Safety concerns for metal contamination
The primary reason for zero tolerance of unplanned contamination by foreign materials relates to consumer safety. Particulates
in parenteral products, for example, can block capillaries and, under worst-case conditions, could result in death. Metal
particulates in oral solutions or solid dosage products could potentially damage teeth if chewed, abrade internal organs,
or pose toxicological concerns.
Most pharmaceutical manufacturing equipment is constructed of stainless steel. This can vary in composition; in general, it
is comprised of chromium, nickel, zinc, or manganese. Minute levels of ingestion are not expected to pose adverse health consequences.
Nonetheless, the mere potential for adverse health or safety impacts from foreign contamination elevates the concern. And
foreign contamination of unknown size, composition, or toxicity actually poses a risk greater than that for known materials.
Industry perspectives on metal contamination
FDA has not established formal limits for foreign material contamination in drug products other than those listed in the United States Pharmacopeia (USP), as follows:
- USP <1>–Injections: "All articles intended for parenteral administration shall be prepared in a manner designed to exclude
particulate matter and other foreign matter. Units with visible particulates shall be rejected."
- USP <788>–Particulate Matter in Injections: "The average number of particles present cannot exceed 3000 per container equal
to or greater than 10 micrometers in size and 300 particles per container equal to or greater than 25 micrometers."
- USP <797>–Pharmaceutical Compounding Sterile Preparations: "All units must be inspected and rejected when visible particulate
matter is detected" (5).
The challenge is to control contamination, not to a limit or specification, but to a level often deemed as "the absence
of visible contamination."
Stainless-steel equipment will eventually wear. For example, table press tooling must be inspected frequently for adverse
wear or pitting. Critical tooling is required to be dimensionally evaluated regularly to ascertain if it is still "in tolerance."
Blenders, agitators, mills, and other moving parts are also known to show wear over time. Where does this missing metal go?
Some of it may be imparted to the product being manufactured. Does this, in itself, constitute adulteration? At what point
does routine, normal wear become a concern? How do you know if missing metal was worn away as micro-dust versus a single piece?
No one would question that bolts, nuts, etc., imparted to products would be unacceptable, but what about the micro-dust?
It appears that most in industry and FDA have come to accept the presence of visible particulate contamination as the limit
for acceptable versus unacceptable contamination. Most individuals with normal vision can detect a particulate in the range
of 40–50 micrometers in size. FDA clarified this "limit" in a 2002 Warning Letter issued to Berlex Pharmaceuticals:
"While it is generally understood in the pharmaceutical industry that normal wear and tear of manufacturing equipment may
lend particulate matter to the products being produced, this type of particulate matter is not visible to the naked eye and
is in the parts per million (ppm) or parts per billion (ppb) range. It is not acceptable to have visually observable contaminants
in your finished dosage form..." (6).
The bottom line for industry is to prevent the presence of those visible particles in the finished drug product.
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