Drug product predevelopment activities deal with the creation of baseline data necessary for the formulation of safe, effective, efficacious and stable drug products. Adequate and timely predevelopment activities ensure a drug product that meets safety, stability, quality, identity, purity and potency (SSQUIPP) requirements and is fit for its intended purpose.
Predevelopment tasks involve all the activities aimed at establishing API/Excipient physicochemical properties: pre-formulation and feasibility formulation to aid in the selection of desirable dosage form [6.1] ; feasibility process development and scale-up to aid in the selection of desirable processing equipment and train; a sterilization study aimed at determining the most suitable means of achieving drug product sterility (for sterile products) [6.2] and a feasibility of primary packaging study [6.3], aiding in the selection of primary and secondary packaging equipment and train. Predevelopment activities also support determining overall process configurations with quantified critical process and quality parameters for eventual clinical and commercial manufacturing processes.
In the context of this discussion, the term pre-formulation encompasses the activities associated with the characterization of the physical and chemical properties of a drug substance — including understanding the drug’s response to potential manufacturing, processing and/or packaging conditions — and stressors used to decide a product’s formulation.
Pre-formulation activities (both discovery and development) are focused on assessment of biopharmaceutical properties of early drug development candidates (EDCs); and their subsequent optimization through determination and/or definition of drug substance physicochemical properties to support the formulation of stable, effective and safe dosage forms.
This process allows developers to determine the feasible and ultimately, optimal conditions to ensure a pharmaceutical product (drug product and excipients) capable of being reliably delivered in a stable and bioavailable form [6.4]. Interactions with all components are essential to support evaluation of drug product safety, stability, quality, identity, purity and potency.
Figure 1 shows a predevelopment flowchart involving the pre-formulation and feasibility formulation activities. The number and extent of the activities performed will depend on the complexity of the project including dosage form, route of administration, target organ, disease area and regulatory strategy, to mention but a few.
The drug product development process starts with process chemists screening hundreds, and sometimes thousands of compounds that may potentially impact desired therapeutic area(s). Out of these, few survive the initial screening as EDCs. The remaining few are then subjected to preliminary physicochemical characterization tests and compatibility tests to establish their physicochemical quality and performance attributes. Once accomplished, the established EDCs are subjected to preliminary bioavailability tests in animal models. The EDCs that are still viable for further development are then called new chemical entities. This process falls within the purview of discovery pre-formulation. During pre-formulation activities, well structured physical and chemical characterization experiments appropriate to the intended dosage form are designed to generate critical information on the API and excipients.
The generic drug product development typically follows a somewhat abbreviated development pathway compared to branded drug product, but some characterization and/or deformulation followed by characterizations still need to be performed as shown in the Predevelopment flowchart.
During feasibility formulation, development focuses on the physical properties of drug substances and excipients. It is vital that these variables are thoroughly characterized to minimize the potential of encountering costly delays resulting from stability failures occurring later in the drug development process. Pre-formulation studies are designed to evaluate drug substance and excipient properties necessary for the formulation of a stable, efficacious and safe dosage form compatible with delivery system. These include evaluation of drug-excipent compatibility (which affects physicochemical stability) and physiological bioavailability.
The solid state physical properties of a drug substance are normally evaluated during early development and divided into microscopic (molecular, particulate) and macroscopic (organoleptic, bulk) properties. Molecular properties typically include crystallinity, amorphicity, polymorphism, solubility and hygroscopicity. Particulate properties include morphology, size, size distribution, shape, surface area, surface texture and dissolution profile.
Macroscopic properties encompass organoleptic and bulk properties. The organoleptic properties include drug substance appearance, color and odor, while the bulk properties include density, cohesivity or flowability deformation, moisture content and particle packing.
In addition to early API identity characterizations (structure, functional groups, reactivity, active sites), the chemical characterizations of drug substance and excipients at the predevelopment stage are designed to support pre-formulation development and start early with analytical method development for measuring drug purity, degradation under normal and stressed stability conditions, and compatibility with excipients. The analytical methods developed are also used for potency evaluation of the feasibility formulations with respect to label claim at the completion of manufacture as well as throughout stability testing during the development process.