Eli Lilly Humalog Manufacturing Facility, Carolina

Eli Lilly Humalog Manufacturing Facility, Carolina, Puerto Rico

In April 2001 Eli Lilly announced it was constructing a new biotech bulk manufacturing facility in Carolina, Puerto Rico. Construction started in July 2002 and, following validation and commissioning, the plant was in production by mid-2005. The 300,000ft² facility produces the rapid acting insulin product Humalog, the manufacture of which requires the use of recombinant DNA technology.

FACILITY AND PRODUCTION

The facility was initially planned to cost $250 million. However, the construction design was expanded to include a dedicated warehouse facility, a utility building, an administration building and an independent laboratory facility for the site, increasing the total investment to $450 million and raising the number of new employees from 300 to 450.

It was important for Eli Lilly to get the plant into production as quickly as possible as the world insulin market is growing daily (with more and more diabetics) and new long acting insulin products such as Humalog (insulin Lispro injection) are in demand.

INSULIN / HUMALOG PRODUCTION

The plant consists of five operational suites. The first is the media preparation area where the bulk media is formulated before inoculation and up-filling to the pre-fermentation vessels to begin the fermentation.

The second is the fermentation suite (consisting of three 15,000L bioreactors) and associated storage tank farm.

The third is the pre-purification area where the Escherichia coli are killed and broken down (lysed) to harvest the pre-proinsulin. The pre-proinsulin is separated out from the cell debris by centrifugation and filtration.

The fourth area is the refolding suite where the pre-insulin is treated with buffers to assist it in attaining its tertiary structure. The pre-proinsulin may still be attached to other peptides added to it by the E. coli so further purification is required.

The final area is the downstream purification suite where the pre-proinsulin is cleaved using trypsin to modify its primary structure and then separated by chromatography and finally crystallised.

The chromatographic process is monitored by protein-specific analysis using enzyme-immunological methods that make it possible to detect even the smallest possible by-products. The purity of the insulin is measured at every intermediate stage of production by the In Process Control (IPC) laboratory.

The product insulin (lispro) can then be used to formulate Humalog, which is a mixture of insulin lispro and insulin lispro protamine. Humalog is a fast acting insulin which can be administered in a variety of forms - via injection and from an insulin pen injector. It may soon be available to inhale.

CONTRACTORS FOR THE HUMALOG PLANT

The architects for the plant were Caribbean Architects and Engineering. The lead contractors responsible for overall project management and civil engineering were Fluor Daniel. The contractor responsible for the fabrication and erection of the structural steel in the new buildings of the facility was Cives Steel Company of the United States.

PACIV were responsible for the automation of the plant and the control systems along with instrument validation. CPI Engineers were the consultants for the process engineering in the new plant.

The process piping and the installation of the plant equipment was undertaken by Kinetic Systems Caribe Inc of Vega Alta, Puerto Rico. The cleanrooms in the facility were provided and installed by the McIlvaine Company of Illinois, United States. CREW provided technical services and on-site logistics capability.

RECOMBINANT DNA TECHNOLOGY

The new plant uses recombinant DNA (rDNA) technology to produce insulin by a fermentation method. Human recombinant insulin is produced by inserting the insulin gene into a suitable vector. The most readily amenable is a non-pathogenic weakened strain of the common bacterium Escherichia coli. The bacteria produce insulin that is chemically identical to its naturally produced counterpart.

Human insulin is the only animal protein to be made in bacteria in such a way that its structure is absolutely identical to that of the natural molecule. This reduces the possibility of complications resulting from antibody production.

In chemical and pharmacological studies, commercially available rDNA human insulin has proven indistinguishable from pancreatic human insulin. Initially the major difficulty encountered was the contamination of the final product by the host cells, increasing the risk of contamination in the fermentation broth. This danger was eradicated by the introduction of purification processes.

The entire procedure can now be performed using yeast cells as an alternative growth medium, as they secrete an almost complete human insulin molecule with perfect three-dimensional structure. This minimises complex and costly purification procedures.

ELI LILLY IN PUERTO RICO

Eli Lilly already had a large presence in Puerto Rico with three other plants; two in Carolina manufacturing APIs for Prozac, Darvocet and Axid with a form-fill-seal facility, and one fermentation plant in Mayaguez that produced bulk antibiotics.

Eli Lilly, operating as their Caribbean subsidiary Lilly del Caribe, therefore were able to draw on an already established base of skilled employees to plan the construction of a major new biotech manufacturing facility.

In addition, the company received government incentives provided by Puerto Rico's 1998 Tax Incentive Act. This created tax breaks for a wide range of economic sectors (including a special R&D tax deduction) as well as initiating a flat corporate tax rate, ranging between 2% to 7%.

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Eli Lilly began production of the insulin product Humalog at its new bulk manufacturing facility in Carolina, Puerto Rico, in mid-2005.
Eli Lilly began production of the insulin product Humalog at its new bulk manufacturing facility in Carolina, Puerto Rico, in mid-2005.
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Pro-insulin and human insulin, showing where the trypsin cleavage occurs.
Pro-insulin and human insulin, showing where the trypsin cleavage occurs.
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Scanning electron micrograph of <i>E. coli</i> as used for recombinant DNA techniques.
Scanning electron micrograph of E. coli as used for recombinant DNA techniques.
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Humalog pen used for dispensing the insulin by a non-injection technique.
Humalog pen used for dispensing the insulin by a non-injection technique.
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Insulin crystals from the purification process.
Insulin crystals from the purification process.
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