Topical Products
for topical products, highlighting the importance of documentation and managing the process closely from the start. Material sourcing will have just as much impact as working with the right equipment and testing methods.
Topical formulation technicalities
Successful process design requires extensive analysis and preparation prior to implementation. Important variables in topical formulation will require experimentation and innovative solutions. Some of the most crucial elements to consider are:
• Identifying/profiling the API • Optimal concentration of viscosity agents
• Degradation of APIs depending on formulation composition
• Appropriate filler and preservative ingredients
• Sterile filtration requirements (for sterile topicals, e.g. sterile ointments) and temperature impact • Packaging preferences • Storage and transportation
Once the drug needs are defined and a topical formulation is selected, the focus moves to process planning and implementation. The right equipment is imperative for manufacturing steps, including mixers, emulsifiers, mills, and agitators. Scale-up is a major hurdle for semi-solids because liquid systems exhibit more variability regarding mixing and mixing environments and often change when transferring from lab to plant, much more so than in solid dosage form processes. Temperature control is also critical due to its effects on viscosity and other properties. Some formulations with the same exact composition can have different density and viscosity simply due to the path taken during manufacture, for example longer mix times or temperature excursions. To achieve the
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temperature ranges required during manufacturing, jacketed vessels can be employed, heating or cooling as needed. With automation advances, there are now electronic recipes available to control temperature and mixing speeds. In principle, the run being completed today can be an exact replicate of what was done yesterday using this approach, which is very useful for semi-solids.
In-process sampling and characterization is employed to confirm that the manufacturing run is progressing within specification, typically when the bulk semi-solid is made and prior to filling into bottles or tubes. In some cases, specific samples during bulk manufacture are needed (for example, to assure pH is where it needs to be in a pH- sensitive process).
Testing topicals
Like all prescription products, topical dosages must be fully tested and meet specifications
prior to release. Some aspects of semi-solid analytical work are unique, such as viscosity, but to a large extent, most of the same methods that are used for traditional oral solid dosage analysis are applied. The difference is that topical dosage form analysis focuses on the structure of the emulsion or any heterogeneity instead of the particulate structure analyzed for capsules and tablets. One method that is truly unique to topical dosage forms is in-vitro release testing (IVRT), which mimics how a topical formulation will penetrate and interact with human skin. It achieves this by placing a synthetic membrane or cadaver skin across an opening followed by application of the test product. Beneath the ‘skin”’ or synthetic membrane is a solution that simulates the environment just under the skin and in IVRT testing samples of the solution are taken periodically to see how
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much active drug has penetrated this membrane. This type of testing is generally done when equipment changes happen or during technology transfers. In some cases, the FDA will require the applicant to conduct IVRT testing on every batch due to concerns around batch-to-batch reproducibility. Topical dosage form products will also need to be tested for bioburden to demonstrate that they do not harbour any microbial contaminants. Topicals often contain water as an ingredient, making them more susceptible to microbiological contamination than oral solid dosage forms. Bioburden and microbial testing needs will vary based on the drug product being formulated but must be exhaustive. Depending on the type of product, topicals will undergo the following tests: ● Bioburden testing to measure the population of viable microorganisms in a product
The Ekato 150L Mixer Homogenizer is used for semi-solid manufacturing from 40 to 150L employing either high or low solid-liquid shear and comprises a jacketed main vessel and 75L side vessel under PLC temperature control. There is also a clean-in-place (CIP) system to ensure safe and highly-efficient cleaning of the equipment.
Summer 2020
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