CRED Getting the CMC Dossier Right 2024

29/08/2024

Common deficiencies: Particle size

⚫ The issue:

● Assessors on the ‘look out’ for: Poorly soluble drug substances

● The issue – Particle size - Critical Quality Attribute – Impact on the drug product – dissolution,

– bioavailability, pharmaceutical equivalence – stability

● Information inadequate – control of particle size distribution; single point only – lack of supporting batch data; comparative batch data with reference product/ biobatch – Particle size reduction method description ● May also be raised in 3.2.P.2!

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Common deficiencies: Particle size

⚫ Exemplary MOs

● There are major concerns that control of the particle size of the drug substance has not been addressed in view of the known low solubility of the drug substance and the effect of this critical parameter on bioavailability. A comprehensive discussion should be provided on the particle size proposed for the product. – The specification for the drug substance should include a comprehensive profile for particle size using appropriate, validated methodology. The particle size distribution as a critical parameter should be expressed as d90, d50, and d10 , according to the Ph Eur monograph. – The specification for particle size distribution should be based on representative commercial batch data confirming batch to batch reproducibility and should reflect the particle size distribution of the biobatch . ● The drug substance is present as a suspension in the drug product, its particle size is considered critical quality attribute (CQA) affecting the efficacy and safety of the drug product. The particle size and particle size distribution of the drug substance have not been adequately addressed throughout the dossier: – The drug substance manufacturing process to ensure this CQA is consistent and achieves a justified target specification is not addressed. – The applicant has failed to characterise this CQA in the development pharmaceutics . – The particle size analysis of the drug substance is inadequate. The size classification is too coarse; only one batch is examined. The material is not from the proposed supplier. – The applicant has failed to compare the drug substance particle size in the test and reference products. – The absence of suitable controls for particle size in the drug substance specification is not acceptable.

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