# Pharmaceuticals and fermentation: from molecule to medicine: Key terms, quiz and sources Source page: https://www.materialinsights.org/learn/chemicals/pharmaceuticals-and-fermentation/review/ [Understanding Chemicals](https://www.materialinsights.org/learn/chemicals/) / [Module 10: Pharmaceuticals and fermentation: from molecule to medicine](https://www.materialinsights.org/learn/chemicals/pharmaceuticals-and-fermentation/) Wrap-up ## Pharmaceuticals and fermentation: from molecule to medicine: review ### Key terms **Active pharmaceutical ingredient (API)** : The molecule in a medicine that produces the therapeutic effect, also called the drug substance. **Excipient** : An inactive ingredient, such as a filler, binder, disintegrant or lubricant, used to make the API into a usable dose. **Primary and secondary manufacturing** : Primary manufacturing makes the API; secondary manufacturing formulates it into the drug product. **Overall yield** : The fraction of theoretical product that survives a multistep route, equal to the product of the step yields. **Enantiomer** : One of two mirror-image forms of a chiral molecule, which can differ in biological effect. **Polymorph** : One of several crystal arrangements of the same molecule, with different dissolution and handling properties. **Genotoxic impurity** : A trace impurity that could damage DNA and must be kept below a very low daily exposure limit. **cGMP** : Current Good Manufacturing Practice: the regulators' rules for quality in making medicines and APIs. **Design space** : The validated range of process conditions within which a manufacturer must operate to assure quality. **Multipurpose plant** : A batch plant of general reactors, filters and dryers used in campaigns for many different products. **Granulation** : Agglomerating fine powder with a binder into dense, free-flowing granules for tableting. **Pyrogen (endotoxin)** : A fever-causing substance, chiefly bacterial cell-wall debris, that must be absent from injections. **Fermenter** : A sterile, stirred and aerated vessel in which microorganisms make a product. **vvm** : Volumes of air per volume of broth per minute, the usual measure of fermenter aeration. **Fed-batch** : A fermentation or cell culture to which nutrients are added during the run, while product stays in the vessel. **Titre** : The concentration of product in a fermentation broth or cell culture, usually in g/L. **Downstream processing** : The recovery and purification of a product from fermentation broth or culture. **Precursor** : A chemical fed to a fermentation that the organism builds into the product, such as phenylacetic acid for penicillin G. **Immobilised enzyme** : An enzyme fixed to a solid support so it can be reused and kept out of the product. **Cost of goods sold (COGS)** : The manufacturing cost of a product: for a drug, the API plus formulation and packaging. ### Try it in the table - Open the "[Small-molecule APIs](https://www.materialinsights.org/chemicals/apis/)" tile and compare its price per kg with Pollak's atorvastatin figures ($2,000/kg API, $50,000 per kg in tablets). Where on the value chain does the tile sit? - In the "[Paracetamol](https://www.materialinsights.org/chemicals/paracetamol/)" tile, look at the main producing countries and the price. Paracetamol is one acetylation step from p-aminophenol: what does that suggest about whether cost is set by chemistry or by intermediate supply? - Open "Antibiotic intermediates (6-APA, 7-ACA)" and check where production is concentrated. Compare with Pollak's remark that China is now the main source of large-volume generic APIs such as penicillins. - Compare "[Citric acid](https://www.materialinsights.org/chemicals/citric_acid/)" and "Amino acids (lysine, methionine)": both are fermented from [sugar](https://www.materialinsights.org/commodities/sugar/), but lysine yields 40-50% on carbohydrate while citric acid can approach 112% on sucrose. How do their prices per kg compare, and how much of each price could sugar alone account for? - In "[Bioethanol](https://www.materialinsights.org/energy/bioethanol/)", look for the share of cost from feedstock. Kent says continuous fermentation barely lowers ethanol cost because raw materials dominate: does the tile bear that out? - Open "[Industrial enzymes](https://www.materialinsights.org/chemicals/enzymes/)" and "[Pharmaceutical excipients](https://www.materialinsights.org/chemicals/excipients/)". Both are sold in far larger tonnages than most APIs. Note their main end uses and price levels against the APIs they help to make. ### Final quiz A 20-step synthesis runs at 90% per step. Roughly what overall yield results? 0.9 to the power 20 is about 0.12. Losses multiply, so long routes need very high step yields. In Shreve's penicillin batch, about 300 kg of procaine penicillin G comes from a 45,000 L fermenter. What titre is that? 300,000 g / 45,000 L is about 6.7 g/L, in line with Shreve's broth concentration of 5-10 mg/mL. Kent later reports 20-30 g/L from improved strains. Why do Kent and Dryden say batch or fed-batch operation dominates for antibiotics and organic acids, despite continuous operation being easier to control? Dryden cites contamination and mutation hazards; Kent notes highly mutated strains are easily overtaken in prolonged cultures. Which step in citric acid recovery produces gypsum? Sulphuric acid frees citric acid from calcium citrate and precipitates calcium sulphate, about 1.34 t per t citric acid on stoichiometry. Kent states the investment in recovery facilities in an antibiotic plant is about how large compared with the fermenters? Kent gives about four times; recovery handles dilute, viscous broth and multiple extraction and purification steps. What makes immobilised glucose isomerase in a continuous packed bed so much cheaper than soluble enzyme in batch? Kent's Table 31.11 shows reactor size, enzyme use and residence time all far lower, giving conversion cost of 1 against 100 for soluble batch. According to Pollak, roughly what is the API's share of a branded drug's selling price? Pollak says the API accounts for less than 10% of the sales price; cost of goods including formulation and packaging is about 20%. Why are most monoclonal antibodies made in CHO cells rather than in E. coli? Kent and Pollak explain that mammalian cells perform folding and glycosylation that many large proteins need; they are slower and far costlier per kg. [Next module: How a classic specialty chemical market works: the synthetic dye industry →](https://www.materialinsights.org/learn/chemicals/how-a-specialty-market-works-dyes/) ### Sources for this module - Kent, J.A. (ed.), Handbook of Industrial Chemistry and Biotechnology, 12th ed., Springer 2012: Ch 11 Chemistry in the Pharmaceutical Industry (Kadow et al.) · pdf pp. 401-406, 422, 425-427 - Kent (2012), Ch 17 Agrochemicals (formulation types) · pdf pp. 671, 673 - Kent (2012), Ch 30 Industrial Biotechnology: Discovery to Delivery (Chotani et al.) · pdf pp. 1139-1146, 1151, 1157-1158, 1166, 1173-1174, 1178-1180 - Kent (2012), Ch 31 Industrial Enzymes and Biocatalysis (McAuliffe) · pdf pp. 1184-1185, 1208, 1213, 1215-1218 - Kent (2012), Ch 32 Industrial Production of Therapeutic Proteins: Cell Lines, Cell Culture, and Purification (Zhu et al.) · pdf pp. 1229, 1239-1245 - Austin, G.T., Shreve's Chemical Process Industries, 5th ed., McGraw-Hill 1984: Ch 31 Fermentation Industries · pdf pp. 596-608, 615-619 - Shreve (1984), Ch 40 Pharmaceutical Industry · pdf pp. 813-823, 835-840 - Gopala Rao, M. and Sittig, M., Dryden's Outlines of Chemical Technology for the 21st Century, 3rd ed., East-West Press 1997: IIID Fermentation Industries and Ethyl Alcohol · pdf pp. 337-344 - Dryden (1997), IVH Pharmaceutical Industry (incl. Penicillin) · pdf pp. 563-577 - Pollak, P., Fine Chemicals: The Industry and the Business, 2nd ed., Wiley 2011 · pdf pp. 27-29, 35, 55, 63-67, 75, 90-91, 185-187, 225, 239-240 - Wittcoff, H.A., Reuben, B.G. and Plotkin, J.S., Industrial Organic Chemicals, 2nd ed., Wiley 2004 · pdf pp. 72, 568, 649 ## Other sections - [Module overview](https://www.materialinsights.org/learn/chemicals/pharmaceuticals-and-fermentation/index.md) - [The pharmaceutical value chain](https://www.materialinsights.org/learn/chemicals/pharmaceuticals-and-fermentation/p1/index.md) - [Making the API: multistep batch chemistry](https://www.materialinsights.org/learn/chemicals/pharmaceuticals-and-fermentation/p2/index.md) - [Formulation: turning powder into a dose](https://www.materialinsights.org/learn/chemicals/pharmaceuticals-and-fermentation/p3/index.md) - [Fermentation: microbes as chemical plants](https://www.materialinsights.org/learn/chemicals/pharmaceuticals-and-fermentation/p4/index.md) - [Enzymes, biologics and the economics](https://www.materialinsights.org/learn/chemicals/pharmaceuticals-and-fermentation/p5/index.md)