Angie Drakulich was editorial director of Pharmaceutical Technology.

Angie Drakulich

Regulatory science underpins innovation and practices in drug manufacturing. The most common definition of 

 is a discipline that creates new tools, standards, and approaches for use in assessing the safety, effectiveness, quality, and performance of products. 

 DAN WARD/BUENA VISTA IMAGES/GETTY IMAGES 

In October 2010, FDA issued a framework for advancing regulatory science for public health, which focused on the following: accelerating delivery of new medical treatments; improving pediatric and children's health; protecting against emerging infectious diseases and terrorism; enhancing safety and health through informatics; protecting the food supply; modernizing safety testing; meeting challenges for regulating tobacco; and setting a collaborative implementation framework. 

Following that framework, in August 2011, the agency released a strategic plan for advancing regulatory science at FDA, largely focused on science-based decision-making to improve public health. Part of this initiative identifies specific standards, methods, and questions for drug reviewers to use in their review process. The overall effort builds upon the agency's Critical Path Initiative, launched in 2004, to drive innovation in scientific processes, which includes the 2011 report that prioritized eight areas, which included support for new approaches to improve product manufacturing and quality. 

Academia’s role in the future of pharma manufacturing and regulation, by Angie Drakulich JUPITERIMAGES/THINKSTOCK IMAGES  

FDA has launched several Centers for Excellence in Regulatory Science and Innovation (CERSI) to carry out these priorities (see 

). The agency's initiative in regulatory science also was enhanced with the passage of the Food and Drug Administration Safety and Innovation Act (FDASIA) in July 2012. Section 1124 of FDASIA calls for improving medical product decision-making through guidance documents and the adoption of tools, methods, and processes. The US Health and Human Services (HHS) Secretary must issue performance reports on these goals for fiscal years (FY) 2014 and 2016. 

spoke to FDA about these issues in a special interview on the future of bio/pharmaceutical regulation. 

 In August 2011, FDA released a strategic plan, 

Priority 3 of that plan focuses on product manufacturing and quality, including enabling the development and evaluation of novel and improved manufacturing methods to improve product quality, namely through continuous manufacturing, novel manufacturing technologies, excipients and complex dosage forms, and process analytical technology (PAT) and quality-by-design (QbD) approaches. What does FDA and the industry hope to gain by focusing on these areas?  

 FDA is responsible for protecting the consumer through the availability of quality products. These approaches focus on good, sound science in achieving a high quality product. By applying QbD and understanding the role of excipients and complex dosage forms, a higher level of product and process understanding will be obtained. The other approaches (PAT, continuous manufacturing, and novel manufacturing technologies) utilize that understanding to achieve a more robust and capable manufacturing processes, resulting in higher product quality. With this higher level of product quality, the product failure rate is expected to drop, which in turn, will increase product availability, and reduce product cost. Therefore, by focusing on these science-based approaches, FDA is confident that the overall quality of pharmaceutical products [will] continue to increase. 

Where are CMOs headed? A Q&A with DSM Pharmaceutical Products CEO Alexander Wessels, by Angie Drakulich  

Modernizing manufacturing approaches for pharmaceuticals, such as through QbD, continuous manufacturing, and/or PAT, has the potential to benefit industry, regulators, and patients. Already, there have been multiple reports of quality and cost benefits to manufacturers through the use of QbD and/or PAT approaches. For patients, these approaches can lead to increased assurance of quality and product availability. For regulators, it potentially means less regulatory oversight postapproval due to regulatory flexibility (e.g., design space) filed with the application. FDA is currently pursuing additional pathways to ease postapproval changes for well-understood and controlled processes under a robust quality system. 

Continuous manufacturing, although new to most pharmaceutical manufacturing, is a commonly used technology in food and chemical processing. As more companies are gaining experience with continuous manufacturing, benefits are emerging, including cases of reduced manufacturing scale-up issues, reduced material usage in development, and flexible manufacturing capacities. Because of the changing dynamics of new drugs toward more specialized, lower-volume products, continuous manufacturing could become more commonplace in the years ahead. 

Finally, it is becoming increasingly important to understand the interactions between drug(s), excipients, and device components as pharmaceutical dosage forms are becoming more complex, such as multiple active ingredients in a single drug product or drug–device combinations. The higher level of understanding should allow for more robust products that deliver their intended performance when either planned or unplanned changes are introduced. 

The future quality laboratory, according to ISPE, by Angie Drakulich RYAN MCVAY/THINKSTOCK IMAGES  

 Priority 3 in the strategic plan also calls for developing new analytical methods, including those to determine 'similarity' between reference products and biosimilars as well as tools to detect physical properties of complex dosage forms. What gains are hoped for among agency scientists in these analytical areas?  

: Advances in analytical methods to determine 'similarity' between reference products and biosimilars as well as tools to detect physical properties of complex dosage forms will allow for greater confidence that there are no structural differences between products or that any differences observed are minor. For biosimilars, this will reduce uncertainty and allow for a targeted development program. This can also facilitate the development and approval of generics with complex dosage forms as well as inform control strategies for quality of complex originator products. 

 Priority 3 of the August 2011 strategic plan calls for reducing microbial contamination of medical products. What specific goals does FDA have in this area? 

: FDA has attempted to identify and study specific gaps in pharmaceutical manufacturing. Studies are ongoing on sterilizing filtration, effects of terminal- sterilization energies on classes of products, and methods for detection of elusive microorganisms in drug components and manufacturing environments.   

Filtration studies have included microbial penetration rates based on the cell's size and filter matrix composition as well as penetration due to time on various filters with two sizes of growing microorganisms. The goal of these studies is to improve filter-validation studies that previously were shown to have vulnerabilities. Future steps in the research will look into solution conditions that encourage miniaturization of the cells, neutralize cells, or filter surface charges that enhance cell entrapment on filter membranes. 

Many products are manufactured using aseptic processing, which may be less effective than terminal sterilization. Some other surgical products are not manufactured to be sterile at all, also posing risk. Each of these situations is the result of risk assessments that are based on the nature of the product and its vulnerability to sterilizing energy or other conditions. FDA and NIPTE [National Institute for Pharmaceutical Technology and Education] have initiated studies of products (the initial focus is surgical antiseptics) to assess the effects of sterilizing energy on selected products. The goal of these studies is to define conditions that may allow manufacturing to use processes intended to produce a sterile product, which is safer for use in surgical procedures. 

Nonsterile products often require a demonstration that microorganisms, normally expected to be in the product, will not grow or are killed. A similar demonstration is expected of sterile products that may be used several times (e.g., multidose vials). However, there exist microbial strains that can resist preservatives used to control contamination, and some of these strains even grow in the presence of the antimicrobial agents. If allowed to grow, large numbers of microorganisms may reach a potentially infectious dose upon exposure to patients. Among these species are common water bacteria that CDC [Centers for Disease Control and Prevention] have shown to be difficult to detect using compendial methods. In collaboration with CDC and with help from the University of Michigan, we are examining culture methods for recovering these organisms from pharmaceutical water and products. Alternative technologies for their detection are also being considered. The goal of these studies is the development of methods to reliably detect these potential contaminants.  

 One way to improve regulatory science (from a drug review standpoint) is to work with the industry directly to identify and fill in scientific and technological gaps that exist across drug development and manufacturing. FDA has created a few grant-based CERSIs, specifically with Georgetown University (GU), the University of Maryland (UMD), and the State of Arkansas. Will the agency be opening any additional centers of excellence? 

: We hope in future to fund one to two additional CERSIs, outside the region, but if and when, depends on availability of funding. 

Can you comment on the staff training workshops held to date with these centers and their benefit to agency reviewers? 

: Agency reviewers have had the opportunity to participate in training events sponsored by both UMD and GU CERSIs. These events have provided continuing medical education to staff and opportunities to network with leading researchers from around the country. Additionally agency reviewers have also had the opportunity to maintain their scientific and medical skills by participating in clinical work, research, or teaching opportunities at UMD and GU CERSI. 

: Section 1124 of FDASIA states that the US HHS Secretary should have a strategy and implementation plan 'for advancing regulatory science for medical products in order to promote the public health and advance innovation in regulatory decision-making' by July 2013. What is FDA's role?  

: FDA is taking the lead in developing the Strategy and Implementation Plan for Medical Products as required in Section 1124 of FDASIA. 

Are any additional major goals expected beyond FDA's current strategic plan surrounding regulatory science? 

: No, FDA expects to stay within the framework outlined in the Strategic Plan for Regulatory Science. The major areas of focus outlined in the Strategic Plan for Regulatory Science identify broad areas where advances in regulatory science are needed and are thus quite comprehensive. It is expected that the annual progress reports, which will follow in 2014 and 2016, will include more detailed information on specific accomplishments related to regulatory science. 

: Part of FDASIA helps to fund FDA foreign inspections through new user fees (i.e., the Generic Drug User Fee Amendments of 2012 [GDUFA]). Starting in 2014, inspections will use risk-based methodologies. What factors will the agency use to determine whether and when to inspect a foreign facility? 

 We have yet to finalize the revised risk-based approach although FDASIA Section 705 outlines the factors relevant to evaluating risk. All facilities will be inspected sooner or later. Firms new to FDA will be a priority as would be firms that are seeking approval for a type of manufacturing operation that is new to that site. FDA will consider establishing different frequencies for active ingredient and finished dosage form production facilities. Facilities that make sterile drugs will likely be a higher priority than other types of production. GDUFA expects the frequency and rigor of domestic and foreign facility inspections to be equitable, which makes good sense for all drugs, so the risk-based model will have to ensure this is achieved. 

: FDASIA calls for the agency to issue guidance by July 2013 that defines when an inspection may be denied or limited. What is the status ?  

: As required by Section 707 of FDASIA, FDA is currently working on a draft guidance that will address the scope of actions or inactions that constitute a delay, denial, refusal or limitation of an inspection. Section 707 deems a drug misbranded if it is produced in a facility for which an inspection is delayed, denied, refused, or limited. This provision is important because it creates a strong incentive for all facilities, including foreign facilities, to allow FDA to conduct timely and complete inspections. If a domestic facility delays, denies, refuses, or limits an inspection, FDA has jurisdiction to obtain an inspectional warrant. Prior to FDASIA, however, FDA did not have an effective tool to facilitate the cooperation of foreign facilities with inspections. Now, if a foreign facility delays, denies, limits, or refuses an inspection, FDA may refuse entry for all drug products produced in that facility. This will save FDA time and resources and help ensure the safety of our drug supply.     

 FDASIA allows for FDA to use inspection information from other governments and agencies. Can you elaborate on this and other information-sharing? 

 FDA inspection reports are generally detailed accounts of each inspection that include the purpose, description of the breadth and depth of coverage, findings, and significant discussions with a firm's staff. FDA would be able to make use of comparably detailed reports from our counterparts and, under FDASIA Section 712, FDA would be able to recognize a foreign government's inspections once a review and audit of their system verifies their inspections to the satisfaction of FDA. FDA currently shares inspection reports, as well as data-systems access, with counterpart national regulatory agencies that often use these reports or inspection findings in lieu of their own inspection. Fortunately, there now exists an organization of pharmaceutical inspectorates that harmonizes drug regulatory practices: the Pharmaceutical Inspection Co-operation Scheme (PIC/S). FDA became a member of PIC/S approximately two years ago. Membership gives FDA an opportunity to work with fellow PIC/S member authorities to ensure that inspection standards are robust and followed. 

 Regarding imports, FDASIA notes that foreign manufacturers must demonstrate the regulatory status of their drug as well as cGMP compliance and prove facility registration within the US; otherwise, the agency has the right to destroy noncompliant imported drugs under a $2500 value. These rules are set to take place in July 2014 after further regulations are developed. How will the new standards differ from current import and foreign registration requirements?  

: FDASIA provides FDA clear authority to require information about drugs offered for import and to refuse admission if it is not provided, which strengthens FDA's ability to monitor imported drugs for compliance with applicable laws. Similar to many other countries, FDASIA places the burden on the importer or product owner to prove its drug complies with applicable US requirements. These import authorities strengthen FDA's ability to evaluate imported drugs for compliance with US laws and regulations. The authorities also enable FDA to better target higher risk products and prevent violative products from entering the United States.   

FDASIA also grants FDA explicit authority to destroy violative drugs refused admission to the United States if they are valued at $2500 or less. Before FDASIA's enactment, FDA had no independent administrative destruction authority. Instead, FDA could only issue a 'notice of refusal of admission' for noncompliant drugs offered for import. Once FDA issued a 'notice of refusal of admission,' FDA had to rely on Customs and Border Protection (CBP) to either export or destroy the noncompliant import under the Tariff Act (19 U.S.C. 1595). By granting FDA administrative destruction authority after adequate notice and hearing, for violative drugs valued at $2500 or less, these new FDASIA authorities will not only create efficiencies and transparency in the import process, but also strengthen FDA's ability to protect public health. 

 How will these new requirements affect the supply chain and drug shortages? 

 The new drug safety authorities FDASIA grants FDA reflect a more comprehensive and transparent view of the drug supply chain. For instance, FDASIA Section 714 requires that commercial importers register with FDA, and Section 703 requires that drug-product listings identify excipient information. By granting FDA new authorities that more accurately reflect the entire drug lifecycle, FDASIA better equips the agency to protect public health and minimize consumer exposure to unsafe, ineffective, and poor quality drugs in today's globalized supply chain. FDA will continue all efforts to address and prevent drug shortages while implementing these new requirements, which are anticipated to further strengthen efforts to assure the safety and quality of drugs for US patients.  

Articles

FDA talks about the changing scope of regulatory science and its effect on drug reviews, site inspections, and overall approaches.

A Look Ahead at Manufacturing and Regulation

Where will the future of manufacturing lead us?

From time to time, it's important to take stock of the industry from both a retrospective and prospective point of view. Throughout 2012, we celebrated 35 years of 

, looking back at major advancements in technology, drug development and manufacturing approaches, and regulatory science. As we enter 2013, we are eager to envision what the future of bio/pharmaceutical manufacturing will bring. In this issue, in fact, a special report focuses on emerging regulatory trends, including new FDA approaches to drug reviews and inspections. You also will find a few new looks across PharmTech's pages, redesigned to address our growing industry coverage as well as to introduce you to our digital platforms. 

 But getting back to science and manufacturing, we've asked our editorial advisory board members to provide their perspective on the future of bio/pharmaceutical manufacturing. Below are a few highlights.  

"I believe that more companies will turn to continuous manufacturing. Continuous manufacturing allows companies to manufacture the desired dosage form in less time as well as the desired amount of drug product reducing inventory costs. Continuous manufacturing equipment can be installed in less space, thereby reducing energy and maintenance costs. QbD and PAT concepts can be incorporated within the process, reducing regulatory risks at the same time that financial benefits increase." 

—Rodolfo J. Romañach, Recinto Universitario de Mayaguez, Puerto Rico

"Pharmaceutical manufacturing has to become more efficient, more sustainable, 'greener' and safer for the patient. New technologies such as PAT and continuous manufacturing (with on-line quality assurance and real-time release) will help to develop products and processes according to the QbD principles and achieve these goals." 

—Griet Van Vaerenberg, GEA Pharma Systems

"The future of pharmaceutical manufacturing must nor resemble its past. Automation has changed the face of much of our society in the past 20 years, however the industry is somewhat paralyzed with respect to applying automation effectively in the manufacturing environment. The reasons are numerous and can be summed up in a single word: fear. Our industry fears change, 21 

 Part 11, validation delays, inflexible operation, and more. We don't make cars, electronics, or anything else other than pharmaceuticals the way we did in 1980, so it's past time to embrace technologies that can make pharmaceutical products faster, more consistently and of substantially higher quality." 

"The future of pharmaceutical manufacturing lies in outsourcing. Generally, contractors manage plants at much higher utilization levels than do the multinational pharmaceutical companies, thus reducing unit cost. The divestiture of plants by merged global pharmaceutical companies to CMOs provides for significant capacity, which is viewed by multinationals as further opportunity to reduce cost. With the need to reduce costs, networking with contract manufacturers is the future." 

 "Manufacturing and distribution—already regarded by regulators as 'one process'—will continue to merge their joint significance as we strive to create greater supply-chain integrity and provide the protection from falsified medicines that patients demand from manufacturers. Guidance such as that contained in USP Chapter 1083, the recent pedigree initiatives, and the new European GMP/GDP regulations will start to close the gaps that we know exist, but there is a long way to go for manufacturers and their partners." 

 "The future for pharma and biotech appears to be in a state of flux. The activities covering R&D and manufacturing are no exception. The need to 'go global' is no more a concept but a reality. What comes next is finding partners who already have a global platform. One has to make a careful assessment for short-listing potential partners." —

"Biological medicines are a growing proportion of healthcare budgets. Increasing pressures to deliver more cost-effective therapies mean that the biotech industry needs to continuously modernize to respond effectively to future challenges. With personalized medicines on the way, innovative manufacturing strategies will be needed to bring manufacturing close to the patient. Advances in process and analytical technology are required to generate predictive small-scale mimics of processes, with data processing tools to help elucidate the interactions between multiple variables. Well-characterised processes are easier to scale up and out, allowing rapid manufacture and deployment of product." —

Sharon Grimster on behalf of the BioIndustry Association Manufacturing Advisory Committee. 

From time to time, it's important to take stock of the industry from both a retrospective and prospective point of view.

A Look Ahead for 2013

 is a discipline that creates new tools, standards and approaches for use in assessing the safety, effectiveness, quality and performance of products. 

 Dan Ward/Le Club Symphonie/Ian Nolan/Getty Images			

In October 2010, FDA issued a framework for advancing regulatory science for public health, which focused on the following: accelerating delivery of new medical treatments; improving paediatric and children's health; protecting against emerging infectious diseases and terrorism; enhancing safety and health through informatics; protecting the food supply; modernising safety testing; meeting challenges for regulating tobacco; and setting a collaborative implementation framework. 

Following that framework, in August 2011, the agency released a strategic plan for advancing regulatory science at FDA, largely focused on science-based decision-making to improve public health. Part of this initiative identifies specific standards, methods and questions for drug reviewers to use in their review process. The overall effort builds upon the agency's Critical Path Initiative, launched in 2004, to drive innovation in scientific processes, which includes the 2011 report that prioritised eight areas, which included support for new approaches to improve product manufacturing and quality.  

FDA has launched several Centres for Excellence in Regulatory Science and Innovation (CERSI) to carry out these priorities. The agency's initiative in regulatory science was also enhanced with the passage of the Food and Drug Administration Safety and Innovation Act (FDASIA) in July 2012. Section 1124 of FDASIA calls for improving medical product decision-making through guidance documents and the adoption of tools, methods, and processes. The US Health and Human Services (HHS) Secretary must issue performance reports on these goals for fiscal years (FY) 2014 and 2016. 

) spoke to FDA about these issues in a special interview on the future of bio/pharmaceutical regulation. 

PTE: In August 2011, FDA released a strategic plan, Advancing Regulatory Science at FDA. Priority 3 of that plan focuses on product manufacturing and quality, including enabling the development and evaluation of novel and improved manufacturing methods to improve product quality, namely through continuous manufacturing, novel manufacturing technologies, excipients and complex dosage forms, and process analytical technology (PAT) and quality-by-design (QbD) approaches. What does FDA and the industry hope to gain by focusing on these areas? 

 FDA is responsible for protecting the consumer through the availability of quality products. These approaches focus on good, sound science in achieving a high quality product. By applying QbD and understanding the role of excipients and complex dosage forms, a higher level of product and process understanding will be obtained. The other approaches, (PAT, continuous manufacturing and novel manufacturing technologies) utilise that understanding to achieve a more robust and capable manufacturing processes, resulting in higher product quality. With this higher level of product quality, the product failure rate is expected to drop, which in turn, will increase product availability, and reduce product cost. Therefore, by focusing on these science-based approaches, FDA is confident that the overall quality of pharmaceutical products [will] continue to increase. 

Modernising manufacturing approaches for pharmaceuticals, such as through QbD, continuous manufacturing and/or PAT, has the potential to benefit industry, regulators, and patients. Already, there have been multiple reports of quality and cost benefits to manufacturers through the use of QbD and/or PAT approaches. For patients, these approaches can lead to increased assurance of quality and product availability. For regulators, it potentially means less regulatory oversight postapproval due to regulatory flexibility (e.g., design space) filed with the application. FDA is currently pursuing additional pathways to ease postapproval changes for well-understood and controlled processes under a robust quality system. 

Continuous manufacturing, although new to most pharmaceutical manufacturing, is a commonly used technology in food and chemical processing. As more companies are gaining experience with continuous manufacturing, benefits are emerging, including cases of reduced manufacturing scale-up issues, reduced material usage in development, and flexible manufacturing capacities. Because of the changing dynamics of new drugs toward more specialised, lower-volume products, continuous manufacturing could become more commonplace in the years ahead. 

PTE: Priority 3 in the strategic plan also calls for developing new analytical methods, including those to determine 'similarity' between reference products and biosimilars as well as tools to detect physical properties of complex dosage forms. What gains are hoped for amongst agency scientists in these analytical areas? 

 Advances in analytical methods to determine 'similarity' between reference products and biosimilars, as well as tools to detect physical properties of complex dosage forms, will allow for greater confidence that there are no structural differences between products or that any differences observed are minor. For biosimilars, this will reduce uncertainty and allow for a targeted development program. This can also facilitate the development and approval of generics with complex dosage forms, as well as inform control strategies for quality of complex originator products. 

PTE: Priority 3 of the August 2011 strategic plan calls for reducing microbial contamination of medical products. What specific goals does FDA have in this area?

 FDA has attempted to identify and study specific gaps in pharmaceutical manufacturing. Studies are ongoing on sterilising filtration, effects of terminal- sterilisation energies on classes of products, and methods for detection of elusive microorganisms in drug components and manufacturing environments.   

Filtration studies have included microbial penetration rates based on the cell's size and filter matrix composition as well as penetration due to time on various filters with two sizes of growing microorganisms. The goal of these studies is to improve filter-validation studies that previously were shown to have vulnerabilities. Future steps in the research will look into solution conditions that encourage miniaturisation of the cells, neutralise cells or filter surface charges that enhance cell entrapment on filter membranes. 

Many products are manufactured using aseptic processing, which may be less effective than terminal sterilisation. Some other surgical products are not manufactured to be sterile at all, also posing risk. Each of these situations is the result of risk assessments that are based on the nature of the product and its vulnerability to sterilising energy or other conditions. FDA and NIPTE [National Institute for Pharmaceutical Technology and Education] have initiated studies of products (the initial focus is surgical antiseptics) to assess the effects of sterilising energy on selected products. The goal of these studies is to define conditions that may allow manufacturing to use processes intended to produce a sterile product, which is safer for use in surgical procedures. 

Nonsterile products often require a demonstration that microorganisms, normally expected to be in the product, will not grow or are killed. A similar demonstration is expected of sterile products that may be used several times (e.g., multidose vials). However, there exist microbial strains that can resist preservatives used to control contamination and some of these strains even grow in the presence of the antimicrobial agents. If allowed to grow, large numbers of microorganisms may reach a potentially infectious dose upon exposure to patients. Among these species are common water bacteria that CDC [Centres for Disease Control and Prevention] have shown to be difficult to detect using compendial methods. In collaboration with CDC and with help from the University of Michigan [US], we are examining culture methods for recovering these organisms from pharmaceutical water and products. Alternative technologies for their detection are also being considered. The goal of these studies is the development of methods to reliably detect these potential contaminants.  

PTE: One way to improve regulatory science (from a drug review standpoint) is to work with the industry directly to identify and fill in scientific and technological gaps that exist across drug development and manufacturing. FDA has created a few grant-based CERSIs, specifically with Georgetown University (GU) [US], the University of Maryland (UMD) [US], and the State of Arkansas [US]. Will the agency be opening any additional centres of excellence?

 We hope in future to fund one to two additional CERSIs, outside the region, but if and when depends on availability of funding. 

PTE: Can you comment on the staff training workshops held to date with these centres and their benefit to agency reviewers?

 Agency reviewers have had the opportunity to participate in training events sponsored by both UMD and GU CERSIs. These events have provided continuing medical education to staff and opportunities to network with leading researchers from around the country [US]. Additionally, agency reviewers have also had the opportunity to maintain their scientific and medical skills by participating in clinical work, research or teaching opportunities at UMD and GU CERSI.  

PTE: Section 1124 of FDASIA states that the US HHS Secretary should have a strategy and implementation plan 'for advancing regulatory science for medical products in order to promote the public health and advance innovation in regulatory decision-making' by July 2013. What is FDA's role? 

 FDA is taking the lead in developing the Strategy and Implementation Plan for Medical Products, as required in Section 1124 of FDASIA. 

PTE: Are any additional major goals expected beyond FDA's current strategic plan surrounding regulatory science?

 No, FDA expects to stay within the framework outlined in the Strategic Plan for Regulatory Science. The major areas of focus outlined in the Strategic Plan for Regulatory Science identify broad areas where advances in regulatory science are needed and are thus quite comprehensive. It is expected that the annual progress reports, which will follow in 2014 and 2016, will include more detailed information on specific accomplishments related to regulatory science. 

PTE: Part of FDASIA helps to fund FDA foreign inspections through new user fees (i.e., the Generic Drug User Fee Amendments of 2012 [GDUFA]). Starting in 2014, inspections will use risk-based methodologies. What factors will the agency use to determine whether and when to inspect a foreign facility?

 We have yet to finalise the revised risk-based approach although FDASIA Section 705 outlines the factors relevant to evaluating risk. All facilities will be inspected sooner or later. Firms new to FDA will be a priority as would be firms that are seeking approval for a type of manufacturing operation that is new to that site. FDA will consider establishing different frequencies for active ingredient and finished-dosage form production facilities. Facilities that make sterile drugs will likely be a higher priority than other types of production. GDUFA expects the frequency and rigor of domestic and foreign facility inspections to be equitable, which makes good sense for all drugs, so the risk-based model will have to ensure this is achieved. 

PTE: FDASIA calls for the agency to issue guidance by July 2013 that defines when an inspection may be denied or limited. What is the status? 

 As required by Section 707 of FDASIA, FDA is currently working on a draft guidance that will address the scope of actions or inactions that constitute a delay, denial, refusal or limitation of an inspection. Section 707 deems a drug misbranded if it is produced in a facility for which an inspection is delayed, denied, refused or limited. This provision is important because it creates a strong incentive for all facilities, including foreign facilities, to allow FDA to conduct timely and complete inspections. If a domestic facility delays, denies, refuses or limits an inspection, FDA has jurisdiction to obtain an inspectional warrant. Prior to FDASIA, however, FDA did not have an effective tool to facilitate the cooperation of foreign facilities with inspections. Now, if a foreign facility delays, denies, limits or refuses an inspection, FDA may refuse entry for all drug products produced in that facility. This will save FDA time and resources and help ensure the safety of our drug supply.  

PTE: FDASIA allows for FDA to use inspection information from other governments and agencies. Can you elaborate on this and other information-sharing?

 FDA inspection reports are generally detailed accounts of each inspection that include the purpose, description of the breadth and depth of coverage, findings and significant discussions with a firm's staff. FDA would be able to make use of comparably detailed reports from our counterparts and, under FDASIA Section 712, FDA would be able to recognise a foreign government's inspections once a review and audit of its system verifies its inspections to the satisfaction of FDA. FDA currently shares inspection reports, as well as data-systems access with counterpart national regulatory agencies that often use these reports or inspection findings in lieu of their own inspection. Fortunately, there now exists an organisation of pharmaceutical inspectorates that harmonises drug-regulatory practices: the Pharmaceutical Inspection Co-operation Scheme (PIC/S). FDA became a member of PIC/S approximately two years ago. Membership gives FDA an opportunity to work with fellow PIC/S member authorities to ensure that inspection standards are robust and followed. 

PTE: Regarding imports, FDASIA notes that foreign manufacturers must demonstrate the regulatory status of their drug as well as cGMP compliance and prove facility registration within the US; otherwise, the agency has the right to destroy noncompliant imported drugs under a $2500 value. These rules are set to take place in July 2014 after further regulations are developed. How will the new standards differ from current import and foreign registration requirements? 

FDASIA provides FDA clear authority to require information about drugs offered for import and to refuse admission if it is not provided, which strengthens FDA's ability to monitor imported drugs for compliance with applicable laws. Similar to many other countries, FDASIA places the burden on the importer or product owner to prove its drug complies with applicable US requirements. These import authorities strengthen FDA's ability to evaluate imported drugs for compliance with US laws and regulations. The authorities also enable FDA to better target higher risk products and prevent violative products from entering the US. 

FDASIA also grants FDA explicit authority to destroy violative drugs refused admission to the US if they are valued at $2500 or less. Before FDASIA's enactment, FDA had no independent administrative destruction authority. Instead, FDA could only issue a 'notice of refusal of admission' for noncompliant drugs offered for import. Once FDA issued a 'notice of refusal of admission', FDA had to rely on Customs and Border Protection (CBP) to either export or destroy the noncompliant import under the Tariff Act (19 U.S.C. 1595). By granting FDA administrative destruction authority after adequate notice and hearing, for violative drugs valued at $2500 or less, these new FDASIA authorities will not only create efficiencies and transparency in the import process, but also strengthen FDA's ability to protect public health. 

PTE: How will these new requirements affect the supply chain and drug shortages?

The new drug-safety authorities FDASIA grants FDA reflect a more comprehensive and transparent view of the drug supply chain. For instance, FDASIA Section 714 requires that commercial importers register with FDA and Section 703 requires that drug-product listings identify excipient information. By granting FDA new authorities that more accurately reflect the entire drug lifecycle, FDASIA better equips the agency to protect public health and minimise consumer exposure to unsafe, ineffective and poor quality drugs in today's globalised supply chain. FDA will continue all efforts to address and prevent drug shortages while implementing these new requirements, which are anticipated to further strengthen efforts to assure the safety and quality of drugs for US patients. 

Where are CMOs headed? A Q&A with DSM Pharmaceutical Products CEO Alexander Wessels by Angie Drakulich

DSM Pharmaceutical Products received an award for best CMO in the summer of 2013 from the second annual BioPharma Asia Industry Awards in Singapore. 

discussed industry trends in pharmaceutical outsourcing with DSM Pharmaceutical Products CEO Alexander Wessels. 

DSM Pharmaceutical Products CEO Alexander Wessels			

In your experience, what capabilities are CMOs now expected to have that they didn't have 5 or 10 years ago?

 DSM's stake in the pharma outsourcing market is based on a global portfolio of resources to continuously serve changing customer needs and bring real value as the pharma industry shifts business models. This requires a breadth and depth of expertise in the various areas of pharmaceutical technology that can be applied to customer challenges for increasingly efficient processes. We are embedding such innovations across our mammalian, microbial, chemical and finished dosage platforms. In the area of process analytical technology (PAT), for example, DSM has demonstrated the efficiencies and safety of microreactor technology for the commercialscale production of APIs as an example of process intensification to achieve more efficient commercial production, better manage manufacturing volumes and drive down total costs. In this way, we can challenge current process technologies with innovations in process intensification for next-generation manufacturing solutions.  

FDA talks about the changing scope of regulatory science and its effect on drug reviews, site inspections, overall approaches.

are based in New Jersey, so when Hurricane Sandy hit last month, we were all affected. Flooding and high winds destroyed many coastline homes along with well-known destinations across Atlantic City, the Jersey Shore, and the neighboring Manhattan boroughs. Suburban communities and businesses (including many US biopharma manufacturing headquarters) across the state were without power for days and schools were shutdown for a week or more in several counties. President Obama declared the state, along with New York, a major disaster area. The entire ordeal was quite surreal, and our team considers ourselves to be lucky that we made it through unscathed. Our thoughts go to those still recovering from the storm and trying to get back to normal. 

Many common questions arose during the hurricane and its aftermath, including how long food products could be considered safe to eat without refrigeration and where the closest open gas station was to refill generators. Pertaining to our industry were questions about medications that required refrigeration (primarily injectables and liquids), prescriptions that needed refilling (many doctors' offices and drugstores were closed due to flooding and power outages), and drug products that had gotten wet or been lost in the storm. 

Fortunately, FDA has a consumer webpage devoted to drug safety after a natural disaster, whether it be exposure to fire, unsafe water (key for drugs that have to be reconstituted), or lack of refrigeration. Certain life-saving drugs (e.g., insulin) can be used even if not cold as long as they are not past their expiration date, says the agency webpage. There is also FDA information on medical devices and their safety during a crisis, and even an agency guidance aimed at sales representatives on how to deal with lost or stolen drug samples in the aftermath of a disaster (looting in general was quite prevalent after Hurricane Sandy).  

There are also some rules of thumb to follow in any emergency-preparedness plan. Many patient advocates recommend having on hand a 30-day supply of regularly used medicines (both prescription and over the counter), as well as extra quantities of devices needed to administer medications. But as a consumer, it seems there should be even more information available for those unfortunate times when something out of human control affects the medications we need. As an asthmatic, for example, I was concerned about my inhaler's pending expiration date and not being able to get a refill without having to go the emergency room, which by the way, would have been impossible given that the end of my street had a 60-foot tree and power lines lying across it.  

I recognize that drug labels are already quite lengthy, but it may be worthwhile to add a few more details. For instance, language may focus on how long a cold-chain medicine can go without refrigeration, or how long a drug exposed to excessive heat can be considered safe, or the reasons behind drug-product expiration dates. Some of these details may be in medication guides that come with drug products, but even those of us in the pharma industry know that the majority of end users do not read those packets in full or keep them. This is probably an area where FDA and pharmacists can do a better job educating consumers about the importance of medication guides. 

Another piece of information worth including on labels may be where to find information during emergency situations. As so many discovered during Hurricane Sandy, we rely heavily on technology to get our information. Smart phones, in particular, became indisposable in the aftermath of the storm when power outages held hostage traditional television, phone, and Internet access. Pharma companies could consider, for example, having active Twitter feeds during emergencies so that people can still access crucial information. 

Various disasters and crises are bound to affect the global community in the future. Now is the time to think about the crucial information we will need to have on hand—and attached to our medications—when that next disaster strikes. 

PDA's strategic plan calls for maintaining valuable and effective relationships with global regulators.

When Disaster Strikes at Home

 The PhRMA Research & Hope Awards go beyond solely scientific awards to include honorees for patient advocacy and volunteer work. Why do you think this broader scope is important? 

 The awards honor people who have gone to tremendous lengths to improve the lives of patients suffering from various diseases, with the focus of the 2012 awards being Alzheimer's disease. It's important to recognize not just medical advances and research but also the people who are working to alleviate suffering through caring directly for patients. These people are very often family members and loved ones. It's through collaborative efforts among many stakeholders that we can best hope to achieve the goal that we all have–to help stop the suffering caused by Alzheimer's disease.  

 Along these lines, in your experience, what major two or three challenges do researchers face in finding a drug to prevent and/or treat Alzheimer's?  

All neurological diseases are complicated and AD is no different in that regard. We are still working to increase our overall understanding of AD and to identify approaches through which we can help to modify its course and/or provide symptom relief.  

That said, there are many challenges that we've faced and continue to face in our research. Many of the latest setbacks that we've seen in the recent studies that have not met their primary endpoints can be attributed to at least two factors. First, the treatments being tested had significant side effects that limited the doses that could be administered, which may have also limited their effectiveness. Second, these studies have reinforced a collective opinion in the field that we may need to start treatment years before patients begin to show symptoms. However, that means being able to identify people who are at risk for developing AD in the first place, and that research is still ongoing.  

 Because Alzheimer's is so complicated and because of certain R&D/clinical study setbacks in recent months, some reports have stated that people are giving up hope, as well as research funds, toward curing Alzheimer's. What might be your argument or response to these reports? 

AD is one of the most challenging and devastating diseases of our time, causing untold physical, emotional and financial suffering to patients and their caregivers. We are trying to find new therapies that can help to prevent or slow its onset and that may help to alleviate the disease symptoms. We cannot let ourselves lose sight of the fact that this disease has tremendous human and economic costs. 

Yes, there have been many setbacks, but with each setback we can learn new information, draw new conclusions and move the field forward. From this perspective, we don't consider them "failures," per se, but rather, stepping stones.  

We know that finding new therapies to help Alzheimer's patients will not be easy, but AD research remains a top priority for Merck. We will continue to make strides and believe that we are already on our way. 

 A report from PhRMA and the Alzheimer's Foundation talks about delaying the onset of Alzheimer's Disease, and specifically how even just a 5-year delay in onset can save millions of healthcare and medical dollars. What's your perspective on delaying the onset versus preventing the disease altogether? What are the benefits of disease modification in Alzheimer's patients?  

There are currently no treatments on the market that can slow the progression of AD and few treatments to control some of the symptoms. Of course, preventing the disease altogether is the ultimate goal, but delaying the onset has not only tremendous financial benefits, but significant personal benefits for those dealing with the disease every day. Currently, patients and their families are grateful for even the very modest improvement in symptoms that current treatments afford. Until a cure or prevention is found, delaying the onset of this disease for as long as possible would be a "win" for all concerned. 

An overarching goal of our industry is to improve people's quality of life in terms of better health, and delaying onset of AD for as long as possible would help to contribute to that goal. 

The industry, including Merck, has been focused on the amyloid hypothesis for more than 10 years. Do you think this is still the route to follow, and why? What other comparable possibilities do you think are worth pursuing? 

While the exact cause of AD remains unknown, the amyloid hypothesis is currently the most widely accepted explanation. The hypothesis states that AD is caused by the accumulation in the brain of beta-amyloid (Aβ) protein fragments, which are formed when BACE and γ-secretase enzymes process the amyloid precursor protein. These Aß  proteins are sticky and clump together into aggregates such as amyloid plaques that can have toxic effects in the brain. There is a substantial amount of evidence supporting the amyloid hypothesis, including an overwhelming amount of human genetic data that implicates the A  peptides as being involved in the etiology of AD. 

The amyloid hypothesis suggests that one of the ways to alter the molecular cause of AD is to inhibit the activity of BACE. With these so-called BACE inhibitors, the production of Aß  proteins would be stalled, thus possibly impacting the onset of AD. 

Despite several investigational compounds and monoclonal antibodies that have tested the amyloid hypothesis with little if any success, we believe that BACE inhibition represents a hopeful approach for AD patients. We have shown that BACE inhibition reduces levels of the A  peptides to a greater degree than other treatments that have been tested. Therefore, BACE inhibitors are a promising means for testing the amyloid hypothesis. 

That said, however, we are equally dedicated to finding non-amyloid approaches and symptomatic therapies for AD, and are continuing our research in those areas. 

 Clinical-trial results thus far evaluating the safety and tolerability of the Merck BACE team's MK-8931 in 40 healthy adults aged 18 to 45 has associated single doses of MK-8931 with marked reductions in amyloid beta peptide concentration levels. Can you provide a brief background on this compound? Why is this finding important? What are the next steps and timeframe planned for Phase II and/or III studies? 

 Merck is currently focused on advancing our most promising BACE inhibitor, MK-8931 – an investigational compound designed to inhibit A  production as well as reduce existing amyloid plaques in the brain – as a new approach to treating AD. We believe that this compound would be the first to modify the underlying cause of AD, as per the amyloid hypothesis. 

The development of small molecule BACE inhibitors with drug-like properties, i.e. inhibitors that are orally available, can cross the blood-brain barrier and bind to the target, has been a significant challenge for pharmaceutical researchers. However, our internal research has overcome this challenge with the development of MK-8931. MK-8931 has been shown in Phase I human testing to suppress A  formation and was generally well tolerated in healthy subjects. 

Based on these Phase 1 results, Merck is moving forward with the next phase of clinical development in mild to moderate AD patients. Given that BACE inhibitors work at what is thought to be an early stage of the disease process (production of Aß), we are also planning to test MK-8931 in patients at the earliest detectable stage of the disease (so-called prodromal AD patients).  

 Looking ahead 15 to 20 years, where do you expect the industry will be with Alzheimer's R&D? Do you foresee any major changes or breakthroughs within this time period? 

 There are many researchers pursing a number of different approaches to treating AD, and we are very hopeful that the next few years will yield some answers to what is really a difficult scientific problem and a terrible human condition. There is also an unprecedented degree of communication and collaboration between pharmaceutical companies and with regulatory authorities to find better and more efficient ways to bring treatments to Alzheimer's patients. We still have a long way to go as an industry, but we believe we are going down the right path. 

An interview with Eric M. Parker, Ph.D., Executive Director and Neuroscience Site Lead, Merck Research Laboratories, about the Merck BACE team's winning research.

Innovation in a Leading Disease Target: Alzheimer's

 This word is at the heart of bio/pharmaceutical development and manufacturing, whether innovators are targeting a new cell line or formulation, a drug delivery target or method, an analytical or packaging approach, or a quality system. As FDA Commissioner Margaret Hamburg said in April of this year at the Boston NEHI conference on "Bridging the Innovation Gap," innovation "is an issue that is important to us all, whether you come from industry, from academia, from clinical practice, or from government." She spoke about the challenges facing R&D and product pipelines, including patent-cliff implications, stating that, "The trend lines for innovative products relative to investments in research and development are not what any of us would like."  

(IMAGE: DAN WARD; BUENA VISTA IMAGES/GETTY IMAGES)

As an example, Hamburg pointed to the current "golden age" of biomedical discovery in which the industry has sequenced the human genome to reveal potential drug targets and made gains in high throughput screening and nanotechnology, and yet has not necessarily translated these developments into therapies or cures. Hamburg proposed in her speech that a potential solution to this innovation gap requires a "comprehensive, integrated strategy that engages the full 'eco-system.'" 

Such a strategy would include "new and strategic investments in research," and "true collaboration by stakeholders," including "strong leadership from business, academia, and government," she said.  

looks at some of the collaborative efforts taking place among these stakeholders to continue to advance innovation in drug development and manufacturing. The following pages highlight honors given to graduate students and professors as well as bio/pharmaceutical R&D and manufacturing teams throughout 2012. As we prepare to enter the year 2013, we hope these individuals and their hard work will provide inspiration for further pharma innovation. 

DRUG-PRODUCT INNOVATION STRATEGIES AMONG BIG PHARMA

 publishes a report on the top 50 pharmaceutical companies based on global sales of prescription drugs. These companies have managed to stay ahead of the game as the industry faces multiple patent expiries and a changing landscape that includes new outsourcing models, capacity-sharing, and consolidation strategies. 

asked the top companies in this list to talk about their innovation strategies, with a specific focus on drug development and manufacturing. These companies include, in order: Pfizer (New York) with 2011 global prescription sales of $57.7 billion; Novartis (Switzerland) with sales of $54 billion; Merck (New Jersey) with sales of $41.3 billion;  and Sanofi (France) with sales of $37 billion. Below are their responses. 

Kevin Nepveux, vice-president, Global Technology Services, Pfizer Global Supply

"Innovation is a mindset, not a process that can be turned on and off. Organizational strategists tell us that behaviors eat process for breakfast, yet the tendency to separate 'hard' technical skills from the 'softer' communicative skills that drive global workforce interaction persists. Technical-based organizations continue to place great value on the 'hard' skills. We instead need to better understand how our technologists interact with each other, our businesses and their environmental challenges to inspire the everyday innovations as well as breakthroughs.  

"In 2010, Pfizer Global Supply (PGS) reexamined its approach to innovation. We'd designed our tactics to inspire creative thinking, but our follow-up metrics included chasing after projects' monetary value. We began to see the categorization of projects as innovative to meet the fiscal metrics, rather than the unleashing of a mindset to derive truly creative solutions. It was time to reinvigorate our innovation methodologies.  

"We conducted a year-long listening tour at our manufacturing locations and with our technical groups. We formed a diagonally hierarchical global team to steer the development of the new approach, with executive team sponsorship and participation, a manufacturing mechanic operator, technologists, and the organizational levels in between—all with equal seats at the strategy table.  

"Today, our deliberately small headquarters' innovation office trains innovation coaches around the world. This 200-plus global network has responsibility to build local innovation ecosystems and to adapt innovation tools to local needs and cultures. Rather than being in the business of innovation, innovation is instead employed at the needs of the local business.  

"The ideas need to come from everywhere within our global organization, but innovation must be nurtured from the top. Sure, we still need to show the fiscal value of all of this effort. However, we have seen significant payback in a short time by shifting our focus to changing the innovation mindset first, and to allow value to emerge as an outcome of a new way of thinking and behaving. The PGS technologists of tomorrow are not the same mold as the past, and neither is our business." 

Timothy Wright, global head of development 

"There is a consensus in the pharmaceutical industry that we need to accelerate the pace of drug development. If we fail to do so, we won't keep up with the rising health challenges facing our society. Novartis has made good progress with some strong shifts in our approach to drug development. One shift is to invest in developing multiple indications simultaneously (rather than serially), where we advance compounds in more than one clinical setting in parallel, thereby increasing the likelihood that drugs get to patients faster. Once you understand the disease biology and the molecular pathways involved, then each compound can be tested simultaneously in multiple diseases that share the same pathway. An example is our mTor inhibitor everolimus, which is now approved in the US for five cancer indications (under the tradename Afinitor) and renal transplantation (under the tradename Zortress), and our orphan drug Ilaris, originally approved in a very rare genetic disease and now continues to be developed in larger disease populations, including gouty arthritis and heart disease. 

"Another solution to tackling the innovation drought is collaboration and knowledge-sharing. The cost of developing a drug has risen exponentially. Currently, it takes an average of 10 years and costs on average $4 billion to bring a new therapy to market. This model is not sustainable. We need to work together across industry, academia, and government to make our innovation dollars work harder. Only by working together can we make sure new and innovative treatments get to the patients who need them the most." 

Rich Tillyer, senior vice-president, Discovery & Preclinical Sciences, Merck Research Laboratories 

"The opportunities for Merck and the pharmaceutical industry to impact human health are real and numerous given the continuing rapid evolution of biomedical science, but this rapid evolution will not happen without a continued investment in R&D and emphasis on innovation. Innovation in R&D is a critical success factor and Merck understands that this requires a long-term commitment. 

"At Merck, our focus lies in developing first- and best-in-class medicines that will make a meaningful difference for patients. To realize this goal, we need to establish a culture of innovation fueled by collaborations with internal and external partners, and with a focus on growing talent. We will continue to drive these initiatives in 2013 and beyond to ensure that our pipeline of candidates remains strong and continues to advance toward the patients who need our medicines."  

Marc Bonnefoi, head of the Sanofi North America R&D Hub

 "Sanofi is evolving its R&D approach to be able to access the best ideas, science, and people in research. This requires a combination of both internal and external innovation and is implemented through the creation of geographically focused integrated research hubs in which Sanofi scientists increasingly partner with external teams. R&D hubs have been created in North America, with a special emphasis in the Boston area, as well as in Germany and Asia, and a project for implementing a hub in France is being discussed. 

"For many years, the pharmaceutical industry designed drugs from biological targets that were not always well validated and in areas where the path to clinical proof-of-concept and ultimate validation in patients was uncertain. We screened scores of molecules to see whether they had any effect on different disease models that were often incompletely qualified. There were too many assumptions regarding the biology of diseases. Today, we seek to begin with an understanding of the underlying cause(s) of a given disease and work to develop a solution to interfere with that process.  

"We are trying to integrate a translational approach to these efforts, applying the knowledge from patient populations and medical experience much earlier in the R&D processes. To make these translational research efforts a reality, Sanofi is using the ability to translate to the patient situation as a yardstick to judge the quality of projects. None of this can be done by Sanofi R&D alone: we have great people and fantastic ideas, but no one organization can single-handedly tackle the complexity of human chronic diseases, which remain beyond our reach at the moment. By effectively implementing open innovation and raising the bar for projects to be accepted into development and reach further investment milestones down the road, Sanofi expects to create one of the best portfolios in the industry." 

STUDENT INNOVATION ACROSS THE PHARMA SCIENCES

At the 2012 American Association of Pharmaceutical Scientists (AAPS) Annual Meeting in Chicago, graduate students across the country were honored for their research and work in bio/pharmaceutical innovation. Symposium awards were given to graduate students in the areas ranging from analysis and pharmaceutical quality to ocular drug delivery and disposition. 

 had the chance to talk with a few of the recipients about their work.  

Biotechnology category winner David W. Woessner noted that his team's work at the University of Utah on "Synthetically Lethal Combinations for Chronic Myeloid Leukemia (CML) Therapy-Disrupting Dimerization of Bcr-Abl and Secondary Leukemia Specific Pathways" demonstrates the first development of a protein/peptide-based therapeutic for CML.  

"While current therapies in the clinic (tyrsosine kinase inhibitors [TKIs]) act on the ABL portion of the protein, we are demonstrating efficacy by targeting the BCR portion, necessary for oligomerization and activation of the tyrosine kinase. Additionally, this work also exploits a combination therapy approach early in development," he said. Future research in this area has already moved towards combination therapy approaches, explained Woessner. "There are now essentially five TKIs that effectively treat CML. Combinations with other small molecules that target leukemic stem cells, but not normal/healthy hematopoietic stem cells are highly valued. We will continue to see trials for drug combinations," he said. 

Mamta Kapoor of the University of Connecticut also won in the biotechnology category. Her research, "Elucidation of Cellular Uptake Mechanism of Novel Ternary Anionic-siRNA Lipoplexes," aimed to obtain an understanding on formulation-cell interaction that may facilitate faster formulation optimization to achieve efficient delivery. "This research area is interesting because it involves a mechanistic approach to comprehend the rate-limiting steps to proficient intracellular delivery of therapeutic agents," Kapoor explained. The mechanistic studies "have helped in understanding the contribution of formulation components in the uptake process and consequent bioactivity." Looking ahead, Kapoor's team intends to repeat the studies with other novel formulations. 

Lakshmi Prasanna Kolluru, who won in the drug design and development interface category, focused on the "Design and Development of Albumin-based Theragnostic Nanoparticles for Tumor Targeted Drug Delivery." Based at Mercer University, the PhD candidate was inspired as a teenager by a cousin, a cancer patient suffering from the side effects of chemotherapy. "She was disturbed psychologically when she had lost her hair due to side effects and this spurred the interest in me to focus on cancer research. So, when my professor gave me the freedom to design a project, I opted to work on development of a delivery system that targets anti cancer drugs to tumor and reduces the side-effects of chemotherapy," said Kolluru. Looking ahead, the grad student says the university team is "planning to decorate this delivery system with dual-targeting probes to examine the efficacy of the targeting ligands 

 for selective localization of the drug in the tumor region." 

Jiban Jyoti Panda of the International Center for Genetic Engineering and Biotechnology in New Delhi and of the FM University of Balasore, Odisha, India, won in the category of formulation design and development for the paper, "Self-Assembled Dipeptide Nanotubes, Nanovesicles and Nanogels: Potential Vehicles for Targeted Tumor Drug Delivery." The research focused on testing the potential of nanotechnology in cancer therapy. "Different types of polymeric, inorganic, and metallic nanoparticles have been investigated for their potential for effective tumor delivery and therapy. However, there are many factors which prevent the development of these nanoparticles for safe human use," Panda explained. "We tried to develop peptide-based nanoparticles, which are expected to be highly biocompatible due to their peptidic origin. Moreover, because the greatest problem with peptide-based drugs or systems is their low 

 stability, we tried to develop nanoparticles from designed small peptides with the modified amino acid a, -dehydrophenylalanine (?Phe), residue, which is unique and would provide the nanostructures with enhanced assembling behavior and resistance to enzymatic degradation leading to better stability." 

Panda's next goal is to demonstrate the efficacy of these systems in other tumor models and to prove their broader application potential, such as peptide-based nanosystems that may target tuberculosis, AIDS, and other global diseases.  

University of California–San Francisco student Rachel Jean Eclov won for her research into "

Characterization of ABCG2 Enhancers," in the category of pharmacokinetics, pharmacodynamics, drug metabolism, clinical pharmacology and translational research. "Previous research on MXR functionality has been mostly aimed at functional (coding) variants of MXR. My research is unique in that it looks for how other types of genomic variations can alter MXR expression and thus drug disposition. I utilize epigenetic tools to unravel how MXR expression can be tissue specific or transiently increased or decreased," she explained.  

"I then consider how genetic variation in identified regulatory elements can alter the transcriptional properties of that element. Although other epigenetic research has been published, the majority of it is on variations in regulatory elements that cause developmental defects. My research uses epigenetics to identify genetic variations that impact the more subtle world of drug disposition where the effects of these variations are not as obvious but can be just as severe." In terms of how Eclov's research may affect future industry work, she says, "Even though my research is only at the initial edges of understanding of the genetic regulation of an ADME gene, it can be used as a general template for others to research the genetic regulation of their own gene of interest. It shows that there are many ways a gene's expression can be epigenetically regulated and thus deregulated in cancers or by drug treatment. It is also important for scientists to realize that noncoding genetic variants found in large screens, like a GWAS, could be very relevant 'hits' and that there are tools out there to help develop epigenetic models for the function of these variants." 

Another University of Connecticut student, Ekneet K. Sahni, won in the category of manufacturing science and engineering for "Contact Drying in an Agitated Filter-Dryer: Experiments and Simulations." Says Sahni about the research, "Despite recent advances made towards understanding the drying phenomena, intricacies involved in the process not only due to the coupled nature of the process involving heat, mass, and momentum transport but also from their dependence on the material properties and drying conditions, do not allow quantitative predictions with extreme accuracy. The penetration model has been long known and considered as the industrial standard for contact drying. Nevertheless, it has disadvantages in the consideration of granular mechanics due to its continuous nature. Until recently, most of the DEM-based heat transfer work was either two-dimensional or in static granular beds." Sahni explains that the winning work was the first study employing 3D-DEM "to better understand the granular behavior in an agitated filter-dryer by investigating the effect of process variables on the drying performance. Major consideration has been given to the effect of speed, which has not been clearly understood in literature."  

In terms of the work's relevance to future studies, Sahni says, "Along with improving our confidence for the use of DEM as an emerging tool, it fills the gap in the literature for discrete approaches. The benefits are also seen in reduced developmental resources and manufacturing costs without any production delays. Hence, process-modeling based on product development can reduce the time required to get products to market as well as the healthcare costs by saving resources. Takeaways for the scientists are that a priori performance predictive tool is developed that can help in predicting the final outcome even for the process parameters outside the range studied and for any material which gives it an edge over other designs as well as models which are mainly restricted to the parameters and/or material studied." 

Brief PowerPoint presentations from each of the above graduate students appear on 

. For a full list of all the AAPS 2012 Symposium Graduate Student awards, visit 

A look at the year's leaders in innovation strategy, including the top bio/pharmaceutical companies and award recipients from AAPS, PhRMA, and CPhI.