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EXECUTIVE SUMMARY1. Insu lin is the horm one secreted b y the |3
cells of the Islet tissue in th e tail of thepancreas of all
animals. Insulin is required by the body for the utilisation
ofglucose by all cell s for en ergy a nd cellular respiration.2. In
the absence of insulin, the disease D iabe tes m ell itus will set
in leading to in-creased blood sugar levels and if it is not
controlled by insulin treatment ininsulin dependent diabetics, the
patients will develop various complicationsand can die within
eighteen mo nths of the onset of the disease. Hence ins ulinis a
very essential drug and all these years, it was being manufactured
byisolating it from the cattle and pig pancreas . Recently
biotechnological m etho dshave been developed for producing highly
purified insulins and the humaninsulin.3. According to WHO reports,
the insulin dependent diabetic population isincreasing by 3 to 5% a
year in the world. The various studies at All India
Institute of Medical Sciences, New Delhi, Diabetes Research
Centre, Madrasetc., reveal that on an average of nearly 5% of the
Indian population hasimpaired glucose tolerance. Fortunately nearly
95% of these are non insulindependent. Based on all these studies
nearly 3 in 1000 in urban India can beconsidered as insulin
dependent diabetic with greater family aggregation ofdiabetics.
Thus on the wh ole the diabeties incidence is high and in kee ping
withthe world trend , it is increasing. The assu mp tion tha t the
incidence is prevalen tam ong affluent people is no longer valid.
The Gujarat and Orissa stud ies h aveidentified ma lnutrition also
as a factor for diabetic incidence.4 . Based on all these factors,
a detailed evaluation of the insulin d em an d projec-tion had been
publish ed in Ind ustrial R esearcher in April 1986. These e
xpertshave projected the insu lin requirem ent of India by 1989-90
to be arou nd 4413MU.5. Against such a requirement projection, The
Boots Company (India) Ltd. hadbeen sanctioned a capacity of 2780 MU
with an installed capacity of 3475MUat present.6. Recently, from
1985, Synbiotics (Baroda) has been perm itted to imp ort
highlypurified insulin from Novo,Denmark and re-vial that for
marketing in India.
They are at present im porting and marketing nearly 20 MU of
insulin vials perannu m. The product even though costly, is
required for those cases d evelopingreactions to the conventional
insulin and in cases where insulin resistance isdevelo ping d ue to
antigenic effects.7. M.J. Pharmaceuticals (Gujarat) import about
Rs. 3 to 4 lakhs worth of bulkinsulin from Eli Lilly and Co., USA.,
to be vialed in India and exporte d to USSR.This qua ntum of
insulin will not be available for the Indian req uirem ents.
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8. U nder these circumstances the actual man ufacture is arou nd
3475 MU asagainst requ irem ent of 4413 MU b y 1989-90. There is
also abou t 20 MU of thehighly purified insulin im ported. T hus
there is still a dem and gap of 918 MU .This gap is likely to grow
wider and wider with the demand increasing bynearly 12-15 % per
year according to the study in Indian Researcher.9. The technology
used by the Boots Com pany (India) Ltd., is the conventional
process of extracting insulin from frozen p ancr eas of slaug
htere d an im als. Sincethe Indian slaugh tered animals are not
specially bred for m eat, they are m al-nourished and often not
healthy, with the result the efforts to produce insulinfrom their
pancreas prove d to be uneconom ical. India today does not have an
yorganized slaughter ho use, wh ere specially bred anim als are
slaughtered andthe important organs remo ved, preserved and p
rocessed scientifically. There-fore, the Boots Com pan y has to
impo rt the pan creas in a frozen state from U.K.and then process
it locally. Approximately 10,000 kg of pancreas will berequired to
produce 1 Kg. zinc insulin crystals.10. Since the num ber of
slaughtered animals in the developed countries is related
to their meat dem and , the availability of the pancr eas, and
therefore th e insulinfrom that natural source has a considerable
limitation. This naturally hascreated a world-wide insulin
shortage. India without an organized meatpacking indu stry for
meeting its meat requirem ents by specially breed ing th eanimals
for slaughtering, will have to depend entirely upon the
developedcoun tries for their frozen p ancr eas n eed s. This is
goin g to be a big lim iting factorfor insulin production in future
b y this conventional technology in India.11. Fortunately, a
breakth roug h h as occurred in the insulin produ ction
technology,through the development of Biotechnological techniques.
Even before thebreakthrough for the development of human insulin by
biotechnological
techniques, technological developments did take place to purify
insulin toreduce its antigenicity. This lead to the preparation of
purified and highlypurified insulins like (i) single peak (SP)
insulin and single component (SC)insulin of Eli Lilly, (ii) mono
-com pon ent insulins of Novo , (iii) highly purifiedand rarely im
mun ogenic (HP & RI) insulins of (Nordisk) an d (iv) Desphe
Betainsulin of Hoechest. These insulins were prep ared from the
conventional porcinand beef insulins, by purifying them through
chromatographic and electro-phoretic techniques. This is the second
phase in the development of insulinprodu ction technologies.12.
Even with these highly purified insulm s certain allergic reactions
wer e no ticed,because the pig and cattle insulins are structurally
different proteins fromhum an insulin. The prim ary structure of
the insulin is a mo nom er protein chainconsisting of 51 amino
acids in tw o chains A a nd B, with a molecular w eight
of6000Daltons.13. The therapeutically used conventional insulins
are derived from pig p ancreas
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or beef pancreas (often as mixture of both). The insulins of
these two specieshave different aminoacids sequence to hum an
insulin. The pig insulin differsfrom human insulin in one
aminoacid, while the beef insulin differs in threeamino acids.
These variations make the porcine and bovine insulins moreantigenic
to the humans. The ideal insulin to be used for the treatment
ofdiabeties mellitus is therefore the human insulin. It is in this
context thebiotechnological approaches to produc e hum an insulin
arose.
14. Between the years 1980-82, wh ile Eli Lilly in collaboration
w ith a b iotechno logyResearch company, G enentech, developed a
process of produ cing insulin bythe recombinant DNA technology,
while No vo in Den ma rk and LaboratoriesLeo in Spain developed and
started the hum an insulin produ ction technologyby enzym ic
modification of the porcine in sulin.lij. The recombinent DNA
technique consists of the in vitro incorporation of thesynthetic
genes of the A and B chains of the insulin mo lecule from the p
cellsof the islets of Langerhans from the human pancreas into a
non-pathogenic
laboratory strain of E.coli K.12 strain plasmid DNA. This new
recombinantplasm id DN A is reinserted into the E.Coli. These
bacteria are cloned in c ultu reto get rid of those cells not
having the recombinant plasmid . The pur e clonedorganism s are
then persu aded to express the insulin gene, which p rodu ces
theinsulin. The plant for pro duction of this insulin was formally
opene d on 5thAp ril 1982 at Speke, Liverpool (U.K.)16. Novo an d
Leo approached the production of hum an insulin by enzymic mod
i-fication of the porcine insulin (Emp insulin). These companies
have startedman ufacturing their hum an syn thetic insulins from
1981-82.17. Further develop men ts also have occurred in insulin
produ ction technology inthat Lilly has also produ ced
biotechnologically the hum an proinsulin (A an d Bchains linked
with C Pep tide, which is the precu rsor of insulin in the pancrea
s)and by enzymic cleavage producing the human insulin. More
recently theprocess for insulin genetically enginee red from yeast
also has been d eve lop ed.These also, are likely to be in the
market soon, as new technology for humaninsulin produ ction.18. Thu
s the world over has progressed from the conventional porcine an d
beefinsulin from the pancreas of slaughtered anim als to more
purified and highlypurified insulins and from there has even taken
off to develop the technologyof converting the porcine insulin to
hum an insulin by enzym ic modification andalso completely mo ving
aw ay from the limited anim al sources to the recom-binent DNA
techniques for the produ ction of hu m an insulin.19. As far as
India is concerned it is still pro du cing th e conven tional insu
lin. Someefforts are being mad e at the dep artm ent of Genetic
Engineering at Jawa harlalNe hru University, Ne w D elhi to produc
e the A and B chains by biotechnologi-
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cal me thod s. The work has progress ed v ery satisfactorily a
nd soon they can beexpected to have a workable technology
developed.20 . The Boots Co mp any (India) Ltd. has been w orkin g
on purification of the con-ventional insulins. In short India has
no m odern insulin technology at prod uc-tion level and is relying
on one com pany us ing the old conventiona l tech nologyto meet
about 75% of the cou ntry 's real insulin ne eds.21. It is und er
these circumstances the following recom men dations are ma de.
(a) In view of the steadily increasing de m and -sup ply gap for
this essential lifesaving drug namely insulin, it will be necessary
to expand the present p ro-duction of insulin even by the conv
entional pro cess. Since at presen t o nlyone company is engaged in
its production, ap art from their expansion, evenone more unit for
the produc tion of the conventional insulins in India willbe of a
great advantage for uninterrupted production and supply of
thedrug.(b) Purified ins ulins are necessary for cases dev elopin g
allergy and other hy-persensitivity reactions. As of today they are
being imported. Bootscompany (India) Ltd. are developing the
technology for these in India.Some of the National Lab oratories
havin g strength s in Biological pre pa ra-tions can also take up
this area of wo rk on a prio rity.(c) The enzymic modification of
porcine insulin to prod uce h um an insu lin isnow well
established. No R&D work is being done in India on this
atpresent. Apart from the need for hum an insulin in this
country,the devel-opm ent of this type of technology by itself is a
technological challenge forthe Nation and therefore some National
laboratory must consider thisproject on p riority basis.(d) The
production of hum an insulin through D N A technology is a great
brea k-throug h an d this will help in meeting the wo rld requirem
ents of insulin infuture, whe n the cattle and po rk pancreas
availability in the wor ld will getredu ced . The biotechnological
process develop ed by Lilly is in pro duc tionand this will also
undergo major changes soon to improve the processthrough the
proinsulin production and using yeast instead of E.coli. InIndia
R&D work on the production of insulin A and B chains has
beenprogressing satisfactorily at the Genetic Engineering Dept, of
Jawaharlal
Nehru University, New Delhi. In order to hasten the translation
of thetechnology developed at JNU, it will be wo rthwhile to have
one or tw opharmaceutical companies also to participate in taking
the process to pro-duction technology either by sponsorship of the
program me or acquiringthe process at a specific stage of the
development and get the projectthrough on a time-bound program me .
Depa rtment of Biotechnology canorganise a task-force for a coordin
ated tim e-bou nd pr og ram m e, since theyhav e the necessary
infrastructure and experts for such projects.4
