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Manufacturing of Insulin

Fawad Akram 12063123-065

Haseeb Hassan 12063123-029
Hassan Masood 12063123-083
Ali Shahbaz 12063123-081

 Insulin is a peptide hormone, produced by beta cells of the

pancreas, and is central to regulating carbohydrate and fat
metabolism in the body. Insulin causes cells in the liver,
skeletal muscles, and fat tissue to absorb glucose from
the blood. In the liver and skeletal muscles, glucose is
stored as glycogen, and in fat cells (adipocytes) it is
stored as triglycerides. When control of insulin levels fails,
diabetes mellitus can result. As a consequence, insulin is
used medically to treat some forms of diabetes mellitus.
Natural Production of Insulin

 Naturally, Insulin is secreted by the Pancreas.

 Pancreas has two important functions :
1. Producing hormones – insulin and glucagon which
regulate blood sugar levels.
2. Producing pancreatic digestive enzymes.
 Insulin is released when any of the several stimuli are
detected– stimuli include ingested protein and glucose in
the blood from digested food.
Insulin is synthesized as preproinsulin in pancreatic β-cells. It
contains a signal peptide which directs the nascent polypeptide
chain to the rough endoplasmic reticulum. Then it is cleaved as
the polypeptide is translocated into lumen of the RER, forming
proinsulin. Proinsulin is transported to the trans-Golgi network
(TGN) where immature granules are formed.

Proinsulin undergoes maturation into active insulin through

action of cellular endopeptidases known as prohormone
convertases (PC1 and PC2), as well as the exoprotease
carboxypeptidase E. The endopeptidases cleave at 2 positions,
releasing a fragment called the C-peptide, and leaving 2 peptide
chains, the B- and A- chains, linked by 2 disulfide bonds. The
cleavage sites are each located after a pair of basic residues and
after cleavage these 2 pairs of basic residues are removed by
the carboxypeptidase. The C-peptide is the central portion of
proinsulin, and the primary sequence of proinsulin goes in the
order "B-C-A”

The resulting mature insulin is packaged inside mature granules

waiting for metabolic signals (such as leucine, arginine, glucose
and mannose) and vagal nerve stimulation to be exocytosed
from the cell into the circulation.
Effects on Health

 The absence of Insulin not only interrupts the normal

functioning of the body, but produces depression of
essential functions and in some severe cases it may
prove fatal.
 Insulin Disturbance causes:
 Diabetes mellitus
 Metabolic syndrome
 Insulinoma
Industrial Manufacturing

There are two leading pharmaceutical industries

manufacturing Insulin round the globe.

1.Eli Lilly & Co. using the E.Coli Bacteria Process

2.Nova-Nordisk using the yeast to produce Insulin.
Eli Lilly’s Mode of Insulin Production

 Beef and Pork Pancreas glands are refrigerated at -20°C,

roto-ground and the meat slurry is treated with Ethyl
Alcohol after acidification.
 With the use of the continuous countercurrent extraction in
six continuous centrifuges over extraction tanks, the gland
slurry is extracted with acidulated alcohol.
 From the sixth centrifuge, the cake is processed in a hot-
fat fry tank and discharged through another centrifuge to
separate waste from the “Fried Residue”, which is
drummed and sold.
Eli Lilly’s Mode of Insulin Production

 The crude alcoholic extract is run from two strong

extraction-centrifuge units into a collection tank from
which the extract is neutralized with ammonia and filter
aid added.
 In a continuous pre-coat drum filter, the cake is separated
and washed, the clear liquor going to the re-acidification
 In evaporators, the first stage removes alcohol, with
subsequent waste-fat separation. The extract goes to a
chill tank, with filter aid added, through a filter press and
into the second evaporator.
Eli Lilly’s Mode of Insulin Production

 From the second evaporator, the concentrated extract is

filtered and conducted to the first salting-out tank,
followed by filter press filtration with filtrate to sewer and
salt cake to purification for the second salting out. A
filtration follows with filtrate to sewer.
 The second salting out product is crystallized twice to
furnish Iletin (insulin) crystals.
Eli Lilly’s Mode of Insulin Production
Nova-Nordisk’s Mode of Insulin Production