Amy Ritter was Scientific Editor, BioPharm International.

Amy Ritter, PhD

In response to concerns about the sustainability of US drug-development efforts, FDA has released a 

Driving Biomedical Innovation: Initiatives to Improve Products for Patients

. The report outlines several steps that FDA will take to spur biomedical innovation and ensure that such innovation can be quickly translated into safe and effective therapies. Input used to compile the report was obtained from a broad spectrum of stakeholders, including members of large pharmaceutical companies, small biotech companies, academic researchers, and patient advocacy groups.

The report outlines major areas in which FDA will be launching initiatives to address feedback obtained from stakeholders. They include:

Rebuilding FDA’s small business outreach services

: FDA will establish a FDA Small Business Liaison program and a Young Entrepreneurs program, as well as establish a new partnership with the US Small Business Administration.

Building infrastructure to drive and support personalized medicine

: FDA will invest in regulatory science and clarify agency policies to support the emerging field of personalized medicine.

Creating a rapid drug-development pathway for important targeted therapies

: To clarify the pathway for rapid development of promising therapies, FDA will host a series of scientific meetings intended to achieve a common understanding of steps needed when an investigational drug being studied for a serious disease shows exceptional promise during the early stages of development.

Harnessing the potential of data mining and information sharing while protecting patient privacy

: FDA is rebuilding its IT and data analytic capabilities and establishing science enclaves that will allow for the analysis of large, complex datasets while preserving patient privacy.

Training the next generation of innovators

: FDA is designing a new Future Innovators Program under which promising candidates will be brought into the agency for training and experience. This program will provide FDA with important outside expertise and perspective while equipping these innovators with highly marketable skills and experience.

Streamlining and reforming FDA regulations

: The agency is reviewing its current regulations to identify burdensome, unclear, obsolete, ineffective, or inefficient regulations.

The report comes at a time when new drug applications have fallen to record lows, despite continuous increases in research and development budgets. FDA hopes that the initiatives outlined in this report will promote innovation, help developers overcome challenges in product development, and speed the delivery of safe and effective treatments to patients. In her introduction to the report, FDA Commissioner Dr. Margaret Hamburg says, “It is important to note that while these are important first steps to address the immediate concerns before us, this is an ongoing initiative at the agency and will be expanded beyond the reforms outlined in this document.”

Articles

In response to concerns about the sustainability of US drug-development efforts, FDA has released a report that outlines several steps that FDA will take to spur biomedical innovation and ensure that such innovation can be quickly translated into safe and effective therapies.

FDA Outlines Strategy to Spur Biomedical Innovation

The CRO Pharmaceutical Product Development (PPD) will be acquired by the Carlyle Group and Hellman and Friedman in a deal valued at approximately $3.9 billion. PPD shareholders will receive $33.25 per share in cash, and PPD will become a privately held company after completion of the transaction. PPD employs more than 11,000 people worldwide and provides contract preclinical and clinical development services to the pharmaceutical and biotechnology sectors.

The Carlyle Group is a global alternative asset manager, and Hellman and Friedman is a private equity firm. Funding for the deal will come from the two companies, along with external debt financing commitments provided by Credit Suisse, JP Morgan, Goldman Sachs, and UBS. The transaction is expected to close in the fourth quarter of 2011.

“Fred Eshelman and PPD’s management team have built a leading and extremely high-quality global research and services organization that will continue to help pharmaceutical and biotech companies develop new drugs at lower costs,” said Karen H. Bechtel, managing director and head of the healthcare group at Carlyle, in a 

. “We look forward to helping expand and enhance PPD’s platform and broad spectrum of therapeutic expertise.”

The CRO Pharmaceutical Product Development (PPD) will be acquired by the Carlyle Group and Hellman and Friedman in a deal valued at approximately $3.9 billion. PPD shareholders will receive $33.25 per share in cash, and PPD will become a privately held company after completion of the transaction.

Private Equity Firms to Acquire PPD for $3.9 Billion

The surge in the number of biologics in the drug-development pipeline, over  900 according to the latest report from the Pharmaceutical Research and Manufacturers of America, introduces pressure on manufacturers to handle increasing numbers of small-volume products (1).  In fill-finish operations, this means manufacturers must have the ability to quickly and efficiently switch their fill line from product to product without compromising product quality or sterility.  Manufacturers are beginning to take advantage of the benefits afforded by single-use technologies to address these needs. 

Single-use technologies are now widely-accepted tools in drug manufacturing, particularly manufacturing of biologics. A recent biomanufacturing survey in 

 indicated that 66% of respondents use at least some disposable components in their manufacturing operations, and an additional 9% of respondents indicated that they use all disposables (2).  Disposable upstream-processing tools, such as bioreactors and media storage containers have made a natural transition from bench-top to large-scale cell culture, and have evolved in size and complexity to fit the special needs of manufacturing-scale operations.  Disposable downstream-processing tools have also been adapted to meet the demands of large-scale bioprocessing.  At the very end of the biomanufacturing line is the fill-finish operation, where single-use technologies are just beginning to make inroads.  

IMAGE: INFLUX PRODUCTIONS, PHOTODISK, GETTY IMAGES			

Fill-finish is the last step in the manufacturing operation, after which the product is passed to the patient. As such, product quality and the possibility of contamination are of special concern when a manufacturer is considering whether to implement single-use technologies.  The fill occurs downstream of the last filtration step, so there is a heightened sensitivity to sterility risks and the introduction of particulates. As with all disposable applications, product/material interactions and extractables and leachables are also concerns.  

In some cases, manufacturers may be reluctant to switch to a disposable line from a well-validated stainless-steel fill line, where process engineers have extensive experience in cleaning and validating the system and are confident in their quality control operation. Kent Payne, vice-president and general manager of Development Services at Catalent Pharma Solutions indicated that in general, a big obstacle to adopting single-use technologies in other parts of the manufacturing process has been a reluctance to change. "The biggest challenge we faced in successfully applying single use systems elsewhere was first changing mindset to be open to new approaches from what we were used to," he says.  For single-use systems, validation of sterility and integrity is done by the supplier of the components, rather than the manufacturer.  Handing these important quality checks over to another party requires a leap of faith that some may not be comfortable making. 

On the other hand, single-use technologies offer advantages over stainless systems in control of contamination.  In the PharmTech survey, a majority of respondents listed reduced risk of contamination as an advantage to single-use systems (2).  A single-use filling line can be configured to have fewer connection points than a fixed-pipe line, thus reducing the risk of microbial contamination.  Moreover, since the line is only used for a single product, there is no risk of carryover contamination.  Althea Technologies uses disposable technologies in all of its fill operations.  According to Chris Duffy, vice-president of operations, "Preventing cross-contamination is an issue that Althea takes very seriously.  To ensure that there is no carryover from project to project, Althea has stringent changeover procedures and operates its fill facility with disposable technology in virtually 100% of our fill operations, from small-scale Phase I clinical supplies to commercial manufacturing." 

Perhaps the biggest benefit to be gained by implementing a single-use filling line is the savings in time gained by eliminating the cleaning and validation steps. Nathan Beyeler, process engineer at Merck Sharp and Dohme, cited the decrease in changeover time as being an important factor in the decision to implement a single-use fill line. "Market pressure and good business sense dictate that we need to use our filling assets for manufacturing product, not for getting ready to manufacture product," he says. "The need to get the most product out of the process is increasingly critical to the business. That said, the paradigm of a few blockbuster vaccines allowing for long campaign operation and few product-to-product changeovers is under pressure as products portfolios become more focused on multiple (lower annual volume) biologics. This means that a production facility is faced with the challenge of more frequently changing the facility and equipment over to process different products. The reduction of changeover time has therefore become one of the primary influences in our decision to implement single-use technology for current filling facilities."  

Indeed, Beyeler reported a reduction in changeover time from 16 hours to two hours when switching to a single-use line.  In addition, a recent report produced by authors from Millipore demonstrated a similar reduction in total processing time, from 19 hours to 1.5 hours, when switching from a stainless system to a single-use system (3).  

On average, biotech companies outsource 81% of their fill-and-finish requirements. Biotech and pharmaceutical companies with in-house capabilities outsource 40% of their requirements (4).  This means that CMOs are handling a large variety of filling operations, and can benefit from the flexibility afforded by single-use systems to handle multiple products.  Althea's Duffy notes, "Stainless equipment requirements vary from client to client.  When not in use, these must be stored and when they are placed back into service must be cleaned again."  The ability to quickly reconfigure the line to accommodate different size runs, different biosafety requirements, or different product containers adds greater flexibility to the filling operation.  

It is often the case that equipment evolves to fill an unmet need, and this is the case with disposables for fill-finish. At its simplest, a filling line can consist of a product container bag, a pump and a filling needle, all connected by plastic tubing. Disposable filling lines, suitable for smaller-scale fills are available as "plug-and-play" systems, where the line comes fully assembled and presterilized, ready to be used.  Such systems are adequate for small-scale fills, but do not operate at high speed and may not be suitable for high-viscosity products.  

Pump technology has improved to the point where disposable filling lines are feasible, but further improvements are possible.  Peristaltic pumps have only recently achieved the accuracy required for fill applications.  They are still limited by speed, and the tubing that runs through the pump is subject to degradation and deformation over time.  Plastic, disposable, rolling-diaphragm pumps are currently available and offer an alternative.  However, more rigorous applications requiring high volume, high speed, or high pressure, may be places where stainless steel continues to be the better choice. 

There is plenty of room for new technology to adapt to these challenges.  Beyeler says, "At the moment, I think what has been offered is that which is the easiest and least risky to develop from the equipment vendors, a single-use version of what is already on the market. Some equipment suppliers for upstream processing have innovated beyond the 'also in single-use' type of approach and have developed specifically new technologies. As vendors increasingly see the potential competitive advantages for single-use technologies I am looking for them to specifically invest R&D in developing innovative filling technologies." The requirements for speed and cost-effectiveness in multiproduct manufacturing will drive the development of new disposable technologies for fill-finish operations. 

2. M. Hoffman, "Bioprocessing and Sterile Manufacturing" supplement to 

3. E. Jenness and V. Gupta, supplement to 

Single-use components in the fill–finish line provides increased flexibility to multiproduct manufacturers.

Single-use Technologies in Fill–Finish Operations

User Fee Waivers, Reductions and Refunds for Drug and Biological Products

 that outlines FDA's policies for issuing waivers, refunds, or reductions in prescription drug user fees. The newly issued 

 is a revision of a 1993 guidance titled 

Draft Interim Guidance Document for Waivers of and Reductions in User Fees

Under the Prescription Drug User Fee Act (PDUFA), FDA is authorized to assess application fees for certain human drug and biological product applications or supplements. In addition, FDA can assess annual product fees for certain approved drug and biological products, and annual establishment fees for the facilities in which those products are made. 

Under PDUFA, FDA will grant a waiver or reduction in fees  if an applicant meets the eligibility criteria under one of the following provisions:

A waiver of reduction is necessary to protect the public health

The assessment of the fee would present a significant barrier to innovation because of limited resources available to the person or other circumstances

The applicant is a small business submitting its first human drug application to the secretary for review.

The guidance describes the types of waivers and reductions available under the user-fee provisions of PDUFA and describes FDA’s current thinking on the criteria for meeting eligibility requirements for each type of waiver.  A section on exemptions and refunds discusses orphan designated products, applications submitted by state or federal government entities, and instances where an application was withdrawn before any substantial work was performed by the agency.  The guidance also describes the procedures for requesting waivers, refunds, or reductions, and discusses the procedure for reconsiderations and appeals of FDA decisions on such requests. 

FDA has issued a guidance titled User Fee Waivers, Reductions and Refunds for Drug and Biological Products that outlines FDA's policies for issuing waivers, refunds or reductions in prescription drug user fees.

New FDA Guidance on User Fee Waivers, Reductions, and Refunds

President Obama released his plan for deficit reduction on Sept. 19, 2011, and included in the 

 are several provisions that would affect US drug makers if enacted. The first is a proposal to reduce the period of exclusivity for biologics from the current 12 years to seven years. In addition, the practice of evergreening—extending the exclusivity period by making minor changes in product formulation—would be prohibited. According to the report, “The Administration’s proposal strikes a balance between promoting affordable access to medications and encouraging innovation to develop needed therapies. The proposal will result in $3.5 billion in savings over 10 years to federal health programs including Medicare and Medicaid.”

Another provision would give the Federal Trade Commission the authority to prohibit pay-for-delay agreements, in which a manufacturer of an innovator product pays to delay the entry of a generic drug onto the market. The proposal is intended to increase patient access to generic drugs and biologics, and the administration projects that the policy would save federal health programs $2.7 billion over 10 years.

Also included in the plan is a proposal to align Medicare drug-payment policies with Medicaid policies for low-income beneficiaries. The plan would require the same drug rebates that are offered to Medicaid recipients to be offered under Medicare Part D. It is estimated that the policy change would result in $135 billion in savings over 10 years.

FTC Finds 60% Increase in Pay-to-Delay Deals

President Obama released his plan for deficit reduction on Sept. 19, 2011, and included in the 80-page report are several provisions that would affect US drug makers if enacted.

White House Deficit Reduction Plan Targets Biologic Exclusivity Period

 the roll-out of its Changing Diabetes in Children program in India, making India the seventh country to participate. The aim of the program is to contribute to meeting the fourth UN Millennium Goal—to reduce child mortality—by breaking down the barriers that prevent children with Type I diabetes in developing countries from receiving proper care. The program is currently operating in six countries—Bangladesh, Cameroon, the Democratic Republic of the Congo (DRC), Guinea, Tanzania, and Uganda, and Novo Nordisk plans to launch the program in Kenya within the next few months.

The program provides free insulin, blood glucometers and strips for children with Type I diabetes. A comprehensive training manual for healthcare professionals and diabetes educators has been developed as well as locally adapted educational materials for children and their families. In India, there are plans to open 12 Changing Diabetes in Children clinics covering a total of 10 Indian stages, making it the most extensive program launch to date.

It is estimated that there are 50 million people living with diabetes in India, and the program’s goal is to reach 2500 children by its completion in 2015. By that time, a sustainable cooperation with local partners, including governments and diabetes foundations should be in place. The program is designed to provide immediate, short-term access to diabetes care, while building a framework for a lasting and long-term solution. According to the 

, “When the Changing Diabetes in Children program ends, our hope and intention is that it is properly embedded in the national healthcare systems and will continue as a government initiative.”

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Novo Nordisk announced the roll-out of its Changing Diabetes in Children program in India, making India the seventh country to participate.