Elemental impurities have been a hot topic since 2009 when the International Conference of Harmonisation (ICH) commenced work on a new standard to provide a global policy to limit these impurities in drug products and ingredients. Their guidance document, Q3D, reached step 4 in December 2014, meaning the final draft is recommended for adoption to the regulatory bodies of the European Union, Switzerland, Japan, USA and Canada.
Since then, the United States Pharmacopeia (USP) announced in March 2015 that 1st January 2018 will be the effective date for General Chapter . A revised version of this chapter has been published in the Second Supplement to USP 38-NF 33 and became official on 1st December 2015. This version contains limits for 15 elements that align with the ICH Q3D Step 4 document. The existing chapter detailing the current colorimetric methods will remain effective until the 2018 date, however, early adoption of is allowable under revised General Notices Section 5.60.30.
From a European perspective, the Committee for Medicinal Products for Human use (CHMP) set an implementation date of June 2016 for new marketing authorisations and December 2017 for all drug products on the EU market to comply with the ICH guidelines. Following this, the European Pharmacopeia (Ph.Eur.) Commission announced its implementation strategy in April 2015, choosing to reproduce verbatim the ICH Q3D guideline in the Ph. Eur. chapter 5.20. References to the existing heavy metals testing Chapter 2.4.8 will be removed to align with the publication of the 9th edition of the Ph. Eur. due for implementation on 1st January 2017. Chapter 2.4.8 will remain applicable until ICH Q3D comes into force for a given formulation.
So with the June 2016 date fast approaching for compliance of new marketing authorisations in the EU, what should manufacturers be doing in order to prepare themselves for compliance?
Assess the Risk
ICH Q3D provides a means of assessment and control of 24 elemental impurities using the principles of risk management as detailed in ICH Q9. It establishes permitted daily exposure (PDE) limits for each element, expressed in µg/day, calculated using published toxicity data and set according to the route of administration. The elements are divided into three classes based on their toxicity and likelihood of occurrence with limits applicable to finished formulations based on a maximum dosage of 10g/day. Compliance is not directly applicable to excipients or the drug substance, however, USP does state “elemental impurity levels present in drug substances and excipients must be known, documented, and made available upon request”.
A risk assessment should therefore be conducted, taking into account the levels of impurities in each component of the formulation as well as the proportion of that component being used in the drug product. Other important factors include container closure systems used and the manufacturing process of the formulation (including equipment and intentionally added catalysts and/or reagents). These all have the potential to affect the impurity profile of a product.
As a measure of the significance of the observed or predicted elemental impurity level, a control threshold has been defined by Q3D as 30% of the established PDE. If the risk assessment fails to show that impurities will be consistently below this level, controls will need to be applied which could include setting specification limits for excipients, drug substance and the drug product.
Q3D states that “At the time of submission, in the absence of other justification, the level and variability of an elemental impurity can be established by providing the data from three (3) representative production scale lots or six (6) representative pilot scale lots of the component or components or drug product. For some components that have inherent variability (e.g., mined excipients), additional data may be needed to apply the control threshold”.
Fill the Gaps
In order to appropriately complete product risk assessments there is obviously a heavy emphasis on knowledge of the manufacturing process and the raw materials used in the formulation. The benefits of Quality by Design (QBD) can’t be ignored, particularly with respect to New Drug Applications (NDA)/ Marketing Authorisation Applications (MAA). Control of elemental impurities should be fundamental in the design of the formulation and manufacturing process, removing, where possible, or at least reducing the requirement for routine analysis.
In the case of existing marketed products, manufacturers are in many cases requesting information on the levels and variability of elemental impurities from their material suppliers for use in the risk assessment exercise. The reality is that not all suppliers have this information and while many are conducting their own internal analysis to obtain typical data, the manufacturer is often left with gaps in their information.
As a result, screening analysis is being utilised to plug these gaps. Q3D refers to the Pharmacopoeias for analytical methodology, with the USP chapter detailing ICP-OES (ICP-AES) or ICP-MS and the Ph. Eur. ICP-OES, ICP-MS as well as additional techniques that may be suitable. All parties involved in the Pharmaceutical Discussion Group (PDG), a collaboration of USP, Ph. Eur. and Japanese Pharmacopeia (JP) confirmed in Tokyo, 30th June-1st July 2015, their commitment to harmonise their respective general chapters on testing procedures for elemental impurities.
Both ICP-OES and ICP-MS offer multi element analysis over a large linear range, making them ideal choices for screening. From a practical perspective, however, ICP-MS can determine concentrations 1000 times lower than that of ICP-OES and as sample preparation will involve dilution, ICP-OES struggles to meet the required specification limits for some of the elements in Q3D, particularly arsenic and mercury. Consequently ICP-MS is the method of choice for elemental impurity screening.
Quantitative screens have been performed at Butterworths on drug substances, excipients and products using ICP-MS, looking at the 24 elements laid out in ICHQ3D. A calibration for each element is produced from two standards set an order of magnitude apart. The lowest standard is equivalent to the target
quantitation limit. A third standard, prepared from alternative sources, acts as an independent quality control standard. This provides a check that the stock solutions used are correct. Generally, samples are prepared in duplicate, with an additional preparation being spiked with a known quantity of all the elements of interest. The spike provides confirmation that all the elements have been recovered and that there were no losses during the preparation. The data obtained from the standards, spike and duplicate preparations provide a significant amount of verification data demonstrating that the method used is fit for its intended use with a particular material or formulation. The quantitative data obtained from the screen can then be used as part of the risk assessment to determine what, if any, ongoing controls will be required.
If, during the risk assessment process there are elements identified that are of concern (i.e. consistently above the 30% control threshold) and it is deemed appropriate to routinely analyse a raw material or finished product then full validation of a method specific to that material will be required.
Elemental impurity control changes are upon us. The ICH Q3D guideline offers a clear framework to assess and control the risk in order to achieve compliance for drug products. A combination of existing knowledge of raw materials, containers and the manufacturing process supplemented with supplier knowledge and analytical screening can provide a robust understanding of the risk and help to direct actions to mitigate it. The process should also be looked on as an opportunity to feedback learning into the R&D process to enable compliance and quality to be inherent in all future drug products.