Last Thursday, FDA issued an interim final rule requiring manufacturers that are the only producer of certain drug products to report all manufacturing interruptions to the agency. Early notification will help FDA work with drug manufacturers and doctors to make sure that patients have access to life-supporting products. The interim rule was spurred by President Obama’s Oct. 31, 2011, executive order, which directed FDA to reduce and prevent drug shortages.

But the agency is not relying on just one tactic. In addition to the interim final rule, FDA is developing a tracking database to monitor drug shortages. The database will record the numbers of shortages, the reasons for shortages, and what steps FDA is taking to address and prevent them. The database is a high priority for the agency, which hopes to complete it in 2012.

Also, several observers have expressed concern that unscrupulous organizations could attempt to reap large profits from drug shortages. In response, FDA has begun analyzing reports about drug stockpiling and exorbitant pricing. The agency plans to provide the Department of Justice with information about these reported activities, and the Department will determine whether they are consistent with the law. This issue is on Congress’s radar, too: Senator Charles E. Schumer (D-NY) recently introduced a bill to make price gouging on scarce drugs a federal crime.

As any supply-chain professional knows, having one source of a crucial item is far from an ideal situation. If a drug is crucial but not profitable, we may not see new sources spring up to provide additional supply-chain security. But FDA’s initiatives promise to ease the threat of drug shortages and reduce patients’ suffering.

If you missed yesterday’s blog, the winner of the Innovation Awards was Glycotope for its GlycoExpress platform technology, which optimised glycosylation of antibodies and other biotherapeutics. The award was received by a very proud and happy Jens Pohl, managing director on Oct. 25, 2011.

In other news, UBM Live announced its plans for ICSE USA, which will debut at the Pennsylvania Convention Centre in Philadelphia and run from May 22-23, 2012. Apparently, 60.2 % of ICSE Europe visitors indicated that North America is the main target for business development, and ICSE USA seeks to address this trend. “ICSE USA’s introduction, in conjunction with Pharmapack North America, EAST Pack and MD&M is a win-win across the board. The combined events offer a platform for US companies that are working to address the upcoming blockbuster drugs [patent] expirations to connect with global business contacts and partner with and vice versa,” said Haf Cennyd, brand director of ICSE in UBM’s Show Daily magazine.

RX-360 in 2012

In a press conference Oct. 25, Guy Villax, board member of the RX-360 Consortium and CEO of Hovione, Portugal, was pleased to discuss the recent activities of RX-360 and the positive feedback received from medicines agencies. RX-360 brings together industry and regulators to address the issues of counterfeits and other interruptions to the supply chain, ultimately to protect the safety of patients. Villas was keen to note that RX-360 is a transversal trade organisation that is open to everyone, referring to membership trends in waves, the first being pioneers, the second a flood of suppliers, and the suspected third wave a deluge of generics companies. With current membership at 70 organisations globally, RX-360 has been working closely with regulatory authorities, including the FDA, EMA and WHO, and seems to have won positive feedback from everyone with hopes to expand further afield; Brazil is a target for 2012.

Giving examples of potentially adulterated acetonitrile and the effects of the tsunami and subsequent radiation leaks in Japan earlier this year, one of RX-360’s aims is to provide early identification of issues followed by rapid response, disseminating information through the website and social media channels at virtually no cost.

RX-360 has recently concluded its Audit Pilot, which aims to improve efficiency in the system through two routes. Sharing of redacted supplier audits through a secure database is the first, with joint audits offering further opportunities; sponsor companies can plan ahead through RX-360 and request joint audits to be conducted by a vetted third party auditor. The audit campaign will be rolled in 2012, and is particularly relevant as the Falsified Medicines Directive (FMD) will make it mandatory to conduct audits of all API suppliers every three years.

EXCiPACT – International Pharmaceutical Excipients Certification

RX-360 also sets standards of quality and offers best practice examples, providing summaries of proposed, draft and enacted legislation. Notably, RX-360 has adopted the EXCiPACT standard for excipients, another NPO initiative whose representative, Folker Ruschatz, BASF Pharma presented at a press conference organised by the European Fine Chemicals Group (EFCG). Ruschatz, an EFCG board member, stressed that excipients need to be as closely monitored as APIs in the supply chain, and will also be impacted by the FMD. One of EXCiPACT main objectives is to make risk assessments easier, requesting an increase in periodical, physical audits whilst also reducing the economic burden. Ensuring that cGMP and cGDP standards are set for today and the future, the last year has seen EXCiPACT raising funds with plans to establish an advisory board and begin operations on Jan. 25, 2012. Once again, feedback has been very positive from regulatory bodies, and I hope to be able to report progress at PharmTech.com.

Finally, Guy Villax graced the stage for a second time on behalf of EFCG, this time to talk about the FDA’s proposed Generic Drug User Fee Act (GDUFA, seemingly pronounced ger-doo-fer), which seeks to raise funds of $299 million for FDA “to allow the FDA to do their job on a global scale.” This means, from the Vilax’ point of view, that FDA will be able to accelerate the approval process, promote faster access to lower-cost, higher-quality medicines, and level the playing field―all major steps forward for generics. Watch this space for news and upcoming information.

Thank you for reading, and see you in Madrid in 2012!

After their daughter suffered seizures following the administration of a diphtheria–pertussis–tetanus vaccine, Russell and Robalee Bruesewitz went before the “Vaccine Court” that Congress established in 1986 to adjudicate such claims. The tribunal, which has decided against two out of every three plaintiffs, found that the Bruesewitzes had failed to prove that the vaccine had harmed their daughter.

Seeking compensation, the family filed a product-liability lawsuit. Their lawyer argued that Wyeth-Lederle, the vaccine’s manufacturer, had the technology to produce a less reactive, purified pertussis vaccine, but declined to do so. The case was moved to federal court at the company’s request, and a series of judges ruled that federal law prohibited the case from proceeding.

The case hinged on the 1986 law that created the Vaccine Court. It states that vaccine manufacturers cannot be held liable for damages arising from a vaccine-related injury or death “if the injury or death resulted from side effects that were unavoidable even though the vaccine was properly prepared and was accompanied by proper directions and warnings.”

The Court’s decision sets out an interpretation of this language, which Justice Ginsburg found confusing. “If a manufacturer could be held liable for failure to use a different design, the word ‘unavoidable’ would do no work,” wrote Justice Scalia in the Court’s opinion.

But Justice Sotomayor’s interpretation of the clause was exactly the opposite of Scalia’s, showing that the confusion has not been dispelled. The “text, structure, and legislative history compel the conclusion that Congress intended to leave the courthouse doors open for children who have suffered severe injuries from defectively designed vaccines,” she wrote in her dissent.

The Court’s decision means that patients can only seek redress from the Vaccine Court, and not through civil lawsuits. Since the Vaccine Court’s compensation fund comes from an excise tax on vaccines, drug companies will not have to pay any damages resulting from claims of harmful vaccines. The Supreme Court’s decision protects manufacturers from having to pay ruinous amounts in damages, but making patients pay compensation when drugmakers’ products cause harm strikes me as distinctly unfair. I think we need legislation that restores patients’ rights to seek damages, re-establishes accountability for drugmakers, and helps ensure an adequate supply of vaccines for the country.

Half of the respondents said the biggest area of risk is raw materials sourced outside of the US. Sixty-one percent said contaminated or nonconforming raw materials was the top threat in the next five years.

Drug counterfeiting and diversion were seen by executives as major threats to their global supply chains in the next five years, with 44% and 35% of respondents, respectively, citing them as risks. Forty percent of all respondents that produce life science products reported that their company’s products have been counterfeited or illegally diverted. The report says that these threats were “virtually non-existent” as little as 10 years ago, which underscores the rapid growth of the problem of counterfeit drugs.

The growth of globalization presents challenges to industry that the report grouped into three broad categories: on-demand visibility, control over the supply network, and the need for collaboration.

In terms of visibility of their supply chains, 77% of executives said that their primary means of gaining visibility into suppliers’ practices is a periodic audit, 25% said they share common practices and 3% have access to real-time data. The report states that the lack of on-demand visibility is due to the slow speed of gathering information about a company’s supply chain. Regarding the ability to merge data from multiple locations to provide a global view of the supply chain, 66% said they could do it, but they must manually aggregate the data; 15% said that it was not possible; and only 19% said they could do it in real time.

When asked about track-and-trace and serialization technologies, which can help industry gain control over the supply chain, survey respondents said the hurdles to implementing such technology are cost; difficulty of implementation; lack of industry standards; and lack of regulatory requirements and guidance. In terms of specific technologies in use or planned by the executives, 79% said their company uses barcodes, 57% use 2D barcodes, 34% use RFID, 17% use GPS tags, and 8% use none of these measures. Most executives said they could track manufacturing location (84%) and genealogy such as raw material, ingredient, etc., (73%), but 50% or less were able to track elements such as transaction history, chain of custody, record of ownership, environmental storage conditions, and ePedigree.

Industry executives identified the need for collaboration, and said their preferred method for creating best practices around standards is through industry consortium such as the Pharmaceutical Supply Chain Initiative, the Experimental Physics and Industrial Control System, and the Rx-360 consortium.

According to a press release by Bennet’s office, the bill would strengthen manufacturing quality standards, enhance the US Food and Drug Administration’s ability to track foreign manufacturing sites, and increase the authority of FDA to make drug product recalls. In his release, Bennet noted that there were 1742 drug recalls in 2009, a record amount, and a 400% increase from 2008. The release also indicated that most of the recalls were related to manufacturing quality and testing.

The bill would provide better tools to investigate threats to drug quality and safety, such as by granting FDA the authority to assess civil penalties for violations of the Food, Drug and Cosmetic Act and to subpoena documents and witnesses. The bill also specifies measures for facilitating exchange of information between FDA and other regulatory agencies and protecting industry whistleblowers that wish to bring information to FDA.

To boost manufacturing standards, the bill would require companies to institute quality-management plans to ensure the quality and safety of their drugs and drug components, including strong supplier oversight, as well as increase documentation in the manufacturing supply chain for drugs. The bill would also provide new oversight of over-the-counter (OTC) drugs by not having OTC drugs assigned to a lower-risk category for site inspection because of their status. To improve tracking and risk-assessment tools, the bill would require FDA to establish accurate, interoperable information systems to track all plants making drugs and active pharmaceutical ingredients (APIs) for the US.

The legislation is supported by industry groups. The Society for Chemical Manufacturers and Affiliates (SOCMA), the US trade association representing custom and batch manufacturers, including contract manufacturers of APIs and pharmaceutical intermediates, and the Bulk Pharmaceuticals Task Force (BPTF), an affiliate of SOCMA, support the measure. “SOCMA and BPTF thank Senator Bennet for introducing this common-sense legislation, which will strengthen FDA and increase public health and safety by providing additional quality controls on drugs and their ingredients,” said BPTF Chairman Brant Zell of Cherokee Pharmaceutical, in a SOCMA release. “…This bill is a good starting point in giving the FDA more authority, tools, and resources, to help ensure a safer US drug supply.”

In response to the bill, Pharmaceutical Research and Manufacturers of America (PhRMA) Senior Vice-President Ken Johnson said: “The lifeline of America’s biopharmaceutical research companies is the safety and integrity of the products they develop. Brand-name pharmaceutical companies make tremendous investments in quality-control systems and take extensive measures to help protect patient safety and to help prevent adulterated ingredients from entering into America’s prescription drug supply,”he said in a PhRMA statement. “In addition, drug manufacturing for the US market—regardless of where it occurs—is regulated under good manufacturing practices (GMP) by the Food and Drug Administration. These GMP requirements help to assure the safety, quality and purity of drug ingredients that are used in the US prescription drug supply.”

Following the heparin incident several years ago, there was much Congressional attention to the issue of drug-manufacturing oversight, including of overseas facilities, and in finding ways to improve regulatory enforcement of the increasing more global and longer pharmaceutical supply chain. A key piece of legislation was the passage of the Food Safety Enhancement Act of 2009 (HR 2749) by the US House of Representatives in 2009, and which was subsequently referred to the Senate Health, Education, Labor, and Pensions Committee for consideration.

Changing legislative priorities punctuated by high-profile policy issues such as healthcare and financial-industry reform, however, put the issue of drug-safety on the legislative backburner. Although Congress is not likely to do anything with the recently introduced bill before the summer recess, it is encouraging that at least the subject is back on the legislative agenda and that it is something to monitor for the upcoming fall legislative session.

But can regulation prevent ‘falsified’ medicines entering the supply chain? I spoke to Gary Noon, CEO of patient safety company Aegate for his expert opinion on the validity of the proposed legislation.

How can this new legislation be enforced?

Gary Noon: European legislation will establish some very important legal principles; first, that this is a matter of public health, which is of utmost priority, and second, that there can be no weaknesses across member states that could risk counterfeits being able to enter. By this the commission intends to establish a harmonized approach and a minimum standard of security measures that must be adopted. We believe this is extremely important legislation and, within the commission’s remit to provide member states with clarity, it will be enforceable.

I would, however, urge EU lawmakers to ensure that protection of the legal supply chain is not hindered or interrupted in any way by broadening the scope of this directive to encompass the complex issue of internet pharmacies. A phased approach to this legislation may be in the best interests of patients and the healthcare industry-focusing on the legal supply chain, with high street pharmacies, in particular, as a priority.

One of the aspects within the legislation will be a mechanism that can ensure patients do not receive falsified products by authenticating medicines before they reach the patient, ie, at the point of dispense. This is available today. Our own service, which is already fully operational in three member states and being installed in two others, enables individual medicinal packs to be authenticated by pharmacist before dispensing.

Is this truly a legal move or just an official call for better patient education?

GN: We very much hope that the legislation includes public education. These efforts will go some way to ensuring the public seek medicines from qualified health practitioners and help drive them away from unregulated internet sources.

Our research, carried out within five major European countries, identified that around 9% of consumers have purchased prescription drugs online at least once. This despite the dangers of doing so, and even though 69% of those surveyed agreed that it is “a bad idea or dangerous.”

Do you think legitimate pharmacies just need to catch up with their online counterparts and provide a convenient 21st century service?

GN: In our opinion there is much confusion relating to online pharmacies. Let’s be clear, illegal online pharmacies supplying fake medicines to the public is not 21st century medicine. Consumers need to be able to know without doubt what the reputable online sources of prescription medicines are.

Illegally operating internet pharmacies often do not require a prescription before a purchase can be made — they also do not have a bricks and mortar presence and neither is there likely to be a pharmacist employed. How to encourage patients to use mail order and high street pharmacies, rather than buying from dubious sources online? Aegate’s research revealed that only 4 per cent of consumers would continue to buy prescription medicines online if their traditional pharmacists had a specialist tool to confirm the authenticity of medicines — a reason to believe legitimate pharmacies can very quickly provide a 21st century service.

Hamburg emphasized that the agency’s interest in working more closely with USP is part of a larger policy position by FDA to seek collaborative models between regulators, industry, and other organizations to meet the rising need for science-based regulation in an increasingly complex and global supply chain. “After I become Commissioner, many people began asking whether the agency is now leaning pro-industry or pro-consumer,” said Hamburg in her remarks to the USP Convention. “This is the wrong way to think about FDA’s role. Both consumers and industry groups have a tremendous stake in a strong FDA that takes science-based action on behalf of public health….An FDA that can promote health and well-being through quality products and acts quickly and strategically to protect consumers from unsafe products earns the trust and confidence it needs to do its job well.”

To meet that goal, Hamburg outlined two major priorities: increasing FDA’s scientific capacities to strengthen the field of regulatory science and responding to the growing demands of globalization as evident by the exponential increase in FDA-regulated imports (i.e., drugs, food) to the United States. She estimated that 20 million shipments of FDA-regulated imports are expected to come into the US this year from more than 150 countries compared with approximately 6 million shipments 10 years ago. “FDA simply does not have—and will never have—the resources to inspect every foreign manufacturer, or every shipment of products from overseas. So the new global reality requires that we build partnerships to handle the load,” she said.

Hamburg said that such an approach requires FDA to work more closely with other national regulatory authorities, other international and national organizations, and with industry. “We must find new ways to harmonize standards and approaches, as well as share information,” she said.

Part of that effort, says Hamburg, is to further build a collaborative relationship with USP. “Clearly many of our interests and priorities are aligned,” she said. “In some earlier discussions with USP, we have talked about opportunities and strategies to promote public health through our work together. There is a lot to be done,” she said.

She said that one of the most pressing tasks is to update monographs, pointing to a successful collaboration between USP and FDA in updating standards for heparin in the wake of the problems with adulterated heparin. “This type of collaboration is essential…and can be used as a model for how to move forward proactively to modify monographs in a way that they can identify counterfeited or intentionally adulterated products…before they enter the healthcare system,” she said. “Now, we must jointly identify drug ingredients and products that would benefit from an up-to-date monograph..starting with those that have the greatest impact on public health.”

FDA’s Office of Regulatory Affairs supports the USP Reference Standard Program through a Cooperative Research and Development Agreement, and Hamburg spoke of three future initiatives to take place under this agreement to expand efforts to promote the quality, purity, and efficacy of current and new drugs. First, Reference Standard Candidate Assessments will test standard candidate materials that are controlled substances. Second, to combat economic adulteration, FDA and USP will exchange information on hand-held device applications designed to screen drugs for adulteration or contamination and will explore ways to integrate the requirements of those new technologies into USP’s documentary standards. And third, FDA will assist in the development and modernization of USP monographs providing enhanced tests and assays to better assess and characterize drug ingredients and products.

Adapting regulatory and compendial approaches with a mindset to more collaborative efforts to deal with the evolving dynamics of the pharmaceutical industry is a positive development. The complexity and broadening of the global pharmaceutical supply chain, along with the greater complexity of new drug development, requires FDA, other national and international regulatory bodies, standard-setting organizations, and science-based organizations, to raise the bar in oversight through new models of cooperation, better use of scientific technologies, and risk-mitigation strategies. The recently announced initiatives between USP and FDA are  good steps in that direction.

Befitting the theme of INTERPHEX, many of the discussions will focus on manufacturing processes. For example, PharmTech Editor-in-Chief Michelle Hoffman will be talking to Tim Freeman, Freeman Technology’s (Malvern, UK) director of operations, about the complexities of powder dynamics. I’ll be discussing spray drying and lyophilization with Jim Searles, director of process and product development at Aktiv-Dry (Boulder, CO), and Steve Nail, senior research scientist at Baxter Pharmaceutical Solutions (Deerfield, IL).

Reflecting our magazine’s broad scope, we’ll also be talking to attendees about issues that arise beyond the plant floor. Patricia Van Arnum, PharmTech’s senior editor, will discuss the future of process automation and control with Siemens (Berlin). And PharmTech Managing Editor Angie Drakulich will moderate a panel regarding the best ways to use radio-frequency identification to bolster supply-chain security.

Perhaps one of the most interesting features will be a question-and-answer session held on Wednesday, April 21 at 10:30, when officials of the US Food and Drug Administration will respond to audience queries about the deficiencies the agency frequently encounters in abbreviated and new drug applications. The Q&A will follow their presentation as part of the Signature Series of lectures hosted by Pharm Tech. Neither the Signature Series nor the FDA Q&A will be videotaped. If you’d like to participate in this unprecedented opportunity, please come to the exhibit floor’s main stage (which is near the registration desk).

Taped interviews will all be available on our website after the show! Check out the full preliminary program.

According to newspaper reports, such as those in The Guardian and The Telegraph, shortages have been reported for more than 40 drugs, including treatments for cancer, lung disease, blood clots, asthma and epilepsy. There is more than enough supply to satisfy demand. The problem is parallel trade. 

“For months I have been concerned about the potential impact on patients’ health on a small number of medicines being sold abroad by speculators,” Mike O’Brien, UK Health Minister, said in a statement. “Rather than selling drugs to NHS patients as they should, they are selling them abroad for greater profit.” 

As O’Brien says, this issue has been ongoing in the UK for months. In August 2009, the Association of the British Pharmaceutical Industry (ABPI) published a briefing on medicines supply that revealed a 1156% increase in the number of emergency medicine deliveries, from 6134 in January–May 2008 to 77020 in the same period in 2009. 

The root of the problem lies in the fact that UK medicines are generally cheaper than elsewhere in Europe. The current low value of the British pound also provides further financial incentive for UK wholesalers, pharmacies or dispensing doctors to order extra medicines and sell them abroad for higher prices. According to IMS health, 11% of the UK’s pharmacies and a small number of dispensing doctors exploit the system in this way in a trade worth more than £30 million ($47 million) a month.

 This practice is not illegal in the EU. UK newspaper The Guardian also claims that before the value of the pound collapsed, UK wholesalers and pharmacies were buying and importing drugs that were cheaper in Europe. 

To address the issue, the UK’s Minister for Health and Secretary of State have called for a summit to be held in early March with all those organizations involved in the supply of medicines. 

“The government believes that this spirit of collaboration is the best way to further minimize the risks to patients,” said O’Brien. “That is why the Secretary of State and I have called a summit in early March 2010 with all those organizations involved in the supply of medicines to better understand the issues involved and what might be done to address them.”