Pharmaceutical development

PHARMACEUTICAL DEVELOPMENT

Pharmaceutical development provides the drug product needed for preclini-cal and clinical studies to identify the biological mechanism of a new drug and its clinical utility. In designing the drug product, functions of phar-maceutics seek to fulfill three key requirements: (a) manufacturability to robust and reproducible quality; (b) stability to the worst-case shipping, storage, and use conditions; and (c) adequate bioavailability with a desired, reproducible pharmacokinetic profile. Pharmaceutics work is carried out through all stages of drug discovery and development to provide stage-appropriate drug product for preclinical and clinical testing, to bridge the studies carried out at different stages of development, and to enable com-mercialization of a product and process that ensures reproducible manufac-ture of a high-quality drug product.

Pharmaceutical scientists work on developing suitable dosage forms for drug administration at different stages of drug development. These might include, for example, a parenteral solution formulation during efficacy and toxicology studies in vitro and in animal models. During phase I studies, the formulation could be a suspension, drug-in-capsule (DIC), or drug-in-bottle (DIB) formulation. During phase II studies, a more representative tablet or capsule formulation might be developed, which is further refined for phase III dosing and commercialization.

In designing the drug product, pharmaceutical development consider-ations include the target population (children or adults), the amount of drug to be given in each dose, storage stability of the drug product, the characteristics of the drug and disease state, preferred route of adminis-tration, drug stability, and robustness of the manufacturing process. An early assessment of the properties of the desired dosage form can contribute greatly to the speed of the drug development process.

Preformulation and formulation studies

Preformulation studies are initiated to define the physical and chemical properties of the agent, followed by formulation studies to develop the initial features of the proposed pharmaceutical product or dosage form (e.g., liq-uid, tablet, capsule, topical ointment, intravenous [IV] solution, and trans-dermal patch). The final formulation includes substances called excipients in addition to the active pharmaceutical ingredient (API). Preformulation and formulation studies take approximately 3 years and occur concurrently with preclinical (animal) and clinical studies. Depending on the design of the clinical protocol and desired final product, pharmaceutical scientists are called upon to develop specific dosage forms of one or more dosage strengths for administration of the drug. The initial formulations prepared for phases I and II of the clinical trials should be of high pharmaceutical quality, meet all product specifications, and be stable for the period of use.

Three key goals of pharmaceutical development are to ensure the delivery of stage-appropriate drug product with acceptable (a) stability, (b) bioavailability, and (c) manufacturability.

Stage-appropriate drug product design

The drug product used for testing at earlier stages of development, such as preclinical or phase I, is generally different than the one used at later stages. Stage-appropriate drug product design takes into consideration the objectives and requirements for each stage. For example, during animal toxicology studies, the objective is primarily to maximize exposure and allow the administration of large doses. At this stage of development, stor-age stability requirements are minimal and the drug product can be han-dled in carefully controlled manner in the laboratory setting. Therefore, a high-concentration solution dosage form may be preferred at this stage of development. The objective in the later stages of development, such as phases II and III studies, is to be as similar as possible to the final com-mercial formulation and process. Thus, a market-image formulation is generally developed for those later stages of development.

Stability

A drug product is expected to maintain the chemical purity (i.e., chemically unchanged API) and physical integrity (e.g., the same polymorphic form) of the drug, physical integrity of the dosage form (e.g., no breakage of tablets), and reproducible drug release from the dosage form throughout the projected storage period under recommended storage conditions.

The stability requirements for drug product are different at each stage of drug development and depend primarily on the anticipated duration of storage and the storage conditions (e.g., refrigerated or room temperature) for the animal and human studies. For commercialization, the stability requirements are based on the target shelf life at the desired FDA-approved label storage conditions. Generally, no less than 18 months of shelf life is considered commercially viable.

Harmonization of stability requirements across the companies involved in new drug development for product commercialization across different regions of the world is carried out through the guidelines provided by the International Council on Harmonisation (ICH). These guidelines define the storage conditions that can be considered representative of year-round weather in different regions of the world. For example, for the United States and Western Europe, normal room temperature storage conditions have been identified as 25°C, with a relative humidity of 60%.

Bioavailability

vital aspect of any dosage form is to be consistent (dose-to-dose and batch-to-batch) in delivering the total amount of drug into the systemic circulation and the rate at which it is delivered (bioavailability) from the drug product. Optimization and control of drug product properties that ensure robust manufacturing, physicochemical stability, and reproducible drug release help ensure consistent bioavailability. Drug substance and drug product attributes that impact drug release and bioavailability are identified, and the mechanistic basis of their impact are studied. In vitro assays are developed to measure drug release, and their results are cor-related with in vivo performance. Such a correlation between in vitro and in vivo performance is termed in vitro–in vivo correlation (IVIVC).

In silico modeling of drug absorption is commonly used to understand and predict a drug’s behavior after administration. These models are a complex array of equations that are solved simultaneously using a comput-ing software, such as the commercially available GastroPlus® or Simcyp®, to identify pharmacokinetic properties (e.g., ADME rates) as an outcome of drug (e.g., solubility), dosage form (e.g., dissolution rate), mode of admin-istration, and species characteristics.

In addition to achieving reproducible bioavailability of a given dosage form, pharmaceutical scientists pay attention to changes in bioavailability through different phases of drug development due to change in animal spe-cies (e.g., bioavailability differs among rats, dogs, monkeys, and humans, even with the same dosage form, due to differences in physiology), transla-tion of animal data into humans (e.g., solution administration to animals by IV route vs. oral solid dosage form for human administration), changes in dosage form (e.g., capsules in phase I vs. tablets in phase II), changes in human patient populations (e.g., normal healthy volunteers vs. patients suffering from a chronic disease state such as renal impairment), or other factors of human drug administration (e.g., bioavailability in the fast-ing state can be different than that in the fed state and in special patient populations, such as pediatric and geriatric patients). Extensive dosage form characterization and bridging studies (e.g., relative bioavailability of two different dosage forms) are carried out whenever any significant change is made to the dosage form.

Manufacturability

The ability to reproducibly manufacture drug substance and drug product with predefined acceptable quality attributes in a robust manner at a stage-appropriate scale of manufacture is critical to ensuring that consistent dos-age form is used throughout development. For drug products in late-stage development, such as phase III clinical trials, and in preparation for com-mercialization, in-depth investigations are carried out to understand and carefully control the incoming raw materials, manufacturing process, and the quality of the output drug substance or drug product through well-designed mechanistic and statistically controlled design-of-experiment (DoE) studies.

Critical quality attributes (CQAs) of the drug product are identified. These are the quality attributes that can impact the patient, such as delivered dose uniformity or the content of impurities. Critical material attributes (CMAs) of incoming raw materials, such as excipients, are delin-eated. These are the physicochemical properties of the raw materials that impact the CQAs of the drug product. In addition, critical process param-eters (CPPs) of the manufacturing process, the parameters that impact the CQAs, are identified. A control strategy is then put into place. It identifies how the CPPs and CMAs would be controlled, so that the CQAs would be predictably within the specifications from batch to batch. These represent the quality-by-design (QbD) development paradigm and are communicated to the regulatory agencies in an NDA or a BLA filing.