Update on the European Pharmacopoeia policy on elemental impurities – Excipients of natural origin

In January 2017, the EDQM published an update on the European Pharmacopoeia (Ph. Eur.) policy on elemental impurities in which the special case of excipients of natural origin was highlighted. At the time, and based on feedback gathered from stakeholders during workshops and conferences, the Ph. Eur. Commission decided to make an exception for these substances and keep the specific elemental impurity tests in the corresponding individual monographs. This was considered particularly necessary since the intrinsic nature of elemental impurities in natural-origin excipients is such that they are amongst the major potential sources of elemental impurities in medicinal products. Continued elemental impurity testing was therefore seen as critical to quality control. However, it was also made clear that as new data became available, opportunities for revision of the set of individual metal tests in monographs would be examined. The success of this initiative would be heavily reliant on support from stakeholders.

Since 2017, the group of experts dealing with inorganics – Group 9 – has therefore continued to work on the individual monographs for excipients of natural origin. Their first step was to collect batch data from stakeholders and compare it with the corresponding individual monographs. Each case was scrutinised closely and, where necessary, the individual elemental impurity tests were revised to reflect more closely the actual quality of substances available on the European market. The Group deleted specific elemental impurity tests when the contaminant was found to be process-related or where batch data showed that it was not actually present in the substance. On the other hand, specific tests were kept for elemental impurities that continued to be detected in production batches or were added for any new elemental impurities found. In both cases, appropriate limits were set based on available batch data.

While assessing individual elemental impurities, Group 9 took into consideration the control threshold of 30% of the established permitted daily exposure (PDE) for oral dosage forms laid down in the ICH Q3D guideline. Parenteral intake was considered where appropriate. If batch data showed levels consistently higher than the control threshold, specification limits were either kept or updated in the case of existing elements and introduced in the monograph for new elements.

The individual monographs concerned now show a tailored list of existing and new elemental impurities (where applicable) together with their limits, to facilitate their control. A certain degree of flexibility in the choice of method to be used has been allowed by including a simple reference to general chapter 2.4.20 Determination of elemental impurities. This allows manufacturers to use any method that fulfils the validation requirements described in the general chapter.

When completed, draft revised monographs on excipients of natural origin are published in Pharmeuropa for public consultation. To date, 11 monographs describing new elemental impurities and two showing updated limits for existing impurities have been published. Group 9 still has 17 monographs left on its work programme to be discussed in the framework of the Ph. Eur. policy on elemental impurities.

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