FDA Perspectives: An Overview of the CDER Drug Recall Root Cause Research Project

A drug recall often begins with a company determining that it has a product in the market place that is an actual or potential health hazard or otherwise is in violation of the US Code of Federal Regulations (CFR). To protect the public health, a company can initiate a voluntary recall at any time. Firms also may initiate a voluntary recall in response to a request by the US Food and Drug Administration that is triggered by a significant violation or concerns of a potential health hazard. Recalls may also occur due to anticipation of hazards violation or a state agency finding. The current FDA recall program, described in Chapter 7 of the FDA Regulatory Procedures Manual (RPM), and in other related procedures such as the Investigations Operations Manual (IOM), implements 21 CFR Part 7, Subpart C Recalls. FDA's Guidance for Industry: Product Recalls, Including Removals and Corrections also defines the agency's current thinking on recall programs and recall management (1–4).

When a company believes that one of its marketed drug products poses a potential or confirmed health hazard to the public, the company must notify the FDA recall coordinator for its district (there are 19 districts in the United States) and collect information for the coordinator. FDA's product recall guidance is specific as to the information, including the reason for the recall, to be submitted: "Please explain how the problem occurred and the date it occurred. Explain how the problem was discovered and the date discovered" (4).

The guidance also requests information about the root cause of the problem: "We recommend that you provide this information to your local District Recall Coordinator once the root cause has been established. It is important to establish the root cause of the problem so that appropriate preventive measures can be taken" (4).

If the investigation is inconclusive in determining a root cause, that information should be reported to the district coordinator. The district coordinator will gather the information, including the recall strategy provided by the firm. FDA's Center for Drug Evaluation and Research (CDER) then assesses the potential health hazard and scope of the problem. The goal of the firm and FDA is to remove the hazardous or violative product from the market as rapidly as possible to protect the public health. For this reason, all efforts are directed toward learning as much as possible (and as soon as possible) about the product and the potential danger to take appropriate action to resolve the situation.

To date, this recall program has focused predominantly on individual recall events. FDA's efforts to look for and examine drug-recall trends during the past several years have been limited in their depth of data mining and analysis. There is a need for a "big picture" overview of major recall categories, accompanied by an analysis of the associated fundamental root causes. To gain this overview, FDA initiated the Recall Root Cause Research (RRCR) project in September 2007.

The recall root cause project

Background. The RRCR project began in the Division of Manufacturing and Product Quality (DMPQ), which falls within CDER's Office of Compliance (OC). Product quality scientists in OC and FDA's Office of Pharmaceutical Science were interviewed to set priority areas of greatest interest for the research project. Identified recall categories include, but are not limited to, subpotency, dissolution, and microbial contamination. The RRCR project is meant to provide a robust assessment of available drug-product recall information using knowledge of pharmaceutical manufacturing and applied statistics to identify important recall patterns and trends. The four questions to be answered by this research project are:

• What recall categories have the greatest impact on patients relative to safety, efficacy, and availability?

• What can we learn by looking at recalls in the aggregate?

• What are the manufacturing root causes of the drug recalls?

• How can FDA systems be improved to better identify emerging trends?

The project will provide a retrospective assessment of drug recalls that reviews information from related available data sources. Specifically, the project will find and review text information, archived data, metadata for Class I and Class II recalls (see sidebar, "Classes of recalls"), CGMP issues such as labeling, and selected focus areas using FDA records. The timeframe and sampling frame are defined for the information to be assessed. Independent factors extracted from the archived records are defined as well, and data sets have been developed and populated. These sets are summarized to establish the scope and range of the recalls; the summaries will be used to explore potential cause-and-effect relationships.

Classes of recalls

Benefits and goals. The integral relationship between designing quality into a drug product and process, as well as future defect prevention, has not always been evident in the pharmaceutical development process. Understanding true root causes can lead to a mechanistic understanding of how manufacturing flaws and quality defects can be prevented during the design and process qualification stages, and through continual life-cycle improvements. Anticipating, monitoring, and detecting signals of process drift will help maintain a state of control, reduce variation, and improve process performance. Rational risk assessment derived from root-cause analysis can be applied to identify and address areas of potential manufacturing vulnerability that should receive special attention to prevent quality problems.

In addition to its retrospective analysis of recall root causes, the RRCR project will assess FDA's overall system for capturing certain drug-recall information. Currently, the information available is used to administratively manage recalls; it is less used to understand the recall process itself or to improve it. This project will address working on the process so that CDER staff are able to generate more accurate root-cause information and function more efficiently. The end result will refocus part of the FDA recall program on taking a more systematic approach to assist in defect prevention action in addition to taking action on individual recalls.

Ultimately, as a result of the RRCR project, it is hoped that problem solvers will recognize that enhanced collection and analysis of recall root cause information prompts the need for further investigation and attention to the origins of product variability.

As the current FDA recall program transitions to one that augments the intense review of one recall at a time to one that incorporates robust trending mechanisms, it will be more common for FDA to identify meaningful patterns. The RRCR project, by contrast, will provide the time and resources needed to see the big picture of similar recall cases and their causes.

Currently, recalls are summarized by class and by specific defect category over a defined time period. The RRCR project's thorough datamining of various related cases will provide insights into current practices that lead to variability. It is hoped that the study findings will help the industry focus on common recall problems and solutions because FDA will be able to perceive and share with industry major trends that individual firms cannot. In addition, the RRCR project's description and quantification of complex issues can help to provide feedback to investigators, compliance staff, reviewers, and industry for further attention and action. For example, many recalls are initiated for failure of dissolution while on a stability program. The project will examine, What can be learned from these recalls that can be summarized and will be useful to both FDA and industry?

It is also hoped that the project will find alternative ways of looking at recall data and generate new ideas and hypotheses for further assessment. Information gathered should illustrate how process design and knowledge management programs can be enhanced to anticipate potential problems in production.

Summary

The operational goals of the RRCR project are to review and summarize classes of recalls and other focus topics to determine potential root causes. These root-cause findings can then be used to identify major trends. The information and understanding gained through the project can be used not only at FDA to improve programs, but also to support industrial process development and qualification activities and to assist investigations into product quality problems. Ultimately, application of the RRCR project's enhanced practical knowledge of root causes can lead to reduced risks to the public health.

The RRCR project will bring attention to recalls from an analytical viewpoint. Qualitative and quantitative summaries will present the critical information in different formats yielding new insights into the root causes. Trends and patterns will be identified and evaluated to assist the agency and industry.

Project leaders expect that recommendations from the project will lead to suggestions for improving drug manufacturing and product quality. These recommendations will be communicated internally at FDA as well as to industry, through journal articles and public presentations at conferences (5).

For more information on CGMPs, please contact CDER's Division of Manufacturing and Product Quality. See the following website for more information, including subject contacts: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/default.htm.

NOTE: Minor editorial changes per the authors have been made to the online version of this article after original publication (as of Nov. 13, 2009).

Lynn Torbeck* is a principal statistician at Torbeck and Associates and a member of Pharmaceutical Technology's editorial advisory board, tel. 847.424.1314, Lynn@Torbeck.org. Richard Friedman is the division director of the Division of Manufacturing and Product Quality in the Office of Compliance at the US Food and Drug Administration's Center for Drug Evaluation and Research (CDER). Michael Smedley is the branch chief for the Recalls, Shortages and Certificates Branch of CDER's Office of Compliance's Division of Manufacturing and Product Quality.

*To whom all correspondence should be addressed.

Submitted: June 24, 2009. Accepted: July 9, 2009.

References

1. Code of Federal Regulations, Title 21, Food and Drugs (Government Printing Office, Washington, DC), Part 7, Subpart C, Recalls.

2. FDA, Chapter 7: Recall Procedures, Regulatory Procedures Manual, March 2007, www.fda.gov/ora/compliance_ref/rpm/pdf/ch7.pdf, accessed July 9, 2009.

3. FDA, Investigations Operations Manual 2009, www.fda.gov/ora/inspect_ref/iom/default.htm, accessed July 9, 2009.

4. FDA, Guidance for Industry: Product Recalls, Including Removals and Corrections (Rockville, MD, 2003), www.fda.gov/ora/compliance_ref/recalls/ggp_recall.htm, accessed July 9, 2009.

5. L.D. Torbeck, "Recall Root Cause Analysis," presented at the FDA/PDA Joint Regulatory Conference, Washington, DC, Sept. 9, 2008.

This article represents the views of the authors and not of FDA.