Citing interviews with stakeholders, GAO recommended creating an information clearinghouse, through which companies could share information anonymously on adulterated ingredients with FDA and other companies. A clearinghouse could help FDA disseminate information about adulterated products quickly and enable the agency and industry to respond to adulteration rapidly. If the clearinghouse were managed by a neutral third party, it could ensure that the information did not identify specific companies.

This strategy could help allay industry’s concerns about sharing information when an adulterated ingredient has not entered into commerce. Companies are afraid that they may be sued if they reported that a supplier intentionally adulterated a product and the accusation is later found to be baseless. A wrongful accusation “can have serious consequences, such as compromising the integrity of the company’s brands and products if certain information became public,” according to the report.

Because potential adulterants often are unknown or unidentified, it can be hard for FDA to detect them. “For example, during the heparin incident, the available test methods for heparin were not able to detect the contaminant oversulfated chondroitin sulfate,” said the report. “Industry may be the best source of tests to detect adulteration because companies develop such tests to monitor the products they receive from their suppliers; however, industry officials indicated that they are often reluctant to share such information because it is proprietary.”

By eliminating details that could identify specific pharmaceutical companies, an information clearinghouse could allay industry’s concerns, help FDA dedicate its resources efficiently in the event of potential adulteration, and protect citizens from ingesting harmful drugs. It sounds like a win for all involved. GAO has done us a service in writing this report, and I hope FDA takes its recommendations seriously.

“It is sad to realize that we live in a world in which some criminals are willing to maximize profits by placing poisons in products like infant formula, toothpaste and medically necessary drugs. But it is a reality we must face. And, more importantly, it is a reality that we must become more proactive in dealing with,” Hamburg said.

Hamburg gave several examples of high-profile cases of the harm that fake and adulterated drugs can cause, including the deaths of children in Haiti, Panama, and Nigeria, due to cough syrup and teething medication poisoned with diethylene glycol; the injury and deaths caused by adulterated heparin in 2008; and adverse reports of ineffective insulin, which is believed to have lost its potency after it had been stolen months before and most likely had not been handled properly.

FDA used lessons learned from the heparin crisis to develop a risk-based approach for identifying drugs and active pharmaceutical ingredients that could be targeted for adulteration. Hamburg explained:

“To date, the FDA has systematically ranked more than 1000 active pharmaceutical ingredients in order of their respective risk of economically-motivated adulteration, based on a multifactorial risk-based model that we developed. A subset of these high-risk ingredients is targeted for additional sampling and testing at the border. In addition, FDA is working to reduce the risk that counterfeit or adulterated drug products reach consumers in the US market by developing standards for track-and-trace systems that enable the identification of these products and facilitate efforts to recall them.”

Hamburg said that in addition to new anticounterfeiting technologies such as track-and-trace and authentication systems, more regulatory authority is needed by the agency to help keep counterfeit drugs out of the supply chain. “It is clear that FDA needs new regulatory tools that provide the authority we need to meet the challenges we face in today’s increasing globalized marketplace,” she said. “And we look forward to working with Congress on legislation that will give FDA the ability to protect Americans from harmful drugs and medical products—and fulfill our fundamental public health mission.”

More than a hundred governmental and industry stakeholders attended PSM’s inaugural event to discuss solutions to fight counterfeit and adulterated medicines. The Generic Pharmaceutical Association recently became a member of PSM, joining organizations such as the Biotechnology Industry Organization, European Federation of Pharmaceutical Industries and Associations, National Association of Boards of Pharmacy, Pharmaceutical Research and Manufacturers of America, and World Health Organization in the global effort to eradicate unsafe drugs.

Hamburg’s remarks can be viewed on C-SPAN’s video library.

For further reading, see PharmTech’s recent special report on anticounterfeiting technology, “Authentication and Pharmaceutical Protection: An Industry Roundtable.”

Earlier this month, Commissioner Margaret Hamburg announced six steps to improve the timeliness of FDA’s enforcement actions. These steps (e.g., setting postinspection deadlines, prioritizing follow-up on Warning Letters, and taking action in response to public-health risks) seem so commonsensical that I wonder why they had not been taken before.

Evidently recognizing the importance of international facilities, FDA plans to double its foreign inspections for good manufacturing practice this year. The agency has established many offices around the world and plans to establish a Middle East location this fall. It also intends to staff its office in Mexico City by Nov. 1, 2009.

Sometimes the agency inspects the wrong facility because it has faulty information, but FDA is now drafting a direct final rule that would require more manufacturing-site information on drug-product applications, according to Drug Industry Daily. The rule could reduce the number of unnecessary inspections and prevent inspectors from barking up the wrong tree.

I’m heartened by these measures. This flurry of activity tells me that FDA is trying to identify the flaws in its procedures and come up with appropriate solutions. Reinforcing its international offices, requiring accurate information, and moving quickly are critical to reducing our exposure to potentially hazardous products. I’ll give Commissioner Hamburg credit for these efforts and hope that they meet with success.

Using digital microfluidics, recombinant enzyme technology, and magnetic nanoparticles, Robert Lindhardt and his team at RPI created a functional prototype of an artificial Golgi organelle, which the researchers say it is the first time an artificial Golgi apparatus has been developed, according to a RPI press release. The Golgi apparatus (also just referred to as Golgi) is named after the Italian physician Camillo Golgi, who first identified it in the late 1890s. The Golgi is an organelle, similar to miniature organ in a cell, made of a network of sacs piled together into a stack. Within the natural Golgi, biomolelcules are modified posttranslationally, by undergoing glycosylation, for example, and can then be packaged for both intra-and extra- cellular distribution. Understanding how the Golgi works provides insight into how it modifies biomolecules as well as the molecule’s resulting structure and function.

The researchers’ artificial Golgi is a small microfluidics chip that simulates some of the actions of the natural Golgi’s activities, including the enzymatic modification of glycosaminoglycans. Using an inactive precursor of heparin, the researchers found that the artificial Golgi could efficiently modify the material to make it functional and suggest that an artificial Golgi could lead to a faster and safer method for producing heparin. Their work is detailed in a recent article in the Journal of the American Chemical Society (1). A recent Scientific American article further reported that Lindhart and his team hope to create a synthetic endoplasmic reticulum (ER) , the organelle in which ribosomes are located and where protein synthesis and folding takes place, and will explore the potential of integrating an artificial Golgi with the ER.

Building our understanding and broadening the availability of the “tools of the trade” in biopharmaceutical development is an important mission, and let’s hope that such efforts continue.

References

1. R.J. Lindhart et al., “Toward an Artificial Golgi: Redesigning the Biological Activities of Heparan Sulfate on a Digital Microfluid Chip,” J. Am. Chem. Soc. 131 (31), 11011-11048 (2009).

Last Thursday, the agency opened offices in New Delhi and Mumbai, India. The offices are staffed with technical experts who will work with Indian government and industry officials to develop certification programs for medical products exported to the US. The staff also includes inspectors who will check facilities that manufacture products for the US market. Last fall, FDA opened similar offices in three locations in China.

And last Wednesday, the agency launched a pilot program to determine the feasibility of setting up a supply-chain monitoring network. FDA is asking qualified drugmakers to volunteer supply-chain information for drugs and APIs sourced outside the US. Companies will need to demonstrate control of drugs from the time of manufacture to the time they enter the US.

I think these measures are sorely needed. I’m happy to see FDA take meaningful steps toward securing the supply chain. Offices in major drug-producing countries will help the agency promote good manufacturing practices and perform inspections. The pilot program could lay the basis for a valuable infrastructure to ensure the safety of drug imports. I applaud the agency’s initiative. Here’s to its success.

Barton asked GAO to review FDA’s handling of the contaminated-heparin problems of 2007 and 2008. In his letter, he notes that FDA’s statements to the media in July 2008 indicate that the agency had “conclusively linked” deaths of three patients infused with heparin to oversulfated chondroitin sulfate found in specific lots of the drug manufactured by Baxter Healthcare (Deerfield, IL). Yet when Barton requested information, the agency told him in October 2008 that it was merely “possible” that heparin caused two of the deaths and that it could not assess whether heparin caused the third death.

Baxter’s own investigation concluded that it was unlikely that heparin had caused any of the three deaths. But FDA did not interview Baxter to get more information about the deaths, according to Barton’s letter.

Which way is up? Are we to believe FDA’s public statements or those the agency made to Barton? Why didn’t FDA seek more information from Baxter? Without clear and consistent statements from FDA, we can’t be sure how to use drugs safely.

“Heparin was a wakeup call,” demonstrating that we “need vigilance throughout the supply chain,” she explained. Woodcock added that solving these issues is “going to take a lot of harmonization” given the challenges present. These challenges, she said, include: an explosion of global manufacturing, increased complexity of the supply chain, greater potential for exploitation, a global regulatory system that is still fragmented, US erosion of inspectional coverage, and a lack of modern IT systems.

We all know that FDA’s resources are slim in comparison to the demands placed upon the agency. Even though FDA continues to increase the number of inspections it carries out each year, its global coverage is on the decline because of the number of new sites entering the market. Therefore, every part of industry must hold up to its own responsibilities in this growing supply chain in order to create a “worldwide safety net,” said Woodcock.

Manufacturers, for example, must take responsibility for pharmaceutical quality of their products and for the integrity of their own supply chains. Regulators must adopt standards that ensure a safety net and take actions against poor quality, while enabling continuous improvement. Standards and technical organizations need to reach consensus on technical standards. Professional and technical societies must develop and update standards and disseminate them to industry via educational opportunities.

Woodcock said FDA is trying to do its part by continuing with the Pharmaceutical Quality for the 21^st Century initiative, intensifying its international outreach with programs such as Beyond our Borders, and by keeping track of inventory of manufacturing establishments and movement of product. More efforts may crystallize after the upcoming presidential election, alluded Woodcock, such as the FDA Globalization Act and other legislation currently circulating within Congress.

Plenary speakers representing Shanghai’s FDA and the EMEA had similar messages for the PDA/FDA audience. Both Tang Minhao, deputy director of the Shanghai Municipal Food and Drug Administration, and Emer Cooke, head of EMEA’s inspections sector, presented action plans that include broader international reach and greater collaboration with other regulatory bodies. Minhao pointed out that although China is not quite at the “peak” of the mountain for regulatory standards, it is en route and plans to meet the US at the top soon. He said China is doing this by creating more transparency, more effective administrative resources, and additional harmonization concepts.

With the US, European, and Chinese authorities all seemingly on the same page at today’s plenary session, industry should feel a sense of optimism as harmonization efforts continue. But only time will tell how effective harmonization efforts will be—hard work and commitment to implementation (and change) will be required amongst all parties.

At the American Chemical Society national conference, scientists from Rensselaer Polytechnic Institute and the University of North Carolina reported they had created the first fully synthetic heparin and had created it at the milligram-dose level, which is the largest dose of heparin ever created in a lab. The project actually began two years ago, but the contamination incident helped foster awareness with the problems associated with traditional methods. As a synthetic, the drug has a higher level of purity than animal-sourced heparin and because the synthetic “backbone” comes from the familiar E. coli bacteria, manufacturers can produce it under controlled processing conditions. The team hopes to go to human clinical trials within 5 years.

Other researchers are looking at developing drugs that perform the same function as heparin but may be safer to produce. Researchers at Afid Therapeutics (Lansing, MI) said they had successfully demonstrated in vitro and in vivo efficacy of a “traceless” anticoagulant that reportedly mimics heparin. The drug produces only carbohydrates and amino acids upon degradation in the blood. Although no other details regarding the mechanisms of the anticoagulant are available, the important toxicity studies revealed that the viability of the mammalian cells did not change.

These are only two of several efforts undertaken to ensure safe production of heparin or heparin alternatives while fulfilling global demand. If you read or hear about others, be sure to let us know.

Late last month Brown sent a letter to Merck’s President and CEO Richard T. Clark requesting information on the company’s outsourcing practices, including the amount of outsourcing the company does, from what countries, and the mechanisms for ensuring the chain of custody in its supply chain. Brown also had requested information on Pfizer’s outsourcing practices in June following testimony by Pfizer officials in April before the HELP committee. The committee held hearings to evaluate FDA’s inspection process following the well-publicized incident of contaminated heparin from a Chinese supplier.

The heparin incident was a wake-up call because it revealed unforeseen vulnerabilities in a pharmaceutical company’s supply chain. What it wasn’t and should not be is an invitation to blanket criticism of outsourcing.

Outsourcing is a well-established practice within the pharmaceutical industry. The sponsor or pharmaceutical company is responsible for ensuring the quality of its materials, whether produced internally or sourced externally, a situation not only required by regulation but also dictated by sound business practices for both the pharmaceutical company and its suppliers. This situation is not new.

It is also true that during the past several years, major pharmaceutical companies, including Pfizer and Merck, have been more vocal about how outsourcing fits into their strategies by publicly stating plans to increase their levels of outsourcing as part of cost-savings and resource-allocation efforts through supply-chain optimization and rationalization of internal manufacturing facilities.

What is important now is that the current debate on drug-import safety not be reduced to a debate on outsourcing. Outsourcing, whether done in the pharmaceutical industry or in other industries, is a hot-button political issue, particularly when it involves offshore suppliers. It evokes opposing views of free-trade versus protectionism and the resulting implications that those decisions may have on local economies.

Let’s keep the discussion to what it should be—a thoughtful examination on how to improve drug-import safety, including the inspection process of foreign drug-manufacturing facilities, and what, if any, specialized considerations need to be taken in monitoring the pharmaceutical supply chain.

According to Woodcock, analysts observe that pharmaceutical companies buy outsourced ingredients to take advantage of “lower, less stringent standards in some parts of the world.” But doesn’t FDA exist to ensure that there is no such advantage to be taken? Even if other countries have lower safety standards, FDA is supposed to be a firewall to protect patients from unsafe products.

In a letter to Woodcock, Brown took the next logical step: he asked her to estimate the volume of ingredients sourced from countries with weak safety standards, to estimate the cost of protecting the public from potentially contaminated ingredients, and to name the tools FDA needs to hold drugmakers accountable.

Brown also put industry, in the person of Gerald Migliaccio, Pfizer’s vice-president of quality, in the hot seat. Migliaccio said cost savings was a major reason that pharmaceutical companies outsource ingredients and processes. In a letter to Migliaccio, Brown asked how much Pfizer saved each year by outsourcing.

In theory, Pfizer would pass its savings along to consumers, but Brown dryly noted, “There is no evidence that outsourcing is translating into any savings for patients in the US.” On the contrary, Americans pay higher prices than anyone else for prescription drugs, Brown said. On top of that, America must spend extra money to mitigate the risk posed by ingredients produced in countries with weak safety regimes.

Brown’s questions raise the point that outsourcing should benefit patients as well as industry. It’s fine for industry to profit from outsourcing if it brings efficiency and savings. But advantages for industry should not come at patients’ expense. Brown’s investigations won’t necessarily have major results, but I’m glad to see a legislator taking his responsibilities seriously and using his power to exercise oversight for the public good.