If any of these quality tests fail to produce correct results, a good batch of pharmaceuticals could be delayed, leading to
wasted time, resources, and money; if the biopharmaceutical is unstable, it becomes unusable. If a quality control laboratory
erroneously clears a bad batch for distribution, this could result in a pharmaceutical company's worst fears—product recalls,
patient injuries, and wasted money.
Consider what would happen if a manufacturing company that tests pipette performance every six months learns that one pipette,
or several, have failed but a batch or product whose quality was tested with the faulty pipette already has been released.
If the product is on the market, this situation would require notifying the FDA and developing a protocol for additional testing.
If the drug already has been consumed, the company is at risk for a product recall and potential liability.
LIQUID DELIVERY QUALITY REQUIREMENTS
In light of the severe consequences that can arise from improperly functioning liquid-handling instrumentation, most would
conclude that federal regulations must tightly govern equipment performance verification and quality control systems. Unfortunately,
this is not the case. Although regulations do exist, they are broad and open to interpretation; most have not caught up with
advancements in liquid-handling technology.
For example, the FDA's Food, Drug and Cosmetics Act of 1938 simply states that drugs must be safe, pure, and effective, and
that to achieve these goals, manufacturing processes must be controlled.
21 Code of Federal Regulations (CFR) 211, establishes Good Manufacturing Practices. Two sections of this ruling are relevant to liquid handling. Subpart D states
that equipment used to manufacture drugs should "be routinely calibrated, inspected, or checked." Subpart I emphasizes laboratory
controls and requires calibration of all instruments, including liquid-handling devices, "at suitable intervals in accordance
with an established written program." It is left up to individual laboratories to define and defend their choices.
Laboratories are also required to follow standards established by the United States Pharmacopeia (USP), but USP has little
to say about liquid handling. Chapter 31 specifies accuracy requirements for volumetric flasks, transfer pipettes, and burettes,
but has not yet issued guidelines about hand-held manual or automatic pipettes, or automated liquid handling equipment.
GUIDELINES EMERGE TO OUTLINE BEST PRACTICES
It is evident that liquid-handling processes advance more quickly than corresponding regulations. For example, the transition
from glass to hand-held manual action pipettes created the need for new standards and for preventive maintenance policies
in liquid delivery devices. Similarly, the current trend toward extremely low volumes and higher density formats (e.g., high-density
microtiter plates) has driven the need for new measurement and calibration methods, as well as the need to select from and
standardize the best of these new methods. Because regulations provide inadequate guidance for modern laboratories, independent
organizations release standards and guidelines to improve industry operations and promote best practices.
Current Good Manufacturing Processes (cGMP), FDA's initiative to continually improve Good Manufacturing Practices, recognizes
that static regulations cannot keep pace with the highly dynamic pharmaceutical industry—especially when considering the often
lengthy regulation revision process. This initiative provides laboratories with current best practices to avoid the need to
continually amend federal requirements. For the most current information, cGMP relies on input from FDA personnel and quality
control experts from industry, academia, government, and consumer groups, as well as from a number of independent regulatory
bodies.
The International Society for Pharmaceutical Engineering (ISPE), whose mission is to train and educate pharmaceutical manufacturers,
is one such organization that contributes to cGMP. ISPE produces Good Automated Manufacturing Processes (GAMP) Good Practice Guide: Calibration Management. This guide takes a structured approach to setting up a calibration management system that follows the validation life cycle
and is oriented towards engineering process control. It emphasizes criticality assessment and corrective actions, including
documentation of non-conformance events. This guide does not have specific information on liquid handling; but because liquid
handling is a frequent source of equipment non-conformance events, the principles here are worth noting, particularly in light
of present FDA enforcement focus on corrective and preventive actions.
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