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Article From :Jinan health and medical technology co., LTD Add time:2016/06/17 PV :


Trends in Peptide Manufacturing: A Move toward Lower Costs

Since 1970, the US FDA has approved 45 peptide drugs, nearly all injected, infused, or implanted Ainslow-release, depot formulations. Few com-panies have created peptide drugs delivered by other methods.

lthough actively investigated, strategies for transdermal, oral, inhalation, spray, and intranasal delivery of peptides gen-

erally have not been commercially successful. Some contributory causes for this situation include the fact that peptides:

•Are high in molecular weight.

•Have a short half-life in vivo.

•Are not bioavailable enough.

•Are too charged.

The real but less apparent reason, however, is cost.

Cost of Peptide Drugs

During the past 40 years, manufacturing costs for peptide drugs actually have decreased dramatically. In 1995, the lowest manufacturing cost for leupro-lide acetate, an Active Pharmaceutical Ingredient (API) containing a nine-amino-acid, gonadotropin-releasing hormone (GnRH), was about $200 per gram. Today, industrial-scale production of an API consisting of a 36-amino-acid peptide can cost under $100 per gram.

Despite dramatically reduced manufacturing costs, as late as 2003 many peptide drugs were still too expensive to administer cost-effectively except by injection or infusion. One thing contributing to this problem is the design of delivery devices or vehicles.

For example, metered-dose inhalers (MDIs) can deliver only up to about 20% of the loaded dose, with overall biovailability of a GnRH peptide actu-ally deposited in the deep lung from the device at 10% [1]. This fact means that 90% of the drug is wasted. If you throw away 90% of a drug that costs $200 per gram, the drug really costs $2,000 per gram. The waste effectively increases the unit cost per dose of the inhaled drug ten-fold, making it impractical to commercialize the drug and impossible to com-pete with the same drug when injected or implanted.

To consider alternative administration of peptide drugs, the APIs must cost on the order of $50 per gram.

Production of Peptides

In 1995, the peptide API that companies produced on the largest scale worldwide was leuprorelin (leuprolide acetate, also known as Lupron and Lupron Depot), with an annual requirement of about 10kg per year, manufactured in 2kg batches.

In those days, researchers also could synthesize other contemporaneous peptide drugs, but man-ufacturing in a recombinant manner was simply much cheaper because of the following factors:

•The prohibitive cost of amino acids and solvents

•The primitive manufacturing methods for synthetics
•The use of outdated plants located in expen-sive parts of North America and Europe

 

During this period, the US FDA approved several recombinant peptide drugs: Forteo (pTH 1-34), Natrecor (nesiritide, BNP-32), and GlucaGen (glucagon 1-29). Even the process for manufacturing first-genera-tion Angiomax (bivalirudin) was developed initially as a combined recombinant-synthetic process.

Since 2003, three main factors have reduced man-ufacturing costs for synthetic peptide drugs:

1.Sourcing of raw materials and intermediates from China and India

2.Increased manufacturing scales from 10s to 100s or even 1,000s of kilograms

3.Location of plants in progressive, third-world countries close to sources of raw materials

Today, manufacturing of newer peptide drugs is com-pletely synthetic at very low costs per unit relative to pre-2003, and synthetics dominate the peptide mar-ket worldwide. Such drugs include Fuzeon at one metric ton per year, Angiomax at 400kgs per year, and many other peptides at 5kgs to 100kgs per year.

Sourcing of Raw Materials and Intermediates

Pre-2003, China and India were virtually unrecog-nized as suppliers of raw materials, amino acids, resins, and solvents for synthetic peptide manufac-turing. Companies sourced amino acids almost exclusively from Japanese (Ajinomoto), North American (Synthetech, ChemImpex), and European (Bachem, Senn Chemicals, Sygena) suppliers.

Today, China and India provide almost all raw mate-rials and intermediates for peptide manufacturing.

Increased Scale of Manufacturing

The dynamics of peptide manufacturing changed dramatically in 2003 when the US FDA approved the peptide drug Fuzeon (enfuvirtide) for HIV, and using the scale of one metric ton, Roche projected requirements for the API of this drug at its facility in Boulder, Colorado.

With over 100 manufacturing steps to make Fuzeon with its 36 amino acids, each 1kg of the pure peptide requires 25kgs of raw materials, even with a highly optimised manufacturing protocol.


At lower scales, fixed costs for labor, facilities, and regulatory requirements, etc and variable costs for raw materials have a cost ratio of about 50:50. At very large scales, the manufacturer can amortize the fixed costs over many more units, allowing them to fall to 20% of total cost and leaving the variable cost of raw materials to dominate at 80% of total cost.

In response to this new practice of manufacturing on a larger scale, suppliers began manufacturing raw materials, the relevant amino-acid derivatives and solvents, in multi-ton batches, which drove down costs of raw materials worldwide. After scale-up, the price for some Fmoc-protected amino-acid deriva-tives, the dominant building blocks for peptides, plummeted to 20% of pre-2003 prices.
As a result, amino acids are no longer the most expensive raw material used in peptide manufac-turing. The dominant cost has become solvent acqui-sition, use, and disposal. Newer, large-scale, peptide manufacturing plants now use solvent tank farms; closed-system, solvent-handling systems; and on-site distillation for recovery.

Location and Configuration of

Manufacturing Plants

Three practices related to the location and config-uration of manufacturing plants also have reduced costs:

•Locating manufacturing plants in progressive third-world countries, such as India and China, reduces costs for labor and facilities.

•Locating plants very near the suppliers of amino acids and solvents saves on the costs of acquisition and transportation of raw materials.

•Building a manufacturing plant to a state-of-the-art configuration, including a tank farm and distillation system, can reduce costs related to the acquisition, handling, and dis-posal of solvents by as much as 90%.

Trends in the Pharmaceutical Industry

Pfizer has said that it will outsource 30% of its man-ufacturing, much of it to Asia, to take greater advan-tage of global manufacturing and research and development [2]. For instance, Pfizer will outsource most of the manufacturing of its cholesterol medi-Copyright, CSC Publishing. Tine Lipitor® in preparation for competition from generic versions.

These plans followed Pfizer’s announcement that it would shut down its manufacturing sites in the USA— Brooklyn, New York and Omaha, Nebraska — and would sell a third manufacturing site in Feucht, Germany. These cuts, in addition to the closure of several research sites, are part of its plan to cut its workforce worldwide by 10%, or 10,000 jobs, and save $2 billion per year in costs.

Companies such as Genzyme, Unigene, and Charles River Laboratories, among many others, have announced significant new manufacturing facilities in China. Their subsidiaries in the USA will buy the majority of raw materials and interme-diates for biopharmaceutical manufacturing from Chinese suppliers.

As shown in Figure 1, a Contract Manufacturing Organization (CMO) with a new plant in a progres-sive, third-world country that sources raw materials and intermediates from Chinese and Indian suppli-ers has significant cost advantages at larger scales.
   

Conclusion

Altered sourcing of raw materials and newer manu-facturing techniques have had profound implica-tions for the cost of manufacturing synthetic pep-tides. The cost to manufacture a peptide API has plummeted with the reduction in the cost of raw materials and the conversion to very large-scale manufacturing. Today, optimized manufacturing plants can make a ton of a 36-mer peptide for less than $ 100 per gram, 500kgs of a 20-mer peptide under $100 per gram, or 100kgs of an 8-mer peptide for less than $100 per gram. At scales of 10kg and above, the trend for costs of peptides is clearly down. Several CMOs are now capable of manufacturing highly-purified, synthetic peptide APIs for $100 per gram using solid-phase chemistry and/or hybrid fragment condensation in solution at scales of 25kg to 100kg per batch. Future costs of APIs will trend below $100 per gram at larger scales.

With effective risk management on the part of CMOs, suppliers in China and India will continue to reduce costs for raw materials and intermediates, resulting in a further reduction in the price of the APIs that CMOs manufacture for their clients, espe-cially at increasing scales.

At $50 per gram, a wider variety of delivery systems for peptide APIs can be successful.

References

1. Patton, et al. The lungs as a portal of entry for systemic drug delivery. The Proceedings of the American Thoracic Society. 2004, 1:338-344.

2. Pfizer. Analyst Meeting in Hong Kong, November 30, 2007.

Jim Hampton, MS, is executive vice-president of business development and cGMP sales at AmbioPharm, Inc. He is responsible for contract man-ufacturing of synthetic peptides and small molecules to be manufactured under cGMP as generic peptide APIs and APIs for human clinical trials. Since 1995, he has developed and maintained worldwide business relation-ships with scientists in academia, government, and private industry. He has managed over 300 projects involving cGMP-grade peptides in scales from grams to kilograms in manufacturing facilities at Peninsula Laboratories, Bachem, American Peptide Company, and AmbioPharm.

 

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