Drug development and production

Development is the conversion of a biologically active compound into a safe marketable product. It is a multi-disciplinary process, which requires the collaboration of teams of workers from many different disciplines. Its success is dependent on their skills and judgement. This chapter will outline the work carried out by these teams in the main areas of the development process. The activities in many of these areas are interdependent, which means that they should take place consecutively or at the same time. Consequently, as speed is of the essence in all development work, these activities will require careful planning and coordination. 

Fundamentals of Medicinal Chemistry, Edited by Gareth Thomas 

Drug synthesis------Acute and subacute toxicology-------- Preclinical trials ---- Phase I trials 

Submit MAA report ---------- Analysis of trial data ----- Phase III trials ------- Phase II trials 

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Manufacturing process The descriptions of the manufacturing steps for the drug substance and product should include process flow diagrams and discussions of critical scale-up steps and process development history and process validation activities, together with assessment of the equivalence or differences in batches used for various studies. 

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... 

Stability of a drug substance and product is monitored throughout the development and clinical phases. This monitoring requires stability-indicating assay methodology, and this is a subject that is separate from performulation per se. In most instances, the major, feasible decomposition products are identified early [51], and as such it is known if the pathways are hydrolytic, oxidative, or photochemical. 

R D Focus. This database service [66] provides information on over 7000 drugs in active development. The service monitors the development, efficacy, and status of pharmaceuticals from early clinical testing through to launch. Data are gathered through direct contact with manufacturers and research organizations. It appraises both the scientific and commercial aspects of drug development and is searchable by product, by phase, by mechanism of action, and by country. R D Focus product is commercially available in several formats. 

GI ADRs are some of the most frequently reported in all phases of clinical drug development and for marketed products, as illustrated by the 700 drugs that are implicated in... 

Pharmaceutical companies have to be continuously vigilant and forecast the future directions of drug development and regulatory requirements. They have to use their core technical competencies to deliver a pipeline of products to remain competitive and profitable in the long term. 

Impurity testing is pivotal in pharmaceutical development for establishing drug safety and quality. In this chapter, an overview of impnrity evaluations of drug substances and products by HPLC is presented from both the laboratory and regulatory standpoints. Concepts from the development of impurity profiles to the final establishment of public specifications are described. Useful strategies in the identification and quantification of impurities and degradation products are summarized with practical examples to illustrate impurity method development. 

Table 12 gives an orientation help for CE separations sorted by pharmaceutical substances published in review articles. As this chapter focuses on the technical development of drug substances and products, only drug substances and drug formulations are covered. A useful compendium of CE applications in the pharmaceutical environment can be found in the book Capillary Electrophoresis Methods for Pharmaceutical Analysis written by G. Lunn. The book covers more than 700 active pharmaceutical ingredients and contains short method descriptions, sample preparation steps, and references. 

Whole proteins, including monoclonal antibodies, are the fastest-growing class of therapeutics. Compared with traditional small molecule drugs, much additional analysis is necessary for their development and production due to their large size and complex structure. The protein construct and its formulation have to be optimized during development, and its structural integrity must be closely monitored during production. 

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