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Understanding of scale-up parameters and use of process analytical technology are important to meet demand for larger batch sizes.
Topical drug products have unique characteristics compared to other dosage forms, including particular challenges in development and clinical manufacturing. Pharmaceutical Technology spoke with Jason Carbol, Chemistry, Manufacturing, and Controls manager and senior formulator with Dow Development Labs (DDL), a contract development and manufacturing organization (CDMO) in California that specializes in the development, manufacture, fill, and release of topical drug products, about recent trends in topical drug development and manufacturing.
PharmTech: What do you see as the most significant changes affecting product development and clinical trial manufacturing and packaging in the past few years?
Carbol (DDL): For topical product development and manufacturing, one of the big challenges is scale up. There seems to be a shift to move to bigger batch sizes more quickly than ever before. Good laboratory practice (GLP) animal studies are requiring larger amounts of material than in the past, partly due to changes in FDA guidance and requirements for GLP repeat-dose cumulative toxicity studies in minipigs. Studies that used to require 5–10 kg of material are now requiring 30–50 kg. Additionally, sponsors are trying to accomplish more in single studies rather than in multiple studies, which necessitates more material for the study. These larger batch sizes are challenging for benchtop R&D development work, as the formulation and process development is very quickly being transitioned from small scale to medium or large scale. Scale-up engineering was a relatively small part of the formulator’s job in the past; however, it is now becoming a larger part. Another challenge is identifying contract manufacturing organizations that are capable of large-scale batch manufacturing and filling of topical products, as there are a limited number of large-scale/commercial contract manufacturers with experience with semi-solid products.
PharmTech: What are some of the technical challenges of scale-up and how can these be addressed?
Carbol (DDL): A key challenge in scaling up is retaining the product’s desired cosmetic elegance, viscosity, and physical stability. Topical products are fundamentally difficult to scale up due to the vast changes in physical forces seen at the bench scale vs commercial scale. At a larger scale, mixers tend to be much more powerful, but mixing efficiency tends to decrease. One option for increasing mixing efficiency is to mix for a longer duration, but the product may then be subjected to forces never experienced at the bench scale during development. Additionally, it is very difficult to heat and cool at the benchtop scale similar to what will be done at the commercial scale. The effect of the time and temperature during heating and cooling during commercial-scale processing can often result in unexpected physical product changes, such as changes to viscosity. Lastly, the mass of the commercial amount of product manufactured is significant; the product on the bottom of the vessel is experiencing pressures never developed with a benchtop process. Understanding all these forces is critical to a successful scaleup.
Predictive formulation and process work at small scale that can help with scale up is increasingly important. Developing new tools to identify pitfalls early and then develop solutions is key. Some of the interesting technologies are real-time data tools used during processing. Good work is being done to integrate mixers that will measure viscosity (and as a result, torque) during processing. This information can then be used to map out a product and its characteristics over time and/or temperature.
In addition, FDA is showing an increasing interest over the past few years in evaluating what are referred to as the Q3 properties of semi-solid products. These are the formulation microstructure properties (e.g., crystalline habit, effects of sheer on viscosity, particle size) and they must be studied and assessed during the scale-up manufacturing of these products. Scale, equipment, and manufacturing process can all greatly affect the product microstructure, particularly droplet size and viscosity. Special care needs to be taken to be sure all the microstructure characteristics developed on the bench-scale product are maintained throughout scale-up development.
Topical semi-solid products are becoming more complicated. With the wider acceptance of screening tools, such as in-vitro permeation testing, the resulting data has pushed some drugs into complicated delivery systems that sometimes include high solvent loads and/or high surfactant loads. Previously, these formulations would have been discarded as potentially irritating; however, these delivery systems are more often being pursued due primarily to superior skin penetration screening data. These products can be difficult to manufacture and scale up for a variety of reasons. For example, some of these products have high alcohol content or other flammable material content and some have high levels of surfactants. High alcohol products have flammability considerations when manufactured (explosion-proof-rated manufacturing suites are required). High surfactant systems can have compatibility challenges with other ingredients and/or with packaging, and they can present foaming concerns as well.
PharmTech: What are some of the key challenges for small-scale manufacturing, such as for clinical trials, and what are some best practices in this area?
Carbol (DDL): A big challenge in small-scale manufacturing is associated with cleaning. Cleaning validations are expensive and time consuming, yet the small clinical batches may only be made once. Disposable or single-use equipment is becoming more of an option, but using disposable equipment becomes increasing difficult when the scale is moving from small (1–10 kg) to medium-sized (10–50 kg) batches.
Developing unique, cost-effective solutions for fully custom, one-time-use, dedicated equipment is a key challenge. In contrast to single-use systems for biologics (aqueous solutions at room temperature), for example, topical semi-solid products may require processing that includes temperature cycling. The ability to heat and melt waxes (in what would be mainly plastic-based systems for biologics) is of concern with respect to integrity of the plastic and leads to leachable/extractables issues. Additionally, ingredients that are used in topical semi-solid products are not always water-based and thus compatibility issues come into play. In addition, the need for high-speed and high-shear mixing in a one-time use system is not yet well-addressed for semi-solid products. Mixing dynamics is critical, and therefore, there is a need for a good single-use high efficiency mixing system.
Another challenge is with respect to the use of digital technology as it relates to manufacturing small-scale clinical materials. For small-scale GMP manufacturing, many systems are still easier to accomplish via pen and paper. Many new electronic tools exist for the pharmaceutical industry, but being strategic about which ones to incorporate into small manufacturing processes is difficult. Many systems are difficult to justify on a cost-benefit basis and may be needlessly complicated.
PharmTech: What are some of the key challenges in packaging for clinical trials?
Carbol (DDL): Packaging topical drug products into tubes, jars, sachets, applicators etc. is always challenging. For small clinical batches, filling tubes in a fully manual filling process used to be the norm. Now, with larger batch sizes, manual filling is becoming cumbersome. However, large fill lines are not practical, and cleaning validations are again an issue. Developing fast, accurate, cheap, one-time use filling equipment is ideal. Filling can be accomplished at times with small semi-automated equipment, but when more unique packagings are desired, such as applicator pens, syringes, single dose applicators, or sachets, creative solutions are needed.
Another packaging trend we have noticed is that some of our clients would like to have the product in a representative final packaging, even during early clinical trials. Historically, final packaging was decided much later, closer to phase III/commercial stage. With tube manufacturers having minimum order quantities of approximately 10,000 units, orders for small clinical trials can be impractical.
Topical products in clinical trials can be uniquely challenging due to the potential for variability of dosing. How much to provide (package) to each study subject requires thought and planning. When the indication is a fixed site (the face, for example) it is easier to estimate use than for psoriatic subjects when anywhere from 5% to 20% body surface area may be involved. Sometimes dosing cards or cups that provide a guide for the amount to dose are used, but most often a description of the amount to express from a tube (e.g., pea size) is all that is provided. Having additional packaged product ready and available for dispensing to subjects may be an important aspect to clinical trials involving topical products, depending on the product and study design.
Vol. 44, No. 3
When referring to this article, please cite it as J. Markarian, “Challenges in Clinical Manufacturing for Topical Drugs,” Pharmaceutical Technology 44 (3) 2020.