Three-tiered approach to prevention of metal contamination
Table I: Summary of metal contamination control activities with example applications.
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Any comprehensive approach to prevention of metal contamination in drug products requires a three-tiered approach: Prevention,
removal, and detection. Examples of each activity can be seen in Table I.
Prevention. Preventing the introduction of visible metal particles into the process is the best approach to ensuring acceptable product.
There are several key preventive activities that should be considered in a comprehensive approach.
Intentional actions are used to design the equipment or process to eliminate potential sources of metal contamination. This
proactive approach to product or process design should include the use of specific risk assessment tools. By using proper
design, future issues can be avoided.
Issues with metal contamination can often be traced to inadequate preventive maintenance (PM) or excessive intervals between
PM. Increasing the frequency and rigor of PM for high-risk equipment (e.g., that with moving parts or in direct contact with
product) can often reduce contamination potential.
Metal-to-metal contact should be prevented. There are alternatives to metal parts and, whenever possible, these should be
used in high-risk areas. The use of proper barriers can reduce or eliminate the potential for contamination with metal and
other foreign matter. Work toward closed systems wherever possible and consider constructing other barriers (such as transparent
thermoplastic boxes or shields) when open systems cannot be avoided.
Proper equipment cleaning and inspection cannot be overstated. By ensuring careful inspection with appropriate documentation
(e.g., measurements and photographs), you can more readily identify excessive or unacceptable wear on equipment. The use of
infrared (IR) analysis or vibratory evaluation tools can also help predict the potential for catastrophic equipment failure.
The use of a formal, documented process to identify all potential sources of metal contamination and the risk each poses is
an essential element to a comprehensive and proactive prevention approach. A failure mode and effects analysis (FMEA) can
ultimately identify every potential failure, guiding you to an acceptance of the risk posed or reduction or elimination of
that risk.
Removal.
Two primary methods are employed to effectively remove metal particles from product during manufacturing.
The use of filters to protect solutions is well established. A formal review of the process to identify any "new opportunities"
for filters or safety screens can often pay dividends. It is not unusual that issues occur after the final filtration or screening
that can result in product contamination. So examine systems as close to the final packaging as possible.
Similarly, in-line magnets are effective in removing rogue metal particles. Though stainless steel is typically not conductive
to magnets, very small particles are often electrically charged, making them susceptible to earth magnets.
Detection.
When prevention and removal activities have failed to effectively eliminate foreign metal contamination from product, systems
for detection are typically employed as a final protection against adulterated product.
The use of metal detection systems is broadly accepted as effective for many manufacturing systems. However, the effectiveness
of these systems is dependent upon a variety of factors.
Systems vary sigificantly in sensitivity, speed of detection, and overall reliability. The ability of the system to detect
a metal particle is a function of the system aperture size or proximity of the system to product; as an example, because the
aperture size for tableting operations is smaller than that available for bulk powders, the tableting system can detect a
particle 10x smaller than can a bulk system.
A system's flow rate can affect particle detection—the higher the flow rate, typically, the lower the detection sensitivity.
Some materials limit the system sensitivity. Additionally, the type of metal involved can impact the sensitivity of the system.
For example, ferrous metal is much more sensitive to detection than stainless steel.
The use of a product diversion system in conjunction with metal detection systems will help ensure product protection is comprehensive.
The use of manual diversion or product segregation can be ineffective if not perfectly executed.
Finally, the entire approach described above must be supplemented with some level of statistically-based product inspection.
Full, 100% inspection is not advocated, but some risk-based inspection that can truly help identify concerns is key. The use
of ongoing monitoring or statistical process controls can identify adverse trends or support the PM program.
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