Examining excipients
Adulteration of excipients is of growing concern in today’s global supply chain and the US Pharmacopeia has made several changes to protect patients. Philip Payne, investigative partner of testing laboratory RSSL, highlights the latest requirements
Most recently, the deaths of at least 24 children in Bangladesh in July 2009 were attributed to products contaminated with DEG, while more than 80 Nigerian children died after ingesting teething syrup contaminated with DEG between November 2008 and January 2009. These were by no means isolated or new incidents. In October 2006, a number of illnesses and deaths in Panama were linked to cough syrup that was found to be contaminated with DEG.
There has also been a focus on melamine following the widespread contamination of dried milk originating from China, which led to health scares concerning infant formulas, and many thousands of other food products being withdrawn from sale.
The FDA issued a guidance document entitled “Pharmaceutical Components at Risk for Melamine Contamination” during the summer of 2009, in which a wide range of pharmaceutical ingredients are identified as being at risk. These include some that have an obvious connection with milk, such as lactose and caseinate, but many others with no obvious connection, such as guar gum and albumin.
countering contamination
While contamination with DEG and melamine clearly arise from deliberate and criminal acts, there are plenty of other ways for excipients to become contaminated.
Such contamination may occur at all stages of production, storage and distribution, and as much as possible, drug manufacturers need to be aware of all the risk factors and vulnerabilities connected with their supplies of excipients, and to carry out routine screening for known risks.
Environmental contaminants, such as heavy metals, are one of these known risks and another hot topic within the USP right now, with new approaches being proposed to replace the existing methods in General Chapter <231> Heavy Metals.
As it happens, there has been much debate over the revisions to Chapter <231> as the USP attempts to prescribe general methods that take account of the latest analytical methods and are appropriate to every situation. Some idea of the challenge involved can be appreciated by noting that the USP, EP and JP all differ in their approaches to elemental contaminants, and attempts to harmonise them have now been abandoned.
Metal impurities are rightly a cause for concern and heavy metal testing is a long established requirement in pharmaceutical production. The USP has included a general test for heavy metals since volume VIII of 1905, which used sulphide precipitation to detect antimony, arsenic, cadmium, copper, iron, lead and zinc.
As it happens, the purpose of the test had more to do with prevention of mislabelling than prevention of contamination, since heavy metal salts were often used in therapy and so one had to know which salts were present in a treatment.
The emphasis on residual contamination came in 1942 with the introduction of volume XII in which a lead-containing standard was included in the test.
The aim was to detect potentially poisonous heavy metal residuals, such as lead and copper, since these were widely used in production equipment at the time. Interestingly, metals such as iron, chromium and nickel were not revealed by the test.1 It is the limitation of the ‘wet chemistry’ methods described in USP Chapter <231> that led to the decision to revise the Chapter, and it is fair to point out that the current compendial methods were all developed before the introduction of modern analytical instruments.
However, the methods in Chapter <231> do ‘suffer’ from the fact that they involve subjective visual examination and comparison of the sample solution with a lead standard. The validity of this comparison relies on several assumptions, all of which can be questioned.
It is no surprise, therefore, that additional chapters for the control of specific metals and other inorganic impurities have been added to the pharmacopoeia over the years. Significant amongst these in the USP was Chapter <730> Plasma Spectrochemistry, which gave laboratories the opportunity to use techniques such as inductively coupled plasma with either mass spectrometry or atomic emission spectroscopy (ICP-MS, ICP-AES) for the analysis of metal contaminants.
eliminating subjectivity
The advantage of ICP methods is that they can provide specific detection and quantification for each of the elements expected to give rise to a positive response in the compendial methods. The subjectivity of the compendial methods is eliminated with ICP technique, which is also quicker in some cases, requires a smaller sample size and gives a higher recovery of all the elements of interest. The sample preparation method for ICP, for example, is less likely to lead to the loss of the volatile elements.
In opening the door for heavy metal limit testing to be carried out using ICP-MS and other plasma spectrochemistry, the revised USP <231> does not entirely rid itself of every problem. Indeed, any standard method, whether for metals or any other chemical contaminant, always runs the risk of being either too general, or unable to deal with particular circumstances. That said, there has to be some uniformity in approach to testing for contaminants.
Of course, it is one thing to analyse an excipient knowing what kind of contamination might be expected, and quite a different matter to devise a testing programme that detects and identifies the unexpected. After all, thinking back to the DEG issue referred to above, before it actually occurred, who could seriously have imagined that anyone would have been likely to deliberately add a known poison to glycerin?
investigating contaminants
Routine screening of excipients should be robust enough to pick up low levels of contaminants and to flag up an out of specification (OOS) result that obliges further investigation. Thereafter, a skilled and experienced chemist, backed by a well-equipped laboratory should have a wide range of techniques at his/her disposal to extract and identify the rogue peak in the sample.
In investigating an OOS result it is important, of course, to exclude the possibility that it is the test, rather than the sample, which was at fault.
On this point, in 2006 when the FDA published its Guidance for Industry on Investigating Out-of-Specification Test Results for Pharmaceutical Production, it was surprisingly limited in its requirements. It merely required that ‘the source of the OOS result should be identified either as an aberration of the measurement process or an aberration of the manufacturing process’.
From the laboratory’s perspective it is far more useful to drill down to the detail and assign the error more specifically, e.g. dilution error or wrong sample weight used. The laboratories at RSSL Pharma would always seek to assign a conclusion to any investigation, i.e. calculation error, method error, equipment error, technician fault or genuine OOS.
This affords the opportunity to analyse OOS results for specific trends to highlight potential weaknesses in our own Quality System, and also provides greater assurance that an OOS result reported as arising from manufacturing error is indeed genuine. The MHRA has also been addressing the issue of OOS results. The Inspectorate held a seminar on this topic in March 2010, and expects to publish its own guidance very soon. At the time of writing, no date has been given for its release.
tracing manufacturing errors
Where a manufacturing error is identified, the Investigative Partner at RSSL Pharma is on hand to take the investigation further, advising on potential sources for the contaminant and strategies for avoiding a recurrence of the problem. This support does not only apply to investigations involving the contamination of excipients, but to any other contamination event, or any other failure of the pharmaceutical or its packaging.
In conclusion, while excipients play no clinical role, they do of course, play a crucial role in ensuring that the active ingredients are delivered to their target and in ensuring that the overall quality of the pharmaceutical product is maintained.
Any contamination of the excipients is therefore unacceptable, and the pharmacopoeia should be used in tandem with bespoke methods to ensure that all cases of contamination are detected and identified.
Thereafter, it is always in the interests of manufacturers to work our how and where the contaminant entered the supply chain so that appropriate steps can be taken to avoid a recurrence, and where necessary, to enforce improved standards on suppliers.
references:
1. Pharmaceutical Chemical Analysis: Methods for Indentification (sic) and Limit Tests. Ole Pedersen, Taylor & Francis (2006)
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