These dosage forms provide key advantages over other liquids, but federal guidelines advise caution in manufacturing.
The broad category of liquid oral doses includes a diverse group of dosage forms, from monophasic forms like syrups, spirits, elixirs and extracts, to biphasic forms like suspensions, emulsions and mixtures. While each of these types of oral formulation can be helpful for pediatric and geriatric patients who have difficulty swallowing, each type is ideally suited to particular kinds of active pharmaceutical ingredients (APIs) and target product profiles (TPPs).
Liquid suspensions, for their part, provide an ideal dosage type for APIs that must remain in solid form, while becoming part of a liquid. By suspending particles in a solvent, liquid suspensions yield an oral dosage form that is easy to swallow, while keeping the API fully intact. However, the US Food and Drug Administration has recently noted significant regulatory problems surrounding liquid oral suspensions, making these dosage forms particular targets for inspection.
This article provides a brief overview of advantages of liquid oral suspensions, along with key considerations in their design, and potential regulatory issues surrounding their manufacture.
Liquid oral suspensions make drugs easy to administer while keeping APIs structurally intact.
Each category of liquid oral dosage form offers its own advantages and disadvantages. For example, while syrups remain widely popular due to their high stability, long shelf life, and relatively palatable taste, their aqueous nature makes them unsuitable for APIs soluble in water. On the other hand, a biphasic form like an emulsion would be poorly suited for a volatile API that needs to be fully dissolved in ethanol; such an API would be far better preserved in an elixir, whose ethanol could dissolve the API and hold it in liquid form.
One key advantage of a liquid suspension is its ability to preserve the structure of the API without any dissolution, while still delivering it to the patient in a liquid form that is easy to swallow. Because the API is not completely dissolved, a suspension can also deliver a higher concentration of API than an equivalent volume of liquid solution. In fact, the liquid nature of a suspension can provide high flexibility in the precise dose delivered at any given time.
However, the particles in a liquid suspension become unevenly distributed over time, as they settle to the bottom of the container. This means a bottle of liquid suspension must be vigorously shaken prior to use, lest the patient receive inconsistent doses. This makes suspensions unsuitable for use by patients who may forget to shake the container, or who may otherwise fail to measure the correct dose from a bottle of fully dispersed API.
Liquid oral suspensions must be designed for easy dispersal and reasonable viscosity.
The design of a liquid oral suspension entails a number of key considerations, pertaining both to the drug’s efficacy and the formulation’s usability. On the efficacy side, the liquid’s pH may need to be adjusted to prevent degradation of the API. But at the same time, excipients such as pH buffers can sometimes reduce the API’s bioavailability, which means it’s crucial to vet all excipients for compatibility with the drug’s intended usage.
Meanwhile, the TPP for any commercially successful liquid suspension should include a viscosity that makes the product easy to swallow, without excessive foaming that may interfere with the patient’s digestion. The liquid must be designed to have a palatable taste, perhaps through the use of artificial flavorings or sweeteners. However, in liquid suspensions intended for pediatric use, the sweetening agent should be less than 5mg/kg of patient body weight.
Like any liquid dosage form, a suspension is vulnerable to microbial contamination throughout the bottling process. Throughout the entire manufacturing pipeline, the API must be handled in a clean environment, and must be protected from dilution unless absolutely necessary. Before shipping a batch of liquid suspension that has been stored for some time, several bottles should be visually inspected and tested for sterility, stability and potency.
The FDA places liquid oral suspensions under scrutiny, demanding care from manufacturers.
While liquid suspensions don’t pose any particularly intense hazard risks, several recent FDA inspections have uncovered microbiological contamination, inaccurate potency, and instability in liquid oral suspension batches. Since many pediatric and geriatric patients may already have difficulty accurately measuring doses, inconsistencies and contaminations present elevated risks to these populations.
For all these reasons, the FDA has placed facilities that manufacture liquid oral suspensions under heightened scrutiny. Recognizing that not every suspension demands intensive sterilization procedures, the FDA nonetheless mandates the use of heating, ventilation and air conditioning (HVAC) systems designed to filter contaminants from the manufacturing area, and to prevent dust from excipients or other substances from inadvertently entering containers in which a liquid suspension is being bottled.
To offset the danger of microbiological contamination, the FDA requires that all raw materials be inspected for trace levels of common microorganisms, and that the final suspension be re-inspected at the time of bottling. Due to the risk of non-uniformity and inconsistent potency, the FDA highly recommends that the suspension be continuously agitated throughout the filling stage, and testing at the end of the filling process to ensure that segregation has not taken place. And because many oral suspensions do not remain stable throughout their labeled shelf life, the FDA recommends storing test batches for extended periods and re-testing them to measure degradation in vitamins and other active ingredients.
These federal guidelines are straightforward and easy to follow, for a contract manufacturing organization (CMO) whose experts are familiar with preproduction pipelines and regulatory compliance for liquid oral suspensions. By ensuring the facility’s manufacturing practices remain in alignment with federal guidelines like these, a pharma developer will be well positioned to produce a liquid oral suspension that achieves success at the commercial scale.