Documentation formulation support

The analytical group produces all of the CMC documents that support the above messages. The support is derived mostly from bridging analytical data that demonstrate technical equivalence between the proposed market formulation and the clinical formulation(s). Technical data from analytical comparability studies or in vivo bioequivalence studies can be used to demonstrate equivalence after synthesis, formulation, packaging, site, and/or process changes. 

These facts must be kept in mind when evaluating the efficacy data with this antidepressant. The best evidence supporting this warning is the recent approval of the sustained release version of bupropion. Three double-blind studies were done to support the submission of this formulation for approval. The FDA concluded that all three of these studies failed to show that the sustained release version of bupropion in the doses used (i.e., less than 450 mg per day) was superior to placebo in the treatment of outpatients with major depression (bupropion summary basis of approval). As a result, this formulation was approved on the basis of bioequivalence with the immediate release formulation. The FDA in its approval documents did not specify why it chose to approve this formulation without efficacy data. One possibility is that there are reasons to believe that the sustained release formulation is less likely to cause seizures than is the immediate release version at comparable doses. In contrast to these failed studies, two relatively small studies published in 1983 reported that immediate release bupropion at doses up to 600 mg per day was superior to placebo in the treatment of inpatients hospitalized for major depression (165, 166). 

Several different and well-documented computational models are supported by PC SPARTAN Pro. No one method of calculation is ideal for all applications. The most sophisticated quantum-chemical models may yield excellent results but may be too expensive for routine treatment, and it will usually be necessary to contend with lesser treatments. Practical models are not likely to offer the best possible treatment formulation. Compromise is almost always an essential component of model selection therefore, when selecting models compromises must be made between the best formulation and approximation. 

CMC. By far, the greatest challenges come in the CMC area. Questions of stability (of API and product), of impurity profiles, of unknown mechanisms of action, and of packaging/shipping/storage requirements are common stumbling blocks that require careful address in IND submissions. The three key criteria are the three Cs Careful (accurate, technically correct, supported by documentation), Complete (timely, thorough), and Calculated (accurate formulations and calculations). 

The protocol is a written document (see Section II.C.I) that describes the necessary parts of a stability study. It details the basic plan that will be executed, and its two major components include the tests to be performed and the schedule of testing that is planned. The types of batches that require a protocol are clinical, formulation development, registration, and marketed product. In addition, compatibility of a product with a vehicle (e.g., an injectable product in an intra venous saline solution) is often studied to support the use of injectable products for hospital use. Probe stability studies are generally more experimental in nature and may not be suitable for a formal written protocol. 

In patients with ARDS, improved outcomes have been documented using a low carbohydrate formulation supplemented with specific fatty acids (eicosapentaenoic acid and gamma-linolenic acid) and antioxidants. When compared with a high fat formulation, the specialized diet was associated with fewer days of ventilatory support, fewer ICU days, and fewer new organ failures. Therefore it has been recommended that this specialized formulation be considered for patients with ARDS. ... 

The data quality and consistency has a significant influence on the LCA results. Depending on the goal and the required precision for decision support, the requirements are to be formulated on the quality of data (e.g. on its precision, completeness, and representativeness). In this context, the sources of the data (of the LCA to be carried out) have to be named and the used data base with reference to the upstream processes (e.g. electricity production and productiOTi of basic materials etc.) should be documented. Any assumptions made, e.g. any estimations, should also be mentioned. 

Effect of Pressure, Temperature, and Substrate. An extensive study was made with the silica films with respect to the mechanism and kinetics of film formation (4). It is reasonable to suspect that the general conclusions formulated in this work with respect to pressure, temperature, and nature of the substrate are applicable to most of the other oxide films discussed in this report. Support for this viewpoint is also documented in regard to the incorporation of water into the films (5). 

Many of the points raised in this section have been mentioned in the earlier sections on formulation and device. A Guidance for Industry document in draft form was issued by the FDA during 1999, Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products Chemistry, Manufacturing and Controls Documentation (FDA 1999). This document provides a plethora of information on issues the FDA will consider in submitted documentation supporting the approval of nasal products. There are over 1,600 lines in the document, and industry comments have been invited. Whilst the final document has yet to be issued, the draft is still an important reference. A brief review of the content of this draft document follows. 

Validation today is a key issue, and we may ask whether the work we do in formulating and developing a process has anything to do with industrial validation. The validation of a formulation or process, or for that matter, an apparatus or analytical method, is the demonstration (documented) that it behaves as it is intended to. It is therefore logical to conclude that if the documented development work (including that carried out using statistical design) supports the process and formulation, it must be considered a part of validation. 

Those products that have good biocidal action against these microorganisms can be considered effective. Yet, surprisingly, many manufacturers of over-the-counter (OTC) formulations do not have documented evidence of effectiveness from in vitro studies [time-kill and minimum inhibitory concentration (MIC)] to support their label claims for preoperative skin preps. In vivo studies performed on human volunteers are designed to assure that the products are anti-microbially effective within 10 minutes of application and are antimicrobially persistent for up to 6 hours postapplication. 

Then patents can be submitted that permit umestricted exploitation (rare). The idea is formulated in written form and supported by the results of some laboratory experiments. The basic structure of a patent document follows ... 

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