Challenges in Topical Drug Manufacturing

An ideal topical formulation can be produced using a simple, flexible process. Most topical formulations developed today, however, are complex and therefore require tightly controlled processing parameters. September’s Equipment and Processing Report contained an article that described five critical process parameters: temperature, rates of heating and cooling, mixing methods and speeds, mixing times, and flow rates. Following are additional strategies to optimize the manufacturing process for topical dosage forms.

Use process-control tools

Although preserved topical products do not require the strict process controls involved in sterile manufacturing, a well understood and controlled process is crucial.  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 microcrycrystalline 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. DPT resequenced the product and added the amine post-emulsification. This change maintained the quality of the product and eliminated negative effects on the formulation and potential danger to staff.

Protect APIs from degradation

The manufacturing process must be designed to protect APIs from physical degradation.  Some APIs, such as retinoic acid compounds, are sensitive to both UV light and oxygen.  These APIs can be protected by using yellow or amber light that is free from harmful low-wavelength UV rays and by using nitrogen, argon, or another inert gas to purge the product of oxygen.

Identify equipment constraints

The manufacturer must be able to perform all processes using its current equipment capabilities. The scale-up path for a 1:10 batch size from the pilot or clinical size to commercial level must exist with similar equipment. Guidance from FDA’s Scale-Up and Postapproval Changes Semisolids (SUPAC-SS) Working Group provides the basis of comparison for the design and operating principles of equipment (1).

Consider regulatory requirements

Satisfying regulatory requirements for the scale-up or transfer of a process can be challenging. To scale up a process used for clinical batch manufacturing or transfer a commercial process to a new manufacturing site, the equipment must at least be of the same materials of construction and employ the same type of mixing, as defined in the SUPAC-SS guidance (1).

Consider an outsourcing partner

The manufacturing process can influence a topical product’s stability and performance.  If a formulation is transferred to a contract manufacturer, changes in mixing speeds, temperature controls, and order of ingredient addition may be needed.  Outsourcing formulation development and manufacturing to a contract development and manufacturing organization (CDMO) allows technology transfer, scale-up, and manufacturing to take place at one location, which ensures project continuity.

Reference

• FDA, Guidance for Industry, Nonsterile Semisolid Dosage Forms, Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation (Rockville, MD, May 1997).

Michael Lowenborg is research and development manager at DPT Laboratories, 3300 Research Plaza, San Antonio, TX 78235, tel. 210.531.7125, Michael.Lowenborg@dptlabs.com