Formulation Development

Formulation development activities will be based on achieving the desired product profile and can be summarized by a series of goals (Fig. 9.4). The formulator will need to (1) create a dosage form that (2) delivers the active ingredient (3) to the intended site of action (4) in an amount required to achieve the desired effect with (5) minimal adverse effects (6) over the desired time course in (7) a consistent and reproducible manner. For example, if the product profile for a specific drug is an oral product taken by adults no more frequently than twice a day with blood levels to be between 50 and 400 |g/mL, the formulator will have a relatively clear path to develop prototype formulations. Based on the half-life of the drug, the formulator will be able to decide whether a controlled release or immediate release product will be required. Because adult patients will be self-administering the product, they can narrow the selection to a tablet or capsule. Initially, the target blood levels will be based on data from several different species of animals and later in development from human data. The formulator should have the commercial viability of the product in mind relatively early in the development of the product. This includes a product that can be easily and repro-ducibly manufactured with a reasonably low cost of goods. The product should be physically and chemically stable for a commercially viable period. This is typically between 2 and 4 years, preferably at room temperature, but other storage conditions may be required. It can take 6 months or longer from the time a product is manufactured until it reaches a pharmacy or hospital and this time needs to be taken into account.

The product should be as convenient to use as possible by the patient and/or the caregiver. A few examples of these include prefilled syringes, patches applied once a week instead of capsules taken two or three times daily, and antibiotics requiring a 3-day treatment period instead of a 10-day course. Differentiating the product from competitive products in some useful fashion should be considered throughout the development process. This is most important for products that offer a marginal therapeutic or adverse effect profile compared with other products in the same class. A premium price can be charged because of its good value to the health care system if this is accomplished.

Adequately characterizing the active ingredient is a critical and necessary step in developing a successful product (Fig. 9.5). Complete characterization is not technically required until the time of the marketing application, but a basic understanding is needed for the initial Investigational New Drug (IND) application. The more information that is available earlier in development can assist in avoiding later pitfalls. Basic characterization includes elucidation of the structure of the active ingredient. New chemical entities (NCEs) should be examined for stereochemistry, isomers, polymorphs, and very early in development salt selection. Structural modifications of the original drug and the impact on activity are needed to be assessed, especially for both potentially new improved products and patent protection against future competitors. Characterization of a biotechnology product can be more complicated and may include determining secondary and tertiary structures, degree of glycosylation, biological activity, isoform activities, impact of truncation of the molecule, amino acid sequence changes, pegylation, presence of neutralizing antibodies, and immunogenicity of the compound. These items can have a significant impact on both safety and efficacy of the compound and also possibly ease of manufacturing and patent protection.

From very early in development through commercialization, the impurity and degradation profiles of the active ingredient should be examined. Impurities and degradation products are supported by toxicology studies and later by human clinical data. Changes in these levels or differing profiles may require additional toxicology studies to ensure the safety of the product is not affected. Additional studies will add to cost and may

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