Regulatory Focus™ > News Articles > Final Guideline on Antibiotic Impurities Focuses on Manufacturing Processes

Final Guideline on Antibiotic Impurities Focuses on Manufacturing Processes

Posted 13 July 2012 | By Alexander Gaffney, RAC 

The European Medicines Agency (EMA) has released final its final guideline on how to set specifications for impurities present in antibiotics not covered by other internationally-harmonized guidelines.

European regulators note in the guidance that antibiotics produced by a fermentation process are less precise and create more product variability and impurities than do other synthetic processes. Because many of these processes-including semi-synthetic fermentation-do not fall under the scope of the International Conference on Harmonization's (ICH) Q3, the Veterinary International Conference on Harmonization's (VICH) GL10 or GL11 guidelines, or the European Pharmacopoeia's guidelines, EMA said it saw the need to provide guidance to sponsors on the subject.

"Thresholds are given in the guideline for reporting, identification and qualification of related impurities for antibiotics medicinal products whose active substance is produced by fermentation or semi-synthesis," explained EMA in the guideline. "In cases where the active substance consists of a mixture of closely related compounds, where it may be difficult to apply general thresholds, general guidance is given on how to set specific thresholds and specifications and on how to qualify impurity profiles."

Impurity Specifications Must be 'Justified'

EMA notes the "impurity profile depends very much on the manufacturing process," as the impurities can be different even when the same organism is involved. As such, EMA said it is requesting a "detailed description of the fermentation steps" to be included in the product's general monograph, including purification steps used after initial manufacture. In limited cases, it may be permissible to utilize a "suitable specification" for starting materials and impurities, though EMA said these must be "justified" to the agency.

Any intermediate steps between initial manufacture and purification must also be detailed to EMA. The agency said in all cases it is considered preferable to reduce the number of intermediary steps and "optimize purifications steps as far as possible."

The agency also explains that each identified impurity, unidentified impurity, unspecified impurity and the total number of impurities must have limits set unless it is "not practically possible to identify an individual impurity." In such a case, "sufficient evidence of its structure" must be provided to determine if it is an impurity or related to the parent compound. EMA's guideline establishes thresholds for these impurities.

Read more:

EMA - Guideline on Setting Specifications for Related Impurities in Antibiotics

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