July 2022
Real CMC Tips and Insights

published 3 Aug 2022

Since the beginning of July 2020, we have published weekly Regulatory tips and insights from our Regulatory experts on our Real Regulatory LinkedIn page, as a service to our followers. The tips we published in July 2022 are collected here, for convenience. Make sure you follow  Real Regulatory Ltd and Real CMC for regulatory news, reports and hints.

Cross-Checking of Formulae

Inconsistencies between unit formulae in 3.2.P.1 and manufacturing formulae in 3.2.P.3.2 are very common. Make sure that the quantities in the formulae can easily be converted into each other by multiplying or dividing by the number of dosage units in the batch. To minimise the effect of rounding, derive the unit formula from the batch formula and not the other way round, and choose an appropriate number of decimal places. Also check the total weights or volumes - do the quantities in your composition tables add up to the stated totals? Have density, overfills and overages been taken into consideration and clearly stated?  

Secondary & Tertiary Packaging

Module 3.2.P.7 of the dossier should focus on primary packaging - the packaging that comes into direct contact with the product. Secondary packaging should only be described briefly, unless it is functional (providing additional protection or serving to deliver the product). If functional, additional relevant information should be provided, such as a specification. No information on tertiary packaging should be presented.

Drug Substance Specifications

The applicant's specification for a drug substance presented in the MA dossier should match that of the ASMF or CEP holder, unless certain tests can justifiably be omitted e.g. superfluous tests or limits that are too tight. The applicant's specification may include additional tests, if critical to the quality of the drug product e.g. bacterial endotoxins. If there is more than one drug substance supplier, the applicant's specification for the substance should consolidate the various sets of specifications.

Biowaivers for SODs

For solid oral dosage forms, biowaivers for additional strengths are possible if the qualitative composition and manufacturing process are the same, the strengths are quantitatively proportional (excluding coating components, capsule shells, colours and flavours), and supportive in vitro dissolution data are available. If the drug substance constitutes less than 5% of tablet core weight, some deviation from quantitative proportionality is permitted. Each layer of bilayer tablets is considered independently. Fixed combinations are more complicated, therefore detailed worked examples have been provided by the PKWP in Q&A 6.4.



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