Real Time Metal Analysis During Pharmaceutical Manufacturing
A schematic diagram of the proposed simultaneous XRF module installed over a conveyor
carrying drug powder/slurry for continuous online real time metal analysis. The block diagram shows the
various electronics, control and data acquisition modules as well

    The ability to rapidly measure metals at low ppm levels is becoming increasingly important in pharmaceutical manufacturing and there is a need to develop low cost instruments that can be used for real time online detection and analysis during manufacturing of pharmaceutical drugs and compounds. In general there are three main methods of incorporation of metallic impurities in the product during manufacturing, as described below:

  • Metallic Catalysts: Metallic catalysts are extensively used during manufacturing of
    pharmaceutical drug compounds. These include metals such as Palladium, Rhodium
    and Iridium, which must be removed after the steps involving catalysis to avoid
    incorporation of these metals in to the final products
  • Production Equipment: Another source of impurities is the metal particles and
    broken pieces (e.g. broken sieves etc.) from the production equipment such as
    reactors, tanks, filters and pipes. These metals can include Iron (Fe), Copper (Cu)
    and Zinc (Zn) in addition to stainless steel (made of Fe, Cr and Ni) and platinum
  • Raw Materials and Excipients: Lastly, the metal impurities can come from the raw
    materials (plants, animal proteins, rDNA, etc.) and excipients (stabilizers, fillers,
    binders, release agents, flavors, colors, coatings, etc)
    Ensuring the removal of these metal impurities is required to avoid toxicity associated
with heavy metals. The best method for this will be an online instrument that can be used at
point of use in the manufacturing line to continuously detect, measure and analyze metallic
    Current metal analysis technologies include inductively coupled plasma mass spectrometry
(ICP MS) and atomic absorption spectroscopy (AAS) and have been used with the typical
USP<232/233> testing for metal impurities such as Ag, Hg, Cd, Pb and As. The details of these
techniques and the USP testing methods is beyond the scope of this document, but it is
important to note that these approaches "
rely on the use of expensive equipment that cannot be
conveniently co-located with the reaction and purification equipment where metal removal is
performed, thus resulting in the need to transport laboratory samples for testing and adding time
and cost to the drug development process. An improved approach would allow low ppm metals
analysis to be performed at point of use, employing affordable, robust equipment that would be
easy to operate by any lab technician (not requiring specialized training). Ideally, such an
instrument could be used for the continuous monitoring of metal impurities associated with
continuous processing operations. Finally, a technique that would be amenable to detect low
ppm levels of the entire suite of metals commonly used in modern synthetic organic chemistry
(Pd, Rh, Cu, Zn, Fe, Ir, etc.), or at least a few metals, would be preferable to a technique that is
specific to a single metal."
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