Bulk drug synthesis

GMP bulk drug synthesis, including stability studies... 

Chander Mohan was born in 1975 at Dhariwal, Punjab, India. He received his B.Pharm. and M.Tech.(Pharm.) in bulk drugs from Guru Nanak Dev University and the National Institute of Pharmaceutical Education and Research (NIPER), Mohali. After that he worked as senior chemist at Dr. Reddy s Research Foundation, Hyderabad. He then joined Professor M. P. Mahajan s research group in 2002 for his doctoral studies. His research is focused on the synthesis and chemical transformation of C-5/C-6-substituted pyrimidinones. His research interests include synthesis of medicinally important molecules, transition metal-induced transformations in organic synthesis, reaction mechanism and total synthesis of natural products. 

Besides, the pharmacological actions of many compounds are invariably dependent on the shape of molecules and hence, usually play a very significant role. Therefore, if both cis- and tram-isomers are produced in the course of a particular synthesis it may be absolutely necessary to incorporate in the product profile a specific test for the relative proportions of one to the other. This type of control measure strictly conforms the uniformity of composition in the bulk-drug industry and ensures a check on the batch-to-batch variation. 

Description of the bulk drug substance, including structural and molecular formula, process impurities or degradants, specifications, rationale for specifications, safety, approved supplier(s), test methods, validation, and stability. Include basic information on synthesis or derivation of the drug substance, or if applicable, reference supplier drug master file. 

It also should be noted that FDA may request additional preclinical toxicology studies. This will depend on the degree(s) of difference(s) in the profiles, identities, and the levels of impurities in bulk drug substances produced from the pivotal intermediate made by the various routes of synthesis, and whether the finished drug is intended for short-term or chronic use. 

Regarding production of bulk drug substances, specifications for contaminants should be established for all solvents used in the process. A comparison should be performed between the manufacturer s Certificate of Analysis and the submitted specifications, and any discrepancies should be justified. A full description for the route of synthesis should be given, as this is important for the testing and control of impurities and process solvent residues. The FDA expects that, at the time of submission, it will be determined if the drug substance exists in a multiple solid state form (racemic mixture stereoisomer) and whether this affects the dissolution and bioavailability of the drug product. 

Prior to entering clinical trialS/ adequate drug supplies of pharmaceutical-grade material must be available. This may require the development of bulk chemical synthesis protocols or/ in the case of natural product isolation/ adequate amounts of raw materials... 

Development of enantiomeric assay —Synthesis/resolution of individual enantiomers —Safety evaluation of individual enantiomers —Pharmacokinetics of individual enantiomers —Bulk drug enantiomeric composition/purity —Chiral inversion... 

Profile This privately held company was founded in 1972. It is a full-service drug synthesis and chemical services company that performs a variety of laboratory, process scale-up, and manufacturing tasks including development of processes and synthesis routes for new medicinal products, validating bulk pharmaceutical processes, and authoring Drug Master Files. The company also has a pilot plant/small volume manufacturing site in North Andover, Massachusetts. 

The conventional technology for synthesis of trimethoprim from 3,4,5-TMBA was introduced as early as 1970 USA, Canada, countries of W. Europe like UK, Germany, France, Switzerland, Spain, Denmark, Finland, etc. and also India, China and Japan in Asia were manufacturing this bulk drug. 

The FDA has given approval in the past to the concept of a pivotal intermediate. This is an analyzed and well-characterized synthetic intermediate that is usually isolated one to two steps before synthesis of the crude final product, but may be obtainable by more than one synthetic route. To obtain approval, material produced by the several routes must be characterized, especially with regard to the identity and level(s) of impurities and the relative qualities of the finished bulk drug substance produced. In addition, a fairly rigorous set of specifications for the intermediate has to be established to assure its ultimate quality by whichever approved route is used in its production (see section on process controls below). The benefit to the sponsor is that the level of detail describing the various routes used to make the pivotal intermediate does not have to be as... 

Other kinds of start-ups are less risky than nascent pharmaceutical companies. For example, a newly founded custom-synthesis house or a contract manufacturer of intermediate compoimds and bulk drugs may have orders booked long in advance. Depending for its revenues on several fipcos, such a firm is largely independent of the success or failure of any one substance undergoing dmg development. 

One critical factor that the team needed to be cognizant of was the impurity profile of penultimate intermediate emd API (advance pharmaceutical intermediate) that would be derived from a new synthesis. A significant number of clinical trials had already been conducted with kilograms of material that had already been synthesized. A new batch of API that contained an elevated level of an impurity or that contained a new impurity could not immediately be used for clinical trials without a time consuming qualification process. Hence, the task at hand was the discovery and development of a more efficient synthesis with the caveat that no new impurities could be present in the final bulk drug. 

Figure 1 Bulk drugs from natural sources Paclitaxel (antileukemic and antitumor) and lovastatin (inhibitor of cholesterol biosynthesis) are examples of the diverse and complex structures made by plant and microbial cell biosyntheses, respectively. In most instances of such compounds having desirable biological activities, their structural and chiral complexities make chemical synthesis not competitive with isolation from biosynthesis.

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