PDE, MDD and USP <232><233>

USP 232/233

As we work with numerous pharma companies in performing screenings of drug products and their excipients/APIs, validations of methods, and/or conducting release/routine testing, a common point of discussion is the Maximum Daily Dose (MDD) or daily Serving Size.

MDD is directly correlated with the Permitted Daily Exposure (PDE).  As many are aware, USP <232> defines the PDE of 24 Elemental Impurities in Drug Products.  Specifications for the concentration of Elemental Impurities in a drug product (ie. ug/g), are a function of the concentration of Elemental Impurities (EIs) in a drug product, and the MDD.  In simple terms, you need much lower concentrations of an Impurity if your MDD is 100 grams, vs. a MDD of 1 g.

When receiving samples for routine testing, screening, or ultimately, method validation, CSL must know the MDD, to establish specifications in our testing (ug/g).  Given that the Risk Assessment approach prescribed with the ICH Q3D guidelines and Training Modules suggests a 30% of PDE threshold for EIs within a Risk Assessment, we oftentimes are instructed by clients to use 30% of the specification as the base specification (J Value) in our testing.

Within the USP <232> General Chapter, drug manufacturers are offered three options for demonstrating compliance:  Drug Product Analysis Option, Summation Option, and Individual Component Option.  Under the Individual Component Option, reference is made to Table 3, wherein Permitted Concentrations of EIs are based upon a MDD of 10g/day.  The 10g/day MDD is a default value in this case, serving as an aid to discussions between drug manufacturers and their suppliers.

So…why do we mention this?  (ie. Can we get to the point?)

The reason we highlight the 10g/day MDD, is recent feedback we’ve received from clients who have completed submissions within the European Union.  They found that in some cases, regulators were stipulating that their Risk Assessments and method validations, as related to their finished Drug Products, should be done with the assumption of a MDD of 10g/day.  This is significant for Demonstrating Compliance, in that many drug manufacturers have been using actual MDDs, versus the 10g MDD.

In the testing world, this is big.  Given that oftentimes excipients or APIs are found in very small concentrations, and that actual MDDs of Drug Products may be a fraction of the 10g MDD, the testing criteria surrounding small dosage amounts can differ significantly from that for large doses.  Thus, our clients should be cognizant of this when creating their Risk Assessment plans and submitting drug products – or components – for testing and/or method validations.

As always, should you wish to discuss further, or have any questions pertaining to your own Risk Assessment approaches, please feel free to contact us at your convenience.  Email:  info@chemicalsolutionsltd.com, Phone: (717) 697-7536.

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