GSK isn’t the first pharma company to set its eyes on the automobile industry. In 2009, AstraZeneca borrowed some experts in lean manufacturing from Jaguar Land Rover, who were to apply their knowledge of efficient car production techniques to medicines. I’m researching at the moment how the project went so watch this space and hopefully I’ll be able to provide an update on this in the near future.

So what is it that cars and pharmaceuticals have in common? Today, the majority of a car’s value is attributable to suppliers but before this the industry used to be dominated by Western companies, much like the pharma industry. As the industry found the need to implement aggressive streamlining and cost cutting, carmakers now maintain only a few core operations, with everything else taking place across a huge network of contractors.

In the pharma industry, we’re already seeing greater numbers of companies outsourcing certain functions, such as clinical trials, or in-licensing new compounds from smaller companies.

The article (available here) pulls out a lot more similarities between the two industries. If you like pharma and cars then it’s definitely worth a read!

The article doesn’t provide any updates on the GSK partnership, which is a shame because it’s something I’m really looking forward to hearing more about. Where as AstraZeneca was looking to cars for lean expertise, GSK is hoping to extrapolate some of the technology using in Formula 1 racing to improve its R&D, such as seeing whether real-time monitoring technologies can be applied to human studies.

Related articles

 Fast Pharma – The Best of British

Beginning this month, we are featuring monthly reader polls to gain your feedback on key advances in the pharmaceutical sciences and manufacturing. As the scientists and technical experts on the front lines, your input is a crucial component in understanding what the industry has achieved and where it will go in the future. We encourage you to provide your feedback in our first poll, which is examining advances in oral drug delivery and oral product forms. We will share the results with you at PharmTech.com, and along with further analysis, our July issue will take a retrospective and prospective look at drug substance and finished drug-product manufacturing, formulation development and drug delivery, outsourcing, and analytical testing.

We are interested in your feedback as well. In addition to our reader polls, we invite you to provide your input on what you think have been major achievements in drug substance and finished drug-product manufacturing, formulation development and drug delivery, outsourcing, and analytical testing. Lend your expertise and offer your input in the comment section to this blog or email your input to Patricia Van Arnum, executive editor, pvanarnum@advanstar.com. We look forward to hearing from you.

After reviewing its documentation, the company concluded that routine preventive maintenance and requalification of manufacturing equipment at the site was overdue. Ben Venue suspended manufacturing so that it could assess the entire site and take appropriate corrective actions to ensure the safety of its products. The suspension will affect Johnson & Johnson, which markets Doxil, as well as Pfizer, Hospira, and Teva.

Last month, President Obama ordered FDA to take various steps intended to prevent and reduce drug shortages. The agency will require advance notice from manufacturers likely to face manufacturing disruptions, and it will expedite reviews of new drug suppliers, production sites, and manufacturing changes.

These steps, while helpful, do not address an important factor that contributes to drug shortages: manufacturing deficiencies. Even before Ben Venue conducted its own review, FDA found 48 quality concerns during an inspection of the Bedford site in May 2011. FDA likely needs a larger pool of inspectors to oversee drug manufacturing sites more thoroughly. But the government’s current desire for austerity will probably preclude the budget increase that would make hiring possible.

Maybe FDA should prioritize manufacturing sites for inspection if they are among a few that produce a medically necessary drug such as Doxil. Greater attention to crucial sites could identify problems earlier and, ideally, resolve them without disrupting drug supply.

Topical formulations can be used to treat local and systematic indications, offer ease of delivery, facilitate patient compliance, and avoid the problem of first-pass metabolism. Successfully developing a topical formulation requires an understanding of the physiochemical properties, such as release characteristics, composition of the drug-delivery system, and the nature of the drug-delivery vehicle. Manufacturing a semisolid dosage requires implementing a CMC (chemistry, manufacturing, and controls) strategy to ensure stability, photosafety, avoidance of product degradation, and minimization of process impurities. The Pharmaceutical Technology webcast, “Optimizing Topical Drug Formulation and Manufacturing,” provides insight on recent advances in topical drug formulations, the latest regulatory/pharmacopoeial requirements in product quality and product performance, and strategies to optimize manufacturing for topical drug products.

Speakers include: Vinod Shah, PhD, chair of the Special Interest Group, Regulatory Science of the International Pharmaceutical Federation and distinguished pharmaceutical scientist and consultant to the US Pharmacopeia; Majella Lane, PhD, senior lecturer in pharmaceutics at the School of Pharmacy at the University of London; and Michael Lowenborg, R&D manager of formulation and process development at  DPT Laboratories.

Additional information and registration for the webcast may be found here.

The report reiterates that most of the shortages, 132 of the 178 recorded in 2010 were of sterile injectable drugs, including cancer drugs, anaesthetics for surgery, drugs for emergency medicine, and electrolytes for intravenous feeding. According to the report, demand for some of these drugs, particularly oncology drugs, has been rising. The number of vials of sterile injectable oncology drugs shipped between 2006 and 2010 has risen by 14%.

Manufacturing, however, is constrained. The report states that the bulk of sterile injectables is supplied by only 7 manufacturers, and most of the production of a given drug is by three or fewer manufacturers. A dearth of manufacturing capacity is blamed, in part, for the shortages. According to the report, the overall quantity and the range of drugs produced by generic sterile oncology manufacturers over the past 5 years has increased substantially, while the capacity of sterile injectable oncology manufacturing facilities has remained stable. Evidence suggests that manufacturers are diverting capacity from shrinking lines of business, including some of the drugs that have experienced shortages, to growing ones.

The report goes on to say that manufacturing capacity is expected to increase, but that new plants will not come online for another 18 months. In the mean time, the system remains precariously balanced, with unexpected disruptions in supply, such as those caused by manufacturing deviations, likely to result in shortages. The report recommends that FDA expedite the review of new manufacturing facilities, but in the mean time, FDA is focusing its efforts on better prediction. If they get timely notification that a shortage is likely to occur, they can pass the information to other manufacturers, who may be able to divert capacity in time to avert a crisis. An ounce of prevention is worth a pound of cure, especially if the cure is bringing up a new GMP facility.

See related:

President Obama Issues Executive Order to Reduce Drug Shortages

FDA and Department of Health Address Drug Shortages

Drug Shortages Loom Large

The rationale for such an approach is clear. One needs to only look  down the rows of the more than 1800 exhibitors at CPhI to see the requisite  for contract-service providers and suppliers to achieve competitive advantage through product and service differentiation. For pharmaceutical companies, among the more than 25,000 attendees at CPhI, the decision of with whom to partner is crucial for successfully implementing their drug-development and manufacturing strategies.

The strategic partnership model was discussed at a conference session at CPhI. Moderated by Jim Miller, president of PharmSource Information Services and contributing editor to Pharmaceutical Technology, the panel featured presentations from Sanjit Singh Lamba, managing director of the  Knowledge Center for Eisai, Massimiliano Brescia, global pharmaceutical operations at Abbott, and  Philip Pratten, vice-president of business development, contract pharma services with Alkermes.  The panelists discussed the drivers behind the adoption of strategic partnerships and best practices in optimizing such relationships.

For pharmaceutical companies, they face ongoing pressure to reduce costs while maintaining quality and security of supply, are seeking to   reduce their supplier base to more efficiently manage their drug-development activities and manufacturing network on a global basis, and want to gain continuous improvement and innovation in technology, processes, and  project management. For contract service providers, such strategic partnerships are a way to meet the expanding and diverse needs of pharmaceutical customers  by building long-term and stable relationships. The panelists shared perspectives on performance metrics, communication approaches, and best practices in technology transfer in meeting the evolving needs of pharmaceutical companies.

So what is the take-away? Effective relationship builing, project-management competency, continuous-improvement strategies, and supplier innovation are evermore important elements of the toolboxes of contract-service providers.

Looking at the pharmaceutical industry as a microcosm for economic activity, there are certain fundamentals that cannot be ignored: demand in established markets is weak and demand in emerging markets is strong. In 2010, on a constant dollar basis, the North American pharmaceutical market increased only 1.9% compared with 2009, and Europe’s pharmaceutical market increased only 2.4%, according to data from IMS Health. In contrast, the pharmaceutical markets for Asia/Africa/Australia (excluding Japan) increased 14% and 14.2% in Latin America in 2010, both on a constant dollar basis. Admittedly, the sizes of emerging markets are less than established markets. In 2010, North America’s pharmaceutical market was valued at $335 million, Europe’s at $253 million, Asia/Africa/Australia (excluding Japan) at $130 million, and Latin America at $54 million on a constant dollar basis.

What these numbers show, however, is a basic truth that policymakers cannot ignore: when companies are investing, they are investing where there is market demand, namely, in emerging markets. Although some proposals in the President’s plan, such as payroll tax relief or accelerated deductions for businesses, would be helpful to businesses in the short term, they cannot alter the demand–supply fundamentals that are behind the shifts in capital investment.

Within specific sectors, it is more helpful to examine where federal policy can make a difference. One area in the pharmaceutical industry where there seems to be a disconnect in federal policy is in the manufacture of pharmaceutical ingredients and related supply to the US market. A recent report by the US Government Accounting Office (GAO) points to the ongoing challenges that FDA faces in overseeing the foreign drug-manufacturing supply chain. In 2010, GAO estimated that FDA inspected 11% of foreign drug-manufacturing establishments subject to inspection, and that it would take approximately nine years for the agency to inspect such establishments at that rate. In contrast, in fiscal year 2009, FDA conducted 1015 domestic inspections, representing approximately 40% of facilities, which would allow the agency to inspect domestic facilities at the rate of once every 2.5 years. To address this challenge, in its recent report, Pathway to Global Product Safety and Quality, FDA outlined its efforts to increase foreign inspections, increase staffing overseas for such inspections, and other cooperative measures among national regulatory agencies.

Although such efforts are important and necessary from a product-safety perspective, a more fundamental question arises for federal policymakers: is it really prudent for the US to allocate federal resources to increase inspection staff to support offshore manufacturing for pharmaceutical ingredients and products for the US market?  Would it be better policy to align product supply with what can be reasonably overseen by national regulatory agencies through domestic production and in the process not only support but expand domestic pharmaceutical production? Given the regulatory oversight required to ensure quality and safety, a pharmaceutical product is different than other industrial or consumer products, and therefore, the rules of market engagement would seem to differ. There is always much discussion on the value of keeping technology-based and science-based jobs in the US, but in the context of pharmaceutical development and manufacturing, are we really pursuing a cohesive federal policy? That perhaps is the question we should be debating.

See related stories,”Big Pharma’s Manufacturing Blueprint for the Future.”

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Drug shortages are an acute problem that keeps getting worse. Last year, about 211 drugs were in short supply, which was a new record. This year, the number of new drug shortages already has reached 213, according to the University of Utah Drug Information Service. As a result, many patients now have limited access to crucial drugs, such as cancer therapies and medicines for potentially lethal infections. And a Congressional committee is now investigating what appears to be an insult added to this injury.

Rep. Elijah E. Cummings (D-MD) alleges that secondary drug distributors are charging exorbitant prices for drugs that are in short supply. Allied Medical Supply, for example, has charged $990 per vial of cytarabine, a treatment for leukemia that usually costs about $12 per vial. A shortage of leucovorin, which is used to treat advanced colon cancer, has enabled Premium Health Services to charge more than $270 per vial, even though the drug’s typical price is approximately $5 per vial. On behalf of the House Committee on Oversight and Government Reform, Cummings has sent these companies letters asking how much they are making in profits on these drugs.

The biggest cause of drug shortages, according to FDA, is manufacturing quality problems. Fortunately for us, FDA just awarded a multimillion-dollar grant to the National Institute for Pharmaceutical Technology and Education (NIPTE) to improve drug development and manufacturing. NIPTE, a not-for-profit research organization, will use the money for various projects that could help manufacturers better understand their products and processes. For example, NIPTE will seek to develop analytical methods that can characterize complex molecules and enhance control of product quality. The group also will investigate specialized manufacturing techniques for low-dosage and high-toxicity products.

By improving manufacturing quality, NIPTE’s work could help reduce the number of future drug shortages that patients must endure. And FDA will soon provide recommendations for avoiding and mitigating drug shortages. FDA’s efforts are a good sign that it takes the problem seriously, but for many patients, relief cannot come too soon.

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”

In hot-melt extrusion, an amorphous solid solution of the crystalline drug substance is formed under shear and heat. Solubility parameters, combined with other physiochemical characteristics of the drug and excipients, can by used as predictive indicators in selecting initial formulation components. Successfully implementing pharmaceutical hot-melt extrusion dosage product development, however, requires not only careful selection of the active and inactive ingredients, but also of the appropriate processing conditions. Inadequate processing conditions can lead to thermal degradation of polymers, drug, or other formulation components. Melt-extrusion processing temperature, screw speeds, feed rates, and screw design play a crucial role in implementing the technology.

Producing a desired dosage form requires the optimization of both the formulation-development and manufacturing processes. The upcoming webcast, “Pharmaceutical Melt Extrusion Process Development,” examines how initial process parameters can be selected and optimized for a product produced using hot-melt extrusion. The webcast includes speakers from Roche, American Leistritiz, and Evonik, and will be broadcast on Oct. 4. Details may be found here at the PharmTech website.

Reference

1. P. Van Arnum, “Solubilizing the Insoluble,” Pharm. Technol. 34 (11), 50–56 (2011).