Detailed situations
The ultimate goal of this standard procedure modernization is the protection of the consumer from potentially harmful levels
of toxic, elemental impurities in drug products. The manufacturers are the most responsible parties for drug-product quality,
and only by working with them on implementation of new test procedures can patient safety be assured. Part of that work is
to discuss various concerns and how they might be alleviated.
The improved capabilities of the new ICP–MS standard have created some anxiety in parts of the industry. There is a growing
sense that where there were previously no functional controls, there may now be numerous standards, each requiring a different
compliance standard. First, the pledge to harmonize the elemental impurities standards and their limits where and when conflicts
are identified should provide some comfort. While it may appear that all these efforts are independent, in fact, they are
all relying on the same safety data to derive their limits. All parties involved are in the same room in the harmonization
discussion. Differences in scope are mostly due to the regulatory structures in various regions. Second, efforts to survey
the industry through laboratory testing has revealed nothing alarming, either in excipients or in the range of drug products
tested to date (9). These preliminary studies indicate that the tested products will meet the new standard. This survey goes
on as time and resources allow. In spite of this, it is understandable that a change of this magnitude causes consternation
amongst those who must implement the change. All parties involved are working together in concert to address not only harmonization
but implementation as well.
Some concerns persist that this new standard will somehow create a drug shortage when there is no actual risk from elemental
impurity exposure. For example, some component may have a contamination level that is above the criteria and yet is used in
low levels or in low frequencies so that the risk is minimal compared to the benefit of the product. Consider that all the
regulatory agencies involved in modernizing this standard are capable of risk-benefit balancing and part of that is the survey
of products and components previously mentioned. In addition, if there is a known situation, the supplier should be in contact
with the product manufacturer. The product manufacturer then works with the regulatory authority to develop considerations
that might be made to assure continued drug supply. Unless there is a risk to the patient, the drug will remain available
through whatever provision is most pragmatic at the time. There are procedures in place to keep standards revisions from needlessly
making a product out of compliance that was previously compliant. Industry, the regulators, and pharmacopoeias understand
the serious implications of drug shortages, especially those created by activity such as standards modernization and not related
to a change in product quality (10). Consideration for a product can also be made at the level of the standards organization.
In the USP-NF, a special consideration for a product is generally made within the monograph itself. The USP is structured such that the
monograph standard for a particular material or article supersedes that of the general chapter where the metals limits appear.
It is in these monographs where the materials that need special handling are considered. If needed, the regulatory authorities
should be asked to provide timely risk-assessment guidance for industry that can help alleviate industry anxiety.
There are differences between the standards and how they are implemented around the world. These differences go beyond harmonization
at ICH and into the framework of regional regulations. For example, there are differences between the European and USP compendial
standards implementation. The European standards tend to be tests and limits that are applied directly to the components of
a drug product; however, the USP standard is applied to the drug product itself and not directly to the components. Although
USP provides the option for the product manufacturer to demonstrate compliance through testing and summing up the components,
the limit criteria apply directly to the drug product. The USP requirement for components is to know the elemental content
and be able to report it. In order to limit or even eliminate the potential for redundant retesting, there will be a need
for communication between the component manufacturers and the product manufacturers. IPEC has developed a standardized form
that may help create a predictable format for communicating this information to the product manufacturers (11).
Some raw material suppliers and drug product manufacturers have expressed concern that obtaining equipment and expertise for
testing every batch of material is excessively expensive. It may help to explain that testing every batch according to the
standard procedures is not a requirement. This subtle point regarding USP standards is often lost in these discussions (i.e.,
the USP is a compliance standard and not a testing requirement). USP states that the material (article) must comply with the
standard when tested, and that is up to the individual purporting that it complies to come up with a plan for how that is
done. Consider also that USP relies on FDA to enforce its standards. While FDA has yet to produce any specific statement
regarding these chapters, it is common for FDA to allow alternative testing procedures for routine batch-by-batch testing.
There is no need for acquiring enough equipment and expertise for testing every batch by the standard procedure. It should
be enough to have staff and instruments only for the validation and occasional verification that the alternate procedure is
working.
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