The role of GMPs, QbD, and risk analysis in metals testing
FDA regulations state that pharmaceutical manufacturers are ultimately responsible for the quality of the products they produce
and sell and the level of quality achieved by these manufacturers is based on implementation of GMPs. According to the USP 31 General Notices,
"While one of the primary objectives of the Pharmacopeia is to assure the user of official articles of their identity, strength,
quality, and purity, it is manifestly impossible to include in each monograph a test for every impurity, contaminant, or adulterant
that might be present, including microbial contamination. These may arise from a change in the source of material or from
a change in the processing, or may be introduced from extraneous sources. Tests suitable for detecting such occurrences, the
presence of which is inconsistent with applicable good manufacturing practice or good pharmaceutical practice, should be employed
in addition to the tests provided in the individual monograph" (14).
Control is clearly needed when a metal catalyst is used in manufacturing. The manufacturer determines which metal is used
as a catalyst, designs a process to control it, and performs testing to confirm control. However, the proposed applications
of elemental metals testing in the new USP chapter <232> includes the concern for unexpected contamination, where there is no particular metal suspected of being present.
Because contamination is often erratic and may vary within the batch, merely testing a sample does not assure control. Through
the application of GMPs, especially the control of supply chains and supplier assessment/audits, along with appropriate process
knowledge and controls, a manufacturer can determine that the risk of contamination is insignificant and that testing is unnecessary.
Frequent references to instances of contamination need to be looked at more critically. One example of significant metals
contamination, attributed to lack of supply chain controls in China, involved chromium contamination in gelatin capsules.
One challenge likely to arise with respect to ICH Q3D and USP General Chapters <232> and <233> is defining the scope of any product risk assessment. As it presently stands, <232> offers
little in the way of guidance, simply stating that such an assessment should address elemental impurities including catalysts
and environmental contaminants. Chapter <232> does place a specific emphasis on arsenic, cadmium, lead, and mercury due to
their apparent ubiquitous nature (2). As to whether this is a valid concern is contestable; it is certainly somewhat at odds
with the principles of a truly risk-based approach.
For a drug product, there are a number of potential sources of metals. These include raw materials used in synthesis of the
drug substance (e.g., starting materials, catalysts, reagents, and/or or intermediates); the drug substance itself; excipients;
manufacturing equipment (e.g., vessels and utilities used during production of the drug substance and drug product); and environmental
sources (e.g., water, air; and the primary packaging/container–closure system). Extensive and untargeted screening of all
potential sources is neither scientific nor a viable solution. What is required is an appropriate risk-based approach, one
that is aligned with the principles outlined in ICH Q9. Such an approach needs first to define a sensible framework in terms
of the scope of such an assessment. How such a framework can be established is described below, consistent with the initial
draft of ICH Q3D.
Raw materials used in synthesis of the drug substance.
The first question for manufacturers to address is, "How far back in the synthesis should a risk-assessment begin?' Most synthetic
processes involve multiple steps between the registered starting material and the final drug substance. Each step, especially
those employing an aqueous solution, either for the reaction itself or in the form of washes, have the potential to remove
metal residues. Hence, a sensible approach would be to start the assessment from the registered starting materials. Such an
assessment would also include reagents and catalysts used in the synthesis of the active substance.
This scope raises a further question in terms of what, if any, testing should be required for a starting material or reagent
used in the process. The answer is relatively straightforward where the manufacturing route is known for a starting material;
hence, testing can be focused on any metal deliberately used in the manufacturing process. It should be recognized that assessing
materials of commerce, such as simple reagents, is more difficult as the route of manufacture may not be apparent. Nevertheless,
any testing relating to input materials into the synthesis of the drug substance should be focused on known risk as opposed
to being subject to untargeted screening.
It is easy to assume that the removal of the apparent "catch-all" heavy metals limit test, <231>, should be replaced by a
similar general screen, that is, one involving tests for multiple elements. The new USP General Chapter <232> might appear to advocate such an approach, which at a minimum might involve a screen for arsenic, cadmium,
lead, and mercury. However, provided a robust risk assessment of the process has been conducted, considerations for other
key process factors (e.g., water, reagents) should not be necessary. Instead, a true risk-based assessment should focus on
identified risk factors, such as catalyst residues.
Water is a significant potential source of environmental contaminants, including arsenic, cadmium, lead, and mercury. However,
precisely because of this and other concerns relating to water quality, there are strict standards in place that define the
minimum quality of water, such as those defined in ICH Q7 (15). Q7 stipulates that unless otherwise justified, process water
should, at a minimum, meet World Health Organization (WHO) guidelines for drinking (potable) water quality. Such a standard,
augmented in many cases by the use of purified water for API final step, precludes the need to routinely screen the resultant
API for metals potentially arising from water. Furthermore, water quality is routinely monitored (through resistivity/conductivity
measurement) as a part of current GMP.
Air is an extremely unlikely source of metal contaminants and air quality is routinely addressed through GMP control via the use of HEPA filters and heating, ventilation, and air conditioning systems, to achieve the appropriate airborne classification.
Manufacturing equipment, although a potential source, is unlikely to pose a significant risk of metals. The most common materials
are hastelloy and stainless steel. Such materials are resistant to both chemical corrosion and abrasion; this is why they
are used in the industry. Furthermore, in terms of their composition, the major components of manufacturing equipment are
iron, nickel, chromium, and manganese; none of these are considered highly toxic, according to USP or ICH, based on published
data as described in EMA's pending guideline, Specification Limits for Residues of Metal Catalysts or Metal Reagents.