Formulation development phases

Synthesis of active ingredients Preclinical testing Formulations development Phase I, II, III, and IV clinical trials Clinical trials supplies manufacturing Clinical packaging... 

Outsourcing service needs. The specific stage at which the outsourcing service is needed (e.g., proof of concept, formulation development, phase I, II, or III stage or commercial manufacturing). 

Powder flow is most frequently thought of as relevant to formulation development, and there are numerous references attempting to correlate any one of a number of measures of powder flow to the manufacturing properties of a formulation [34—40]. In particular, the importance of physical properties in affecting powder flow has been well documented. Research into the effect of the mechanical properties on powder flow has, however, been very limited. It is, of course, important to be able to determine and quantitate the powder flow properties of formulations. It is of equal importance, however, to determine the powder flow characteristics of bulk drug early in the development process (preformulation phase). Often, the preformulation or formulation scientist is constrained by time, materials, and manpower. Yet certainly the preformulation studies carried out should be meaningful. Well-defined experimental methods and procedures should be used the information generated should be reproducible and permit useful predictions to be made. 

For the dissolution test to be used as an effective drug product characterization and quality control tool, the method must be developed with the various end uses in mind. In some cases, the method used in the early phase of product and formulation development could be different from the final test procedure utilized for control of the product quality. Methods used for formulation screening or BA and/or bioequivalency evaluations may simply be impractical for a quality control environment. It is essential that with the accumulation of experience, the early method be critically re-evaluated and potentially simplified, giving preference to compendial apparatus and media. Hence, the final dissolution method submitted for product registration may not necessarily closely imitate the in vivo environment but should still test the key performance indicators of the formulation. 

A decision tree approach for reducing the time to develop and manufacture formulations for the first oral dose in humans has been described by Hariharan et al.86 and is reproduced in Scheme 3.1. The report summarized numerous approaches to the development and manufacture of Phase I formulations. Additional examples of rapid extemporaneous solution or suspension formulations for Phase I studies have been reported.87,88... 

Preclinical drug development involves understanding of dosage, formulation, and route of administration, typically in animal models, so that safe and effective doses for human administration can be estimated. The drug development phase extends from prechnical assessment through clinical testing. 

Analytical Development of API and Drug Products. Early methods to support synthetic and formulation developments are often developed in the form of potency assay, impurities/related substance assay, dissolution, Karl Fischer, identity, chiral method, and content uniformity. These analytical methods are developed and validated in a fast and timely manner to support all phase II studies. 

Formulation Development. The formulation is finalized based on the experience gained in the manufacture of clinical phase I and II trial materials. Scale-up of the manufacturing process will be completed to qualify the manufacturing capability of the facility. The primary stability study is initiated to assess the stability of the drug product. 

When a new molecule enters the development phase, in most cases only the basic information of the new chemical entity is known (e.g., molecular structure and polymorphic and salt forms). However, we do not know what will happen when it is formulated and stored at ordinary environmental conditions. In other words, there is a high degree of variability around what is known about the molecule and its behavior in a variety of systems. The basic task for development is to reduce this high variability by conducting a series of controlled experiments to make this information known and thus predictable. In fact, by the time a molecule reaches the significant milestone of launch into commercial activities, most of the behavior and characteristics of the molecule need to be known, predictable, and in control. 

Semi-flexible SUDICRETE formulations have strong potential for road paving applications. Though still in the development phase, the materials have shown very high resistance to fatigue damage. 

Antidepressants as analgesics are almost a closed book as far as preclinical and clinical development is concerned. TCAs are an old drug class, and because of the rather problematic side-effect profile, interest in developing new drugs from this class is small. BL-1834 (Bioglan Lab.) is an intranasal formulation of doxepine that is in clinical development (phase II) for the treatment of severe pain. In patents on novel monoamine reuptake inhibitors, pain is usually claimed as a possible indication, but depression and anxiety are mentioned as the primary indications in most cases, and we are not aware of novel... 

The formulation development strategies are similarto thatifoivo PK screening. It is common to use supersaturated solutions in the early phase studies. However, the physical and chemical stabilities of the supersaturation systems should be well understood as the information provided will help formulation scientists to decide if the formulation needs to be prepared daily, weekly or monthly. 

For formulating poor water-soluble compounds, use of cosolvent(s) is one of the simplest and common approach. The approach is also widely used in the early development phase, as limited information is available for the molecule. The approach also allows overcoming dissolution rate limited drug absorption. In addition, solubilized formulations are greatly popular with pediatric, geriatric, and patients with swallowing difculties. 

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