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FDA readies more efficient oversight processes while advancing collaboration with Europe.
Continuing concerns about the quality and safety of prescription drugs, particularly APIs and products made overseas, has spurred efforts by FDA to modernize its drug manufacturing inspection programs at home and abroad to better detect potentially harmful and violative medicines, while streamlining oversight for reliable producers. The ongoing discovery of potential carcinogens in multiple formulations of medicines with ranitidine has prompted recalls, Congressional investigations, and a clamor for more effective oversight of drugs and their ingredients.
To address these and other long-term concerns, FDA’s Office of Regulatory Affairs (ORA) is moving forward with efforts to roll out a much-discussed New Inspection Protocol Project (NIPP), a key component of its initiative to make field inspections more efficient, predictable, and informative (1). ORA is applying the new process first to sterile products in recognition that most serious manufacturing problems and related drug shortages involve contaminated or violative sterile injectables. ORA has conducted several pilot programs to test new methods for inspecting and evaluating manufacturing processes and facilities for sterile drugs and continues to fine tune the program with an eye to full implementation in the near future. Other dosage forms, including bulk powders, transdermal delivery systems, creams, solutions, metered-dose inhalers, terminally sterilized products, and APIs will fall under the NIPP in coming years.
The NIPP is part of a major reorganization of the ORA field force over the past decade, which has established dedicated cadres of investigators for drugs, biologics, medical devices, and other regulated products (2). The aim is to shift the focus of inspections to practices and metrics related to achieving and maintaining a state of quality production, explained Rosa Motta, supervisory consumer safety officer in the Center for Drug Evaluation and Research (CDER), at the PDA/FDA Joint Regulatory Conference in September 2019.
These changes have taken several years to implement, but now the NIPP appears to be near the starting gate. The ability of inspectors to collect data in a structured manner and to submit them in templated inspection reports will enable data analysis that can help focus future inspections on key areas and support informed and data-driven decisions on product and process quality, Motta noted. FDA also is beginning to construct surveillance and pre-approval protocols for inspections of non-sterile products, with plans to follow with similar approaches for API inspections.
A related inspection initiative aims to address manufacturer complaints that investigators raise unexpected and sometimes unfounded issues during site visits, leading to noticeable variation in citations for violative actions. In response, FDA has launched an initiative to improve communications about and industry responses to Form 483 notices issued to companies at the conclusion of site inspections. Agency inspectors use this process to inform a manufacturer of the observations made during the inspection affecting product quality, including the scope of the issues, impact on other drugs, and whether the observations appear to be isolated incidents or global in nature, explained David Jaworski, senior policy advisor in the Office of Manufacturing Quality in CDER’s Office of Compliance, at the PDA/FDA conference.
Manufacturers are expected to address Form 483 observations following an inspection through a comprehensive investigation and development of a corrective actions and preventive actions (CAPA) plan. To avoid delays and often inadequate industry responses, FDA officials seek to provide more details and advice on how companies should meet these obligations. The first step, Jaworski advised, is for the manufacturer to fully understand the Form 483 observations to investigate the issues and conduct a risk assessment on the relative severity of each observation for patient health and product quality. Such analysis then forms the basis of a CAPA plan that describes immediate short-term corrective actions and strategies for addressing root causes of larger or systemic issues. Jaworski also advised manufacturers to submit clear responses-preferably in English-that identify the facility involved and observations addressed.
The larger objective is to facilitate corrective actions, while also enabling FDA to issue warning letters expeditiously when warranted. Clear communications between field inspectors and company officials aims to improve the process for identifying quality problems and making necessary changes leading to long-term improvements.
In addition to updating FDA inspection practices, the ORA field force aims to reduce the need to visit capable and compliant manufacturing facilities in Europe and other regions through full implementation of the Mutual Recognition Agreement (MRA) for drugs with the European Union (3). Under development for a decade, the MRA capability assessment process was completed by FDA and EU regulatory officials in 2019. It is now being implemented so that regulatory authorities may share inspection and quality information and recognize and rely on GMP inspections in each other’s territory. This process is expected to provide a “significant” drop in inspections in both regions, noted David Churchward, deputy unit manager at the UK’s Medicines & Healthcare Products Regulatory Agency (MHRA), at the PDA/FDA conference, citing a 75% reduction in EU inspections in the United States.
Churchward further pointed out that an important benefit for US manufacturers is an end to the requirement that products shipped to EU member states have to submit to EU quality control testing to be imported. While there is no obligation for regulators to accept an inspection report from another agency, all parties may do so, and also stand to benefit from mutual alerts to problems and shared database information on good manufacturing practice issues. Efforts are underway to build confidence further for relying on reports for pre-approval inspections and for third-country site visits. Also planned are efforts to negotiate a similar agreement for veterinary medicines and to extend the drug MRA program to vaccines by 2022. Differences in oversight of clinical trial operations, though, has put on hold for now plans to harmonize inspections in that area.
1. FDA, “Statement from FDA Commissioner Scott Gottlieb, M.D., on New Steps to Strengthen and Modernize Agency’s Oversight and Reporting of Inspections for Sterile Injectable Drugs,” FDA.gov, Nov. 9, 2019.
2. FDA, FDA Program Alignment, www.FDA.gov.
3. FDA, Mutual Recognition Agreement (MRA), www.FDA.gov.
Vol. 32, No. 11
When referring to this article, please cite it as J. Wechsler, "More Consistent Drug Inspection System on Horizon," BioPharm International 32 (11) 2019.