Regulatory science underpins innovation and practices in drug manufacturing. The most common definition of regulatory science is a discipline that creates new tools, standards, and approaches for use in assessing the safety, effectiveness, quality, and performance of products.
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.
The FDA has launched several Centers for Excellence in Regulatory Science and Innovation (CERSI) to carry out these priorities (see sidebar on academia's role on page 28). 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 decisionmaking 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. BioPharm International spoke to FDA about these issues in a special interview on the future of bio/pharmaceutical regulation.
BioPharm: 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: 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.
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.
BioPharm: 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?
FDA: 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.
BioPharm: 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: 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.
ROLE OF CERSIS
BioPharm: 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?
FDA: We hope in future to fund one to two additional CERSIs, outside the region, but if and when, depends on availability of funding.
BioPharm: Can you comment on the staff training workshops held to date with these centers and their benefit to agency reviewers?
FDA: 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.
ADVANCING REGULATORY SCIENCE
BioPharm: 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: FDA is taking the lead in developing the Strategy and Implementation Plan for Medical Products as required in Section 1124 of FDASIA.
BioPharm: Are any additional major goals expected beyond FDA's current strategic plan surrounding regulatory science?
FDA: 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.
FOREIGN INSPECTIONS AND IMPORTS
BioPharm: 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?
FDA: 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.
BioPharm: 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 ?
FDA: 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.
BioPharm: FDASIA allows for FDA to use inspection information from other governments and agencies. Can you elaborate on this and other information-sharing?
FDA: 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.
BioPharm: 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?
FDA: 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.
BioPharm: How will these new requirements affect the supply chain and drug shortages?
FDA: 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.