An Industry Perspective on Harmonization and Implementation of ICH and USP Requirements - Pharmaceutical Technology

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An Industry Perspective on Harmonization and Implementation of ICH and USP Requirements
The US Pharmacopeia's revised General Chapters on elemental impurity limits and testing procedures are set to take effect in December 2012, and are to be implemented by the industry by May 2014.


Pharmaceutical Technology
Volume 36, Issue 11, pp. 58-64, 70-72

In addition, compatibility tests, combined with routine plant monitoring, both of which form part of routine GMP practices, should preclude the need to routinely monitor for metals associated with equipment.

Excipients. Perhaps the most contentious of all the potential sources of metal contaminants are excipients. Excipients broadly fall into three classes:

  • Mineral-based excipients, involving conversion of ores from mines (e.g., titanium dioxide)
  • Plant-derived excipients, such as those grown in the soil (e.g., cellulose derivatives) or harvested in the ocean (e.g. carrageenan)
  • Synthetic excipients, which are generated through synthetic processes (e.g., povidone, polyethylene glycol).

Of most concern are those excipients that are mined. These excipients are very likely to be subject to natural variation, both in terms of metals present and levels. In many cases, the metals content in excipients is inherent from their source and cannot "easily" be purified. Excipient manufacturers may not be able to change the metal content of a material. Also of concern is the difference between bioavailable metal and the total level present in such materials. It is almost certainly the case that a total level derived through an aggressive approach such as HF digestion will significantly overestimate the actual level of the metal biologically available upon ingestion of an insoluble mineral based excipient

Another important factor to consider when assessing the risk associated with an excipient is the contribution of the excipient in weight terms to the drug product. Certainly a number of excipients, for example titanium dioxide used as a table coating, are used at very low levels, although they may themselves contain elevated levels of a particular metal the overall contribution to the levels of metals in the drug product is negligible. Taking such factors into consideration is important if the industry is to avoid an over-reaction to the risk associated with individual excipients.


Table II: Examples of packaging concerns for common classes of drug products. Adapted from FDA container–closure guidance (Ref. 16).
Container–Closure systems. Another potential source of metals is the primary container–closure system (CCS). The scope of any such assessment should be carefully considered. FDA's guideline on CCS (see Table II) provides a useful guide to assist in this process (16).

In the context of metal leachables, the highest risk is associated with liquid formulations. Solid dose formulations, such as tablets in a foil blister pack, have low risk of leaching.

Even where a CCS is in scope, the risk assessment should focus on known potential risks, for example, antimony levels in polyethylene terephthalate (PET), rather than an unfocused general screening.

By conducting a well-designed focused risk assessment it should be possible to accurately assess and counter the risk of metal contaminants without the need for exhaustive analytical testing.

Of note, although the USP has publically communicated how it plans to implement changes and replace use of <231> Heavy Metals in monographs, at this time, it is not clear how the pharmacopeia plans to update and implement changes in other related General Chapters (e.g., USP <661> Closure Systems or USP <381> Elastomeric Components).


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