Formulating products that have the proper composition, viscosity, texture, and stability, and can also be shown to be safe and effective, is both a science and an art. It requires having access to proper techniques and skill sets, state-of-the-art equipment, process scientists and engineers who have a deep understanding of Quality by Design (QbD) principles, and methods for product and process characterisation.

Expertise in analytical testing, validation, and quality control are also essential. The preparation of a semi-solid dosage form – from formulation and development, to scale-up, commercial manufacturing, and packaging – should ideally take place under one roof in a contiguous, end-to-end workflow to avoid unnecessary equipment and process changes. Without proper precautions, knowledge gaps can occur and important details may be overlooked when a product is transferred from one site to another.

Simplicity matters

It is important for a CDMO to understand the market it serves and, in the dermatologic arena, that means the demand for topical agents across a broad array of indications. Staying up-to-date on the latest science and emerging technology is also essential.

Above all else, when it comes to developing and delivering a safe and effective product cost efficiently and on time, simplicity matters. At Cambrex, quality comes first, and the same expectations for quality apply equally to prescription and OTC topical products. Cambrex’s one-stop-shop approach ensures that all aspects of product formulation, analysis, and manufacturing can be performed on-site, by trained scientists and engineers, using the same advanced equipment and validated methods. This applies to new products and tech transfers, thereby avoiding the problems that can arise when existing methods and processes are transferred to a new site. Cambrex provides end-to-end formulation and manufacturing at its Mirabel facility (Québec, Canada) with production of sterile ointments carried out at its Whippany site (NJ, US).

Optimising development and scale-up

When initiating the development of a prescription dermatological product, topping the to-do list is selection of the formulation. Choosing between an ointment, gel, or cream will depend on multiple factors, including the following: the indication, the area to be treated, how the drug will be applied, physicochemical properties of the API, whether the API acts on the skin surface or must be absorbed into the skin, potential incompatibility issues between ingredients, and stability factors.

Physicochemical properties

The texture and quality of any topical formulation is critical. The main targeted attributes are a non-gritty texture, smooth to the touch, pleasant smelling, non-irritating, and easy to apply. To achieve these properties, development work should focus on optimising five key physical characteristics of the product formulation:

• Homogeneity

• Particle distribution

• Grittiness

• Spreadability (ease of application vs. tendency to drip)

• Need for surfactants

Proper equipment is essential. This includes mixers, emulsifiers, mills, and agitators. Temperature control, and specifically the cooling rate during mixing of the oil and water phases, is crucial. Process design studies will identify the ideal temperature ranges for each process step, and precise monitoring will ensure that temperatures remain in the sweet spot needed for adequate mixing at each time point.

Heated and cooled jacketed mixing tanks are required to provide precision temperature control. Appropriate mixing and temperature-control technology is also important during the addition of gelling agents and APIs to ensure proper particle distribution and to maintain the stability and uniformity of the formulation. The extensive range of mixing equipment, temperature-controlled tanks, and filtration vessels available in Cambrex’s development and manufacturing suites allows for experimentation and optimisation of process design and scale-up through to cGMP commercial production.

To ensure that semi-solid dosage forms remain stable and maintain the desired physicochemical characteristics over time, testing must be performed to assess for separation of the oil and water phases, colour or pH changes, crystallisation, changes in particle distribution, and product degradation. Cambrex offers a full range of chemical testing needed to characterise and monitor the properties of products in development.

In vitro release testing to demonstrate bioequivalence

The Scale-Up and Post Approval Change Semi-Solids (SUPAC-SS) Working Group of the US Food and Drug Administration has issued recommendations related to changes in components and composition and in vitro release testing (IVRT) for bioequivalence to support any modifications in formulation, manufacturing (processes and equipment), scale-up/scale-down of production, and/ or the site of manufacture of a nonsterile prescription semi-solid topical preparation.

Cambrex can support Q1-3 testing as follows:

• Q1 = products have the same components

• Q2 = products have the same components in the same concentrations

• Q3 = products have the same components in the same concentrations with the same arrangement of matter (microstructure) and the same permeability rate

Cambrex performs validated IVRT on product development batches and also offers a range of bioassays to demonstrate product potency when applicable.

Bioburden and microbial testing

Products must also be tested for bioburden to demonstrate that they do not harbour microbial contaminants. Cambrex’s microbiology laboratory has the capability to perform all necessary microbial testing. Depending on the product, the range of tests may include the following:

• Microbial limits testing – to determine whether a product complies with compendial specifications; targets specific objectionable organisms and assesses their presence or absence in a product

• Microbial enumeration – quantifies the total number of aerobic organisms and determines a total combined yeast and mould count

• Microbial bioassay – measures the potency of a biological active substance (e.g., an antibiotic)

• Bioburden testing – measures the population of viable microorganisms in a product

• Preservative efficacy testing/Antimicrobial Effectiveness Test (AET) – assesses the effectiveness of the antimicrobial preservatives added to the formula

Simplifying technology and site transfer

Tech transfer presents challenges when it comes to producing semi-solid dosage forms because of the difficulty in achieving the exact same texture, viscosity, and homogeneity of a product when changing even a single method or piece of equipment in the production process.

Site transfer requires a company to go back to the very early stages of product formulation and development, including sourcing and analysis of raw materials, characterisation of critical product attributes, and defining the process design space. Even the smallest details can have a big impact on the end result, especially when it comes to the sensory characteristics and the bioequivalence of a topical product.

The complexities and risks associated with the development and manufacturing of semi-solid dosage forms, whether prescription dermatological drugs or OTC topical products, can be managed with the knowledge, experience, and support of a full-service CDMO partner.

Cambrex has proven expertise in manufacturing a broad range of formulation types at scales ranging from 10kg to 900kg. With commercial semi-solid products on the market, Cambrex offers its customers the technical capabilities, expert people, and advanced technology needed for the seamless transition of a topical product from development to clinical material to large-scale commercial supply.

Simplicity matters when it comes to early-stage product formulation; high-quality, consistent, and cost-efficient scale-up, manufacturing, and packaging, and comprehensive analytical testing and quality control. Cambrex’s one-stop-shop makes it possible to develop and manufacture prescription and OTC products, whether sterile or non-sterile, in one location in a streamlined, cost-efficient workflow. This increases confidence, reduces the risk of uncertain outcomes that can result from changing equipment and processes, and may even accelerate the path to regulatory approval.

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