After I kick-started the conference with a few choice words, notably the idea that many of those present would be unlikely to let me into their kitchens, let alone their sterile manufacturing facilities, the main event began.

Nick Maishman, senior director of parenterals at Pfizer took to the stage first and delivered a very imaginative presentation on the application of operational excellence (OE) within aseptic fill-finish. Using the analogy of Jonny Wilkinson’s kicking ability on the rugby field, Maishman described various states of process capability and process stability in terms of common or special cause variations. Maishman then went into some detail about Pfizer’s root cause analysis (RCA) strategy, which utilises the six sigma DMAIC approach and lean manufacturing principles, a combination that seems to define OE at Pfizer.

A panel discussion on the “regulatory minefield” followed. I was surprised by the openness of the panel but also of the delegates that contributed. Instead of placing regulatory authorities fully in the firing line, as can often be the case, here there was admission that industry too needs to take responsibility for moving forward with quality to address patient safety issues. I would like to thank all of those who contributed to an interesting and perhaps too short discussion.

Alexander Huber, director of sterile and topical plants at Novartis, and, coincidentally, editorial advisory board member of Pharmaceutical Technology Europe, was second to present and focused on operators, in particular “playing it safe” by using risk and people management successfully. Huber outlined some “pillars to success” an analogy that appeared in a number of presentations. The main concept here was ensuring that everybody in the organisation has some level of responsibility for quality and knowledge of risks, and that training and coaching are key to achieving this state.

Tim Simo, director projects, global technical services at Janssen-Cilag offered excellent insight into outsourcing strategies, in particular the idea of “big pharm to big pharma” in a time of overcapacity in some areas of the industry. What followed was a detailed description of a 12-month assessment process that saw 80 potential partners reduced to three over several distinct selection steps.

Philippe Juvin, quality operations director at Genzyme, managed to captivate and entertain the audience with a double-length talk on a bioburden reduction strategy that saw quality and production personnel working more closely together and get on “the shop floor” to fully-understand operator behaviour and the (sometimes unavoidable) errors made. It was a standout presentation that contained some surprises, such as gowning design changes that produced “wow”  level reductions in microbial excursions, and a very frank acknowledgment that the “human” in “human error” is only one part of a chain of events.

And all that was just day one. To get the full story next year, perhaps you’ll have to consider attending yourself… For more information about the Sterile Manufacturing CxO Dialogue and other events, click here.

Be sure to check out our special feature on cleanrooms, which will be available soon in the December issue of Pharmaceutical Technology Europe.

As the unemployment rate hovers around 9.1%, the federal government needs to find ways to create jobs. Congress is debating whether a tax break on repatriated money would prompt companies to hire more workers, as I mentioned last week. Meanwhile, the Obama administration is eyeing another potential means of stimulating job growth: investing in biological research.

When he signed the America Invents Act in September, President Obama committed to developing a National Bioeconomy Blueprint by January 2012. The blueprint will describe ways to manage investment in biological research to improve the nation’s health and create the “jobs of the future.” Aside from identifying potentially productive investments in R&D, the blueprint will also describe regulatory reforms to reduce burdens on biopharmaceutical manufacturers.

Illustrating the maxim that great minds think alike, FDA is already seeking to identify and reform burdensome and inefficient regulations as part of its own initiative to stimulate biomedical innovation. At the same time, the agency plans to establish a common understanding among stakeholders to clear the approval pathway for exceptionally promising therapies. These goals are included in the agency’s recent report titled Driving Biomedical Innovation: Initiatives to Improve Products for Patients.

Biological research is the foundation of a significant portion of the American economy, as the White House website notes. The combined efforts of the president and FDA could help discover and develop new therapies. If they also encourage biopharmaceutical companies to hire new employees, they will help mitigate an urgent problem that has not yet been addressed sufficiently.

Concern about pharmaceuticals in our water supply has been in the public consciousness for a few years now. In 2009, the Environmental Protection Agency found traces of various drugs in fish caught in rivers that receive effluent from wastewater-treatment plants. The drugs were believed to come from doses that people had excreted or flushed down the toilet. In response, FDA updated its guidelines for disposing of drugs. New research, however, shows another potential source of drugs in our waterways.

French scientists investigated fish called wild gudgeon that lived upstream and downstream of a steroid-manufacturing facility owned by sanofi. About 60% of the fish downstream of the facility had both male and female sexual characteristics, as opposed to 5% of the population upstream. Researchers identified pollutants such as diuretics and anti-inflammatory agents in the river. The fish’s abnormalities could prevent them from breeding and also signal problems in other species.

“People think drug release is regulated, but it’s not,” said Joakim Larsson, a pharmacologist at the University of Gothenburg in Sweden, to Nature. But this lack of oversight may end: the European Commission is now considering whether to set limits on common drugs (e.g., ibuprofen and the contraceptive ethinylestradiol) in waterways.

Setting limits might prove difficult, however. Scientists have not yet determined safe limits for many pharmaceuticals in the aquatic environment, or how widespread the problem is, according to Susan Jobling, an aquatic ecotoxicologist at Brunel University in London who spoke to Nature.

The French researchers’ findings certainly are alarming, but regulators won’t have a solid basis for any decisions until more information comes to light. I’m encouraged that sanofi is cooperating with regulatory agencies, researchers, and ecological associations to investigate the scope and root of the problem. In the meantime, the pharmaceutical industry would do well to keep this story in mind, and perhaps review whether it can reduce the potential risks of its waste-disposal procedures.

Also see my previous posts about pharmaceuticals in water:

“Water without Side Effects”

“Hope for Bipolar Fish”

BIO’s ideas for enhancing regulatory science at the agency interest me most, and they likely would have a direct effect on the companies that the agency regulates. One suggestion relates to the independent nonprofit foundation created by Congress to support public–private partnerships that advance FDA’s mission. To help the foundation do its work, Congress should give FDA greater ability to transfer federal funds to it, according to BIO. The idea is worth discussing, but I think it would be even better in the context of an overall increase in FDA funding.

FDA has undertaken many initiatives for enhancing regulatory science, but has been slow to translate results into action. BIO suggests creating an entity within FDA that analyzes the findings from these initiatives and conducts pilot programs to try out promising scientific and regulatory approaches. I think this is an excellent idea. Establishing an office whose duty is to improve regulatory science would lessen the burden of other agency employees. It seems like an efficient way of keeping the agency abreast of current science.

Anyone can criticize FDA, but coming up with ideas for solving the agency’s perceived problems is a tougher job. BIO’s proposals should inform a discussion that involves regulators, representatives from industry, and independent scientists. A collaborative and transparent effort among these parties could help ensure that FDA upholds its reputation as a world-class regulatory agency.

Definitely, says the Hay Group, a management-consulting firm. Big Pharma’s executive-compensation plans reward compliance and short-term financial gains when they should be encouraging risk-taking, according to the firm’s research. About 80% of criteria that determine incentives are financial, and only 12% relate to drug development and commercialization. Although short-term incentives are common, they’re inappropriate for the pharmaceutical industry because of its long product-development processes, according to Hay Group.

In light of Hay Group’s research, the compensation package for former Pfizer CEO Jeffrey Kindler makes no sense at all. The company was facing distinct problems when its board gave Kindler the boot in December 2010. Not only had Pfizer’s share prices languished for four years, several promising drugs had failed in late testing, including a potential replacement for Lipitor. Despite these problems, Kindler got a 60% raise over his 2009 compensation. A performance-related bonus brought his compensation to $4.9 million. Kindler seems to have been rewarded for failure, which, to my mind, is even worse than being rewarded for short-term gains.

To overcome its current challenges, Big Pharma will have to change how it defines, measures, and rewards performance, according to Hay Group’s research. Fortunately, Big Pharma can use mid-sized drugmakers and biopharmaceutical firms as models. These companies “have been much more creative in weaving pipeline and R&D measurements into their incentive strategies,” said Hay Group in a press release. By learning from these firms’ compensation strategies, Big Pharma might match their level of innovation.

It’s easy to blame circumstances for our failings, and harder to admit our own missteps. If it took Hay Group’s recommendations seriously, Big Pharma might reclaim its reputation for innovation. And achieving this goal naturally would be good for the world’s patients as well as for industry.

The problem of slowing growth has been compounded by the difficulty in developing new branded products, according to a Datamonitor analyst. As more drugs lose patent protection, companies’ profits are eaten away by competing generic medicines, and meager pipelines have not been able to compensate for the loss in revenue so far.

In apparent despair of finding worthwhile candidates, several companies have reduced spending on research and development. Other companies have laid off research scientists. The Wall Street Journal reports that Elan cut roughly 65 research jobs at its San Francisco site. The fact that research has borne so little fruit likely is contributing to drugmakers’ decisions to cut staff and spending, although I’m not sure that the approach is a good one.

Enter the US government, a bugbear that industry often decries for imposing burdensome regulations and impeding innovation. To help find promising drug candidates and to demonstrate their potential to the industry, the National Institutes of Health (NIH) plans to found a National Center for Advancing Translational Sciences (NCATS). This new center will gather research from various institutes under one roof, use robotic screeners to identify promising chemicals, and conduct animal and human testing to confirm that the drugs are safe and efficacious.

“I am a little frustrated to see how many of the discoveries that do look as though they have therapeutic implications are waiting for the pharmaceutical industry to follow through with them,” Francis S. Collins, director of NIH, told The New York Times. NCATS will not compete with the private sector, but rather do some of its legwork for it.

I am glad that NIH is putting time, effort, and money into helping discover and develop the new drugs that patients need. Now that the low-hanging fruit has been picked, every extra effort could help bring essential therapies to the market. Pharmaceutical companies should be grateful for the assistance that NIH is trying to provide. It bears mentioning that this is not the first government effort to aid pharmaceutical research, and that companies routinely get other help, such as tax breaks, from the government. A combination of public and private efforts could well help keep the industry strong, and keep patients healthy.

The McDonalds recall is the fourth cadmium-related recall issued by CPSC this year for children’s products. Cadmium is one of the four major toxic elements of concern in consumer products. Together with lead, arsenic, and mercury, these make up “the big four” heavy metals that pose the greatest threat to our health.

The pharmaceutical industry has been reworking guidelines for limits and testing methods in an attempt to keep tabs on heavy metals. As Managing Editor Angie Drakulich discussed in her post last week, FDA recently focused its attention on the amount of lead contamination in dietary supplements. Legislation is under review in the Senate that could give FDA the power to regulate supplements and better control the amount of heavy metals they contain. Additionally, the US Pharmacopeia and ICH are working to update guidelines relating to heavy metals and keeping them out of pharmaceutical products.

For more on heavy metals testing requirements, register for Pharmaceutical Technology’s webcast scheduled for next week on June 14 and 17.

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 a summary analysis of the legislation by the Kaiser Family Foundation, a nonprofit policy research firm, the new law supports CER by establishing a nonprofit Patient-Centered Outcomes Research Institute to identify research priorities and conduct research that compares the clinical effectiveness of medical treatments. The institute will be overseen by an appointed multistakeholder board of governors and will be assisted by expert advisory panels. The law specifies that findings from CER may not be construed as mandates, guidelines, or recommendations for payment, coverage, or treatment, or used to deny coverage. The funding for the institute will become available starting in fiscal year 2010 and will terminate the Federal Coordinating Council for Comparative Effectiveness Research that was founded under the stimulus bill, the American Recovery and Reinvestment Act (ARRA), which passed in February 2009, and which provided $1.1 billion in funding for CER. Following the passage of ARRA, the Institute of Medicine issued a report recommending priorities for CER.

CER seeks to evaluate and compare the implications and outcomes of healthcare strategies such as medical procedures, medicines, and other approaches to address a particular medical condition, according to a Kaiser Family Foundation analysis on CER. CER proponents say it is a valuable tool to improve the quality of healthcare and cut unnecessary costs. CER critics have raised concerns that CER could be a forebearer to healthcare rationing and would circumscribe treatments to patient-specific populations, including approaches in personalized medicine. So, for the pharmaceutical industry, is CER a good thing or a bad thing?

When CER was incorporated into the stimulus bill, the Pharmaceutical Research and Manufacturers of America (PhRMA), broadly supported the concept of CER, but noted that a long-term framework for implementing CER still had to be worked out as part of healthcare reform. “Throughout the discussion of this issue in the stimulus bill, PhRMA maintained its long-standing support for increased government funding of constructive approaches to comparative effectiveness research,” said PhRMA President and CEO Billy Tauzin in a Feb. 17, 2009 statement in commenting on the passage of the stimulus bill.

Since the healthcare legislation was passed, PhRMA has not issued a public statement on the CER provisions in the new healthcare law, but an industry group, the Partnership to Improve Patient Care (PICP), has come out in support of the CER provisions in the new law. PICP was formed in November 2008 to address CER and is comprised of healthcare, scientific, and trade associations, which includes PhRMA and the Biotechnology Industry Organization. “The Partnership to Improve Patient Care has been working for over a year in support of patient-centered CER, and we’re very happy to see it included in the final healthcare reform bill,” PIPC Chairman Tony Coelho said in a Mar. 23, 2010 statement. “Everybody is different, so it’s critical that CER reflect these differences. This legislation will help ensure that CER is used to help doctors and patients make the best treatment decisions possible and not to set coverage guidelines.” He noted that the final bill is consistent with the principles for patient-centered CER adopted and released by PIPC in 2008. PIPC said it will work with other stakeholders to advance patient-centered CER in the coming months.

It was a victory for the pharmaceutical industry that the CER provisions in the newly passed healthcare reform law do not use CER as a requirement for coverage or reimbursement, but the CER provisions, along with other measures in healthcare reform, point to a shifting focus to value-based healthcare. As outlined in the Kaiser analysis, the new law establishes a national quality-improvement strategy that includes priorities to improve the delivery of healthcare services, patient health outcomes, and the health of the population. It creates processes for the development of quality measures involving input from multiple stakeholders and for selecting quality measures to be used in reporting to and payment under federal health programs. The national strategy is due to Congress by January 1, 2011.

The shifting focus to value-based healthcare, with its emphasis on health outcomes, as a means to improve the quality of care, allocate resources more efficiently, and reduce costs, is likely to influence drug development. Clinical studies obviously will still focus on evaluating a given drug’s efficacy and safety as well as measure the effectiveness of a given drug compared with existing therapies, but the focus on value-based healthcare implies a broadening of the scope of clinical research.

For drug companies, comparative clinical research has traditionally been a tool in their own efforts to advance a particular product against competing therapies. What we see now in the movement to value-based healthcare, including CER, is a broader mindset to more critically evaluate all healthcare approaches in treating a particular condition, which includes both pharmaceuticals and non-pharmaceutical solutions. This philosophy implicitly raises the bar in clinical research and widens the competitive field to include not only drugs but also other tools such as molecular diagnostics and medical devices that can work in conjunction with or separately from drug therapies. An important issue to watch is how the underlying philosophy of value-based healthcare may alter drug-development efforts and strategies and the positioning of pharmaceutical companies in non-drug-based healthcare solutions.

Before this program, according to the agency, some firms submitted multiple and delayed written responses to Form 483 observations, sometimes over many months. Because FDA reviewed all of these responses before making a decision on whether to issue a warning letter, the process delayed enforcement  and compliance. Now, however, FDA “will not ordinarily delay the issuance of a warning letter in order to review a response to an FDA 483 that is received more than 15 business days after the FDA 483 was issued,” according to an announcement in the Federal Register.

If a response to a Form 483 is received after 15 business days, FDA says it does not plan to “routinely include a response on the apparent adequacy of the firm’s corrective actions in the warning letter.” Instead the agency “plans to evaluate the response along with any other written material provided as a the direct reponse tot he warning letter.” FDA maintains the discretion to issue a warning letter regardless of whether any responses are received.

The program appears to apply the 15-day limit regardless of the number of observations on the Form 483. One hopes this program will help add a greater level of urgency, especially in situations that apparently have not been taken seriously until a warning letter has been issued. I do not want to think some firms may have deliberately delayed compliance by submitting their responses weeks apart, but I can see how the assumption can be made. On the other hand, investigating the cause of some observations and developing a corrective action can be a time-consuming process such that delayed and multiple responses are not uncommon. One hopes, then, this program will be a good first step toward achieving the tough, no-nonsense enforcement the agency needs without also overburdening the industry.