Marco normativo y regulatorio

As a promising compound is characterized for biologic activity, it is also evaluated with regard to chemical and physical properties that have a bear- ing on its ultimate and successful formulation into a stable and effective pharmaceutical product. This is the area of responsibility of pharmaceuti- cal scientists and formulation pharmacists trained in pharmaceutics. When suffi cient information is gleaned on the compound’s physical and chemical properties, initial formulations of the dosage form are developed for use in human clinical trials. During the course of the clinical trials, the pro- posed product is developed further, from initial formulation to fi nal formulation and from pilot plant (or small-scale production) to scale-up, in preparation for large-scale manufacturing.

To provide suffi cient quantities of the bulk chemical (drug) compound for the sequence of preclinical studies, clinical trials, and small-scale

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vital in developing label instructions for use and storage, assigning product expiration dating, and packaging and shipping.

INITIAL PRODUCT FORMULATION AND CLINICAL TRIAL MATERIALS

An initial product is formulated using the infor- mation gained during the preformulation studies and with the consideration of the dose or doses, dosage form, and route of administration desired for the clinical studies and for the proposed mar- keted product. Thus, depending upon the design of the clinical protocol and desired fi nal product, formulation pharmacists are called upon to develop a specifi c dosage form (e.g., capsule, suppository, solution) of one or more dosage strengths for administration by the intended route of administration (e.g., oral, rectal, intrave- nous). Additional dosage forms for other than the initial route of administration may later be developed, depending on patients’ require- ments, therapeutic utility, and marketing assess- ments. This is especially important if the drug may be administered to children.

The initial formulations prepared for Phase 1 and Phase 2 of the clinical trials, although not as sophisticated and elegant as the fi nal formula- tion, should be of high pharmaceutical quality, meet analytical specifi cations for composition, manufacturing, and control, and be suffi ciently stable for the period of use.

Often during Phase 1 studies, for orally admin- istered drugs, capsules are employed containing the active ingredient alone, without pharmaceu- tical excipients. Excipients are included in the formulation for Phase 2 trials. During human tri- als, studies of the drug’s ADME are undertaken to obtain a profi le of the drug’s human pharma- cokinetics and biologic availability from the formulation administered. Different formula- tions may be prepared and examined to develop the one having the desired characteristics (see Chapter 5). During Phase 2, the fi nal dosage form is selected and developed for Phase 3 trials; this is the formulation that is submitted to the FDA for marketing approval.

Clinical supplies or clinical trial materials comprise all dosage formulations used in the clinical evaluation of a new drug. This includes the proposed new drug, placebos (inert sub- stances for controlled studies), and drug products against which the new drug is to be compared distribution in a lipophilic–hydrophilic phase

system and indicates its ability to penetrate bio- logic multiphase systems.

Dissolution Rate

The speed at which a drug substance dissolves in a medium is called its dissolution rate. Dissolu- tion rate data, when considered along with data on a drug’s solubility, dissolution constant, and partition coeffi cient, can provide an indication of the drug’s absorption potential. For a chemical entity, its acid, base, or salt forms, as well as its physical form (e.g., particle size), may result in substantial differences in the dissolution rate.

Physical Form

The crystal or amorphous forms and/or the par- ticle size of a powdered drug can affect the dissolution rate, thus the rate and extent of absorption, for a number of drugs. For example, by reducing the particle size and increasing the powder fi neness and therefore the surface area of a poorly soluble drug, its dissolution rate in the gut is enhanced (through greater exposure of the drug to gastrointestinal fl uid) and its bio- logic absorption increased. Small and controlled particle size is also critical for drugs adminis- tered to the lung by inhalation. The smaller the particle, the deeper is the penetration into the alveoli. Thus, by selective control of the physical parameters of a drug, biologic response may be optimized.

Stability

The chemical and physical stability of a drug substance alone, and when combined with formu- lation components, is critical to preparing a suc- cessful pharmaceutical product. For a given drug, one type of crystal structure may provide greater stability than other structures and may therefore be preferred. For drugs susceptible to oxidative decomposition, the addition of antioxidant stabi- lizing agents to the formulation may be required to protect the potency. For drugs destroyed by hydrolysis, protection against moisture in formu- lation, processing, and packaging may be required to prevent decomposition. In every case, drug sta- bility testing at various temperatures, conditions of relative humidity (RH)—as 40°C 75% RH/30°C 60% RH— durations, and environments of light, air, and packaging is essential in assessing drug and drug product stability. Such information is

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Manufacturing Practice guidelines (36), as outlined in Chapter 3.

THE INVESTIGATIONAL