October 28, 2019 PAP-Q3-19-CL-034
Semisolid dosage forms are intended for external application, either topically on skin surfaces or mucous membranes (eyes, nasal cavity or inner lining of cheeks) or via suppositories to rectal and vaginal tissues. They include ointments, creams, gels, pastes, rigid foams and emulsions and are designed to enable penetration of the active drug substance through these surfaces via immediate- or extended-release mechanisms.
While oral delivery remains the most common route of administration, topical delivery has some advantages, including the ability to treat local indications, the avoidance of first-pass metabolism — which can be a problem for ingested drugs — reduced side effects due to external application and ease of use for greater patient compliance.1,2 For manufacturers, semisolids are advantageous because formulation development can generally be completed more rapidly than for other dosage forms.2
Most semisolid formulations consist of the API uniformly dispersed along with appropriate excipients, emulsifiers, rheology modifiers (to control viscosity), antimicrobial agents, antioxidants and/or stabilizing agents in a suitable base.
Each type of semisolid has its own structural elements; most have multiple phases (oil, water and the API, if it is not completely soluble) and specific components that often have well-defined physical properties. The choice of ingredients for a given semisolid formulation depends on the type of semisolid, the nature of the API(s) and the desired release profile.2
The overall global market for topical drugs, including semisolids, liquids, solids and transdermal products, is estimated by market research firm Markets and Markets to be expanding at a compound annual growth rate of 5.7% from $93.2 billion in 2019 to $123.2 billion by 2024.3 This modest increase in demand is attributed to a rising incidence of skin and eye diseases and diabetes. This increase is attributed to the aging of the global population and a rise in income levels throughout emerging markets. Semisolid formulations claimed the greatest market share in 2019; by route of administration, dermal delivery is dominant.
Though perhaps easier to formulate than oral and other dosage forms, semisolid drugs require specialized process expertise to ensure the production of high-quality products. These drugs must, in general, be uniform in appearance and physically smooth with minimal grittiness.4 They should also have a pleasant scent, be easy to apply to the target areas and not cause irritation upon use. Five key properties that must be carefully controlled are homogeneity, particle distribution, spreadability, grittiness and surfactant use.4
Homogeneity is important, because semisolids involve more than one phase, and all phases must be properly blended to achieve the desired result. The API as well as all excipients and other ingredients, must be uniformly distributed throughout the mixture. Homogeneity achieved in the production vessel must be maintained in each product unit, whether that is a plastic or metal tube or a plastic or glass jar.4 The consequences of inadequate homogenization can range from lumpy mixtures to nonuniform API distribution, both of which lead to reduced product efficacy.
Because many semisolid drugs contain particles suspended in solution, uniformity of the particle sizes and their distribution is important.4 This attribute is particularly important for APIs that have poor water solubility — a rapidly increasing percentage of drug candidates in development today.
Semisolid drugs must also exhibit appropriate spreadability to ensure that the desired therapeutic affect is achieved, because spreadability determines the distribution of the API over the area to which the semisolid is applied.4 Poor spreadability can also lead to patient dissatisfaction. Spreadability correlates with the viscosity of the drug product and can be impacted by temperature and the particle distribution. Grittiness is related to particle size and shape, while proper surfactant use enables the formation of emulsions and suspensions of oil and aqueous phases and is crucial to achieving stable formulations.4
Given the complex ingredients and the need to generate specific structural elements, specialized expertise is required to ensure the production of high-quality semisolid drug products on a commercial scale. Careful control of the manufacturing process is essential to providing fully homogenized products containing the appropriate particle sizes and distributions of APIs and excipients in stable emulsions or suspensions.
For instance, adding specific ingredients to the appropriate phase (oil or water) can lead to enhanced product stability.2 The rate of addition can be important for avoiding undesirable behaviors involving polymers. Addition of antimicrobials at the end of a process helps minimize undesired interactions. Prevention of API degradation under the manufacturing conditions and minimization of process impurities must also be assured. Formulations for controlled- and extended-release semisolid products add a further layer of complexity.
Unlike for oral solid dose drugs, manufacturing processes for semisolid products cannot be halted mid-way through the batch record without risking loss of the entire batch. Process optimization work must be completed in advance, and operators must ensure that everything required for completion of a run is ready before initiation of a process.
An appropriate method for pulling samples must also be established for monitoring the progress of semisolid production runs. While the level of control required is not as strict as that for sterile manufacturing processes, it is essential that the sampling process be designed to minimize the likelihood that contaminants will be introduced into the vessel.
Finally, scale-up to commercial quantities must result in a process that provides a product with the same properties observed in the development laboratory and pilot plant. The equipment, therefore, must be similar (same materials of construction with the same mixing systems) at all scales, and its scalability must be clearly demonstrated.2
The most important factors when moving to commercial production of semisolid drugs are the mixing/homogenization times/speeds and temperature control. Mixing times become more critical as a process is scaled up, because they depend on the quantity of material that is involved. In most cases, mixing is not achieved in a single pass through a homogenization pump. The material typically needs to circulate through the pump multiple times. Properly calculating the time that is required to complete a sufficient number of passes is, therefore, essential. Minimizing mixing times is important for prevention of ingredient degradation and reducing process run times.
The mixing speed determines the level of shear to which the formulation ingredients are exposed, which influences droplet size and dispersion, particle size and particle size distribution, and other physical characteristics.2 If sheer levels are too high, mixing can also lead to degradation of some ingredients.
Establishing and maintaining the correct temperature is also necessary when manufacturing high-quality semisolid products. The temperature can impact the homogeneity, particle distribution and spreadability, and heating is often required to achieve appropriate mixing.4 If the temperature becomes too high, however, some ingredients may degrade or the desired structural elements may collapse. Monitoring and precise control of the temperature are essential for meeting product specifications and avoiding any impacts on the individual ingredients in a semisolid formulation. Control of heating and cooling rates is equally important for avoiding burning and precipitation/crystallization, respectively.2
UPM’s Bristol, Tennessee plant includes a Solids Formulation R&D Facility, modern manufacturing suites and a state-of-the-art, full-service analytical laboratory. We have the capacity to produce up to 750 metric tons of creams and ointments annually.
Our commercial vessels range from 200 to 2000 gallons, with finished products packaged on our automated jar or tube lines. UPM also has the ability to manufacture semisolid products in 200- to 300-gallon pressure vessels. Once filled, weight verified and capped/sealed, jars and tubes are labeled with the lot number and date. Each unit is subjected to inspection, and then the product is placed loose or bundled together into shippers. We currently have an offline serialization solution in place and are preparing to meet aggregation requirements.
Most importantly, we have extensive experience in formulation development and the development and scale-up of production processes for semisolid dosage forms, enabling us to rapidly establish optimal processing conditions for creams and ointments intended for use as over-the-counter or prescription medications.
As a full-service CDMO, UPM welcomes projects at any point in the development cycle. With access to reasonable information about the product and existing or potential processes, we can rapidly evaluate a project to determine whether we can implement it with our existing systems or, if not, what additions/modifications would be required.
We are here to help our customers get their products into the hands of the patients that need them. At UPM, we have an open-door policy. Customers are encouraged to seek our assistance and ask the hard questions. We are always available — from the top executives through project managers and project scientists and engineers.
By offering such flexible, affordable and rapid outsourcing services designed to meet our clients’ specific development and manufacturing needs, we are able to form truly collaborative relationships and provide highly customized solutions to meet aggressive development and commercialization timelines and project budgets.
Robert N. White III serves as the Manager of Manufacturing for UPM Pharmaceuticals. He has an extensive background in technical services, manufacturing and process validation and is professionally certified in tablet compression and fluid bed operations. In his current role Robert leads all the Manufacturing teams involved with the Manufacturing, Packaging of Semi-Solids. Robert graduated with a Bachelor’s Degree in Physics from King University.