It can be challenging to evaluate whether a proposed semisolid drug product will be suitable for its intended purpose (i.e.

complex product quality assessment).

Depending upon formulation and manufacturing processes, even products that are Q1/Q2 equivalent could theoretically have

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Q3 differences in their arrangement of matter that may have the potential to impact dosage form performance.

Furthermore, it can be challenging to evaluate potential failure modes for semisolid drug products, because of the wide variety of complex microstructures that can exist within dosage forms that are non-specifically termed creams, lotions, gels, ointments, etc.

To address these regulatory science challenges, and to advance FDAs mission to make safe and effective drug products available to the American public, it is essential to keep pace with current technologies that can better characterize semisolid dosage forms, to help identify potential risk factors and failure modes in the proposed drug product, and to facilitate an efficient, relevant and comprehensive Q1/Q2/Q3 comparison of a proposed generic drug product with the RLD.

OBLECTIVE:
The objective of this work is to support the development of regulatory standards and guidance's for industry regarding the development of semisolid topical drug products, based upon well-defined critical quality and performance attributes that best characterize these products.

DETAILED DESCRIPTION:
A preliminary classification system will be developed to comprehensively inventory the various types of semisolid dosage forms relevant to topical drug products, differentiated based upon their components and anticipated microstructures (e.g.

single vs.

multi-phase gels, oleaginous suspensions, pluronic lecithin organogels, polyethylene glycol or petrolatum-based ointments, oil-in-water or water-in-oil creams, lotions, pastes, etc., each which may have fully or partially dissolved active pharmaceutical ingredient(s) in one or more phases).

A theoretical framework for all potential failure modes for each class of semisolid dosage form will be constructed, and since the product container closure system could be associated with a failure mode, it will be considered as well.

A comprehensive set of quality attributes will be identified for each class, which may include such physical/chemical attributes as opacity, smoothness, odor, color, consistency, water content, osmolality, pH, etc.

However, while it is of interest to monitor all product quality attributes, not all measurable attributes may be critical to product performance or patient acceptability.This project will ultimately help to define critical quality and performance attributes that best characterize topical semisolid drug products.

At the molecular level, critical quality (Q1, Q2 and particularly Q3) attributes may potentially encompass not only the components, but also the relative proportions and form of the phase state(s) in the semisolid, globule size and distribution, particle size and distribution of the drug substance(s) within the phases of the dosage form, polymorphic forms of the drug substance, and other potentially critical characteristics as relevant.

At the macromolecular level, these Q3 attributes may potentially encompass qualities such as rheology, density, homogeneity, and other physical properties.

An essential component of this research would be to identify potential failure modes for different topical semisolid drug products, associate those with variations in critical quality attributes (CQAs) and characterize the formulation, manufacturing or stability-related variables that can influence the CQAs and impact a failure mode (e.g.

cream homogenization speed may influence globule size which may impact therapeutic performance).Different classes of semisolid dosage forms will be studied systematically, using formulation or manufacturing alterations to vary different quality attributes, and then using performance tests to identify those attributes that are CQAs.

Tests of product performance to evaluate the criticality of quality attributes may be performed with appropriately discriminating in vitro release test (IVRT) methods as described in USP <1724>, or in certain cases with in vitro permeation tests (IVPT) using human skin, or by other methodologies capable of evaluating relative bioavailability.

STUDY PHASES:
This project will have several phases as noted below:
1.

Comprehensive description of all potentially measurable physical/chemical qualities of semisolid dosage forms comprised of different components and with different anticipated microstructures and potential failure modes.

2.

Identification and/or development of appropriate methodologies for measuring each of the quality attributes described for each class of semisolid dosage form.

3.

Characterization of formulation/manufacturing variables that impact these quality attributes in each class of semisolid dosage form, and 4.

Utilization of in vitro and/or in vivo measures of product performance to identify those quality attributes that may be critical to therapeutic performance, and which may be associated with a failure mode for a drug product.