How can a company best prepare for an inspection?
Preparation tips include:
- Have the appropriate personnel respond to questions and provide pertinent documents.
- Train employees to answer questions factually during an inspection.
- Designate a host and primary point of contact who will coordinate walk-throughs, employee interviews, and requests for records.
- Follow Current Good Manufacturing Practices (CGMP) and be familiar with Compliance Program 7356.002.
- Maintain required documents and conduct investigations in a timely manner.
What are some common mistakes that could easily be avoided during an inspection?
A firm should always be ready for an inspection by consistently following CGMPs and FDA filing requirements. Each firm should also have a plan or procedure on how to handle inspections by FDA or other external agencies.
What are some of the most important things an inspector looks for?
Manufacturers of FDA-regulated commodities maintain primary responsibility for ensuring that the products reaching American consumers are safe and of high quality. Manufacturers and processors are generally required to employ a robust quality management system, also referred to as Current Good Manufacturing Practice (CGMP). FDA’s role in conducting periodic surveillance inspections, and when using other oversight tools, is to verify that these quality systems are established and operating as required.
FDA also conducts inspections to verify that other regulated entities, such as those involved in the conduct and reporting of FDA-regulated research, are complying with regulatory requirements. If problems are found, FDA uses a variety of oversight and enforcement tools to ensure corrections are made, including additional inspections.
What types of issues could trigger an unannounced inspection?
Prior to the pandemic, domestic drug surveillance inspections were unannounced. Due to the pandemic and surrounding safety concerns, all surveillance inspections are now being announced. The FDA is also currently conducting an unannounced inspection pilot in India where some routine surveillance and for-cause inspections are being conducted unannounced or with short notice, 48 hours or less. For-cause unannounced inspections may be conducted at any time when there is reason to believe a facility has serious manufacturing problems or to investigate a specific problem or product complaint that has come to FDA’s attention.
What have been some of the biggest changes in regulations affecting OSD manufactures?
Though there have not been significant changes in regulations that affect OSD manufacturers, FDA has published draft and final guidance that convey current thinking on manufacturing topics relevant to OSD manufacturers, e.g., “Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing CrossContamination,” “Microbiological Quality Considerations in Non-Sterile Drug Manufacturing,” and “Investigating Out-OfSpecification (OOS) Test Results for Pharmaceutical Production.”
What if anything can nutraceutical manufacturers do to prove to consumers their products are safe and effective, beyond adhering to cGMP?
A nutraceutical is not an FDA-defined product type. Rather, the FDA regulates products based upon how they are intended to be used. Depending on how a nutraceutical product is marketed, it could be regulated as a dietary supplement, conventional food, drug, or other FDA-regulated commodity. Regardless of how the product is marketed, the manufacturer or distributor must follow the applicable FDA regulations. Although federal law generally requires that prescription drugs be shown to be both safe and effective and approved by the agency prior to marketing in the United States, the FDA does not approve dietary supplements, conventional foods, or their labels before they are marketed.
As noted, manufacturers and distributors of products labeled as dietary supplements are responsible for evaluating the safety and labeling of their products before marketing to ensure that they meet all of the requirements of the Dietary Supplement Health and Education Act of 1994 (DSHEA) and FDA regulations, including CGMP requirements for dietary supplements. The FDA has issued regulations establishing the minimum CGMPs necessary for dietary supplement manufacturing, packaging, labeling, and holding activities to help ensure the quality of these products. The FDA conducts inspections of dietary supplement facilities to evaluate compliance with the CGMP requirements; communicates with firms about violative observations, such as through warning letters; and takes enforcement action when appropriate, including recommending judicial action to the Department of Justice.
Any key area(s) we didn’t touch upon, or anything else you’d like to say to the OSD manufacturing community?
To increase transparency and incentivize investment in pharmaceutical manufacturing, the Office of Pharmaceutical Quality in FDA’s Center for Drug Evaluation and Research (CDER) is developing a framework to objectively rate the quality management maturity of pharmaceutical manufacturing sites.
Quality management maturity (QMM) is the state attained when drug manufacturers have consistent, reliable, and robust business processes to achieve quality objectives and promote continual improvement.
FDA regularly evaluates manufacturing facilities and takes action, if needed, to enforce CGMP requirements. FDA investigators look for deficiencies in meeting CGMP, but these evaluations do not measure how far a site’s pharmaceutical quality system rises above the minimum requirements. Simple adherence to CGMP standards does not indicate, for example, that a firm is investing in improvements to prevent supply disruptions.
CDER has proposed the development of a rating system that will help incentivize drug manufacturers to achieve QMM at their facilities. A QMM rating system could inform regulators and purchasers about the performance and robustness of drug manufacturing facilities and give patients increased confidence in the availability of drugs. QMM ratings could also support increased flexibility for manufacturers to make postapproval manufacturing changes with less regulatory oversight, incentivizing continual improvement.
In developing the framework, CDER is considering standardized assessment tools, policy approaches, industry incentives, transparency, and communications. As CDER has started to develop the QMM program, engaged stakeholders have started to identify key challenges to overcome to realize a successful program.
In 2018, FDA announced steps we’re taking to modernize our inspections program with a new way of assessing, recording, and reporting the data from surveillance and pre-approval inspections for sterile drug products.
This New Inspection Protocol Project (NIPP) uses standardized electronic inspection protocols to collect data in a structured manner for more consistent oversight of facilities and faster and more efficient analysis of our findings. The protocols also include additional questions related to quality culture observed in facilities. The new tool is being applied to our inspectional work related to sterile injectable drugs, which have been the subject of sterility problems and shortages in the past. The primary focus of this new tool is to ensure a more streamlined and consistent coverage and reporting of our inspectional activities.
As drug manufacturers resume normal operations after periods where they may have experienced high absenteeism and COVID infections, they should look really closely at any CGMP activities that were temporarily deferred, delayed, or reduced in frequency to determine the potential impact.
Please explain the decision behind starting the Quality Management Maturity (QMM) program.
The 2019 report Drug Shortages: Root Causes and Potential Solutions by the multi-agency Federal Drug Shortages Task Force reported that 62% of drugs that went into shortage between 2013 and 2017 were associated with manufacturing or product quality problems (e.g., substandard manufacturing facilities/processes or quality defects in the finished product). The Drug Shortages Task Force proposed three enduring solutions to the problem of drug shortages; one solution was developing a rating system to incentivize drug manufacturers to invest in quality management maturity (QMM).
The 2021 Biden-Harris Administration 100 Day Supply Chain Review announced actions the Department of Health and Human Services, under which FDA resides, would take to ensure the U.S. has the pharmaceuticals necessary for economic security, health security, and national defense. One of these actions included QMM:
- Create robust quality management maturity to ensure consistent and reliable drug manufacturing and quality performance:
- Recognize and reward manufacturers for mature quality systems that focus on continuous improvement, business continuity plans, and early detection of supply chain issues.
The need for QMM ratings does not, however, indicate that substandard drug products are on the market. Quality management is part of an array of quality. The FDA assesses product quality in regulatory submissions and monitors the quality of drug products in the U.S. market to provide a high level of confidence in the quality of these products. The FDA assesses formulation, process, and facility quality in applications and monitors and inspects manufacturing facilities to assure risks are controlled. This level of control assures quality in drug product batches released to the U.S. market. Mature quality management uses a performance and patient focus to identify areas of improvement and implement changes accordingly.
*Answers are from Multiple FDA Officials, Filtered Through FDA Spokespeople