Manufacture of Large Molecule APIs

By nature, enzymes themselves are chiral and they catalyze a variety of chemical reactions with stereoselectivity. These reactions include oxidations, reductions, and hydrations. Examples of enzymes are oxidases, dehydrogenases, lipases, and proteases. Metoprolol, an adrenoceptorblocking drug, is produced using an enzyme-catalyzed method. 

Non-organic and organometallic catalysts are also used to channel the reactions towards the chiral synthesis pathway. The drug called levodopa, (S)-3,4-dihydroxyalanine, is an effective drug against Parkinson s disease. It is stereoselectively manufactured using catalysts such as rhodium or ruthenium complexes. 

Some drugs are made using chiral building blocks to generate the required chiral centre in the drug. The introduction of chiral centers ensures that the reaction proceeds in the desired direction. The preparation of enalapril, an ACE inhibitor, is an example of the use of chiral building blocks. 

A chiral auxiliary is an intermediate formed by the attachment of a pure enantiomer to an achiral substrate. The attachment, called a chiral auxiliary, restricts the approach of reactants to react in specific ways to produce the chiral molecule. The antibacterial drug, aztreonam, is synthesized using the chiral auxiliary method. 

Chapter 10 Good Manufacturing Practice Drug Manufacturing 

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Manufacture of Large Molecule APIs (Recombinant DNA Methods) 340... 

MANUFACTURE OF LARGE MOLECULE APIs (RECOMBINANT DNA METHODS)... 

The observation of multiple charging of proteins in electrospray ionization attracted much attention all major instrument manufacturers introduced an API system to be used in combination with an electrospray interface. At the same time, it was found that electrospray ionization is not only suitable for the mass analysis of large molecules, but is also a very efficient ionization technique of small polar or ionic molecules, e.g. drugs and their metabolites. In the past few years, hundreds of dedicated API-MS systems equipped with electrospray and APCI interfaces have found their way into many different laboratories, especially within pharmaceutical companies and biochemistry/biotechnology laboratories. 

The manufacturing process for a small molecule API is shown in Figure 10.3. Typically, the chemical reactions are performed in large reaction vessels. For commercial production of an API, the reaction vessel can typically range from 1000 L to 20 000 L in volume (Figure 10.4). 

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