Clasifica ciones de las danzas y los bailes

As one of the three basic tasks of bulk drug process develop-ment, defining and achieving the physicochemical attributes of the bulk drug is pursued throughout the development cycle.

Unavoidably, this effort trails that of the chemical or fermen-tation process, since its target comes from the dosage form development effort.

The difficulty of the dosage form task cannot be underes-timated. Its need for making judgments with partial data actually exceeds that of the bulk development task, as the crucial feedback on the bioavailability and stability of its developmental materials cannot be obtained rapidly, not unlike the feedback that the bulk development team needs as to the suitability of the its bulk drug for the dosage form purposes. Figure 15 is an attempt to depict the scope of dosage form development.

Not to be neglected is the packaging development placed directly downstream from dosage form development.

Sometimes complicated by the fact that the primary package (i.e., that in direct contact with the drug product) may also serve as a drug delivery device (e.g., syringes, eye drop dispensers, intravenous bags) as well as by the issues of interaction between the dosage form and the package’s material or the long-term stability of the drug product within the particular package chosen, the dosage form development function is additionally

buffeted by marketing issues that range from the serious (acceptability by the patient, for example) to the see-mingly frivolous (for example, the marketer’s insistence on a distinct tablet shape that, although harder to manufacture, lacks any apparent redeeming value).

Albeit hampered by a traditional disciplinary divide between pharmacy and the disciplines of bulk process develop-ment, the bulk=dosage development interaction needs to start early and intensely. Not only is the task difficult for the reasons just stated but also there is considerable scope to getting to a firm definition of what is needed. Figure 16 lists the physico-chemical attributes of bulk drugs that must be controlled in the bulk drug process, either directly, such as particle size, or indirectly, such as solid surface area or hygroscopicity.

Those attributes are, of course, set by the very last processing steps of the bulk drugs:

a. the last synthesis step (or the last purification step if a fermentation=extraction process);

Figure 15 The scope of the dosage form development task. The notation ‘‘Do loop’’ refers to the iterative process by analogy to the Fortran language shorthand.

b. the subsequent isolation (usually by crystallization), filtration, and drying;

c. the final solids finishing (size reduction, classifica-tion, blending, and packaging).

Due to the significance of the physicochemical attributes of the bulk drug to its bulk and dosage form stabilities, as well as to the dosage form performance (mostly bioavailability), it has become increasingly frequent to add a recrystallization after the isolation of the final chemical compound and thus generate the bulk drug. Although such additional processing is expensive (its yield loss is incurred with the costliest com-pound), there are significant advantages to consider:

a. The final compound isolation is relieved form the dual burden of simultaneously achieving all the chemical purity attributes and all the physico-chemical attributes.

b. The discontinuity makes the final bulk drug less subject to upstream variations from the more complex synthesis=purification=isolation step.

c. The final recrystallization can provide an additional degree of purification that may be reserved as insur-ance or be part of achieving the final purity.

Figure 16 The physicochemical attributes of a bulk drug.

d. The final recrystallization can be developed with a sharp focus on consistent attributes such as polymorphic content, crystal habit, particle size distribution, surface area, and bulk density. These attributes also define hygroscopicity and are impor-tant factors on bulk and dosage form stability.

e. Regulators are very fond of such recrystallizations (for the above reasons), which can be used to more persuasively present upstream process changes for approval.

The addition of such final recrystallization is depicted in Fig. 17. Given the fact that practically all bulk drugs are crystalline for reasons of processing soundness, purity, stabi-lity, and consistent physicochemical attributes, obtaining registration of a bulk drug in any other physical state usually requires a compelling reason.

As practitioners discover (or should soon discover), crystal-lization skills are paramount among the skills set of the bulk process development (and manufacturing) function.

Figure 17 The final stages of bulk drug processing. A final crys-tallization is often inserted largely, if not strictly, for greater control over the physicochemical attributes of the bulk drug.

Such skills should be nurtured, perhaps even lavished, as well as complemented with a comparable physical chemis-try capability in the analytical R&D function.

This seems a good point at which define the analytical R&D function as far more than the guardian of quality during the preparative work, or the highly skilled developer of assay and related methods, or the arbiter of regulatory issues within the bulk process development. For successful bulk drug process development, the analytical R&D function must be an integral part of the process team: elucidatior, troubleshooter, contributor to the solution of process pro-blems, and intimate partner throughout. Any lesser invol-vement in the process task or a lesser aggregate of skills is a strategic disadvantage in drug development.

Finally, the bulk process and dosage form functions need to collaborate earnestly at the earliest and, if needed, be brought together under irresistible force to overcome the tra-ditional disciplinary gap. For example, the crucial decision on which bulk drug form is to go forward (the sodium salt? the maleate? the dihydrate?) is best made when the bulk process team participates and is able to contribute its resourceful-ness, lest the dosage form team abandon the better bulk drug form because they do not know that its difficult attributes can be managed or fully overcome upstream. It is there that those attributes are set through the actual process in the final reac-tion step and in the finishing steps that follow to afford the final bulk drug.