Implementing a quality-by-design (QbD) approach to developing CPPs has become a necessity. Most notably, a design of experiments
(DOE) can be used to gain an understanding of what processing parameters have the greatest impact on the critical quality
attributes of the final product. This understanding can be used to implement a chemistry, manufacturing, and controls (CMC)
strategy to ensure stability, product performance, and process control in manufacturing a topical drug product. A DOE, for
example, was conducted to determine how the final viscosity of a formula varied based on the amount of shear and temperature
during which the shear is applied. The goal was to produce the product with the highest viscosity. As shown in Table I, the higher rate of shear yielded the best results.
Table I: A design of experiments was conducted to determine how the final viscosity of a formula varied based on the amount
of shear and temperature during which the shear is applied. Emulsification rate was held constant at high rpm.Emulsification
temperature was held constant at 75–80 °C. Emulsification time and the rate of low-shear mixing were varied. The goal was
to produce the highest product viscosity; the higher rate of shear yielded the best results.
Use process-control tools
Even though preserved, topical formulations do not require the strict process controls required in sterile manufacturing,
topical formulations must still have a well understood and controlled process. Emulsions, for example, can be difficult to
process because they are inherently thermodynamically unstable. The use of manufacturing vessels with programmable logic controllers
(PLCs) is one tool that can provide more reliable and accurate control of the pressure/temperature and mixing speed and times.
Add ingredients in the optimal phase and order
Generally, topical formulations comprise one or more phases. Emulsions, for example, primarily comprise an aqueous phase and
a hydrophobic phase. Adding ingredients in the correct phase contributes to overall stability. For example, some polymers,
such as microcrystalline cellulose/sodium carboymethylcellulose, must be dispersed and hydrated prior to adding other ingredients.
Most ingredients have an optimal method of incorporation into a formulation. Preservatives, such as parabens, should be added
just prior to emulsification to reduce time in contact with water-soluble surfactants at elevated temperatures. Polymers (e.g.,
carbomer) and gums (e.g., xanthan) must be added slowly to avoid formation of fish eyes and other partially hydrated, undispersed
material. These problems can be avoided by using eductors (e.g., Tri-Blender and Quadro Ytron dispersers) or by preparing
a slurry of polymer or gum in a medium of low or no solubility (e.g., glycerin or glycols for certain gums or oils for carbomers).
These thickeners act as emulsion stabilizers to keep oils or creams suspended in water and prevent separation. Such thickeners
can be shear sensitive, however, so they must be processed with care.
As an example, DPT Labs was tasked with manufacturing a formulation that was a fatty-acid-based emulsion neutralized using
an amine. With the amine in the water phase upon emulsification, the product immediately gained viscosity, requiring a higher
mixing speed. As the product cooled, the formulation hit a critical temperature in which it rapidly thinned out and began
splashing out of the mixing tank. Resequencing the product and adding the amine post-emulsification, however, maintained the
quality of the product and eliminated negative effects on the formulation and potential danger to staff.