Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Patricia Van Arnum

	Innovation is the cornerstone of the pharmaceutical industry. The challenge to innovation not only entails identifying drugs with clinical efficacy but also in being able to produce and deliver the desired drug compound. An upcoming P

mega-3 Innovations in Pharmaceutical and Diagnostic Markets

, will examine the latest developments for omega-3 prescription drug products, their regulatory status, and recent advances in softgel drug-delivery technologies for omega-3 products.

will broadcast live on Sept. 11 from 10:00 AM EST to 11:15 AM EST with on-demand available following the broadcast. Omega-3s represent a small, but growing segment in the hyperlipidemia market. GlaxoSmithKline’s Lovaza is an example of strong-selling prescription omega-3 available in the United States. The webcast will examine the market opportunities for omega-3s in the hyperlipidemia market and other therapeutic areas as well, explain how monitoring one’s omega-3 index can improve health outcomes, and explore the latest advances in softgel drug-delivery technologies for highly purified omega-3 products.

	Participating in the webcast are: Adam Ismail, executive director of the Global Organization for EPA and DHA Omega-3s (GOED); Dr. William Harris, research professor of medicine at the University of South Dakota and senior scientist, Health Diagnostics Laboratory; Irena McGuffy, manager, softgel formulation, Catalent Pharma Solutions; and David Fulper, director, technology support, Catalent Pharma Solutions.

	Further details on the webcast, including registration details, may be found

Articles

Innovation is the cornerstone of the pharmaceutical industry.

Omega-3s Prescription Products: A Case Study of Innovation

Improving access to quality medicines is an ongoing challenge in the developing world. In addition to overcoming the challenge of bringing drugs to remote or difficult-to-reach areas, there is the problem of substandard or counterfeit drugs entering the supply chain. To help address that problem, a new platform for detecting substandard and counterfeit medicines using microfluidics was recognized earlier this year with a grant through a private–public parntership 

Saving Lives at Birth:  A Grand Challenge through Development. 

Saving Lives at Birth:  A Grand Challenge through Development 

 is an initiative to improve maternal and children’s health. It was launched in March 2011 to seek innovative prevention and treatment approaches for pregnant women and newborns in rural, low-resource settings. The project is a partnership between the US Agency for International Development (USAID), the government of Norway, the Bill & Melinda Gates Foundation, Grand Challenges Canada, and the World Bank. These partners provided nearly $14 million for this grant program's first round of funding and have a commitment of investing at least $50 million in projects in multiyear funding. The first call in 2011 for innovative approaches resulted in the selection of 24 solutions for award. A second call was issued in February 2012 for innovations across three domains: science and technology, service delivery, and ways to stimulate demand for healthcare services at the time of birth. The call elicited more than 500 submissions from almost 60 countries. In July 2012, The Saving Lives at Birth partners nominated 15 innovations for award. Among the innovations recognized was PharmaCheck, a new platform for detecting substandard and counterfeit medicines. 

Developed by Boston University in collaboration with the Promoting the Quality of Medicines (PQM) program, which is supported by USAID and implemented by the US Pharmacopeial Convention (USP), PharmaCheck has reached the proof of concept stage—demonstrating a quantitation linear relationship for analysis of an antimalarial medicine of interest on a microfluidic chip, according to a July 26, 2012, USP press release. The technology addresses shortcomings of current field-based, portable quality- control laboratories currently in use throughout the developing world, including the inability to precisely and accurately measure the percentage of API or other important quality attributes of medicines. The technology is expected to greatly reduce the need for confirmation of field-tested results at fully equipped quality-control laboratories.

“This technology promises to be groundbreaking in the fight against substandard and counterfeit medicines,” said Anthony Boni, pharmaceutical management specialist for USAID’s Global Health Bureau, Office of Health, Infectious Diseases and Nutrition/Health Systems Division, in the USP release. “Inexpensive, easy-to-use and effective, we expect that PharmaCheck will represent a paradigm shift in combating the scourge of poor quality medicines. One of the most exciting elements is the ability to potentially deploy this technology at point-of-use, with an ultimate vision of healthcare facilities, clinics, and hospitals using the technology to verify the quality of the medicines they receive.” 

Muhammad Zaman, associate chair for undergraduate studies, biomedical engineering and professor of biomedical engineering at Boston University is leading the development for PharmaCheck. A project summary provided by Saving Lives at Birth, explained the need for such a device to improve maternal and children’s health. Malaria affects over 50% of the populace in sub-Saharan Africa and contributes to over 200,000 newborn and 10,000 maternal deaths annually worldwide. In 2008, maternal sepsis accounted for 36,000 deaths while neonatal infection caused close to a million neonatal deaths. It is estimated that between 10–30% of drug sales are counterfeit in parts of Africa, Asia, and Latin America and between 30–50% of all anti-malarials are substandard. The primary objective of the project is to develop a device to screen for substandard anti-malarials and antibiotics, thereby improving adverse maternal and neonatal health outcomes with respect to malaria and sepsis. The researchers say there is no device to test counterfeit and substandard drugs in the field thoroughly. To this end, they see PharmaCheck as a user-friendly, cost-effective, contextual and high-throughput device capable of quantitatively measuring active ingredient concentration and drug-release profiles to quickly and accurately screen for spurious medicines. 

“Existing methods of counterfeit drug detection are bulky, qualitative, error-prone and do not take time-based measurements of drug-release kinetics, and thus do not provide information about whether therapeutic levels of the drug are reached and sustained,” noted the summary. “PharmaCheck addresses these shortcomings through affordable fluorescence, dissolution testing, which allows for highly specific and quantitative time-course measurements of drug release. PharmaCheck will offer an affordable, effective tool for local health authorities to better safeguard the efficacy of their pharmacopeia and significantly impact maternal and neonatal health outcomes in the developing world.” 

“This technology is an important breakthrough as we strive to help ensure the quality, safety and efficacy of medicines essential to treating patients suffering from malaria, tuberculosis and HIV/AIDS in developing countries around the world,” said. Patrick Lukulay, vice-president of Global Health Impact Programs for USP and director of the PQM Program, in the USP release. “This will be a very powerful tool with broad application and impact. We are very pleased to be partnering with Boston University in advancing this technology.” 

A look at PharmaCheck, a field-based tool in development that uses microfluidic chip technology for assessing the quality of medicine in the developing world.

Using Microfluidic Chip Technology for Assessing Drug Quality

Greater market pressures have obliged pharmaceutical companies to reconsider their product-development strategies. Product innovation amidst an increasingly competitive market, inclusive of generic-drug incursion in many therapeutic areas, makes developing new drugs ever-more challenging. Orphan drugs, traditionally pursued by smaller biopharmaceutical companies, are becoming an attractive option for mid- to large-sized pharmaceutical companies.  Often supported by favorable pricing from a pharmaceutical-company perspective and filling patient demand for drugs to treat unmet medical need, orphan drugs offer good market potential. 

A recent Thomson Reuters analysis of the economics and investment case for orphan-drug development and commercialization shows that although orphan drugs target much smaller patient populations than traditional mainstream drugs, the favorable pricing for such products and other factors, such as government incentives, smaller and shorter clinical trials, extended exclusivity, and high rates of regulatory approval, make the top orphan drugs a viable alternative to mainstream drugs. Part of that opportunity also comes from the abundance of therapeutic areas for possible drug development. The Thomson Reuters report offers estimates from the National Institutes of Health and the European Organization for Rare Diseases that indicate that there are approximately 7000 rare diseases worldwide and the recognized number of such diseases increases at a rate of 250 diseases per year. 

The orphan-drug market was valued at approximately $50 billion globally at the end of 2011, according to the Thomson Reuters analysis. Spending on orphan drugs currently makes up approximately 6% of total pharmaceutical sales, assuming a total pharmaceutical market of $880 billion. The compound annual growth rate (CAGR) of the orphan-drug market between 2001 and 2010 was 25.8% compared with a CAGR of only 20.1% for a matched control group of non-orphan drugs, according to the Thomson Reuters analysis. Given these comparative growth rates and expectations that approval rates of orphan drugs will continue to be robust, the positive indicators for orphan drugs are likely to continue in the long-term. This growth is in part due to the high number of biologic-based orphan drugs, which are less vulnerable to generic-drug incursion compared to small-molecule drugs, according to the Thomson Reuters analysis. 

The Thomson Reuters analysis evaluated current and future revenue of the top-revenue generating drugs over a drug’s product lifecycle. The average present value, based on 2010 estimates, of orphan drugs was $637 million, which was on par with the average present value of non-orphan drugs of $638 million.  In looking at the value of drugs over a product’s lifetime, Lipitor (atorvastatin), Pfizer’s anticholesterol drug, was found to be the highest valued drug. It generated an estimated $197 billion over its lifetime as measured through discount potential revenue. Discount potential revenue is the discontinued peak value of a drug’s revenue over its lifetime. It is an estimate based on the value of all historical revenues and future projected revenues. The anticancer drug Rituxan (rituximab), by Roche/Genentech, is the second highest ranked drug in terms of discount potential revenue and is the only drug among the top 10 drugs that has significant sales arising from orphan-drug indications, according to the Thomson Reuters analysis.

 The economic value of rituximab shows the strength of the oncology market as a leading therapeutic area for orphan drugs. Approximately 40% of the top 10 orphan drugs are oncology drugs with an estimated average lifetime revenue potential (EALRP) of $70 billion per drug, according to the Thomson Reuters analysis. The remaining 60% of the top 10 orphan drugs have an EALRP of $41 billion per drug. 

 Following rituximab, the next highest ranked orphan drug, as measured by discount potential revenue, is the ophthalmological drug ranibizumab with discount potential revenue of $74 billion, according to the Thomson Reuters analysis. Ranked third among the top 10 orphan drugs is the human-growth hormone drug somatropin (epr) with a discount potential value of $62 billion followed by the oncology drug lenalidomide with a discount potential value of $60 billion, according to the Thomson Reuters analysis. Rounding out the top 10 orphan drugs, based on discount potential revenue, in descending order of discount potential revenues are: imatinib mesylate, filgrastim, glatiramer acetate, recombinant factor VIII;octocog alfa, bosentan monohydrate, and bortezomib, according to the analysis. 

Although orphan drugs are associated with niche therapeutic areas, their market success have been fairly robust. Of the 86 orphan drugs included in the Thomson Reuters analysis, 25 were blockbusters, representing 29% of orphan drugs. Blockbuster drugs are defined drugs with sales of more than $1 billion. That 29% was comparable to the 29%, or 83 out of 291 non-orphan drugs that were considered to be blockbusters. 

One of the benefits of orphan drugs compared with non-orphan drugs is that orphan drugs are protected by additional market exclusivity. In the United States, orphan drugs are awarded a seven-year orphan-drug exclusivity (ODE). Non-orphan new chemical entities are awarded five years of exclusivity upon approval, thereby providing orphan drugs an additional two years of market exclusivity, explains the Thomson Reuters report. The seven-year orphan exclusivity can also begin later in the product’s lifecycle if the new indication is approved after the initial launch. The exclusivity for orphan drugs, however, does not apply to non-orphan indications for a particular drug. Additionally, orphan-drug exclusivity does not have any association with patents and may or may not provide exclusivity beyond the composition of matter patent, according to the Thomson Reuters report. 

Although serving niche areas, orphan drugs offer good market opportunities for pharmaceutical companies and their suppliers.

Evaluating Market Opportunities in Orphan Drugs

On Oct. 1, 2012, the Generic Drug User Fee Act (GDUFA), which was signed into law by President Barack Obama on July 9, 2012, goes into effect and provides important changes for generic-drug manufacturers and producers of generic APIs. The law imposes generic-drug user fees, payable by producers of generic finished drugs and APIs, to provide additional funding to FDA to improve the regulatory review process, including inspections for drug-manufacturing facilities, for generic drugs. These measures, which are supported by the generic-drug and fine-chemical industries, are intended to speed the delivery and ensure the quality of generic drugs (1). 

 
Under the GDUFA, FDA will receive $299 million annually (adjusted for inflation) during the five-year authorization of GDUFA from Oct. 1, 2013 to Sept. 30, 2017 (i.e., fiscal year [FY] 2013 to FY 2017) (2). The user fees required by the GDUFA are: 
 • A one-time fee for original abbreviated new drug applications (ANDAs) pending on Oct. 1, 2012 (also known as backlog applications)
 • Annual fees for API and final dosage-form facilities
 • Fees for new ANDAs and prior approval supplements (PASs)
 • A one-time fee for drug master files (DMFs) (1). 


Seventy percent of the GDUFA fees will be derived from annual facility fees for facilities producing or pending review to produce APIs or finished dosage forms for a generic-drug application, and approximately 30% of the user fees will be derived from one-time application fees (DMF fees and ANDA and PAS fees). Overall fees were structured to reflect the respective weight in the supply chain, so that 80% of the fees are paid by finished dosage form manufacturers and 20% by API manufacturers. In the first year of the program, $50 million of the total GDUFA user-fee funding will be generated by the one-time backlog fee for ANDAs pending (except for ANDAs that are pending but have received tentative approval) on Oct. 1, 2012. Overall, it is estimated that FDA will receive the funding through approximately 750 ANDAs per year submitted electronically, 750 PASs, 350 newly referenced DMFs per year, and 2000 facilities associated with ANDAs (2).


With the additional funding provided by generic-drug user fees under the GDUFA, FDA is obligated to meet certain performance goals with respect to its regulatory review of generic drugs. The GDUFA outlines goals in five main program areas.
  • 

 By the end of FY 2017, FDA will review and act on 90% of complete electronic ANDAs within 10 months after the date of submission. Certain amended applications may have differing metrics.  
  • 

 FDA will review and act on 90% of all ANDAs, ANDA amendments, and ANDA PASs of current review status (whether electronic, paper, or hybrid) pending on Oct. 1, 2012, by the end of FY 2017.
 • 

 FDA will conduct risk-adjusted biennial cGMP surveillance inspections of generic API and generic finished dosage form manufacturers, with the goal of achieving parity of inspection frequency between foreign and domestic firms in FY 2017.
 • Efficiency enhancements: FDA will implement various efficiency enhancements, which include efforts by industry and FDA to populate and maintain databases as necessary for facilities, fee assessments, efficiency, and other enhancements. FDA also will make DMF- and inspection-based enhancements as well as create a current chemistry manufacturing, and controls (CMC) records database to aid in the efficiency of reviews and inspections.
 • 

: FDA will continue or begin various regulatory-science initiatives. Some key issues are continuing quality-by-design initiatives for generic drugs, including developing science-based recommendations for product development, raw material, API and process controls, and life-cycle management of complex dosage forms (e.g., orally inhaled drug products and modified-release dosage forms). Another key goal is to develop a risk-based understanding of potential adverse impacts to drug-product quality resulting from changes in API manufacturing and controls. This effort will aid in the ability to predict the potential impact manufacturing changes will have on product quality, so manufacturers can target assessments and controls on high-risk areas and regulators can focus their reviews on these areas (2).


Industry response to the GDUFA has been largely positive with groups, such as the Generic Pharmaceutical Association (GPhA), the European Fine Chemicals Group (EFCG), and the Bulk Pharmaceuticals Task Force (BPTF), an affiliate of the Society of Chemical Manufactures & Affiliates (SOCMA), supporting the passage of the GDUFA and offering input throughout the legislative process. 

“The historic user-fee legislation—the most important pharmaceutical legislation since the 1984 Hatch-Waxman Act—will provide FDA with additional resources and ensure all participants in the US generic-drug system, whether US-based or foreign, comply with our country’s strict quality standards,” said Ralph G. Neas, president and CEO of GPhA, in a July 9, 2012, GPhA press release. The new fees are expected to reduce the average review time for most generic-drug applications by nearly two years—from more than 30 months today to 10 months by the end of the program’s fifth year, according to GPhA, and will provide increased funding for generic-drug manufacturer facility inspections.

For fine-chemical and API producers, one of the key provisions of the GDUFA is the adoption of a risk-based inspection process to achieve parity in facility inspection between US and foreign manufacturers, a point made by FDA Commissioner Margaret Hamburg earlier this year (3). “Under the GDUFA, FDA will also ensure that manufacturers—foreign or domestic—who participate in the US generic drug market are held to the same, consistent, high quality standard,” said Hamburg at the GPhA Annual Meeting on Feb. 23, 2012 (3). “We will conduct risk-adjusted biennial surveillance inspections of all generic API and finished form manufacturers—with the goal of achieving parity of inspection frequency between foreign and domestic firms by year five. Having the resources to undertake these regular inspections will level the playing field for foreign and domestic manufacturers...”(3).

The fine-chemicals industry agrees. “The Congressionally mandated inspection frequency of every two years has been very difficult to achieve due to insufficient resources within FDA and the rapid globalization of generic-drug manufacturing,” says BPTF Executive Director John DiLoreto. “While US facilities have been inspected approximately every 2.5 years, many foreign facilities have never been inspected at all. Successful implementation of the GDUFA will result in the identification and registration of all drug-production facilities,” he explains. “Previously, FDA even had difficulty determining how many facilities were producing generic drugs that enter the supply chain every day,” he said. By the end of the first five years of the GDUFA, it is expected that all foreign and domestic facilities will be inspected at the same nominal rate of every two years. “This will level the playing field for foreign and domestic producers and establish a balance in drug quality by ensuring that all manufacturers are implementing cGMPs,” says DiLoreto.

Under the GDUFA, FDA will conduct risk-adjusted biennial cGMP surveillance inspections of generic API and generic finished dosage-form manufacturers, with the goal of achieving parity of inspection frequency between foreign and domestic firms in FY 2017. FDA will prioritize inspections of establishments associated with ANDAs that are otherwise approvable or eligible for tentative approval except for an outstanding inspection, as well as establishments associated with ANDAs that have not been inspected previously. In appropriate circumstances, FDA can rely on a routine surveillance inspection in lieu of an application-specific inspection. Generally, FDA relies on a previous inspection of a finished product site occurring within two years of the cGMP evaluation for a pending application, three years for an API site or a control testing laboratory, and four years for a packaging-only site (2). There are exceptions to this general practice, which are usually related to the nature of the drug being processed or the complexity of the associated processing operations. Under the GDUFA, FDA intends to continue the practice of using a risk-based assessment in determining the length of time since the last inspection, guided by a two-year cycle for finished dosage product sites and a three-year cycle for API sites with consideration of the type of finished product or API in the application. For making decisions about pending applications for which FDA does not have current inspection information within the time period indicated, FDA may use previous FDA inspection information and/or use inspection information from another regulatory authority as appropriate (2). 

 “Risk-based inspections will have a positive effect on FDA and generic-drug manufacturers,” says DiLoreto. “In managing resources most efficiently, FDA will be able to focus on those manufacturers having the most difficulty in implementing and maintaining quality drug-production programs. Manufacturing facilities that have never been inspected will be considered high risk, and manufacturers with a history of active successful quality programs will be considered to be lower risk,” he explains. 

Carla Vozone, business development director at Hovione and industry representative of the EFCG during the negotiation process for the GDUFA, also points to the benefit of the GDUFA in “correcting the mismatch that existed in the inspection schedule and the actual supply chain.” Although approximately 80% of APIs for drugs marketed in the US come from India or China, inspections of drug-manufacturing facilities in these countries are not proportional to these levels, explains Vozone. “Parity in inspections is critical to ensure safety of generic medicines,” she says. She also points to the value in the provisions of the GDUFA that provide for a risk-adjusted surveillance inspections system to prioritize inspections of higher-risk facilities. 

Also of significance is increased authority for FDA to deal with low-quality and counterfeit drugs. “Prior to the GDUFA, FDA had little authority to prevent low-quality and counterfeit drugs from entering the supply chain,” explains DiLoreto. As of Oct. 1, 2012, FDA will have the authority to consider misbranded any drugs not produced in a registered and inspected manufacturing facility. All drugs considered misbranded may be destroyed rather that returned so they will not be allowed to enter the supply chain through different supply chain channels, he explains.

As the quality bar for generic drugs and APIs are raised under the GDUFA, the supply chain for generic drugs also may be affected, notes Vozone. “Generic-drug manufacturers will have to do a risk assessment of their supply chains,” she says. Issues, such as increasing secondary sourcing or further evaluations of existing suppliers, will come into play. She also notes that the amount of the user fees, which are still being  determined, will oblige producers to evaluate their cost structures for supplying a given generic API, and as a result, certain producers may exit the market for that product or the sector. These issues will be important to take into consideration in the sourcing strategies for generic-drug manufacturers. 


1. FDA, “Agency Information Collection Activities; Proposed Collection; Comment Request; Generic Drug User Fee Cover Sheet; Form FDA 3794,”  Federal Register 77 (144), 43844–43846  (2012). 
2. FDA, 

 Human Generic Drug Performance Goals and Procedures Fiscal Years 2013 through 2017 

(Rockville, MD), July 7, 2012, www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM282505.pdf, accessed Aug. 15, 2012. 
3. M. Hamburg, “Challenges and Opportunities for the Generic Drug Industry Remarks,” presented at the GPhA Annual Meeting, Orlando, FL, Feb. 23, 2012. 

The Generic Drug User Fee Act seeks to improve and enhance regulatory activities, including achieving parity of inspections between foreign and domestic drug-manufacturing sites for both finished dosage forms and APIs of generic drugs.

Moving to Risk-Based Inspections

Innovation in parenteral drug delivery often comes from the device itself to enable ease of use and greater patient compliance. Several recent developments in parenteral drug delivery involve thin-wall needles for prefilled syringes, an auto-injector with audio and visual functionality, and an improved self-injection system. 

In late July, BD Medical, a segment of BD (Becton, Dickinson and Company), launched the BD Hyflow needle, a 27-gauge thin-wall needle designed for use with BD’s prefillable syringe systems. The optimized inner diameter of the BD Hyflow needle enables injection of highly viscous drug formulations without the use of a larger needle that could be more painful for the patient, according to the company.

The BD Hyflow needle increases flow to facilitate use with auto-injectors and infusors. The new needle technology also reduces the pressure required to inject, a crucial attribute for patients with dexterity limitations and facilitates patient use and compliance. The needle technology represents an alternative to larger needle-gauge systems. BD says the product is one of several the company plans to launch over the next 18 months to enhance the performance of prefilled-syringe systems. 

 Auto-injector with audio and visual functionality 

A roundup of the latest developments for drug delivery of parenteral drugs.

Drug Delivery Insights: Injectable Drugs

Bristol-Myers Squibb has initiated a voluntary recall nationwide of 10 lots of BiCNU (carmustine for injection) previously manufactured by Ben Venue Laboratories, a former, third-party contract manufacturer for the company, to the user level.

The precautionary recall of BiCNU, a chemotherapeutic agent administered to patients in a hospital or other clinical setting, is being initiated following the discovery of one overfilled vial of BiCNU during routine testing. “An overfilled vial of BiCNU represents a significant risk to patients due to the nature of product administration and could result in patients receiving a dose greater than prescribed,” said the company in an Aug. 31, 2012, 

. “There have been no reported adverse events associated with this issue.“

The recall is being conducted in the US, Canada, and countries within Europe, Latin America, and Asia-Pacific for lots previously manufactured by Ben Venue. Bristol-Myers Squibb does not anticipate a product shortage resulting from the recall because current supply is secured through another manufacturer.

Ben Venue announced last year that it was exiting the contract-manufacturing business following manufacturing quality issues at its facility. In December 2011, Ben Venue extended its voluntary suspension of its manufacturing activity at its Bedford, Ohio, facility, which it had first announced in November 2011. The original suspension took place after an internal review indicated that routine preventive maintenance and requalification of some manufacturing equipment was overdue. These issues was noted in inspection findings by FDA, EMA, and other global regulatory agencies. Ben Venue conducted a site-wide assessment to address these manufacturing issues, and in December 2011, indicated that it would resume production as it addressed facility and equipment issues.  

Ben Venue Continues Suspension of Manufacturing Activity at Ohio Facility

Ben Venue Suspends Manufacturing at Bedford Plant

Ben Venue Laboratories Exits Contract Manufacturing Business

Bristol-Myers Squibb has initiated a voluntary recall of 10 lots of BiCNU (carmustine for injection) previously manufactured by Ben Venue Laboratories, a former, third-party contract manufacturer for the company, to the user level.