API synthesis

Bulk API synthesis (GMP or non-GMP) including analytical methods development... 

Bulk API synthesis (GMP and non-GMP) and clinical dosage forms development and manufacture... 

Our biotransformation group (Drs. David Dodds, Alex Zaks, and Brian Morgan) contributed to most of our chiral synthesis projects, although in most cases enzyme-based routes were not selected over chiral induction or classical resolution processes for the short-term needs in API synthesis. This area, however, remains one of huge promise with the prospect of working in water being one of its most appealing attractions. 

The major impurities produced in the process to be scaled up are usually identified at the research stage or in the early phase of developing the process for scale-up. To aid the analyst, impurities are frequently recovered from mother liquors obtained from the final crystallization step—for example, by preparative HPLC. The major ones are synthesized and purified to provide the analytical standards needed to quantify the amounts produced in the API synthesis. Over the course of time, the obvious impurity collection is supplemented by those substances that might be produced in the process, including other enantiomers. These theoretical impurities help to provide answers to almost every query on the impurity profile of the API. 

Analogous presentations to the Review Branch are made for the drug product. Both the chemical and pharmaceutical development presentations are supported by analytical development presentations providing the data to satisfy the FDA that all components of the API synthesis and dosage form preparation are well-controlled. 

There is also a knock-on effect in the pharmaceutical sciences area since they need both to validate that changes in the API synthesis do not affect the dosage form, and also introduce beneficial improvements of their own. 

Chromatographic purification might not be applicable to every API synthesis—for example, when the API itself is very insoluble. However, in these circumstances, ways might be found of introducing the technology, say at the penultimate step, in the bulwark purification of more soluble fragments. 

Ganzer, W.P., Materna, J.A., Mitchell, M.B., and Wall, L.K., Current thoughts on critical process parameters and API synthesis, Pharmaceutical Technology, July 2005. www.fda.gov/cder/OPS/PAT.htm. 

FIGURE 28.5 (See color insert following page 40). Spectrum of active pharmaceutical ingredient (API) synthesis route. 

Process validation /evaluation—Presentation of information in this section of the CTD is a new requirement, and is being actively defined by various agencies at this time. The requirements may be different depending upon the nature of the API synthesis, and the end use of the API (e.g., formal process validation data may be required for the sterility operations... 

The protocol clarifies how to report individual peaks less than the reporting limit and how to determine total degradation products, for example, do not include the main API synthesis impurity in the total sum all peaks greater than the reporting limit... 

However, options are available to adjust for complexity, for example, a PMI calculation has been established by Lilly that sets targets for the PMI of API synthesis based on a correlation between the number of ehiral centres, the number of heteroatoms and the fraction of aromatics in the target molecule. ... 

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