Jill Wechsler is Pharmaceutical Technology's Washington Editor, jillwechsler7@gmail.com.

Jill Wechsler

	To ensure the quality and safety of drugs, biologics, and medical products more efficiently and effectively, FDA is making significant changes in its plant inspection program, including more attention to imports and to foreign producers of drugs for American consumers. An aim is to target manufacturing oversight to more high-risk operations and free up resources for greater scrutiny of foreign facilities in the process. Agency officials also seek to better coordinate and clarify the roles of field investigators and staff from FDA’s Center for Drug Evaluation and Research (CDER) (as well as other agency review centers) in selecting sites, weighing compliance action, and communicating inspection findings to firms. And increased FDA collaboration with foreign regulatory inspectorates promises to reduce redundant site visits and increase oversight of violative situations. 

	After several years of planning, FDA’s Office of Regulatory Affairs (ORA), which manages the agency’s 5000 field inspectors, officially implemented its Program Alignment (PA) initiative in May 2017. This major reorganization shifts ORA from a geographically-based inspection operation to a program aligned by commodities and vertically integrated, with more specialized investigators able to identify and provide more timely information on critical manufacturing issues. Specialized

 for drugs, biologics, medical devices, food, bioresearch monitoring, and tobacco continue to operate out of ORA’s 20 district offices across the United States, with certain offices housing program managers that lead product inspection teams (1). 

	Drugs regulated by CDER and the Center for Veterinary Medicine (CVM), for example, are managed by the Office of Pharmaceutical Quality Operations (OPQO), directed by long-time ORA official Alonza Cruse. He oversees four divisions of pharmaceutical quality operations, each headed by a regional manager, plus a division for quality programs (for compounders and preapproval inspections) and a division for foreign inspections, Cruse explained at the PDA/FDA regulatory conference in September 2017. The aim is to achieve more consistent and timely inspections with reduced uncertainty for industry. 

	Similarly, ORA’s Office of Biological Products Operations, headed by Ginette Michaud, has two operating divisions to oversee the production of blood products, tissues, vaccines, and other products regulated by the Center for Biologics Evaluation and Research (CBER). The Office of Bioresearch Monitoring Operations under Chrissy Cochran also has two divisions, while the Office of Medical Devices and Radiological Health Operations has three divisions. 

	A key goal of the reorganization is to enhance communication and collaboration between field inspectors and center product specialists. This approach for drugs is spelled out in a “Concept of Operations” 

released in August 2017 (2). The 20-page report maps out how ORA and CDER staffers will collaborate in the planning and conduct of inspections and the communication of findings to manufacturers, with decision trees for managing each of the four types of inspections. Increased integration of drug review and facility evaluations aims to achieve more consistency and certainty in regulatory decisions, 

commented FDA Commissioner Scott Gottlieb

	For preapproval inspections (PAIs), a CDER team, including staffers from the Office of Process and Facilities (OPF) in the Office of Product Quality (OPQ), prepares an integrated quality assessment. This assessment reviews information in an application on facilities, processes, and microbiology, plus past inspection reports, to determine whether a PAI is needed for each site listed in the submission. ORA leads any necessary inspection, with CDER participation, and communicates findings to the assessment team. A similar process is involved in planning for and conducting post-approval facility inspections, which may occur following manufacturing changes, particularly for a facility where a PAI has not taken place.

	For GMP surveillance inspections, OPQ’s Office of Surveillance (OS) collaborates with ORA to determine the need, timing, and scope of site visits, based on a facility’s inspection history, type of products produced, and risks previously reported. ORA investigators generally conduct these inspections, informing CDER’s Office of Compliance (OC) if they observe questionable situations. ORA also leads for-cause inspections, interacting with CDER’s OPQ and OC.

	To ensure timely inspections of facilities listed in new drug applications, FDA and industry agreed in the new prescription drug user fee program to delay application approval if a sponsor fails to identify all relevant sites in a submission. The aim is to provide complete facility information for ORA to have sufficient time to inspect and evaluate relevant production sites. The Generic Drug User Fee Amendments (GDUFA II) further establish a pre-submission correspondence process that requires manufacturers of critical drugs qualifying for priority approval to submit information on planned production facilities two months before filing the application-again, to support timely inspection of relevant production sites in tight timeframes.

	A more efficient field inspection program also aims to communicate inspection findings to manufacturers more quickly. GDUFA II specifies that FDA will provide surveillance inspection findings to facility owners within 90 days of completing a site visit, beginning October 2018, and CDER officials expect to apply that goal to all drugs. The aim is for ORA to submit recommendations to CDER within 45 days of post-approval and surveillance inspections so that staff can follow up quickly with the manufacturer. 

	International collaborationThe need to oversee the growing number of overseas pharmaceutical manufacturers also is prompting US and European regulatory authorities to collaborate more on drug inspection activities. FDA and the European Medicines Agency (EMA) are moving forward with a Mutual Recognition Agreement (MRA) that will permit participants to rely more on each other’s inspection reports. By reducing the need to inspect all of more than 1000 registered drug production facilities in Europe, FDA would avoid duplicate site visits and free up resources to support greater oversight of firms in China, India, and other nations. 

 in March 2017 to extend and conclude the MRA negotiating process by July 2019 (4). The process involves FDA observing how EU member states inspect local facilities, and for EU officials to audit FDA’s inspection program. The two authorities also agreed in August 2017 to protect confidential information in inspection reports from public disclosure, which is important for sharing full inspection reports needed to decide whether or not to visit sites on each other’s inspection schedules. The EU completed its assessment of FDA inspection operations in July 2017, and FDA hopes to finish its audits of the 28 EU member states by mid-2019. 

	The current MRA initiative applies to GMP surveillance inspections for most drugs and biotech therapies, but could be extended to vaccines and veterinary products in the future. An important side-benefit of the final agreement may be to end EU batch inspection of US-made products shipped to Europe. In the future, pre-approval inspections might be covered in certain situations, prompting FDA and EU officials to examine how PAIs differ or are the same in the two regions. FDA’s need to complete such inspections in limited timeframes could lead to an agreement that permits 

 or EMA to request that a capable authority conduct a PAI by a certain date. More information on the MRA is available on FDA’s 

ORA Program Division Boundary Maps and Fact Sheets

Integration of FDA Facility Evaluation and Inspection Program for Human Drugs: A Concept of Operations

, CDER, June 2, 2017.
	3. S. Gottlieb, “New Steps to Strengthen FDA’s Inspection And Oversight Of Drug Manufacturing,” 

, FDA.gov.
	4. FDA, “Mutual Recognition Promises New Framework for Pharmaceutical Inspections for United States and European Union,” 

Frequently Asked Questions/The Mutual Recognition Agreement

Office of Global Regulatory Operations and Policy

	When referring to this article, please cite it as J. Wechsler, “FDA Overhauls Inspection Process and Field Operations," 

Articles

FDA seeks to focus on problematic facilities and inform firms quickly about site problems.

FDA Overhauls Inspection Process and Field Operations

	The extensive volume of pharmaceutical manufacturing in Puerto Rico is driving FDA efforts to quickly assess facility damage and logistical problems to ensure continued supply of critical medicines. More than 20 companies, including Pfizer, Eli Lilly, Johnson & Johnson, and Amgen, operate more than 100 medical product facilities in Puerto Rico, according to FDA. As the hurricane loomed, FDA identified more than 40 high-priority essential drugs made in Puerto Rico where short-term disruptions could lead to shortages of certain treatments for cancer and immunosuppressants for transplant patients. About a dozen of those critical products are made only in Puerto Rico, aggravating potential supply issues.

	FDA commissioner Scott Gottlieb provided an update on agency efforts to deal with the devastation caused by Hurricane Maria at a hearing before the House Energy & Commerce Health subcommittee this week. Before beginning his scheduled testimony on FDA policies to expand patient access to investigational drugs, Gottlieb described how dozens of staffers in FDA’s district office in San Juan are working to assess damage to producers of regulated products. A related challenge is to ensure that Puerto Rican residents have access to needed medical products and to a safe blood supply. While most pharma facilities have continued to operate with generators following the loss of power across the island, concerns remain about the potential for continued production of important therapies. Getting Puerto Rico’s large drug manufacturing capacity back online “is a public health priority,” he stated.

	Although most drug manufacturing facilities were not badly damaged, many employees could not get to work due to impassable roads and water and food shortages. To deal with the situation, FDA staff worked with other federal and local agencies to clear debris blocking facilities, assess manufacturer fuel needs for generators, and secure permissions for planes to land and transport critical products to the mainland. The agency reported last week that it was working with five companies to coordinate priority drug transport off the island.

	An FDA hurricane shortages task force is helping to speed regulatory decisions needed to avoid problems and to get production up and running. Gottlieb noted at the hearing that the situation in Puerto Rico was improving, as pharma companies are able to help staff come to work. But he expressed concerns about company supply chains that could require fast FDA regulatory approvals, as with company decisions to shift some production to mainland facilities.

	And even though manufacturers have powerful generators and sufficient fuel to handle operations for the short term, these emergency systems are not designed to run for months, Gottlieb noted, which may be necessary if the local power grid remains unstable over a long period. These are strong facilities with large generators, Gottlieb told the House panel, “but no one expected an impact of this scale.”

	Puerto Rico emerged as a leading producer of US pharmaceuticals in the 1960s because of tax policies that allowed US-based companies to transmit profits made on the island to headquarters without paying federal taxes. This tax advantage was phased out by 2005, but the island continues to offer highly attractive tax rates for manufacturers, and important R&D incentives have brought in more biotech firms and medical device makers.

	That could change if extensive hurricane damage and poor emergency response spurs company departures. The pharmaceutical industry in Puerto Rico is responsible for nearly 90,000 jobs, and medical products and drugs account for more than half of the island’s exports. Decisions by manufacturers to relocate following this disaster, Gottlieb observed, would “jeopardize the island’s economy.” 

FDA and manufacturers strive to prevent drug shortages from Hurricane Maria.

Storm Impact on Drug Supply

 in early August 2017 reauthorizing critical five-year user fee programs that fund FDA oversight of medical products, just in time to avoid major agency disruptions (1). The vote was delayed by contentious debate on Capitol Hill over revising the Affordable Care Act. But once the wrangling over Obamacare fizzled out, the Senate quickly enacted the FDA Reauthorization Act (FDARA). It mirrored the bill approved by the House in early July and was signed by President Trump on August 18. 

	By enacting new fee programs for drugs, biologics, generic drugs, medical devices, and biosimilars before they expired on Sept. 30, 2017, Congress avoided massive FDA layoffs. Equally important for agency staffers charged with implementing new fee policies, this user fee bill is relatively “clean,” benefitting from enactment of the extensive 21st Century Cures Act last December, which tackled many of the more controversial proposals for accelerating and streamlining the development, testing, and review of medical products.

	Key provisions added to FDARA seek to spur development of pediatric cancer therapies and innovative medical devices and to deter import of illegal or counterfeit medicines. The bill reauthorizes the orphan drug grants program, while limiting orphan drug exclusivity awards to products that demonstrate a clear superiority over existing therapies, and it requires sponsors to conduct studies on new tropical disease treatments to qualify for priority review vouchers. Several provisions aim to speed up field inspections of manufacturing facilities and to assess whether delays in resolving deficiencies found in preapproval inspections block new product approvals. The legislation seeks expedited review of responses to inspection observations for priority applications and for those related to drug shortages. 

	Efforts to lower prescription drug prices ended up with largely symbolic language backing patient access to therapies, plus provisions for speeding the development and marketing of generic drugs to enhance market competition. FDARA establishes a priority review track for competitive generic therapies and an accelerated development initiative for high-demand products; brand manufacturers have to update information on products withdrawn from the market to help clarify which drugs have limited competition. 

 (PDUFA VI) aims to make revenues more predictable for FDA by relying more on a new product fee paid by manufacturers that is based on number of approved products. At the same time, PDUFA reduces application fees and discontinues levies for manufacturing establishments and supplements (2). 

	The overall increase in funding will help improve FDA’s electronic submission process and IT initiatives and expand programs for hiring and retaining review staff. Because PDUFA already has reduced review times for new drug applications (NDAs) by achieving more first-cycle approvals, the new PDUFA agreement focuses more on managing the mushrooming demand for development-phase meetings, boosting resources for the breakthrough drug program, advancing the review process for rare disease treatments, and bolstering support for combination products. There’s continued emphasis on advancing model-informed drug development, biomarker qualification, the use of real-world evidence, and incorporating the “patient’s voice” into regulatory decision-making. 

	Manufacturers of drugs, biologics, and generic drugs face added pressure to ensure that all facilities involved in product development and future production are fully identified in applications. Omitting this information in a submission can delay needed facility inspections, says FDA. Under PDUFA, applications that lack full facility information face a three-month approval delay for an NDA or efficacy supplement and two months extra for approving a manufacturing supplement. FDA states that it aims to complete all inspections of clinical and manufacturing sites within six months of accepting a priority application and within 10 months for standard submissions, leaving two months at the end of the review process to address deficiencies found during site visits. 

 (BSUFA II) is revised to collect $45 million in revenues through program and application fees to support product development and review (3). BSUFA also wants manufacturers to identify all planned production facilities in applications and supplements to avoid inspection delays that could add two months to a review timetable. FDA specifies that mid-cycle and late-cycle meetings will discuss chemistry, manufacturing, and controls (CMC) issues, and that it aims to complete all facility inspections within 10 months of application receipt. 

	The BSUFA program will advance through publication of guidance on key regulatory issues, including statistical methods for demonstrating similarity and a final policy for developing interchangeable biosimilars. FDA published 

 on CMC postapproval changes for biological products in August 2017 (4), and a similar document for biosimilars is scheduled for early 2019, along with final advisories on biosimilar naming, labeling, and clinical pharmacology data development. 

(GDUFA II) also increases fees overall, to reflect a greater volume of abbreviated new drug applications (ANDAs) submitted to FDA than originally anticipated. More revenues will come from a new program fee based on approved products and facilities, with large generic-drug makers (more than 20 approved products) paying the full $1.5-million fee in 2018, medium companies (5-19 products) paying about half, and firms with less than five approved generics paying one-tenth the amount, or $160,000 in 2018 (5). Fees for filing an ANDA rise from approximately $70,000 in 2017 to $172,000 in 2018; facility fees for finished drugs and active ingredients remain fairly even, with the exception of a sizeable reduction for contract manufacturing organizations (CMOs). In announcing the 

 (6), FDA notes that it will assess facility fees based on information submitted in applications, rather than relying on company self-identification. 

	A number of key issues failed to make it into FDARA, largely to avoid legislative delay, but they may linger, as Congress is under pressure to deal with the federal budget and tax reform proposals by year-end. One topic that could surface is a proposal for establishing user fees to support expedited review and 

 (7). FDA and manufacturers have negotiated an agreement for accelerating development of OTC monographs, but too late to include it in FDARA. Congress recently held hearings on the program, and it could be included in other health policy legislation this year.

	Another high-profile topic is the right-to-try (RTT) 

approved by the Senate, which promotes access to certain experimental therapies that have completed Phase I testing for individuals with terminal illnesses and no other treatment options (8). Under the Senate bill, patients would not have to apply for FDA approval to access these drugs, and it limits liability of pharma companies, prescribers, and dispensers for problems arising from early use of such products. This aims to encourage manufacturers to provide a test therapy when requested, but still does not require sponsors to agree to such action. House RTT advocates have proposed their own reform bill, and it may take some time to reach agreement on a measure that satisfies all parties. 

PDUFA Reauthorization Performance Goals and Procedures Fiscal Years 2018 Through 2022

Biosimilar Biological Product Reauthorization Performance Goals and Procedures Fiscal Years 2018 Through 2022

CMC Postapproval Manufacturing Changes for Specified Biological Products to be Documented in Annual Reports, Guidance for Industry, Draft Guidance

GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2018-2022

. 
	6. FDA, “Generic Drug User Fee Rates for Fiscal Year 2018,” 

Potential Over-the-Counter Monograph User Fees

Volume 41, Number 10
	October 2017
	Pages: 16–18

	When referring to this article, please cite it as J. Wechsler, “FDA User Fees Promote Manufacturing Readiness," 

Industry and FDA face new fee structures and new challenges in implementing fee initiatives.

FDA User Fees Promote Manufacturing Readiness

	Biopharmaceutical companies developing new competitive biotech therapies have pressed hard for clarity on the testing and data required by FDA to gain market approval of biosimilars that can be filled by a pharmacist without prescriber preapproval. The hope is that a clear process for developing and marketing interchangeable biologics will spur prescribing and switching to these more affordable products.

	So far, progress toward interchangeability has been slow. FDA issued a 

 in January 2017 to clarify the data and testing process for obtaining this status, but biosimilar makers have raised objections that the added testing would not provide important additional information. The guidance recommends clinical switching studies with at least three switches and PK/PD endpoints in order to assess risk to patients alternating between use of the biosimilar and reference product. FDA also seeks studies that use US-licensed comparators and enroll patients to mimic real-life use.

	Multiple comments on the guidance challenge many key recommendations. The Biosimilars Council of the Association for Accessible Medicines (AAM) raised concerns about measuring PK endpoints, ruling out use of non-US reference product comparators, and the possibility of requiring post-marketing data and comparative human factor studies for delivery devices in applications for these products.

	Still to be addressed, pointed out Hillel Cohen, executive director of scientific affairs at Sandoz, is how FDA will govern the naming and labeling of interchangeable biologics. FDA so far has not addressed whether these products will follow the same naming convention set for other biosimilars, and if labels will specify that a product is an interchangeable biologic, Cohen commented at a recent conference sponsored by the Biosimilars Council.

	And as states govern pharmacy practice in the United States, Cohen noted that state drug substitution laws will need to be updated to permit pharmacy-level substitution of an interchangeable biologic for a reference product. More than 30 states have passed or are considering such legislation, but policies vary considerably.

	Another issue is whether interchangeable biologics will be priced higher than regular biosimilars, and how both will compare to reference products. Efforts by brands to discourage biosimilar prescribing recently came to light in a lawsuit filed by Pfizer that charges Johnson & Johnson with utilizing unfair marketing practices to block sales of its biosimilar Inflecta. The Pfizer product, which was approved in early 2016, has struggled to compete with J&J’s Remicade due to J&J contracts with hospitals and insurers that allegedly offer steep rebates on Remicade only if customers exclude coverage for the Pfizer copycat. The success of J&J’s “Biosimilar Readiness Plan” reflects a reluctance of providers to switch patients that are stable on Remicade to Inflecta without a significant cost advantage.

	These issues cast doubts over whether biosimilar makers will invest in the additional testing needed to gain the interchangeability designation in the face of efforts by innovators to discourage switching by physicians and health plans. Biosimilar makers claim that a current brand strategy is to advise prescribers and payers against switching patients to a biosimilar therapy at this time, but to wait for the interchangeable product-which may be a long time coming. 

Biopharmaceutical companies developing new competitive biotech therapies have pressed hard for clarity on the testing and data required by FDA to gain market approval of biosimilars that can be filled by a pharmacist without prescriber preapproval. 

Will Interchangeability Boost Biosimilar Prescribing?

	The challenges in producing cellular and gene therapies and other cutting-edge products that meet standards for safety, efficacy, and quality was high on the agenda for biopharmaceutical companies at PDA/FDA annual joint regulatory conference held on Sept. 11–12, 2017 in Washington, DC. Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), opened the three-day meeting with an update on how the regulatory agency is expediting the development and approval of human cellular and tissue products. A main CBER initiative involves vetting new regenerative medicine advanced therapies (RMATs), including those utilizing gene-editing technology to treat malignancies and diseases.

	Similarly, the National Institutes of Health (NIH) is tapping its expertise in cell biology and tissue engineering to advance regenerative medicine, explained Rosemarie Hunziker of the National Institute of Biomedical Imaging and Bioengineering. She noted that these products require very different manufacturing and dosing processes and raise multiple challenges for scale-up and for keeping cells alive during processing. Some of these issues will be explored by the new National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL), which is being established at the University of Delaware with support from NIH and the National Institute of Standards and Technology (NIST).

	At a later session, Deborah Hursh, senior investigator in CBER’s Office of Tissues and Advanced Therapies (OTAT), described how this relatively new and growing office is devising standards for characterization and potency assays for regenerative products, stem cell therapies, therapeutic vaccines, gene therapies, antivenins and certain combination products. Hursh addressed the importance of controlling the manufacturing process for these products and noted challenges in achieving the right level of product characterization based on critical quality attributes. Patricia Hughes, acting branch chief in the Office of Product Quality in the Center for Drug Evaluation and Research (CDER), discussed new developments in utilizing single-use systems and continuous biomanufacturing to improve microbial control and increase manufacturing efficiency, consistency and flexibility for innovative products.

	Continued industry investment in advanced biologics will raise further regulatory challenges and require innovative manufacturing systems. Marks commented that knowledge gained from early CAR-T and other cutting-edge products should lead eventually to more standardized manufacturing systems. The first applications require greater attention to how a new treatment can target cells, but better understanding of manufacturing processes should emerge as these therapies become more familiar. PDA is continuing the conversation at a December conference on Cell and Gene Therapy in San Diego.

Continued industry investment in advanced biologics will raise further regulatory challenges and require innovative manufacturing systems. 

Manufacturers Seek Strategies for Ensuring Quality of Innovative Therapies

	Amid mounting excitement over remarkable efficacy rates for new genetically modified cellular therapies, regulators and manufacturers alike face continuing challenges for ensuring consistent potency, purity, and identify of these complex therapies. More than 100 experimental chimeric antigen receptor T-cell (CAR-T) therapies are in development, generating optimism that regenerative medicine will transform treatment and lead to cures for many deadly diseases. Such advances, though, require further clarification of regulatory policies governing gene therapy production and quality assurance.

	FDA is considering at least three CAR-T applications, and more are on the way. An FDA advisory 

to recommend approval of Novartis’ new CAR-T, despite concerns about the firm’s ability to process patient T-cells consistently and safely (1). Similar issues have been discussed related to applications for Kite Pharma’s therapy for aggressive non-Hodgkin lymphoma and Spark Therapeutics’ new gene therapy to treat a rare condition causing blindness, which are moving through the FDA approval process. 

	FDA will address these regulatory developments further in a comprehensive framework for oversight of regenerative medicine slated for publication in September 2017. This will be part of a comprehensive Innovation Initiative, Commissioner Scott Gottlieb 

 in July in presenting FDA’s plan for implementing the 21st Century Cures Act (2). New guidance documents will be part of the framework, which covers therapeutic tissue engineering products, human cell and tissue products, and certain combination products intended to treat serious or life-threatening diseases or conditions. Genetically modified cellular therapies, such as those manipulating CAR-T cells, fall under the regenerative medicine advanced therapy (RMAT) umbrella. 

	FDA’s Center for Biologics Evaluation and Research (CBER) is implementing this program, including a RMAT designation process to identify experimental advanced therapies that warrant special attention and advice from FDA. Gottlieb noted in early July 2017 that manufacturers have filed nearly two dozen requests for RMAT designation, and that CBER’s Office of Tissues and Advanced Therapies (OTAT) had granted four. Similar to FDA support for breakthrough therapies, the RMAT designation offers early interactions with FDA staff and the potential for priority review and accelerated approval based on strong preliminary clinical evidence. CBER Director Peter Marks and other FDA officials applaud the RMAT program established in Cures for providing FDA with flexibility in evaluating these cutting-edge products, including the ability to accept a variety of endpoints for RMAT clinical trials. 

	The larger issue for regulators is to ensure consistency in critical quality attributes (CQAs) for identity and purity of these products, a task that has prompted FDA and a number of research organizations to collaborate on setting standards and methods for defining and characterizing these complex therapies and for conducting assays able to measure performance. A Forum on Regenerative Medicine established in 2016 by the National Academies for Science, Engineering, and Medicine (NASEM) is addressing these issues as part of its broader examination of the state of science and strategies for facilitating development of therapies able to generate, repair, or replace patients’ tissues. A June 2017 workshop on “Navigating the Manufacturing Process and Assuring the Quality of Regenerative Medicine Therapies” discussed challenges in evaluating the quality and purity of unique cell populations. The 

 possible mechanisms and technologies for improving methods and capabilities for measuring CQAs and for setting standards to help advance development of these promising therapies (3). 

	The federal government’s National Institute of Standards and Technology (NIST) is 

 to develop measurements critical to characterization of advanced cellular and gene therapies (4). A provision in the Cures legislation directs FDA and NIST to collaborate with stakeholders in developing standards for regenerative medicine, and in 2016 NIST formed a public-private partnership with a group related to the Alliance for Regenerative Medicine (ARM) to advance such industry-wide standards. 

	FDA’s Oncologic Drug Advisory Committee meeting on July 11, 2017 to evaluate Novartis’ CAR-T therapy, tisagenlecleucel-T, addressed difficulties in dealing with variability in the potency and other quality measures related to gene therapy production. From the outset, FDA reviewers said that efficacy was not an issue due to overwhelming patient response to treatment, and that safety would involve long-term post-market assessment.  But the experts sought assurance of security, accuracy, and reliability for Novartis’ complex system for removing blood T-cells from the patient, cryopreserving them for transport to a company processing facility, and shipping transduced T-cells back to the clinic for re-injection into the patient. 

 on the product emphasized the importance of establishing a well-controlled manufacturing process that can consistently produce high-quality CAR-T cells that are safe, pure, and potent (5). FDA notes that the product has unique quality attributes that can directly impact final product safety and potency, and that several manufacturing failures occurred at Novartis facilities in the United States and Germany. Novartis scientists 

 how each batch of patient tissue is handled in dedicated equipment, materials, and personnel in an enrichment process to obtain a highly pure T-cell population and to ensure that the right cells go to the right patient (6). 

	These issues were explored further at the July 2017 

 organized by CASSS on manufacturing quality and regulatory considerations for cell and gene therapies (7). The meeting attracted a record number of participants, reflecting heightened industry interest in discoveries that promise to revolutionize the treatment of serious health conditions. Participants explored strategies for analytical method development, assay validation, product characterization, specification setting, and for establishing relevant manufacturing controls for these highly perishable and biologically complex products. 

	Experts from biopharma companies and research organizations discussed the importance of advanced analytics in evaluating product consistency and purity and in avoiding process variations. They debated the relevance of quality standards set by the International Council for Harmonization (ICH) and how well quality-by-design concepts can help understand and manage change. There were many questions about dealing with variability in raw materials, evaluation of stability, and addressing unique supply chain issues.  

	Bryan Silvey, senior director for quality compliance at Kite Pharma, emphasized that personalized cell therapy production, utilizing a “one lot-one patient” manufacturing platform with a 15-day rapid manufacturing cycle and “a new world of cold chain” transport, must provide a high level of assurance that the patient receives back the correct cells as quickly as possible. Anne Plant, division chief for biosystems and biomaterials at NIST, observed that comparability assessment is key to determining that changes in a production process do not undermine quality and safety, but that such measurements are difficult to define. 

	Mohammad Heidaran, CMC reviewer in CBER’s OTAT, described manufacturing challenges for cellular therapies related to cell variability, lack of reference standards, small lot sizes, limited material for testing, and an often poor understanding of the product. Comparability protocols are important for managing change and can benefit from FDA input on the design and risk that a change poses for product quality. He advised manufacturers to “know your product,” including CQAs and critical process parameters, and to conduct a full risk assessment that links all these factors to product quality. 

	1. PharmTech, “Novartis CAR-T Cell Therapy CTL019 Recommended for FDA Approval,” 

, July 12, 2017. 
	2. S. Gottlieb, “How FDA Plans to Help Consumers Capitalize on Advances in Science,” FDAVoice, 

Navigating the Manufacturing Process and Assuring the Quality of Regenerative Medicine Therapies-A Workshop

, June 26, 2017.
	4. NIST, Regenerative Medicine Biomanufacturing, 

, Oncologic Drugs Advisory Committee Meeting, BLA 125646. 
	6. Novartis, “

Oncologic Drugs Advisory Committee Briefing Document, Tisagenlecleucel (CTL019)

CMC Forum Summer 2017: Scientific Program


	Vol. 41, No. 9
	September 2017
	Pages: 14–16

	When referring to this article, please cite it as J. Wechsler, "Manufacturing Standards Key to Advancing Cellular and Gene Therapies," 

FDA works with industry on strategies for assuring high-quality regenerative medicines.