Overview of Adverse Event Reporting Guidelines for 503B Outsourcing Facilities

Reporting Adverse Events Keeps 503Bs Compliant with FDA and State Boards

503B compounding facilities are required to report adverse events to the FDA through a document submission process to stay compliant with regulators. 503B compounding facilities have noticed an upward trend in audits surrounding adverse events, citing that state boards and the FDA believe adverse events are not being reported properly.  The adverse event reporting requirements apply to prescription drug products regardless of whether the outsourcing facility distributes them pursuant to prescriptions.

History of 503B Guidance: Adverse Event Reporting

In the past, reporting adverse drug events involving compounded medications had not been addressed. However, in 2015 the Adverse Event Reporting for Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act (FD&C) provided guidance to human drug compounding outsourcing facilities submitting adverse event reports to the FDA. The guidance states that under section 503B(b)(5) of the FD&C Act that outsourcing facilities must submit adverse events to the FDA “in accordance with the content and format requirements established through guidance or regulation under section 310.305 of title 21, Code of Federal Regulations (or any successor regulations).”

State boards of pharmacy may require outsourcing facilities and 503A compounding facilities licensed in their state to report adverse drug events. Pharmacists can contribute to the safety of compounded pharmaceuticals by reporting adverse events to the FDA.

Compounding Facilities and Adverse Events

According to the FDA, “Adverse event and other complaint reporting associated with compounded human drug products is a critical mechanism for identifying potential quality problems that may be associated with a particular drug or drug component and which may have been caused by conditions or processes at a facility where the drug or its components were made or handled.”

Pharmacists in both 503A and 503B settings share identified potential issues with compounded products through the FDA’s Compounding Incidents Program, which was founded to protect the public from unsafe compounded drugs. After the compounding entity determines the event is compounding-related, it is entered into the searchable database, and additional research is conducted. 

The FDA released charts showing the number of incidents received through the Compounding Incidents Program by fiscal year and type:

 What is an Adverse Event and When Should it be Reported?

According to FDA, the definition of an adverse event, or an adverse drug experience, is:

any adverse event associated with the use of a drug in humans, whether or not the event is considered drug-related, including those occurring: 

  • in the course of the use of a drug product in professional practice;

  • from drug overdose whether accidental or intentional;

  • from drug abuse or drug withdrawal; or

  • from any failure of expected pharmacological action.

Serious adverse events are an undesirable experience associated with a medical product.  Report serious adverse events when the outcome is:

  • Death

  • Life-Threatening

  • Hospitalization

  • Disability or permanently damaged

  • Congenital/or a birth defect

  • Intervention to prevent impairment of damage

  • Other serious important medical events

Non-serious adverse events include experiences that jeopardize the patient which may require medical or surgical intervention.  As reported by FDA, non-serious adverse events include:

  • Allergic bronchospasm requiring intensive treatment in an emergency room or at home

  • Blood dycrasias or convulsions that do not result in inpatient hospitalization

  • Development of drug dependency or drug abuse

The FDA states that other complaints can cover a wide range of issues like product quality issues, insanitary facility conditions, making misleading or false claims about drugs, and compounding of ineligible bulk drug substances.

FDA strongly recommends that outsourcing facilities report all serious adverse drug experiences associated with their compounded drug products and unexpected adverse drug experiences. Reporting all serious adverse drug experiences, whether expected or unexpected, would provide important information about potential product quality issues or public health risks associated with drug products compounded by outsourcing facilities.

503Bs should submit documentation to the FDA in the case of an adverse event, called an Individual Case Safety Report (ICSR). The ICSR describes an adverse drug experience related to an individual patient or subject.  

Under section 503B of the FD&C Act, outsourcing facilities must submit adverse event reports to FDA in accordance with the content and format requirements established through guidance or regulation under section 310.305 of title 21, Code of Federal Regulations. Violations relating to the FDAs provision are subject to regulatory and enforcement action.

Investigating and Submitting an Adverse Event

Healthcare professionals, compounders, states, consumers, and others can report an adverse event to the Compounding Incidents Program.

503Bs reporting an adverse event to FDA should actively seek to obtain the following four data elements:

1.An identifiable patient (one or more would qualify the patient as identifiable)

a.     Age or age category (e.g., adolescent, adult, elderly)

b.     Gender

c.     Initials

d.     Date of birth

e.     Name

f.      Patient identification number

2.    An identifiable reporter (the person who initially notifies the 503B)

a.     A personal identifier (e.g., name)

b.     A professional identifier (e.g., doctor, nurse, pharmacist)

c.     Contact information (e.g., e-mail address, phone number)

3.     A suspect drug (pursuant to section 310.305)

a.     The report should include known product attributes like active ingredient(s), dosage form, strength, color, lot number.

b.     If there is more than one drug product compounded by the same facility, they should submit one report that notes the drug product considered most suspect by the reporter.

4.     A serious adverse event

a.     You suspect that the death of a patient was the outcome of an adverse event.

b.     If the patient was at a substantial risk of dying at the time of the adverse event or used or continued to use the medial product which might have resulted in the death of a patient.

c.     If the patient was admitted to the hospital or was prolonged in the hospital as a result of the adverse event. Evaluate emergency room visits that do not result in hospital admission.

d.     Disabled or permanent damage occur that resulted in a substantial, significant, persistent, or permanent disruption of a person’s ability to conduct normal life functions not limited to impairment, damage or disruption to the patient’s body structure or function, physical activities and/or quality of life.

e.     Birth defects after exposure to a medical product prior to conception or during pregnancy that resulted in an adverse outcome in the child.

f.      A medical or surgical intervention was needed to rule out in advance, permanent impairment of bodily functions due to the use of a medical product.

g.     The (important medical) event may jeopardize the patient and could require medical or surgical intervention or treatment to prevent one of these outcomes. The development of drug dependence is an example of important medical events.

503B compounders must investigate adverse events that are subject to a 15-day “Alert Report” to the FDA as soon as possible, no later than 15 calendar days after receiving information about the adverse event.

If the 503B wasn’t able to include all four of the data elements in the initial report, due diligence should be exercised and additional information or other elements should be recorded and kept. Additional information about the adverse event should also be reported. A follow-up report should also be sent within 15 calendar days of receipt of any new information. 503Bs should submit reports to the FDA if they have information on at least the suspect drug and the adverse event.

Outsourcing facilities should know the Individual Case Safety Report (ICSRs) implementation guide, and know and understand the FDA’s Adverse Event Reporting System (FAERS) and electronic submissions.

Reviewing Reports Submitted to the FDA

When an incident is received, logged into the database, and reviewed by the Compounding Incidents Program, it is assigned to a consumer safety officer who researches and investigates the reported incident.  

After they review the incident for signals of more significant safety issues, FDA might contact the person who reported the incident to get additional information. Afterward, an expert group will collaborate within the agency to discuss the issue at length. 

Once the incident is investigated, action may be taken, such as:

  • Sample collection and testing at FDA laboratories

  • Notification for information from state authorities or government agencies

  • Inspections, warning letters, recalls or other actions

FDA’s Compounding Incidents Program is dedicated to surveillance and follow-up actions related to safety risks associated with compounded drugs.

Perform Risk Assessments

In deciding whether or not it is necessary to report an incident, 503Bs may perform a risk assessment because it is crucial to effective governance, and underpins the facility's day-to-day practice to ensure patients' health, safety, and well-being.  Risk is the chance of probability at one extreme or the other that a person could be harmed or experience an adverse health outcome if something goes wrong, and how serious the harm may be. Risk assessment involves identifying hazards and analyzing and evaluating risks associated with exposure to those hazards. Quality risk assessments begin with a well-defined problem description or risk question. Once the risks have been identified it is important to communicate and set guidelines to mitigate risks now and in the future and updating or developing company guidelines.

Current Regulatory Enforcement Trends

503B adverse event reporting is an up-and-coming enforcement trend among FDA and state boards of pharmacy. Notably, in June of 2022 FDA issued a warning letter to a prominent 503B citing the firm produced drugs that violate the Federal Food, Drug, and Cosmetic Act (FD&C Act) and failed to meet the conditions of Section 503B in compliance with current good manufacturing practice (cGMP), including insufficient adverse event reporting procedures. 

FDA and state regulators plan to continue inspecting 503Bs across the country, so it is important to remain compliant with reporting adverse events.  FDA keeps a running and current list of FDA compounding inspections, recalls and other actions. This web page lists observations of noncompliance found upon FDA inspection of a 503A or 503B compounding entity. Compounders can study this page as a tool in staying ahead of regulatory enforcement trends.

Does Your Facility Produce Quality Preparations?

If you’re ready to bring quality to the center of your compounding operations, consultants at Restore Health Consulting LLC can help you design a robust quality management system to promote patient safety and regulatory compliance. We can also help with adverse event reporting and risk assessment programs.

Amy Summers