On 1st December 2012 the USP is expected to publish two new chapters covering heavy metals analysis. Chapter <232> Elemental Impurities - Limits, and Chapter <233> Elemental Impurities - Procedures will jointly herald a change in the way that medicines sold in US markets will be assessed for heavy metal impurities.
Heavy Metals Analysis
It won't be until 1st May 2014 that Chapter <232> and Chapter <233> will come into full effect. Then the wet chemistry methods of Chapter <231> will cease to be available for medicines marketed in the USA, although the comparable methods used in the EP and JP will continue.
Significance of changes
Chapters <232>and <233> will give laboratories the licence to use a wider range of more sophisticated methods for analysing heavy metal contaminants. Of course, these methods will still need to be validated for any given product but the expectation is that the spectroscopic methods allowed by the new chapters will be more accurate and more reliable than the colour change reactions given by Chapter <231>.
It is fair to point out that the methods of Chapter <231> were developed before the introduction of modern analytical instruments, and they do have some factors in their favour. They do not require sophisticated instrumentation or specialist expertise, so are easily transferable from one laboratory to another. Hence, a competent laboratory staff member can perform the same techniques with relative ease.
However, the methods rely on several assumptions, all of which can be questioned, and it is fairly evident that the methods are not suitable for analysis of several metals including mercury, tin, selenium and antimony.
It will be obvious to many readers that metal impurities need to be excluded from pharmaceutical products. Of the 4000+ monographs in the USP/NF, there are almost 1000 that specify a limit of heavy metals, in either a drug substance, excipient or drug product. Aside from the direct risk that they might pose to patients, they also have potential to react with pharmaceutical actives, and to denature biopharmaceutical proteins.
Whether present as a consequence of their use as catalysts, or as contaminants from process equipment or other ingredients, metal impurities are potentially commonplace. The control of these impurities may be certified by a vendor of actives or excipients, but pharmaceutical producers must carry out their own tests to demonstrate the absence of impurities before using these ingredients.
The acceptable levels of some 15 elements are set out in Chapter <232> Elemental Impurities - Limits.
- Arsenic, cadmium, mercury and lead, these elements are considered ubiquitous and must be assessed in all cases.
- Iridium, osmium, palladium, platinum, rhodium, ruthenium, chromium, molybdenum and nickel.
The second group of elements may be present in products as a result of being added deliberately, for example, in the form of a catalyst or through interactions with metal components through the manufacturing process.
As the ICH Q3D guideline is still being reviewed and is likely to expand to cover more elements, there is sure to be a further review of Chapter <232>. At this stage the scope of Chapter <232> may be expanded to cover more elements or an informational chapter may be incorporated covering elements of low toxicity.
Chapter <233> sets out procedures for sample preparation and analysis.
The two procedures for analysis are ICP-AES (sometimes referred to as ICP-OES optical emission spectrometry) and ICP-MS.
In ICP-AES the sample solution is fed into an argon plasma which has a temperature of approximately 10,000°C. Under these conditions the sample matrix is destroyed, and individual atoms are released and excited to a higher energy state. As the excited atoms cool they return to a ‘ground state' and release energy in the form of light, the wavelength of which is specific to a particular element.
ICP-MS also uses a plasma, but here the plasma is used to ionise the metal atoms which are then fed into a quadrapole which separates the ions according to their mass to charge ratio.
Both ICP-AES and ICP-MS techniques are able to analyse several elements simultaneously hence sample throughput can be very quick, typically 2 - 3 minutes per sample. The key difference between the instruments is the detection limit. The ICP-MS typically has detection limits 100 - 10,000 times lower than that of ICP-AES. Both techniques are capable of analysing to the levels required by the USP, but ICP-MS does give a much lower detection limit.
Analysts may have to allow for interferences with both techniques but internal software usually deals with these issues. The point was already made at the outset that any method used must be validated.
There are other techniques that can be used for analysis of elemental impurities. These include flame atomic absorption spectrometry (FAAS), which is a simple and relatively cheap technique but has relatively high detection limits, and is relatively slow. Vapour generation atomic absorption spectrometry (VG-AAS) uses a chemical reaction to release metals in the form of gaseous hydrides, and has improved detection limits compared to FAAS. However, it can only be used for arsenic, bismuth, germanium, lead, antimony, selenium, tin and tellurium. Another technique called graphite furnace atomic absorption spectrometry (GFAAS) has very good sensitivity and can be used to look at very low levels of analyte similar to those achieved by ICP-AES. However, it is prone to chemical interferences and can be slow and costly.
On December 1st 2012, the USP will introduce Chapters <232> and <233> and by May 1st 2014 Chapter <231> will cease to exist. The few months between these dates may seem like a long time, but it is not so long when one considers how many monographs will need to be addressed.
However, the ultimate outcome will be worth the effort, and the public will be better protected by use of the more accurate new methods.