CRED Getting the CMC Dossier Right 2024

29/08/2024

Common deficiencies: GMP issues

⚫ Exemplary MOs

● Confirmation of a satisfactory GMP audit of the active substance manufacturing site should be provided. – A new QP declaration relating to a more recent audit of the active substance manufacturer should be provided; this audit should cover all sites involved in the synthesis of the active substance from the redefined starting material. – Manufacture of the active substance should comply with the requirements of Part II of EU GMP, which includes validation of the manufacturing process. – The statement that no process validation is available despite production taking place for 20 years raises serious concern over the GMP and the QP’s GMP statement (in annex 5.22). This should be further discussed, and the report from the audit of the active substance manufacturing site (used to support the QP declaration) provided. ● The last audit for the manufacturing site was conducted over 3 years ago . A QP declaration based on an audit conducted within the last 3 years should be provided. – The GMP certificate provided to confirm compliance with the GMP requirements for manufacture of APIs is not considered acceptable. – Confirmation of a satisfactory GMP audit should be provided with the final Day 106 responses. Absence of a satisfactory QP declaration at this stage of the procedure is now considered to be a Potential Serious Risk to Public Health.

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Common deficiencies: Other concerns

⚫ The issue:

● Sample of 30 products

● Other concerns raised (3.2.S+3.2.P): 1-10 = 4 products 9-20 = 9 products 21-39 = 9 products 40-59 = 4 products 60-80 = 3 products > 80 = 1 product ● Do the ‘other concerns/points for clarification’ matter?

Recent generic application: ➢ Major objections: o Drug substance o Drug product ➢ Other concerns o

An overarching major objection is raised due to the concern regarding the large number of deficiencies on both the drug substance and drug product parts of the application, in particular, relating to the validation of the various analytical methods, limited information on the polymorphic conversion during product manufacture etc. See “other concerns” for details.

Drug substance – 85 points Drug product – 34 points

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