Weevils floating in vials of heparin. Morphine cartridges that contain up to twice the labeled dose. Manufacturing plants with rusty tools, mold in production areas and — in one memorable case — a barrel of urine.
These recent quality lapses at big drug companies show that contamination and shoddy practices extend well beyond the loosely regulated compounding pharmacies that have attracted attention because of their link to an outbreak of meningitis.
In the last three years, six of the major manufacturers of sterile injectable drugs — which are subject to rigorous inspections by the federal government, as opposed to compounding pharmacies, which are generally overseen by the states — have been warned by the Food and Drug Administration about serious violations of manufacturing rules. Four of them have closed factories or significantly slowed production to fix the problems. Nearly a third of the industry’s manufacturing capacity is off line because of quality issues, according to a Congressional report.
The shutdowns have contributed to a shortage of critical drugs, and compounding pharmacies have stepped into the gap as medical professionals scramble for alternative sources. But several serious health scares have been traced to compounding pharmacies in recent years. Authorities said 19 people had died from meningitis in an outbreak traced to a contaminated steroid made by the New England Compounding Center in Massachusetts. Supplies of the steroid, methylprednisolone acetate, became short earlier this year after two generic manufacturers, Teva and Sandoz, stopped making it.
“In the industry, everyone knows that all of the factories are in terrible shape,” said Erin Fox, manager of the Drug Information Service at the University of Utah, which tracks drug shortages. But the public, she said, is still in the dark. “I think people think this is a foreign outsourcing problem, but these factories are in our own country.”
Regulators and manufacturers note that most sterile injectable drugs — products like chemotherapy drugs and anti-seizure drugs like diazepam — sold in the United States are safe and of high quality. Still, several industry observers and former plant employees said that the recent quality issues were troubling and that manufacturers had been reluctant to fix problems because stopping production was simply too costly in a business where profits were driven by volume. Many basic drugs sell for less than a dollar a vial and are made in batches of tens of thousands of vials, run on lines that can operate up to 24 hours at a time.
Manufacturers reject descriptions of their factories as deteriorating and say they are investing hundreds of millions of dollars to make improvements.
“When you read and or hear different people in the industry saying that these are old, dilapidated, rundown facilities — absolutely not true,” said David Gaugh, a senior vice president for the Generic Pharmaceutical Association, an industry trade group. Mr. Gaugh was previously vice president and general manager for Bedford Laboratories, a unit of the manufacturer Ben Venue. He likened some of the older, 1970s-era plants to vintage Camaros or Mustangs, noting that while some old cars are indeed falling apart, others are tended with pride.
“That’s what these facilities are,” Mr. Gaugh said. “They’re maintained muscle cars.”
The manufacturing process garnered more attention in 2009, when Dr. Margaret Hamburg took over as commissioner of the F.D.A. and pledged to get tougher on plant inspections. That year, the F.D.A. cited Teva, the large generic drug maker, for several violations at its injectable drug plant in Irvine, Calif., including that it had failed to catch bacterial contamination of propofol, the anesthesia drug, before it left the factory.
Hospira, the leading manufacturer of injectable drugs, has been a major target of quality complaints. Since 2009, federal regulators have outlined failures in quality control at its plants in North Carolina, California and Costa Rica, leading to several major recalls of products as diverse as faulty infusion pumps and overfilled morphine vials. The company has slowed production at its largest factory in Rocky Mount, N.C., which had the most extensive problems.
Hospira’s manufacturing issues became public months after the company began in 2009 a two-year initiative called Project Fuel, designed to save more than $100 million a year by, for example, shrinking the work force 10 percent.
Critics, including a group of shareholders who have filed a lawsuit against Hospira, claim that Project Fuel led to deep cuts in quality control, including the dismissal of seasoned employees and the failure to maintain equipment. In comments to investors last year, a Hospira executive acknowledged the company had gotten “a little lazy” and was “skating behind the puck.”
Stacey Eisen, a Hospira spokeswoman, said the company supported the F.D.A.’s recent focus on manufacturing quality. “We support the agency in this respect, as we, too, consider the quality of our products to be of paramount importance, and we’re working closely with the agency on all aspects of our quality efforts,” Ms. Eisen said. She said Project Fuel was not about cost-cutting but about reducing complexity across the company and improving productivity.
Late last year, Ben Venue, a division of the German drug maker Boehringer Ingelheim, shut its plant in Bedford, Ohio, after the F.D.A. visited the facility. Agency inspectors reported rusty tools, mold and a barrel of an “unknown liquid” later determined to be urine; the report did not make it clear what the barrel was doing there. Three other companies that make injectable drugs — Sandoz, Luitpold Pharmaceuticals and A.P.P. Pharmaceuticals — have also received warning letters. Earlier this year, Sandoz slowed production at a plant in Quebec to fix problems identified by the agency. All the companies said they took quality seriously and were either working with the agency to address its concerns or had already resolved the issues.
In a particularly vivid lapse, agency inspectors cited the failure to investigate a number of reported problems at A.P.P.’s plant outside of Buffalo, including complaints of human hair and fungal growth in vials.
One former supervisor at the plant said his managers were reluctant to stop the production lines. “It’s like trying to fix your car when you’re driving down the Thruway,” said the former employee, who was recently terminated and said he did not want to be identified because he feared retaliation. Managers ordered shortcuts that compromised quality, he said, and skimped on cleaning to shorten the turnaround time between batches. Afterward, centipedes and spiders were spotted in manufacturing areas, he said.
F.D.A. inspectors cited internal reports of infestations, including a spider and weevils inside vials.
Matthias Link, a spokesman for Fresenius Kabi, the German drug maker that owns A.P.P., said the company was committed to making high-quality medicines and was addressing the inspectors’ concerns. He said Fresenius Kabi had already planned to spend $38 million on improving and expanding the plant before the agency’s warning letter.
The F.D.A. says it has stepped up its efforts to work with manufacturers, hosting conferences to exchange ideas and starting a program with its European counterpart about expectations.
Many of the manufacturers are spending hundreds of millions of dollars to address the problems. Ben Venue has spent more than $300 million to upgrade its factory in Ohio and is opening a new plant that will manufacture cancer drugs. It said on Tuesday that it had resumed some production.
Hospira, whose chief executive has likened its remediation process to “draining the swamp,” expects to spend up to $375 million to address the agency’s concerns. Teva has reopened its factory in Irvine, though it has not yet resumed full production.
The investments are real, said Dr. Sandra Kweder, deputy director of the F.D.A.’s Office of New Drugs. “I would say we are encouraged,” she said. “But we also know it takes three to five years to get one of these plants up and running.”
ggw posted:There was a thread in GBS about a woman who was bit by a snake or snake and received some anti-venom from the hospital. The hospital charged her $80,000 something thousand dollars and the insurance wouldn't cover it and half of GBS was defending the hospital for charging her that much.
Yeah well that's what happened in socialism too.
Experts Aim to Redefine Healthcare and Research Ethics
Jan. 11, 2013 — In what they acknowledge as a seismic shift in the ethical foundation of medical research, practice and policy, a prominent group of interdisciplinary healthcare experts, led by bioethicists at Johns Hopkins, rejects an ethical paradigm that has guided the American system since the 1970s and calls for morally obligatory participation in a "learning healthcare system" more in step with the digital age. The group has authored a pair of articles outlining their arguments and proposal for a new ethical framework, which appear in a special report from The Hastings Center Report, along with seven commentaries from other experts responding to their ideas.
In one article, the authors reject the bright-line distinction between medical research and patient care that has been central to the ethical underpinnings of federal human subject research regulations for decades. They argue that it is increasingly difficult to distinguish clinical research from practice and the daily operations of healthcare organizations, and that widely held assumptions about how research differs ethically from practice may be incorrect. Specifically, the authors challenge the assumption that participation in clinical research by definition offers patients less potential benefits and puts them at greater overall risk than clinical practice, as well as the assumption that research imposes more irrelevant burdens on patients.
In today's healthcare system, the labels "research" and "practice" are poor proxies for what should be our central moral concerns, the authors argue, and no longer serve as an effective guideline for what requires ethical oversight. They point out, for example, that over 50 percent of medical treatments are used without sufficient proof of their effectiveness, and approximately 100,000 die annually from healthcare acquired infections.
"Far too often, doctors do their best but simply don't have the information to tell them which approaches or treatments work best, and patients are suffering for that lack of knowledge," says Nancy E. Kass, deputy director for public health at the Johns Hopkins Berman Institute of Bioethics, and lead author of the article. "We're finding that patients are both underprotected from risks in medical treatment and over-protected from low-risk quality-improvement research, bringing progress to a dangerous stalemate that is costing lives," the authors write.
Instead, the authors say that healthcare should be moving toward a system in which clinical research and clinical practice are integrated, and every clinical encounter is simultaneously an opportunity to provide needed care to patients and also to learn from that to improve the care provided to future patients.
In their second article, the authors put forward a new ethical framework for the integration of research with practice in what the Institute of Medicine calls a learning healthcare system. The framework includes seven obligations, six of which fall on health professionals and institutions, and the 7th on patients:
Respect the rights and dignity of patients
Respect the clinical judgment of clinicians
Provide optimal care to each patient
Avoid imposing nonclinical risks and burdens on patients
Address health inequalities among populations
Conduct continuous learning activities that improve the quality of clinical care and health care systems
Contribute to the common purpose of improving the quality and value of clinical care and health care systems
The framework includes familiar tenets of both medical and research ethics, but also new obligations that the authors acknowledge "substantially revise traditional conceptions" of the roles played by health systems, providers and patients. "In addition to long-standing ethical obligations to ensure that burdens and benefits of research are fairly distributed and that patients are appropriately respected, our ethical framework directs research towards aggressive efforts to reduce or eliminate unfair inequalities in health outcomes and in the evidence base for clinical decision-making," notes Ruth R. Faden, director of the Johns Hopkins Berman Institute of Bioethics and lead author of the article outlining the framework. Among the examples of unfair inequalities the authors say should be addressed by obligation five is the scarcity of evidence for managing chronic illness in pregnant women, as compared to other adults with the same conditions. Women, and their children, would be well-served by a healthcare system that continually learns from patient care.
"The framework also challenges previous thinking in research and clinical ethics by calling for an ethical obligation on the part of clinicians, administrators, payors and purchasers to conduct research to improve health care quality and value, and on patients to contribute to such research," says Faden. The authors write, "Just as health professionals and organizations have an obligation to learn, patients have an obligation to contribute to, participate in, and otherwise facilitate learning," that will improve the quality of the healthcare system.
The authors emphasize, however, that this is not a blanket obligation, regardless of risk. Some kinds of medical research, such as early testing of drugs still unapproved by the Food and Drug Administration, are not included and should always proceed only with the express, voluntary informed consent of the patient, they say. The patient obligation is focused on research that poses no additional risk beyond what patients face in clinical care, and would also exclude research that compares different types of treatments, for example, surgery to medical management. The authors add that the framework also includes obligations to avoid imposing nonclinical risks and burdens on patients, and to protect their rights and interests.
Extraordinary opportunities for learning are lost in our current system, the authors say, because physicians and researchers face significant hurdles in capturing the rich information generated from thousands of daily medical encounters with patients due to overly burdensome oversight and consent rules. The new framework is intended to help reduce these hurdles.
The authors write that they expect their articles will spark debate, and hope they will move the transformation to a learning healthcare system forward, both in its ethical underpinnings and in practice. They write, "We claim no more than a start on a subject that merits extensive investigation, and we welcome suggestions and commentary moving forward…We are in the early days of a progressive realization of a lofty aspirational goal, but given the preventable harm, waste, and uncertainty about clinical effectiveness in health care, efforts to accelerate learning should be given high priority."
e: 
Edited by jeffery ()
jeffery posted:e:
as uh, you can uh, see on the chart on this slide, the uh, prevalence of chuck d and flavor flav has continued to accelerate throughout the lower 48... even despite regulatory action to disapprove of these NMEs...
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Bisphenol S Disrupts Estradiol-Induced Nongenomic Signaling in a Rat Pituitary Cell Line: Effects on Cell Functions
January 17, 2013 Advance Publications Comments Off
René Viñas and Cheryl S. Watson
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch Galveston, Texas, USA
Advance Publication
Abstract
Background: Bisphenol A (BPA) is a well-known endocrine disruptor that imperfectly mimics the effects of physiologic estrogens via membrane-bound estrogen receptors (mERα, mERβ, GPER/GPR30), thereby initiating non-genomic signaling. Bisphenol S (BPS) is an alternative to BPA in plastic consumer products and thermal paper.
Objective: To characterize the non-genomic activities of BPS, we examined signaling pathways it evoked in GH3/B6/F10 rat pituitary cells, alone and together with the physiologic estrogen estradiol (E2). Extracellular signal-regulated kinase (ERK)- and c-Jun-N-terminal kinase (JNK)-specific phosphorylations were examined for their correlation to three functional responses – proliferation, caspase activation, and prolactin (PRL) release.
Methods: We detected ERK and JNK phosphorylations by fixed-cell immunoassays, identified the predominant mER initiating the signaling with selective inhibitors, estimated cell numbers by crystal violet assays, measured caspase activity by cleavage of fluorescent caspase substrates, and measured PRL release by radioimmunoassay.
Results: BPS phospho-activated ERK within 2.5 min, in a non-monotonic dose-dependent manner (10-15-10-7M). When combined with 10-9M E2, the physiologic estrogen’s ERK response was attenuated. BPS could not activate JNK, but greatly enhanced E2-induced JNK activity. BPS caused cell proliferation at low concentrations (fM to nM), similar to E2. Combinations of both estrogens reduced cell numbers below the vehicle control, and activated caspases. Earlier activation of caspase 8 vs. 9 demonstrated that BPS initiates apoptosis via the extrinsic pathway, consistent with activation via a membrane receptor. BPS also inhibited rapid (≤1 min) E2-induced PRL release.
Conclusion: BPS, once considered a safe BPA substitute, disrupts membrane-initiated E2-induced cell signaling, leading to altered cell proliferation, cell death, and PRL release.
