Elemental impurities in marketed products
John Welch, Butterworth Laboratories, urges pharmaceutical manufacturers to prepare sooner rather than later for the impending changes to elemental impurities requirements
Harmonisation of pharmacopoeia methods has a history of making slow progress and it is not surprising that the new instrumental based elemental impurities test has taken time to be implemented. However, the US Pharmacopeia (USP) and European Pharmacopeia (EP) have now set dates for implementation of new monographs of 1st January 2018 and 1st January 2017 respectively. In total, there are 28 elements listed in the various publications. However, companies are required to comply from next for new products.
So what do pharmaceutical manufacturers do until then? Put their heads in the sand and wait for their implementation? Or do they take action and try to find ways they can prepare for what's to come?
A key point that many in the industry have overlooked is the fact that the USP implementation will only apply to finished products with monographs. So that means manufacturers of products like toothpaste and talcum powder do not have to take any action, whereas those of prescription and over-the-counter medications need to be prepared for the changes. How have these manufacturers been preparing?
Pharmaceutical manufacturers are applying the principles of quality risk management, with the risk assessment being based on scientific knowledge and principles as set out in the ICH Q9 guidance document. This process can be described in four steps:
- Identify: Identify known and potential sources of elemental impurities that may be present in the product.
- Analyse: Determine the probability of observance of a particular elemental impurity in the product.
- Evaluate: Compare the observed or predicted levels of elemental impurities with the established permitted daily exposure (PDE) limits.
- Control: Document and implement a control strategy to limit elemental impurities in the product.
The data on elemental impurity content for the components of a drug product can be derived from a number of sources. These include data provided by reagent and/or excipient manufacturers or data previously generated by the manufacturer themselves. However, manufacturers have been finding that there is little or no substantive information on the levels of elemental impurities available for making this risk assessment. There are also materials where it will be difficult to obtain consistent data, e.g., plant derived materials or natural products and inorganic minerals, which may be grown or mined in differing parts of the world, where it may not be possible to set a reliable baseline of typical elemental impurities content. Whilst pharmaceutical manufacturers may push excipient suppliers to provide the data, most excipient manufacturers are not manufacturing materials primarily for the pharmaceutical industry and hence there is little incentive for this information to be generated.
With this lack of reliable data, some pharmaceutical manufacturers have decided to generate the data themselves for their current product ranges. To assess if any particular product or dosage form gives rise to significant levels of elemental impurities, they are using inductively couples plasma (ICP) generic quantitative screening methods for 30 or so common elements. In other cases, where manufacturers use a limited range of excipients, the approach has been to assess multiple batches of raw materials in the same way. This data can then be used for risk assessment and shared across product ranges.
The three major pharmacopoeias — US, European and Japanese — describe procedures based on analysis by ICP. Whilst they do not rule out alternative techniques such as atomic absorption spectroscopy (AAS), X-ray fluorescence (XRF), ultraviolet spectroscopy (UV) and ion chromatography (IC), the standard method of reference will be ICP. Although there are obvious benefits from the use of modern instrumentation in replacing the well-established wet chemistry limit test, manufacturers are faced with a number of considerations before investing in the new technology required.
- The capital expenditure; an ICP-OES costing in the region of £50k, plus an ICP-MS at £125k, together with a closed vessel microwave digestion system for £35k.
- The cost of installation of the equipment, services and ongoing running costs.
- The cost of training of staff in the new technique or, in some instances, the employment of another analyst with the relevant experience to operate the equipment and interpret the data.
These costs then have to be weighed against the level of ongoing testing requirements once the risk assessments of each product have been concluded. This has led to many manufacturers looking to outsource this risk assessment work, rather than investing in new equipment.
Once the risk assessment has been performed, manufacturers are then faced with the decision of what ongoing testing will be required. Whether this is on the finished products or specific raw material components, specific validated methods will need to be produced for the elements of concern.