The development phase

No compound is completely safe. Common salt is an essential component of 

Two other types of study are likely to be required for drugs intended for 

Processes used for the manufacture of drugs are commonly different to the laboratory processes described in the chemical and patent literature, not only because new syntheses are developed but because of the special features discovered during scale-up. Much of this detail is confidential because of 

When the drug is first administered to patients it will be on a very small group. They will be in a closely controlled environment such as a hospital, under the care of consultant physicians working in collaboration with physicians from industry. The patients will have given their consent to the 

A successful application to the regulatory authorities will result in the company obtaining, in the UK, a product licence, covering permission to sell the drug, and a manufacturing licence which is obtained by proving that the company has the facilities to make the drug reproducibly to the required quality. 

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Resoles. Like the novolak processes, a typical resole process consists of reaction, dehydration, and finishing. Phenol and formaldehyde solution are added all at once to the reactor at a molar ratio of formaldehyde to phenol of 1.2—3.0 1. Catalyst is added and the pH is checked and adjusted if necessary. The catalyst concentration can range from 1—5% for NaOH, 3—6% for Ba(OH)2, and 6—12% for hexa. A reaction temperature of 80—95°C is used with vacuum-reflux control. The high concentration of water and lower enthalpy compared to novolaks allows better exotherm control. In the reaction phase, the temperature is held at 80—90°C and vacuum-refluxing lasts from 1—3 h as determined in the development phase. SoHd resins and certain hquid resins are dehydrated as quickly as possible to prevent overreacting or gelation. The end point is found by manual determination of a specific hot-plate gel time, which decreases as the polymerization advances. Automation includes on-line viscosity measurement, gc, and gpc. 

A portion of the effluent is recirculated, ia order to smooth out flow, keep the food concentration constant, lower film thickness and control psychoda flies, and reseed the appHed sewage with acclimatized organisms. The psychoda, or filter fly is a very small iasect that breeds ia thick trickling-filter slimes. It does not bite, but can be a nuisance. Its radius of flight is small, but it can be carried great distances by the wiad. The fly can be controlled ia the development phase by occasional flooding of the filter or chlorination of the appHed sewage. 

In the development phase of catalyst research, testing of the catalyst s chemical and physical properties and evaluation of the catalyst s performance ate two essential tasks. In the manufacturing process, many of the same analyses and evaluations are used for quaHty assurance. A number of the testing procedures outlined eadier for catalyst supports can also be appHed to catalysts (32). 

Definition of the stages in the development phase at which verification can most economically be carried out. 

During the development phase a series of laboratory or pilot-scale batches will be subjected to this stability program. As soon as the process is scaled up to production-size batches, the first few, and at least one per year thereafter will also go on stability. Submission is only possible if the product completes a minimal combination of tests, e.g., one full-size batch for 12 months and two reduced-size batches for 6 months... 

Product specification documents and analytical test methods—In preclinical development, these are important documents and they evolve along with the development phases. Drug substances and products for clinical trials are tested based on these documents, and so are the stability samples. It is critical to ensure that the analyst will perform the right tests against the right specifications with the correct version of the test method. Therefore a mechanism must be in place to control these documents. This can be done manually or with TIMS. A manually controlled system would require the analyst to sign out hard copies of the documents from a central location. After the testing is done, the analyst would have to return these controlled documents to the... 

Cmcial documentation needed in the development phase includes end-user manuals, a unit test summary report, a user acceptance test plan, results of the database design, results and methods employed in the source code evaluations, and a trace-ability analysis. A source code traceability analysis verifies that all code is linked to established specifications and established test procedures. 

During the development phase of the RNA world, there were no functioning processes which were influenced by protein catalysts. 

As a consequence of the above, interest in molecular farming stems from anticipated time and cost savings once the technology is established. The time aspect has three components. The first time constraint occurs in development Although the development phase is beyond the scope of this chapter, it should be mentioned briefly that choosing the correct protein to produce is a matter of time to production. In the case of antibodies, one would like to produce small amounts of several antibodies, eventually selecting those with the highest stability, affinity and optimal performance ac-... 

The development phase invokes many instances where reactions must be optimised quickly because of changes in the route to or specification of the drug substance. The final challenge is to converge upon the most appropriate and environmentally acceptable methods for manufacture. In identifying optimal synthesis conditions, real-time tuning of a mi-... 

On Figure 2 I have shown the number of these new chemicals which have actually been commercialized by the manufacturer or importer as of March 1st of this year. About 30% of the total submissions were commercialized through the end of the 3rd quarter of last year. This seems like a very slow rate of commercialization but the reasons for some companies not following through the development phase with a commercialization phase are common-place in the industry. We made a spot telephone survey of a number of these manufacturers and received the following answers to our questions (Tablell). The chemical industry would say that these reasons are par for the course and undoubtedly could add a few more. 

Research (on medicines). Numerous definitions of research are used both in the literature and among scientists. In the broadest sense, research in the pharmaceutical industry includes all processes of medicine discovery, preclinical and clinical evaluation, and technical development. In a more restricted sense, research concentrates on the preclinical discovery phase, where the basic characteristics of a new medicine are determined. Once a decision is reached to study the medicine in humans to evaluate its therapeutic potential, the compound passes from the research to the development phase. 

Treat with steroids to mollify symptoms, along with supportive care to compensate for oxygen and fluid loss Vaccines are in the development phase... 

VK69 was introduced in the market by Haldor Topsoe in 1996 and has subsequently been installed in the final passes of more than 50 double absorption sulphuric acid plants worldwide. Due to the superior activity of VK69, the S02 emissions can typically be reduced by a factor 2 and new double absorption plants can be designed with less than 40 ppm S02 emission [17], The industrial experience also confirms low deactivation rate and low screening loss as expected from the results obtained in the development phase. 

A sponsor of a medical product entering the development phase must have a clinical development plan, which is created by experienced executives and consultants having expertise and experience in the disease state for which the product is intended. Once the plan is created, with appropriate input from regulators, the plan drives a clinical development budget, with consideration of the desired timeframe for projected producf approval. After the plan is created, the management team determines the "make vs. buy" strategy, which determines the elements of fhe plan that will be outsourced. 

The annual R D expenditure for biopharmaceuticals is around US 19-20 billion. There are estimated to be 2500 biopharmaceuticals in the discovery phase, 900 in preclinical trials, and 1600 in clinical trials. This represents 44% of all drugs in the development phase and 27% of all drugs in both preclinical and clinical trials. The most common target is cancer and monoclonal antibodies and vaccines have the largest amount of R D activities. 

In general, bioequivalence is demonstrated if the mean difference between two products is within 20% at the 95% confidence level. This is a statistical requirement, which may require a large number of samples (e.g. volunteers), if the drug exhibits variable absorption and disposition pharmacokinetics. For drugs for which there is a small therapeutic window or low therapeutic index, the 20% limit may be reduced. The preferred test method is an in vivo crossover study and, since this occurs in the development phase, necessitates the emplo)unent of volim-teers. These studies are, therefore, expensive and animal experiments may be substituted, or in vitro experiments if they have been correlated with in vivo studies. 

Specialised studies may be conducted at any time during the development phase. If a special route is selected as the primary route of administration, then this route will be used throughout. Special routes used to supplement the main toxicology programme will usually be conducted before administration or exposure of man to the test material by the route equivalent to the special route. The duration of dosing recommended for the special routes in different species is presented in Table 3.5. 

How do companies go about the process of disseminating information about their products As discussed above, it is now common place for marketing to become involved early in the development phase of a compound. One of the earliest elements in a promotional campaign, and should... 

The book Science and Corporate Strategy DuPont R D, 1902-1980 by Hounshell and Smith (1988) presents a well-documented story of the long journey of nylon from discovery to the marketplace. A large number of people were involved. The effort received many lucky breaks, as well as entering and abandoning numerous blind alleys, and requiring dedication and determination when things looked bleak. The journey can be divided into a number of phases that overlap in time the exploration-discovery phase, the development phase, and the commercialization-business phases. 

What knowledge and skills are the most valuable for investigators in the exploration-discovery phase, in the development phase, in the commercialization phase, and in the widespread use phase Are these topics already in your curriculum If not, then you need to take electives on your own among courses taught in your university, or you have to acquire them from a business school or a company with a good track record of developing new products ... 

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