labs should calibrate periodically based on elapsed time or usage. Some systems lock when calibrations fall out of date or when titrants fall out of specification.
As Menegotto notes, some labs don’t appreciate this level of intrusion, preferring simple automated reminders or acknowledgements that managers, one hopes, can act on. “If changes are made to certain protocols, the software should provide a login password that demonstrates the operator has the authority to make those changes, and include a field to include reasons for the change.”
For additional resources on titrators, including useful articles and a list of manufacturers, visit www.labmanager.com/titrators