IPEC e-newsletter - Excipients Insight April 2017 - 30-04-17

 

Inside this issue

     

Impurity failings top causes of CEP deficiencies, says EDQM

A lack of discussion on the risk of having potential mutagenic impurities in pharmaceutical substances was the number one deficiency in a sample of 20 Certificates of Suitability (CEPs) filed in the second half of 2015 and early 2016, according to the European Directorate for the Quality of Medicines and Healthcare (EDQM).

The EDQM public document notes that applicants are expected to provide a complete discussion on mutagenic impurities in their application for a CEP in order to meet the requirements of ICH M7, which has been in force since January 2016.

The second most common deficiency listed is related to the impurity profile of starting materials – specifically the "absence or insufficient discussion on fate and carryover of related substances of starting materials (included) to the final substance."

"Applicants need to know what kind of impurities can be found in starting materials, in particular with regard to related substances since usually these are molecules that can react according to the chemistry foreseen by the process, leading to impurities in intermediates and potentially in the final substance," notes the EDQM.

The full list of deficiencies runs as follows:

  1. Absence or deficient discussion on the risk of having potential mutagenic impurities in the final substance.
  2. Absence or insufficient discussion on fate and carryover of related substances of starting materials (included) to the final substance.
  3. Lack of details and/or poor description of the manufacturing process of the substance from the introduction of starting materials (synthesis, narrative description, flow charts, recovery and reprocessing procedures). Incongruences noted between information given in section S.2.2 and section S.2.4.
  4. Non-acceptable starting materials, necessity to redefine them earlier in the process.
  5. Non-adequate or poorly justified specifications in place to control the quality of starting materials.
  6. Non-adequate or missing specifications (and analytical methods) for reagents and solvents (recovered and recycled included) used to manufacture the substance from the introduction of starting materials.
  7. Non-adequate or missing discussion on carryover of reagents and elemental impurities to the final substance.
  8. Non-adequate or poorly justified specifications in place to control the quality of isolated intermediate.
  9. Absence or insufficient discussion on fate and carryover of impurities from synthetic intermediates (included) to the final substance.
  10. Non-adequate or missing information on the synthesis of starting materials and their manufacturers.

 

 

 

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