Amy Ritter was Scientific Editor, BioPharm International.

Amy Ritter, PhD

With pharmaceutical R&D efforts in decline, public-private partnerships are emerging as a way to bolster early stage discovery efforts. In Europe, concern over a dwindling antibiotic pipeline led to the European Commission’s Action Plan Against the Rising Threats from Antimicrobial Resistance, launched in November last year (

). On May 24, 2012, AstraZeneca and GlaxoSmithKline jointly 

the launch of funding for the initiative, to the tune of €224 million ($279 million), to enable development of antibiotics for bacterial infections. According to the press release, the proposed research program will initially focus on three key areas: the development of pipeline antibiotics, including compounds from GSK and AstraZeneca, information sharing, and continuing research and the discovery of new antibiotics.

 its own public-private partnership, the International Immuno-Oncology Network, a collaboration between BMS and 10 cancer research institutes that aims to further the scientific understanding of immuno-oncology. The company hopes that the partnership will facilitate the translation of scientific research findings into clinical trials and, eventually, clinical practice, as well as advance innovation in drug discovery and development.

		Recognizing the larger role that public-private partnerships are playing in today’s drug development environment, the 2012 

 being held in Boston, MA from June 18-21 will be opening with a translational research forum. The forum, titled From Bench to Bedside in a Bioeconomy – Government, Industry and University Models to Catalyze Economic Growth and Patient Access, will explore how universities and their funding partners can move early stage research forward, and will provide specific examples of innovative university models which increase patient access to innovative products and spur economic growth. The keynote address will be given by Robert A. Brown, PhD, president of Boston University, and the forum will include speakers from industry, academia, and NIH.

Articles

With pharmaceutical R&D efforts in decline, public-private partnerships are emerging as a way to bolster early stage discovery efforts. In Europe, concern over a dwindling antibiotic pipeline led to the European Commission’s Action Plan Against the Rising Threats from Antimicrobial Resistance, launched in November last year (see here).

Public-Private Partnerships Step Up

A theme shared by several of Wednesday’s sessions at the AAPS National Biotechnology Conference seems to be how the tools and techniques that have evolved for development of small molecules are spilling over into the design of large molecules.

		Dr. Michael Hall from Amgen presented a talk in which he described the tools and techniques used to evaluate the catabolism and in vivo stability of a peptide-antibody fusion construct. The analysis revealed a site prone to degradation, and the protein was subsequently reengineered to be more stable. Dr. Ho Cho of Ambrx presented data on antibody drug conjugates made using the company’s platform technology whereby the site of conjugation of the toxin to the antibody can be precisely controlled. He showed data demonstrating that moving the site of conjugation affects the biophysical properties, retention time, formation of high molecular weight species, and thermal stability of the antibody drug conjugate. Moreover, he said that for at least 20 antibody drug conjugates, moving the site of conjugation affects pharmacokinetics and pharmacodynamics. What I found striking about the two talks was that developers were doing what amounted to structure-activity relationship analysis, the bread-and-butter of small molecule development. Can protein libraries be far behind?

Live from AAPS Biotech: Large Molecules Mimic Small Molecule Development

AAPS Biotech is holding its annual meeting this year in San Diego, CA, the city with arguably the best weather in the world.

		Tuesday sessions opened with a symposium on the challenges associated with high concentration protein formulations. Dr Vinay Radhakrishnan of Pfizer began with an overview of high concentration protein formulation, showing that the concentrations required of monoclonal antibody therapies have increased from a few mgs/mL for the first approved therapies, to more than 100 mgs/mL for therapies now entering the field. The increase is driven sometimes by therapeutic necessity, and sometimes by the desire to simplify dosing. Whatever the reason, to produce such high concentration protein formulations requires overcoming problems of aggregation and viscosity. Dr. James Colandene of HGS presented a case study of high variability in a fill line caused by the high viscosity of the product and clogging of the fill needles if a pause occurred in the fill line. Some of the variability could be reduced by shortening fill lines, increasing the needle size, and ensuring that the bulk product had equilibrated to room temperature before filling. Dr Rahul Rajan of Amgen presented data on formulations designed to increase stability after freeze-thaw. His group had found that alanine was effective at reducing aggregation of high concentration protein solutions, but was less effective after several freeze-thaw cycles because the alanine crystallized during freezing. He presented data showing that the addition of PEG200 in addition to alanine eliminated the problem, and hypothesized that the PEG did not prevent crystallization of alanine during freezing, but stabilized the protein when alanine was unavailable. Rajan concluded by introducing a pilot plant facility being brought on line at Amgen, where process controls to effectively manage high concentration formulations could be designed, tested, and scaled up in advance of Phase III material production.
		Watch this space for more good weather, and more updates from AAPS Biotech.

Live From AAPS Biotech

Guest blog by Jerold Martin, senior vice-president of Global Scientific Affairs at Pall Life Sciences

	PDA held a successful workshop earlier this spring in Phoenix for over 100 attendees on key elements of the association’s forthcoming Technical Report on Single-use. An important discussion topic was the need for a transparent partnership between the single-use system supplier and the end user. The degree to which the user is dependent on the supplier is significantly greater than for traditional materials. Suppliers must become an integral part of the user’s quality system, which requires unprecedented levels of transparency, data sharing, and management. This issue will be a significant challenge for suppliers and users. However, as stated by Duncan Low of Amgen, “Those who fully embrace true partnerships will be the most successful.”

	Tor Graberg, Chair of PIC/S and Head of Sweden’s Inspection, Medical Products Agency (MPA), provided a favorable European regulatory view to single-use manufacturing. In his talk, he stressed the concept of “documented trust” between supplier and end-user to construct a robust information bridge, particularly in the areas of quality and change control.

	A third key point expressed during the meeting was the need for ongoing operator training programs in the handling of single-use biocontainers for media, bioreactors, buffers, intermediates, and final products. Russell Wong of Bayer Healthcare spoke of Bayer’s awareness training, which is held twice a year on bag handling to train everyone on the handling of single-use biocontainers-including the plant’s fork lift driver.

	I had the privilege of speaking on two topics-current trends in extractables and leachables (E&L) testing, and business models for single-use. New applications of single-use technologies in final drug product formulation and filling have heightened requirements to ensure patient safety compared with established API applications of single-use for media and buffer preparation and storage, bioreactors, and intermediate–bulk API storage. Although new to bioprocess developers, these requirements are well understood by formulation experts who currently conduct E&L studies for final container-closure systems. The safety risks of leachables from single-use filters, tubing, and biocontainers in final formulation and filling are generally low because of short contact times, lower temperatures, and lower surface-area-to-volume ratios compared with final dosage containers. However, a safety assessment must still be conducted and submitted in regulatory filings.

	Business models for single-use manufacturing are an untraditional topic for a PDA meeting, which otherwise tends to focus on more technical manufacturing, quality, and regulatory issues. However, single-use is such a significant change in manufacturing paradigm that process development, quality assurance. and facility design engineers are often challenged to justify the implementation of disposable systems from an economical perspective, as well as a technical and regulatory view. Chris Smalley of Merck and Co. brought these economic principles into focus with an informative presentation on how Merck conducted an economic comparison between stainless-steel and single-use systems for the manufacture of a bulk vaccine.

	The PDA Technical Report is expected to be published by this coming fall, and will offer a basic primer on the economic factors that go into the decision to implement single-use manufacturing that will provide the reader will an expanded sense of their role in the decision process.

	BPSA will hold its 2nd International Single-Use Summit in Washington, DC, July 23–25, 2012. The event is open to all interested participants (BPSA corporate membership is not required) and the BPSA has organized a line-up of expert speakers to provide perspectives on future pharmaceutical markets and the role single-use technologies will play in fulfilling goals for better, faster, more cost-effective therapies. Confirmed speakers include Ken Gronbach, a noted national demographer and author, on global population trends and how they will impact health-care requirements; ABC News senior correspondent Jonathan Karl on the upcoming Supreme Court decision on the Affordable Care Act (otherwise known as ‘Obamacare’); Kim C. Bush of the Bill & Melinda Gates Foundation (Director, Life Sciences Partnership for Global Health) on the foundation’s mission and actions; and biotechnology strategist Eric Langer of BioPlan Associates, on the current growth and demand for single-use systems.

	Single-use adopters (and BPSA corporate members) Merck, Shire, and Catalent will also share user perspectives on the role of single-use manufacturing in drug development, global vaccine acceleration and delivery challenges, as well as perspectives on the pan-global adoption of single-use as an enabler for quick and effective manufacturing. Several panels and networking sessions are planned to facilitate interactions between current and future users and supplier experts on the current challenges and solutions to implementing of single-use technologies in biomanufacturing.

	The event will be held at the Four Seasons Hotel, Georgetown, in Washington, D.C. The full agenda and registration information can be viewed at
	www.bpsalliance.org.

PDA held a successful workshop earlier this spring in Phoenix for over 100 attendees on key elements of the association’s forthcoming Technical Report on Single-use.

Report on Recent and Upcoming Single-Use Meetings

Senators Max Baucus (D-MT) and Chuck Grassley (R-IA) are probing ties between manufacturers of opioid painkillers and medical groups that have advocated for increased use of such drugs for pain management. The intent of the probe is to establish the extent of financial ties between the two to determine whether there has been undue influence of industry on prescribing practices. The impetus for the probe is the high rate of abuse of prescription opioids, and the dangers such drugs pose. According to a 

 from the two senators, deaths from painkiller overdoses have tripled over the last decade and led to the deaths of 14,800 Americans in 2008, exceeding those caused by heroin and cocaine combined.

Letters were sent to Perdue Pharma, Endo Pharmaceuticals, and Johnson & Johnson, asking them to disclose financial ties to 10 medical groups and eight individuals who played a prominent role in setting pain management guidelines. The companies were also asked to provide all communications in regard to the book 

Responsible Opioid Prescribing: A Physician's Guide

, distributed by the Federation of State Medical Boards, and communications in regard to the pain management guidelines published by several medical groups.

The Senators also sent letters to the American Pain Foundation, the American Academy of Pain Medicine, the American Pain Society, the Center for Practical Bioethics, the Wisconsin Pain and Policy Study Group, the Joint Commission on Accreditation of Healthcare Organizations, and the Federation of State Medical Boards asking them to disclose financial support from any company that develops, manufactures, or distributes opioid pain medications.

Senators Max Baucus (D-MT) and Chuck Grassley (R-IA) send letters to opioid manufacturers and pain groups asking them to disclose financial ties.

US Senators Probe Links Between Opioid Manufacturers and Medical Groups

Abbott Laboratories will pay $1.6 billion to settle outstanding issues concerning past sales and marketing practices for its neurologic medication, Depakote. According to a Justice Department 

, Abbott has pleaded guilty to a criminal misdemeanor for misbranding Depakote in violation of the Food, Drug, and Cosmetic Act. The settlement includes a criminal fine and forfeiture totaling $700 million and civil settlements with the federal government and the states totaling $800 million. An additional $100 million will be paid to the states to resolve consumer protection matters, according to an Abbott 

The Justice Department found that Abbott promoted Depakote to control agitation and aggression in elderly dementia patients, a use for which it was not approved. The company also used its sales force to promote the drug to healthcare providers and employees of nursing homes, and created programs and materials to train the pharmacy providers’ consultant pharmacists about the off-label use of Depakote to encourage them to recommend the drug for unapproved use. In addition, from 2001–2006, the company marketed Depakote in combination with atypical antipsychotic drugs to treat schizophrenia, another use for which it was not approved.

Abbott has also executed a Corporate Integrity Agreement with the Department of Health and Human Services, Office of Inspector General. The five-year CIA requires that Abbott's board of directors review the effectiveness of the company's compliance program, that high-level executives certify to compliance, that Abbott maintain standardized risk assessment and mitigation processes, and that the company post on its website information about payments to doctors. The CIA will transfer to AbbVie, the independent research-based company that Abbott expects to launch at the end of 2012.

"We are pleased to resolve this matter and are confident we have the programs in place to satisfy the requirements of this settlement," said Laura J. Schumacher, executive vice-president, General Counsel in the Abbott release. "The company takes its responsibility to patients and health care providers seriously and has established robust compliance programs to ensure its marketing programs meet the needs of health care providers and legal requirements."

Abbott Laboratories will pay $1.6 billion to settle outstanding issues concerning past sales and marketing practices for its neurologic medication, Depakote.