Federal regulations for quality control processes to verify liquid delivery are ambiguous and incomplete, and there are a variety of guides and standards, which add to the confusion. Yet, FDA mandates that laboratories incorporate quality control processes to help ensure the safety, purity, and effectiveness of therapeutics samples. Understanding the processes involved in verifying liquid delivery can help navigate regulations. The processes that depend on volume include standards preparation, aliquoting, and dilution; quantitative tests relying on liquid delivery include yield measurements, purity tests, and cell-based assays. Because liquid-handling processes advance more quickly than corresponding regulations, organizations release standards and guidelines to improve industry operations and promote best practices. Among them are FDA's Current Good Manufacturing Processes initiative and International Society for Pharmaceutical Engineering's Good Automated Manufacturing Practice Guide.
Consider a quality control laboratory that processes 10 to 20 samples of therapeutics per day and releases as many as 20 batches of life-saving vaccines and pharmaceuticals each month. According to FDA requirements, analytical results from laboratory tests—many performed with liquid handling equipment—help to ensure the safety, purity, and effectiveness of these batches.
Federal regulations mandate that laboratories follow liquid delivery quality control processes; however, current regulations are ambiguous and incomplete, and a variety of guides and standards add to the confusion.
Understanding the processes required to verify liquid delivery can help you navigate current regulations, standards, and guidance for calibration procedures.
Table 1. Standards Recommending Liquid Delivery Calibration Best Practices
LIQUID HANDLING AND QUALITY CONTROL
Quality control laboratories routinely prepare samples of therapeutics for testing and produce results that are reviewed, compared with specifications, and used to help decide whether manufactured products are ready for market. Each step in the QC process usually includes one or more liquid-handling processes. Although some of these steps, such as wash phases, do not rely on accurate volumes, many do.
Examples of preparation processes that depend on volume include:
- Standards preparation: QC laboratories need standard materials in defined concentrations to calibrate analytical methods. If standards are inaccurately prepared, calibration will be incorrect and tests that follow will be wrongly reported. This can lead to inaccurate measurement of potency or improper dosage, among other problems.
- Aliquoting: This process, where liquid is taken from a larger sample and dispensed into multiple smaller amounts called aliquots, is highly quantitative. The aliquot volume often figures into future calculations; inaccurate aliquot volumes can skew results and lead to inaccurate decision-making.
- Dilution: A sample solution is mixed with a diluent and a dilution ratio is calculated. Accurate dilution ratios depend on the volumes of both liquids. Because this dilution ratio is used in subsequent calculations, inaccurate dilutions usually create questionable data.
Errors in these and other liquid-handling processes can impact the accuracy of key analytical parameters used to verify the safety, purity, and efficacy of drug batches. Examples of quantitative analytical tests relying on liquid delivery include:
- Yield measurements: Yield measurements provide valuable information about the relation-ship between inputs and outputs of the manufacturing process. When a yield fails to meet defined levels, it often triggers a warning that a manufacturing process may be out of control. However, inaccurate volume measurements can also cause an improper yield measurement, making volume accuracy necessary to avoid false alarms about process yield.
- Purity tests: Qualitative purity tests that detect the presence or absence of foreign or dangerous substances can produce false positive (incorrect identification) or false negative (failure to identify) results if sample volumes are highly inaccurate. Quan-titative measurements that detect levels of impure substances are even more dependent on volume accuracy and can determine the difference between batch acceptance and an out-of-specification investigation.
- Cell-based assays: These analytical methods can be tedious and expensive to prepare and run, because of their complexity and innate variability. Laboratory management should take extra effort to ensure that controllable errors (such as liquid handling error) are eliminated.