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The finalized version of the EMA guideline was issued on 28 June 2006 with an effective date of 1 January 2007 [9]. In terms of the final guideline, a number of key points were addressed, and it would be wrong not to recognize this or to ignore the significant progress made from the original position paper; however, it is equally important to note that concerns remained around several key areas. Outlined below are the key areas that had been addressed and also a reflection on the areas of concern.

The published guidance attempted to clarify how the concepts of the guidance were to be applied to existing substances and products. A concern had been that existing medicines would be required to comply with all aspects of the new guidance. This could have led to there being a perceived shortfall in control strategies or quality for a significant number of medicinal products that had been developed in the years prior to the development of this guidance and furthermore that had proved to be adequately safe across this period. The published guideline included the following specific statement.

“It also relates to new applications for existing products, where assessment of the route of synthesis, process control and impurity profile does not provide reasonable assurance that no new or higher levels of genotoxic impurities are introduced as compared to products currently authorised in the EU concerning the same active substance. The same also applies to variations to existing Marketing Authorisations pertaining to the synthesis. This guideline does, however, not need to be applied retrospectively to authorised products unless there is specific cause for concern.” As examined below, there was considerable uncertainty as to what this term meant in practice; there being no clear definition, at least not initially.

In practice this proved extremely difficult to interpret consistently, both from an industry and regulators perspective, particularly in relation to the potential “catch all” phrase “cause for concern.” The impact of this uncertainty is explored in detail in the following section.

Another addition within the Recommendations section was advice on the scope of investigations in terms of what impurities should be considered as part of an assessment. The guideline stating:

As stated in the Q3a guideline, actual and potential impurities most likely to arise during synthesis, purification and storage of the new drug substance should be identified, based on a sound scientific appraisal of the chemical reactions involved in the synthesis, impurities associated with raw materials that could contribute to the impurity profile of the new drug substance and possible degradation products. This discussion can be limited to those impurities that might reasonably be expected based on the knowledge of the chemical reactions and conditions involved.

Although entirely sensible and reasonable on the face of it, in practice this was difficult to interpret consistently.

Another significant change was the exclusion of excipients from the finalized guideline, this having present in the 2004 draft. A separate specific position paper addressing excipients has subsequently been issued jointly by the Quality Working Party (QWP) and SWP within European Medicines Evaluation Agency (EMEA) (and will be discussed later in this chapter).