快樂小藥師 Im pharmacist nichts glücklich

我覺得這個問題遲早會在台灣出現，看看吧（圖我就不附了）

nejm Volume 361:1525-1527

Robert Steinbrook, M.D. 

Because the public discussion of drugs is dominated by considerations of their safety, effectiveness, and cost, it is easy to forget that medications have to be manufactured from raw materials before they can be prescribed. The continuing shortages of two medications for enzyme-deficiency disorders and of technetium-99m, the radioactive isotope most commonly used in cardiac studies, bone scans, and other diagnostic procedures in nuclear medicine, provide a salient reminder that adequate drug supplies cannot be taken for granted.

The viral contamination of a Genzyme manufacturing plant in Massachusetts, detected in June 2009, caused an unexpected shortage of imiglucerase (Cerezyme), for Gaucher's disease, and agalsidase beta (Fabrazyme), for Fabry's disease. The virus, vesivirus 2117, interfered with the growth of Chinese-hamster-ovary cells, which are used to produce biologic drugs. This problem led to a decline in productivity this year and to two similar instances in 2008, one at the Massachusetts plant and the other at a Genzyme facility in Belgium. The virus has not been shown to cause infection in humans.

Genzyme has managed the shortage of these very expensive drugs by using existing inventories and developing dose-conservation measures. The availability of imiglucerase has had to be limited to children and the most severely affected adults; the company is reviewing other requests through an emergency-access program. For patients with Gaucher's disease, the Food and Drug Administration (FDA) has also expanded access under "treatment protocols" to investigational medications from other manufacturers — velaglucerase alfa, from Shire Human Genetic Therapies, and prGCD, a plant-cell–expressed recombinant glucocerebrosidase enzyme, from Protalix Biotherapeutics. After the Massachusetts plant was decontaminated and additional viral monitoring procedures were implemented, manufacturing of imiglucerase and agalsidase resumed; Genzyme expects to ship drugs from the new production runs in November and December, and the shortages should be resolved thereafter.

Unlike the Genzyme situation, the global shortage of technetium-99m was predictable and will be prolonged. Technetium-99m is generated from molybdenum-99 (see diagram). Almost all molybdenum-99 is produced from highly enriched uranium (concentrations of 20% or more of uranium-235 by weight), and its production depends on nuclear reactors that are old and of doubtful reliability. In recent years, various reactors have been shut down unexpectedly for extended periods. The United States is the primary supplier of highly enriched uranium to these reactors and consumes the majority of the world's supply of molybdenum-99; however, none of the isotope is produced in this country for medical use.

The irradiation of uranium-235 with neutrons produces fission fragments containing molybdenum-99 and other medical isotopes, such as iodine-131 and xenon-133. After the molybdenum is separated from the isotope mixture through chemical processing, it is adsorbed onto alumina columns, which are placed in radiation-shielded cylinders known as technetium generators. The generators are then rapidly shipped to nuclear pharmacies — the pharmacies that prepare and deliver radioactive drugs. The molybdenum decays, with a half-life of about 66 hours, into technetium-99m, which has a half-life of about 6 hours. Technetium-99m emits gamma rays that can be efficiently detected during imaging procedures, and decays into technetium-99, the most common form of the element; it has a half-life of 211,000 years, and thus is essentially nonradioactive. A generator can be eluted to obtain technetium-99m several times a day for a week or more before it needs to be replaced with a fresh generator. After technetium-99m is recovered, it is used to make radiopharmaceuticals for diagnostic imaging.

The current shortage involves two reactors that produce about two thirds of the global supply of molybdenum — the National Research Universal reactor in Chalk River, Ontario, Canada, which opened in 1957, and the High Flux Reactor in Petten, the Netherlands, which dates from 1962. For unrelated reasons, they were both shut down this year — the Canadian reactor in May, after a leak of water contaminated with tritium, a radioactive isotope of hydrogen, was found, and the Dutch reactor in July, for scheduled maintenance.

The shortage is being managed in many ways, including postponement or cancellation of procedures, more efficient distribution of technetium generators by suppliers, more frequent elution of older generators, sharing among facilities, dose adjustments, and the scheduling of imaging procedures on nights and weekends to maximize the use of available isotope. In some instances, other agents can be used, such as thallium-201 for cardiac scanning and fluorine-18 for positron-emission tomographic bone scanning, provided that insurers agree to pay for such bone scans on a temporary basis. In a survey conducted in August 2009 by SNM, a professional organization of nuclear medicine specialists, and the National Association of Nuclear Pharmacies, 60% of the 97 pharmacies that responded reported being affected by the shortage; many had been able to fill less than half the prescriptions they received for technetium-99m–labeled radiopharmaceuticals.

The supply of technetium-99m will probably be problematic until newer reactors become operational and scale up production. There are three major reactors in Europe, one in Canada, and one in South Africa; all are at least 42 years old. The Dutch reactor returned to service in August 2009 but is expected to close in early 2010 for 22 to 26 weeks for repair of the primary cooling water pipes. With the Canadian reactor not expected to return to service until sometime in the first quarter of 2010, another overlap in the reactors' downtime is probable early next year — and the long-term prospects for both facilities are uncertain. Of course, the shortage could have beneficial effects if it leads to more appropriate use of medical-imaging procedures.² Technetium-99m–labeled radiopharmaceuticals, particularly those used in myocardial-perfusion imaging, are important sources of exposure to ionizing radiation, and imaging procedures can contribute to high cumulative doses of radiation.³

The technetium shortage is further complicated by the ongoing controversy about the use of highly enriched uranium in the production of medical isotopes and other nonmilitary applications.¹ Highly enriched uranium is a weapons-grade material that could be diverted for nuclear terrorism. Molybdenum-99 can be made with low-enriched uranium (with a concentration of uranium-235 of <20%), which is much more difficult to make into a weapon; already, some is made that way at newer facilities in Argentina and Australia. It will take years, however, for these facilities and others that are under development to become major suppliers or for other production techniques to emerge. Legislation pending in Congress (H.R. 3276) would promote the use of low-enriched uranium for the production of molybdenum-99 for medical uses, both in the United States and globally.

At least some medication shortages are inevitable. In late September 2009, the drug shortage page on the FDA Web site (www.fda.gov/Drugs/DrugSafety/DrugShortages/default.htm) listed 15 drugs that were in short supply. The reasons included manufacturing delays; increases in the demand seen by manufacturers, sometimes because another manufacturer had left the market; recalls; and shortages of materials. The FDA noted that over the past decade, the number of shortages has increased, for reasons ranging from manufacturing problems, business decisions to stop making certain drugs, continued manufacturing of a product by only one or two companies, and limited manufacturing capacity resulting in delays in the production of one drug while another is made on the same equipment. For example, when the contamination of imiglucerase and agalsidase beta was detected, Genzyme said that it had been operating with lower than usual inventories, having allocated manufacturing capacity at the Massachusetts plant to another enzyme-replacement therapy, alglucosidase alfa, pending regulatory approval to make it at a different facility.

Recent drug shortages should prompt public health officials, industry, and governments to anticipate and prepare for the shortages that seem the most likely and that would have the greatest medical consequences. Contingency plans should be more likely to work than responses improvised after a crisis develops. Providing alternative sources of medications can be inconvenient and expensive and is not always possible. Fortunately, most solutions are faster and less costly than bringing new nuclear reactors online.