Manufacturing of all dosage forms is becoming increasingly specialized, demanding expertise from developers and CMOs alike.
As an active pharmaceutical ingredient (API) is developed into a formulation, the manufacturer must naturally consider how the drug will be administered. The question of dosage forms has more answers today than ever before; ranging from solid oral dosage forms like pills and powders, to liquid forms like solutions and suspensions, to ointments, drops, creams, injectables, and even inhalable vapors.
Each of these dosage forms may be highly suitable for specific types of drugs and certain routes of administration, but entirely inappropriate for others. For this reason, a drug’s dosage form must be considered as part of its target product profile (TPP), from the earliest stages of development. An ideal dosage form combines easy application with high bioavailability, ensuring that the drug reaches its destination, and remains there long enough to achieve its intended effect.
This article will summarize a number of key issues and trends in today’s dosage form development sector, as well as analyses of several dosage forms that remain popular for a wide range of different drug formulations.
Solid oral dosage forms remain popular, but many are becoming far more specialized.
In 2018, solid oral dosage forms represented a full 60 percent of all pharmaceutical manufacturing, accounting for $870 million in worldwide investment. A broad variety of drugs, from simple analgesics to complex controlled-release cancer therapies, can be easily administered in the form of a pill or powder.
Even so, specialized drugs demand tailor-made manufacturing processes; and this is just as true in solid dose manufacturing as in every other pharmaceutical sector. Broad-based “blockbuster” drugs are giving way to niche formulations targeted at specific populations; for example, pediatric, geriatric, anti-abuse and controlled release drugs. Dosage forms for these drugs require specialized small-scale manufacturing processes.
The tight coordination and efficiency required by these manufacturing pipelines demand high agility on the road from clinical trials to commercial manufacturing and regulatory approval. Technical specificity can be difficult to balance with cost-effectiveness, particularly when manufacturing processes must be transferred to new geographical locations during upscaling to commercial production.
For all these reasons, a growing number of pharma developers are partnering with contract manufacturing organizations (CMOs) earlier in the development process than before, in areas from drug design to process engineering, and even navigation of the regulatory pipeline. The solid-dose sector is defined increasingly by specificity, flexibility and collaboration, integrating the development and manufacturing stages into a single highly efficient pipeline.
Liquid oral dosage forms are diverse, but come with significant engineering challenges.
Whereas solid dosage forms are adaptable to a wide range of drug types, liquid oral dosage forms can be adapted to serve a wide variety of patients; particularly individuals who have difficulty swallowing due to age or physical disability. To address the needs of these markets, engineers of liquid dosage forms have developed a number of excipients and formulation types, each suited for particular types of APIs, formulations and routes of administration.
Liquid oral dosage forms fall into the two broad categories of monophasic and biphasic. Monophasic forms dissolve the API in a liquid to yield a fully homogeneous formulation, while biphasic forms do not dissolve the liquid in the vehicle, yielding a suspension or other mixture. The properties of both monophasic and biphasic forms can be adjusted with a range of excipients, from emulsifiers and stabilizers to solubilizers, thickening agents, preservatives, and even sweeteners.
The most well-known monophasic liquid oral dosage forms are syrups, elixirs, extracts and spirits. These typically contain some amount of sucrose, which thickens the formulation and improves its taste, as well as ethanol, which preserves the API and extends the formulation’s shelf life. Biphasic forms, on the other hand, include suspensions, emulsions and mixtures. These forms can be used to create highly stable liquid dosage forms of water-soluble APIs.
But even as liquid oral dosage forms provide great flexibility, they also present a number of unique engineering challenges. Their viscosity and stability can be difficult to balance with bioavailability, solubility, taste and other attributes. In addition, liquid dosage forms are frequently less stable than solid forms, while exhibiting shorter lifespans and greater vulnerability to contamination.
A number of innovative options are developing for ocular, inhalable, and other dosage forms.
In addition to solid and liquid oral dosage forms, engineers have developed a diverse variety of forms targeted at particular bodily systems and routes of administration. Ocular drug delivery systems, which include topical instillations, suspensions, emulsions and ointments, are designed to administer drugs directly to the surface of the eye’s cornea. Some developers are now working on more advanced ocular delivery systems, such as liposomes and nanomicelles; aimed at providing high bioavailability while remaining easy to administer.
Parenteral dosage forms, meanwhile, include intradermal, subcutaneous and intramuscular injections, designed to administer the drug directly to a particular tissue or organ, or into the circulatory system. Sterility remains a key concern for injectables like these, leading many facilities to adopt blow-fill-seal processes that mechanically seal the formulation in its container. Regulatory scrutiny is also particularly intense in this sector, especially in the realm of injectable biologics, which are prone to contamination and degradation during transport and storage.
Dosage options extend beyond even these categories, into aerosols administered via nebulizers or inhalers; patches and other topical dosage forms; and even suppositories. Each of these dosage forms requires highly specialized manufacturing equipment, well-trained staff, and manufacturing partners who understand the intricacies of manufacturing the dosage form, as well as the unique regulatory hurdles surrounding it.
By collaborating with such an expert CMO, the developer can create a pipeline that ensures smooth upscaling from the clinical trial stage to full commercial manufacturing, while minimizing costs and downtime associated with the regulatory approval process. These all remain key concerns in the development of any dosage form, solid, liquid or otherwise; and as products in each of these categories increase in specialization, foresight and collaboration have become more crucial than ever.