“API is defined as any substance or combination of substances used in a finished pharmaceutical Product (FPP), intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to have direct effect in restoring, correcting or modifying physiological functions in human beings."

API’s, the Drug Substances & Finished Pharmaceutical Products are also known as Drug Product.

Drug Substance (API’s) falls into two main categories like small molecule API and large molecule API’s. The quality of the API’s depends on the kind of process adopted for manufacture, quality of the starting raw materials, process parameters, organic volatile solvents used for the extraction etc. It is very much clear that the manufacture of active pharmaceuticals is far more complex than drug product manufacture. However the quality system which is followed in API manufacturing units are less stringent compared to the Drug Product Manufacture.

The manufacture of pharmaceutical products based on small molecule active pharmaceutical ingredients (API) remains critical to global healthcare. The manufacturing landscape is also full of challenges and opportunities. This is due to emerging international markets and rapidly evolving social, economic, regulatory and environmental expectations. The small molecule API’s are produced by the synthetic route and can be characterized easily by various identification techniques like FTIR, DSC, XRD etc. However the large molecule API’s process is very complex compared to the small molecules. For example the molecular weight of human insulin is 5808 daltons where as a small molecule API like paracetamol is 151.169 g/mol

Large molecule API’s are growing and showing promising results in targeted drug therapy with fewer side effects. They are very much in demand for the cancer treatment; auto immune disorder especially the MAB (Monoclonal Antibodies) is of great importance. The biggest challenge is to standardize the process by utilizing the microorganism wherein either microbial cell or mammalian cell based fermentation process is considered and the protein of interest is harvested either from the broth or from the cell by lysis.

The biggest challenge is the cell line selection, cost involved in the purification and characterization during the downstream process. The downstream process involves the chromatographic techniques (Reverse Phase HPLC), size exclusion chromatography using organic volatile solvents and Buffer solutions. The host cell protein which also gets carried through the system will be present in the finished API also. It is important to control the HCP (Host Cell Protein) concentration in the finished API.

Further the biggest challenge in the large molecule API is stability, immunogenicity, characterization and also process lead time and control of the impurities.

Highly potent active pharmaceutical ingredients (HPAPIs) represent a significant change in the way pharmaceutical innovators are using small molecules to deliver new patient therapies, this has lead to many API’s discovery and the advantages are low doses, low risk to the patient, but has many of the manufacturing challenges.

Most of the biotechnological products are peptides (proteins) and poses majority of challenges compared small molecule API’s like market – very niche – below one per cent of the total pharmaceutical market

Reasons are poor physical and chemical stability, poor bioavailability through oral route, (Short half life), expensive and difficult to manufacture, where as there is lot of prediction that going forward the market will have more opportunities for peptide which is going to be more than 15 per cent of the total market.

Challenges in large molecule API synthesis
The large molecule API facility requires huge cost for construction and maintenance. The process involves fermentation up stream process which takes somewhere between (approximate) four to 10 days and requires strict monitoring program like microbiological screening for ensuring the organism of interest is growing, release of protein of interest by the organism if it is an extra cellular protein. Final stage is harvesting and disposition of the spent broth by autoclaving and ensuring the environment aspects are very well taken care of.

Further the downstream process involves multiple steps of chromatographic purification and isolation of the compound of interest followed by the stabilization of the drug substance by the lyophilization (freeze drying) or any other process based on the requirement. The Chromatographic system involves maintenance of the resin column, use of the solvents and buffers for elution etc.

In a nut shell, small molecule API production depends on the synthetic chemistry aspects and the raw material sourcing and in process control plays a very important role, where as in Large molecule API’s the pharmaceutical is derived from a living organism and the behavior of the organism is the key for synthesis. Selection and maintenance of cell bank are very important for the production of the bio pharmaceuticals. The process analytical techniques and the IT infrastructure are important which must be in compliance with the GAMP guidelines (Good Automated Manufacturing Practice).

Examples of peptides which are of importance are streptokinase, Bivaluridine, Eptifibatide etc.

Going forward the bio pharmaceuticals produced by recombinant DNA technology will be gaining lot of importance in pharmaceuticals and would be the best choice for management of many diseases like diabetes, rheumatoid arthritis, cancer and other auto immune diseases.